Gates prophezeit zweite Pandemie

Der nächste Virus wird WIRKLICH Aufmerksamkeit erregen, sagt Bill Gates (mit einem Lachen).

Global vaccine action plan 2011-2020

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Aldous Leonard Huxley (1962): Die ultimative Revolution

Kalifornien, Berkeley
Redenarchiv SA 0269

"Wenn man eine Bevölkerung über einen längeren Zeitraum kontrollieren will, muss man ein gewisses Maß an Zustimmung haben. Es ist äußerst schwierig zu sehen, wie reiner Terrorismus auf unbestimmte Zeit funktionieren kann. Er kann für eine ziemlich lange Zeit funktionieren, aber ich denke, früher oder später muss man ein Element der Überzeugung einbringen, ein Element, das die Menschen dazu bringt, dem zuzustimmen, was mit ihnen geschieht.
Nun, mir scheint, dass das Wesen der ultimativen Revolution, mit der wir mit der wir jetzt konfrontiert sind, genau das ist: Dass wir dabei sind, eine ganze Reihe von Techniken zu entwickeln, die es der kontrollierenden Oligarchie, die die es immer gegeben hat und vermutlich immer geben wird, die Menschen dazu zu bringen, ihre Knechtschaft zu lieben."

~ Aldous Huxley

weitere Infos: https://cognitive-liberty.online/aldous-huxley-the-ultimate-revolution-berkley-language-center-1962-2/

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Sir Julian Sorell Huxley: Von der UNESCO, ihrem Zweck und ihrer Philosophie

"Es ist jedoch unerlässlich, dass die Eugenik vollständig in den Rahmen der Wissenschaft gestellt wird, denn, wie bereits angedeutet, wird das Problem der Verbesserung der durchschnittlichen Qualität der Menschen in nicht allzu ferner Zukunft wahrscheinlich dringlich werden; und dies kann nur durch die Anwendung der Erkenntnisse einer wirklich wissenschaftlichen Eugenik erreicht werden."
~ Sir Julian Sorell Huxley

weitere Infos: https://cognitive-liberty.online/julian-huxley-unesco-and-eugenics/

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Relevante Patente

Patent #WO2015199784A2

Systeme und Verfahren für injizierbare Vorrichtungen
Zusammenfassung
Die vorliegende Erfindung bezieht sich im Allgemeinen auf nanoskalige Drähte und/oder injizierbare Vorrichtungen. In einigen Ausführungsformen ist die vorliegende Erfindung auf elektronische Vorrichtungen gerichtet, die in weiche Materie, wie biologisches Gewebe oder Polymermatrixen, injiziert oder eingefügt werden können. Die Vorrichtung kann zum Beispiel durch eine Spritze oder eine Nadel eingeführt werden. In einigen Fällen kann die Vorrichtung einen oder mehrere nanoskalige Drähte umfassen. Andere Komponenten, wie Flüssigkeiten oder Zellen, können ebenfalls injiziert oder eingeführt werden. Darüber hinaus kann die Vorrichtung in einigen Fällen nach dem Einführen oder Injizieren an einen externen Stromkreis, z. B. an einen Computer, angeschlossen werden. Andere Ausführungsformen beziehen sich allgemein auf Systeme und Verfahren zur Herstellung, Verwendung oder Förderung solcher Vorrichtungen, Kits mit solchen Vorrichtungen und dergleichen.

https://patents.google.com/patent/WO2015199784A2/en

System und Verfahren zum Testen auf COVID-19
Patent US-2020279585-A1
Erfinder: ROTHSCHILD RICHARD A (GB)

Es wird ein Verfahren zur Erfassung und Übertragung biometrischer Daten (z. B. Lebenszeichen) eines Benutzers bereitgestellt, wobei die Daten analysiert werden, um festzustellen, ob der Benutzer an einer Virusinfektion, wie COVID-19, leidet. Das Verfahren umfasst die Verwendung eines Pulsoximeters, um zumindest den Puls und die prozentuale Sauerstoffsättigung des Blutes zu erfassen, die drahtlos an ein Smartphone übertragen werden. Um sicherzustellen, dass die Daten genau sind, wird ein Beschleunigungsmesser im Smartphone verwendet, um die Bewegung des Smartphones und/oder des Benutzers zu messen. Sobald die genauen Daten erfasst sind, werden sie in die Cloud (oder den Host) hochgeladen, wo die Daten (allein oder zusammen mit anderen Vitaldaten) verwendet werden, um festzustellen, ob der Nutzer an einer Virusinfektion wie COVID-19 leidet (oder wahrscheinlich daran leiden wird). Je nach den spezifischen Anforderungen können die Daten, ihre Veränderungen und/oder die Feststellung dazu verwendet werden, das medizinische Personal zu alarmieren und entsprechende Maßnahmen zu ergreifen.

https://pubchem.ncbi.nlm.nih.gov/patent/US-2020279585-A1

Mit einer Spritze injizierbare Netzelektronik integriert sich nahtlos mit minimaler chronischer Immunreaktion im Gehirn
Tao Zhou 1 , Guosong Hong 1 , Tian-Ming Fu 1 , Xiao Yang 1 , Thomas G Schuhmann 2 , Robert D Viveros 2 , Charles M Lieber 3 2

PMID: 28533392 PMCID: PMC5468665 DOI: 10.1073/pnas.1705509114

Zusammenfassung

Die Implantation elektrischer Sonden in das Gehirn ist sowohl für die neurowissenschaftliche Forschung als auch für biomedizinische Anwendungen von zentraler Bedeutung, obwohl herkömmliche Sonden eine Gliose im umliegenden Gewebe hervorrufen. Vor kurzem haben wir über ultraflexible, offenmaschige Elektronik berichtet, die mittels Spritzeninjektion in das Gehirn von Nagetieren implantiert wurde und eine vielversprechende chronische Gewebereaktion und Aufzeichnungsstabilität aufweist. Hier berichten wir über zeitabhängige histologische Studien der Maschenelektronik/Gehirn-Gewebe-Grenzfläche, die aus Schnitten senkrecht und parallel zur Sondenlängsachse gewonnen wurden, sowie über Studien mit herkömmlichen flexiblen Dünnfilmsonden. Konfokale Fluoreszenzmikroskopie-Bilder der senkrechten und parallelen Hirnschnitte, die Mesh-Elektronik enthielten, zeigten, dass die Verteilung von Astrozyten, Mikroglia und Neuronen von 2-12 Wochen einheitlich wurde, während flexible Dünnfilmsonden eine deutliche Anhäufung von Astrozyten und Mikroglia und eine Abnahme von Neuronen für den gleichen Zeitraum ergaben. Quantitative Analysen der Daten von 4 und 12 Wochen zeigten, dass die Signale für Neuronen, Axone, Astrozyten und Mikroglia von der Oberfläche der Netzelektronik bis zur Basislinie weit entfernt von den Sonden fast gleich sind, im Gegensatz zu den flexiblen Polymersonden, die eine Abnahme der Neuronen und eine Zunahme der Astrozyten- und Mikrogliasignale zeigen. Bilder von sagittalen Hirnschnitten, die fast die gesamte Maschenelektroniksonde enthielten, zeigten, dass die Gewebeschnittstelle einheitlich war und dass Neuronen und Neurofilamente bis 3 Monate nach der Implantation durch die Maschen hindurchgedrungen waren. Die minimale Immunreaktion und die nahtlose Schnittstelle mit dem Hirngewebe nach der Implantation, die durch ultraflexible Elektroniksonden mit offenem Netz erreicht werden, bieten erhebliche Vorteile und könnten in Zukunft eine Vielzahl von Möglichkeiten für die chronische Aufzeichnung und Modulation der Hirnaktivität in vivo eröffnen.

Stichworte: Gehirn-Maschine-Schnittstelle; In-vivo-Implantate; minimale Neuroinflammation; neuronale Sonden; ultraflexible makroporöse Sonden.

https://pubmed.ncbi.nlm.nih.gov/28533392/

WO2020060606 - KRYPTOWÄHRUNGSSYSTEM UNTER VERWENDUNG VON KÖRPERAKTIVITÄTSDATEN

Zusammenfassung
(DE) Die menschliche Körperaktivität, die mit einer einem Benutzer bereitgestellten Aufgabe verbunden ist, kann in einem Mining-Prozess eines Kryptowährungssystems verwendet werden. Ein Server kann eine Aufgabe für ein Gerät eines Benutzers bereitstellen, das kommunikativ mit dem Server verbunden ist. Ein Sensor, der kommunikativ mit dem Gerät des Benutzers gekoppelt oder in diesem enthalten ist, kann die Körperaktivität des Benutzers erfassen. Körperaktivitätsdaten können auf der Grundlage der erfassten Körperaktivität des Benutzers erzeugt werden. Das kommunikativ mit dem Gerät des Benutzers gekoppelte Kryptowährungssystem kann überprüfen, ob die Körperaktivitätsdaten eine oder mehrere vom Kryptowährungssystem festgelegte Bedingungen erfüllen, und dem Benutzer, dessen Körperaktivitätsdaten überprüft wurden, Kryptowährung zuweisen.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020060606

CRISPR

Die ersten gentechnisch veränderten Menschen - ein Zwillingsmädchenpaar - sind möglicherweise so mutiert, dass sich ihre Lebenserwartung verkürzt, wie Forschungsergebnisse zeigen.

Prof. He Jiankui schockierte die Welt, als er die Zwillinge genetisch veränderte, um sie vor HIV zu schützen.

Eine in der Zeitschrift Nature Medicine veröffentlichte Studie zeigt jedoch, dass Menschen, die von Natur aus die Mutation haben, die er nachzubilden versuchte, ein deutlich höheres Risiko haben, jung zu sterben.

Experten bezeichneten das Vorgehen von Prof. He als "sehr gefährlich" und "töricht".

https://www.bbc.com/news/health-48496652

METHODEN UND SYSTEME ZUR PRIORISIERUNG VON BEHANDLUNGEN, IMPFUNGEN, TESTS UND/ODER AKTIVITÄTEN BEI GLEICHZEITIGEM SCHUTZ DER PRIVATSPHÄRE VON PERSONEN

https://patentimages.storage.googleapis.com/04/24/12/7c8e8238f4ae9d/US20210082583A1.pdf

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Bevölkerungsreduktion (Doku)

Download: https://www.corona-propaganda.de/bevoelkerungsreduktion-doku.mp4

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Buch: Massenpanik und soziale Bindung – Die Dynamik menschlichen Verhaltens

Buchbeschreibung

Wie verhalten sich Menschen, wenn sie von einem Angriff oder einer Katastrophe bedroht sind? Wie wirkt sich der soziale Kontext auf das individuelle Verhalten aus? Anthony Mawson bietet eine aufschlussreiche Untersuchung des individuellen und kollektiven Verhaltens unter Stress- und Gefahrenbedingungen, als Reaktion auf natürliche und vom Menschen verursachte Bedrohungen und Katastrophen. Das Buch beginnt mit einer Frage zur Interpretation von "Massenpanik" im Kampf und entwickelt sich allmählich zu einer multidisziplinären Analyse der psychobiologischen Grundlagen sozialer Beziehungen und der neuronalen Organisation von Motivation und Emotion. Mawson bietet einen umfassenden Überblick und eine Synthese der Literatur über Massenpanik und Katastrophen und stellt ein soziales Bindungsmodell vor, das die grundsätzlich gesellige Natur des Menschen und den Vorrang von Bindungen anerkennt. Er argumentiert, dass die typische Reaktion auf Bedrohung und Gefahr weder Kampf noch Flucht oder sozialer Zusammenbruch ist, sondern verstärkte Zugehörigkeit und Kameradschaft. Dieses Buch ist einzigartig, da es sich mit den verhaltensbezogenen und sozialen Aspekten von Bedrohung und Katastrophen befasst. Es richtet sich an Sozialwissenschaftler verschiedener Fachrichtungen, an Mitarbeiter der öffentlichen Verwaltung sowie an Fachleute für Katastrophen und öffentliche Gesundheit.

https://www.routledge.com/Mass-Panic-and-Social-Attachment-The-Dynamics-of-Human-Behavior/Mawson/p/book/9781138356504
https://www.jsums.edu/health/dr-anthony-a-mawson/
https://scholar.google.com/citations?user=F2NvKeQAAAAJ

Inhaltsübersicht

Inhalt: Vorwort; Einleitung; Aktuelle Theorien der Panik. Teil I Theorien des Affiliativverhaltens: Theorien der Zugehörigkeit; die Theorie von Walters und Parke; Schutz vor Raubtieren: Bowlbys Theorie. Teil II - Eine Theorie der sozialen Bindung: Erregung und Stimulationssuche: Überblick; Kognitive Karten und Anfälligkeit für Beeinflussung; Zugehörigkeit als Stimulationssuche: eine Theorie der Bindungsbildung; Stimulationssuche und Gruppendynamik. Teil III Panik: Panik als Stimulationssuche; Aggression; Der soziale Kontext der Panik; Panikflucht als affiliatives Verhalten; Überblick über aktuelle Theorien der Panik; Häfen der Sicherheit; Panik als Stimulationsvermeidung. Teil IV: Weitere Überlegungen: Zwei Systeme der Erregung; Auf dem Weg zu einer neurophysiologischen Theorie des emotionalen Verhaltens; Zusammenfassung und Schlussfolgerungen; Verständnis der Massenpanik und anderer kollektiver Reaktionen auf Katastrophen: Aktualisierung; Anhang: Stimulationssuche und die Organisation des Verhaltens; Bibliographie; Index.

Mawson, A. R., & Croft, A. M.. (2020). Multiple Vaccinations and the Enigma of Vaccine Injury. Vaccines, 8(4), 676.
Plain numerical DOI: 10.3390/vaccines8040676
DOI URL
directSciHub download

Show/hide publication abstract

“A growing number of vaccines are administered at the same time or in close succession, increasing the complexity of assessing vaccine safety. individual vaccines are assumed to have no other effect than protection against the targeted pathogen, but vaccines also have nonspecific and interactive effects, the outcomes of which can be beneficial or harmful. to date, no controlled trials and very few observational studies have determined the impact of vaccination schedules on overall health. the balance of the risks and benefits from mass vaccination therefore remains uncertain. recent studies worryingly suggest links between multiple vaccinations and increased risks of diverse multisystem health problems, including allergies, infections, and neuropsychiatric or neurodevelopmental disorders. here, we propose that, in susceptible persons, multiple vaccinations activate the retinoid cascade and trigger apoptotic hepatitis, leading to cholestatic liver dysfunction, in which stored vitamin a compounds (retinyl esters and retinoic acid) enter the circulation in toxic concentrations; this induces endogenous forms of hypervitaminosis a, with the severity of adverse outcomes being directly proportional to the concentration of circulating retinoids. in very low concentrations, vitamin a and its major metabolite retinoic acid contribute to immune function and to the process of immunization, whereas excess vitamin a increases the risk of adverse events, including common ‘side-effects’ as well as chronic adverse outcomes. the increasing rates of allergy, ear infections, and neurodevelopmental disorders (ndds) in countries with high rates of vaccination could be related to mass vaccination and to its impact on liver function and vitamin a metabolism, collectively representing endogenous manifestations of hypervitaminosis a. further studies of health outcomes in vaccinated and unvaccinated groups are urgently needed, to increase understanding of the pathophysiology and treatment of vaccine injury, to identify the risk factors and screen for vaccine injury, to inform public health policy on potential hazards related to vaccination schedules, and to optimize the safety and benefits of vaccines.”

https://www.mdpi.com/2076-393X/8/4/676

Zusammenfassung
Immer mehr Impfstoffe werden gleichzeitig oder kurz nacheinander verabreicht, was die Bewertung der Sicherheit von Impfstoffen immer komplexer macht. Es wird davon ausgegangen, dass einzelne Impfstoffe keine andere Wirkung haben als den Schutz vor dem Zielerreger, aber Impfstoffe haben auch unspezifische und interaktive Wirkungen, deren Ergebnisse nützlich oder schädlich sein können. Bislang gibt es keine kontrollierten Studien und nur sehr wenige Beobachtungsstudien, in denen die Auswirkungen von Impfplänen auf die allgemeine Gesundheit untersucht wurden. Das Gleichgewicht zwischen den Risiken und dem Nutzen von Massenimpfungen bleibt daher ungewiss. Jüngste Studien lassen in besorgniserregender Weise auf einen Zusammenhang zwischen Mehrfachimpfungen und einem erhöhten Risiko für verschiedene systemübergreifende Gesundheitsprobleme schließen, darunter Allergien, Infektionen und neuropsychiatrische oder neurologische Entwicklungsstörungen. Hier schlagen wir vor, dass Mehrfachimpfungen bei anfälligen Personen die Retinoidkaskade aktivieren und eine apoptotische Hepatitis auslösen, die zu einer cholestatischen Leberdysfunktion führt, bei der gespeicherte Vitamin-A-Verbindungen (Retinylester und Retinsäure) in toxischen Konzentrationen in den Blutkreislauf gelangen; dies führt zu endogenen Formen der Hypervitaminose A, wobei die Schwere der negativen Folgen direkt proportional zur Konzentration der zirkulierenden Retinoide ist. In sehr geringen Konzentrationen tragen Vitamin A und sein wichtigster Metabolit, die Retinsäure, zur Immunfunktion und zum Immunisierungsprozess bei, während ein Überschuss an Vitamin A das Risiko von unerwünschten Ereignissen, einschließlich allgemeiner "Nebenwirkungen" und chronischer unerwünschter Folgen, erhöht. Die steigenden Raten von Allergien, Ohrinfektionen und neurologischen Entwicklungsstörungen in Ländern mit hohen Impfraten könnten mit der Massenimpfung und ihren Auswirkungen auf die Leberfunktion und den Vitamin-A-Stoffwechsel zusammenhängen, die zusammengenommen endogene Erscheinungsformen der Hypervitaminose A darstellen. Weitere Studien zu den gesundheitlichen Folgen bei geimpften und ungeimpften Gruppen sind dringend erforderlich, um das Verständnis für die Pathophysiologie und die Behandlung von Impfschäden zu verbessern, die Risikofaktoren zu ermitteln und Impfschäden zu erkennen, die öffentliche Gesundheitspolitik über potenzielle Gefahren im Zusammenhang mit Impfplänen zu informieren und die Sicherheit und den Nutzen von Impfstoffen zu optimieren.

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Definition von Gegenpropaganda

In einer wirksamen Gegenpropaganda wird, im Gegensatz zur Propaganda, im Allgemeinen nur die Wahrheit verbreitet. In der Tat wird Gegenpropaganda allgemein als “wahrheitsgemäße, ehrliche Opposition” zur Propaganda des Gegners verstanden. Gegenpropaganda vermittelt aus moralischen und praktischen Gründen wahrheitsgemäße Botschaften. Während des Kalten Krieges führte der Ruf der Vereinigten Staaten, die Wahrheit zu verbreiten, um die sowjetische Propaganda zu widerlegen, dazu, dass die USA als “Wahrheitsverkünder” angesehen wurden, während die Sowjetunion den Ruf eines “Lügenverkünders” hatte. Herbert Romerstein argumentiert, dass die Verwendung von wahrheitsbezogener Gegenpropaganda dazu führte, dass die USA als ehrlich wahrgenommen wurden, während die Verwendung falscher Aussagen durch die Sowjetunion deren Botschaften diskreditierte. Dieses Beispiel aus dem Kalten Krieg zeigt, wie eine falsche Botschaft diskreditiert wird, wenn die Wahrheit ans Licht kommt. In der Praxis könnte sich eine Gegenpropaganda, die absichtlich oder irrtümlich falsch war, als ebenso parteiisch erweisen wie die Propaganda, die sie bekämpfen wollte. Die Wahrheit zu sagen, stärkt also die Wirksamkeit der Gegenpropaganda und schwächt die Propaganda derjenigen, die als Lügner entlarvt werden. Die Verwendung von Falschmeldungen in der Gegenpropaganda ist nicht wirksam und widerlegt die Propagandabotschaft nicht angemessen. Wird eine Gegenpropagandabotschaft als falsch entlarvt oder soll sie durch eine Lüge beeinflusst werden, schadet dies auch dem Ruf des Senders und verringert seine Fähigkeit, Propagandabotschaften in Zukunft wirksam zu widerlegen.

Gegenpropaganda ist eine reaktive Methode, die schnell eingesetzt werden muss, um einer Propagandabotschaft wirksam zu widersprechen. Oliver Carlson erklärt, dass es umso schwieriger ist, einer Propaganda zu widersprechen, je länger sie als Wahrheit wahrgenommen wird, selbst wenn das Zielpublikum einer gegenteiligen wahren Botschaft ausgesetzt ist. Eine Propagandabotschaft, der nicht sofort nach ihrer Entdeckung widersprochen wird, wird wahrscheinlich zur Grundlage für die Handlungen und Überzeugungen der Zielgruppe.

Die Psychologie liefert weitere Gründe für den raschen Einsatz von Gegenpropaganda. Der Entscheidungsfindungsprozess wird durch kognitive Verzerrungen beeinflusst, die bestimmen, wie eine Person bestimmte Informationen wahrnimmt und wie sie daraufhin handelt. Der Bestätigungsfehler ist besonders relevant, wenn es darum geht, die Notwendigkeit eines schnellen Einsatzes von Gegenpropaganda zu erklären. Der Bestätigungsfehler ist eine Tendenz der Menschen, Informationen zu bevorzugen, die ihre Überzeugungen oder Hypothesen bestätigen. Wenn eine Gruppe ihre Überzeugungen oder Handlungen auf eine Propagandabotschaft stützt, der sie über einen langen Zeitraum ausgesetzt war, ist es schwierig, der Propaganda entgegenzuwirken. Die Gruppe würde in einem solchen Szenario zögern, Informationen aus einer Gegenpropagandabotschaft aufzunehmen, die der Propagandabotschaft widersprechen. Daher ist es wichtig, dass Gegenpropaganda frühzeitig in einer Propagandakampagne eingesetzt wird, um die Möglichkeit einer aus der Propaganda resultierenden Bestätigungsverzerrung zu verhindern. In Propaganda: The Formation of Men’s Attitudes schlägt Jacques Ellul einen weiteren Grund vor, als Reaktion auf eine identifizierte Propagandabotschaft schnell Gegenpropaganda einzusetzen. Er argumentiert, dass sich die Menschheit mehr mit aktuellen Ereignissen und Themen beschäftigt, die die Aufmerksamkeit der Gesellschaft auf sich ziehen. Propaganda, die sich an aktuellen Ereignissen orientiert, weckt die größte Leidenschaft und das größte Interesse der Gemeinschaft. Eine Gegenpropaganda erfordert eine schnelle Reaktion auf die Propaganda, wenn sie aufgedeckt wird. Umgekehrt ist der Einsatz von Gegenpropaganda gegen eine veraltete Propagandabotschaft, die sich auf ein ebenso veraltetes Thema bezieht, für das die Gesellschaft kein aktuelles Interesse hat, wahrscheinlich weniger wirksam.

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Rudolf Steiner zur “Impfung”

„Die Seele wird man abschaffen durch ein Arzeimittel. Man wird aus einer <gesundenAnschauung> heraus einen Impfstoff finden, durch den der Organismus so bearbeitet wirdin möglichst früher Jugend, möglichst gleich bei der Geburt, daß dieser menschliche Leibnicht zu dem Gedanken kommt: Es gibt eine Seele und einen Geist.So scharf werden sich die beiden Weltanschauungen gegenübertreten. Die eine wirdnachzudenken haben, wie Begriffe und Vorstellungen auszubilden sind, damit sie derrealen Wirklichkeit, der Geist- und Seelenwirklichkeit gewachsen sind. Die andern, dieNachfolger der heutigen Materialisten, werden den Impfstoff suchen, der den Körper<gesund> macht, das heißt: so macht, daß dieser Körper durch seine Konstitution nichtmehr von solch albernen Dingen redet wie von Seele und Geist, sondern <gesund> redetvon den Kräften, die in Maschienen und Chemie leben, die im Weltennebel Planeten undSonnen konstituieren.Das wird man durch körperliche Prozeduren herbeiführen. Den materialistischstenMedizinern wird man es übergeben, die Seelen auszutreiben aus der Menschheit.“

R. Steiner (1861-1925), Gesamtausgabe 177, S. 97

***

„Ich habe Sie darauf hingewiesen, daß ja freilich die Menschenleiber sich so entwickelnwerden, daß in ihnen eine gewisse Spiritualität Platz finden kann, daß aber dermaterialistische Sinn, der sich immer mehr ausbreiten wird, durch die Anweisungen derGeister der Finsternis, dagegen arbeiten und mit materiellen Mitteln dagegen kämpfenwird.Ich habe Ihnen gesagt, daß die Geister der Finsternis ihre Kostgeber, die Menschen, indenen sie wohnen werden, dazu inspirieren werden, sogar ein Impfmittel zu finden, um dieSeelen schon in frühester Jugend auf dem Umwege durch die Leiblichkeit die Hinneigungzur Spiritualität auszutreiben.Wie man heute die Leiber impft gegen dies und jenes, so wird man zukünftig die Kindermit einem Stoff impfen, der durchaus hergestellt werden kann, so daß durch dieseImpfung die Menschen gefeit sein werden, die <Narrheiten> des spirituellen Lebens nichtaus sich heraus zu entwickeln, Narrheiten selbstverständlich im materialistischen Sinnegesprochen. (-)Das alles tendiert aber dahin, zuletzt das Mittel zu finden, durch das man die Leiberimpfen kann, damit sie nicht Neigungen zu spirituellen Ideen aufkommen lassen, sondernihr ganzes Leben hindurch nur an die sinnenfällige Materie glauben. (-)So wie man heute gegen die Schwindsucht impft, so wird man impfen gegen die Anlagenzur Spiritualität.“R. Steiner, Gesamtausgabe 177, S. 236

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Historie der Eugenik

https://www.youtube.com/watch?v=3rt1YWvV1fA
Automatische Übersetzung via Untertitel möglich:

Einstellungen (Zahnrad) öffnen:
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ARTE Doku: Bill Gates und das “Genlabor Afrika”

https://www.youtube.com/watch?v=9Sl0As0EAxU

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Zurückgezogene Publikation: “Corona Impfung” beeinträchtig DNA Reparatur-mechanismen

Jiang, H., & Mei, Y. F. (2021). SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro. Viruses, 13(10), 2056. https://doi.org/10.3390/v13102056 (Retraction published Viruses. 2022 May 10;14(5):)

viruses-13-02056-v3

PMID- 34696485
OWN - NLM
STAT- MEDLINE
DCOM- 20211110
LR - 20220528
IS - 1999-4915 (Electronic)
IS - 1999-4915 (Linking)
VI - 13
IP - 10
DP - 2021 Oct 13
TI - SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In
Vitro.
LID - 10.3390/v13102056 [doi]
LID - 2056
AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the
coronavirus disease 2019 (COVID-19) pandemic, severely affecting public health
and the global economy. Adaptive immunity plays a crucial role in fighting
against SARS-CoV-2 infection and directly influences the clinical outcomes of
patients. Clinical studies have indicated that patients with severe COVID-19
exhibit delayed and weak adaptive immune responses; however, the mechanism by
which SARS-CoV-2 impedes adaptive immunity remains unclear. Here, by using an in
vitro cell line, we report that the SARS-CoV-2 spike protein significantly
inhibits DNA damage repair, which is required for effective V(D)J recombination
in adaptive immunity. Mechanistically, we found that the spike protein localizes
in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein
BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential
molecular mechanism by which the spike protein might impede adaptive immunity and
underscore the potential side effects of full-length spike-based vaccines.
FAU - Jiang, Hui
AU - Jiang H
AD - Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm
University, SE-10691 Stockholm, Sweden.
AD - Department of Clinical Microbiology, Virology, Umeå University, SE-90185 Umeå,
Sweden.
FAU - Mei, Ya-Fang
AU - Mei YF
AD - Department of Clinical Microbiology, Virology, Umeå University, SE-90185 Umeå,
Sweden.
LA - eng
GR - 3453 16032,ALF-Basenhet 2020, 2021, AMP 19-982, and LP 20-2256/Umeå University,
ALF-Basenhet,the Lion's Cancer Research Foundation/
PT - Journal Article
PT - Research Support, Non-U.S. Gov't
PT - Retracted Publication
DEP - 20211013
TA - Viruses
JT - Viruses
JID - 101509722
RN - 0 (Antibodies, Neutralizing)
RN - 0 (Antibodies, Viral)
RN - 0 (BRCA1 Protein)
RN - 0 (BRCA1 protein, human)
RN - 0 (COVID-19 Vaccines)
RN - 0 (Spike Glycoprotein, Coronavirus)
RN - 0 (TP53BP1 protein, human)
RN - 0 (Tumor Suppressor p53-Binding Protein 1)
RN - 0 (spike protein, SARS-CoV-2)
SB - IM
ECI - Viruses. 2021 Dec 22;14(1):. PMID: 35062216
RIN - Viruses. 2022 May 10;14(5):. PMID: 35632859
MH - Adaptive Immunity/*immunology
MH - Antibodies, Neutralizing/blood/immunology
MH - Antibodies, Viral/blood/immunology
MH - BRCA1 Protein/antagonists & inhibitors
MH - CD4 Lymphocyte Count
MH - CD8-Positive T-Lymphocytes/immunology
MH - COVID-19/*pathology
MH - COVID-19 Vaccines/immunology
MH - Cell Line
MH - DNA Damage/genetics
MH - DNA Repair/*genetics
MH - HEK293 Cells
MH - Humans
MH - Immunity, Humoral/immunology
MH - Immunosuppression Therapy
MH - SARS-CoV-2/genetics/*immunology
MH - Spike Glycoprotein, Coronavirus/*genetics/immunology
MH - T-Lymphocytes, Helper-Inducer/immunology
MH - Tumor Suppressor p53-Binding Protein 1/antagonists & inhibitors
MH - V(D)J Recombination/*genetics
PMC - PMC8538446
OTO - NOTNLM
OT - *DNA damage repair
OT - *SARS–CoV–2
OT - *V(D)J recombination
OT - *spike
OT - *vaccine
COIS- The authors have declared that no competing interests exist. The funders had no
role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
EDAT- 2021/10/27 06:00
MHDA- 2021/11/11 06:00
CRDT- 2021/10/26 01:03
PHST- 2021/08/20 00:00 [received]
PHST- 2021/09/08 00:00 [revised]
PHST- 2021/10/08 00:00 [accepted]
PHST- 2021/10/26 01:03 [entrez]
PHST- 2021/10/27 06:00 [pubmed]
PHST- 2021/11/11 06:00 [medline]
AID - v13102056 [pii]
AID - viruses-13-02056 [pii]
AID - 10.3390/v13102056 [doi]
PST - epublish
SO - Viruses. 2021 Oct 13;13(10):2056. doi: 10.3390/v13102056.

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Medikamentenverabreichung über Mikronadeln

Yin, Y., Su, W., Zhang, J., Huang, W., Li, X., Ma, H., … Wang, H.. (2021). Separable Microneedle Patch to Protect and Deliver DNA Nanovaccines against COVID-19. ACS Nano
Plain numerical DOI: 10.1021/acsnano.1c03252
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“The successful control of coronavirus disease 2019 (covid-19) pandemic is not only relying on the development of vaccines, but also depending on the storage, transportation, and administration of vaccines. ideally, nucleic acid vaccine should be directly delivered to proper immune cells or tissue (such as lymph nodes). however, current developed vaccines are normally treated through intramuscular injection, where immune cells do not normally reside. meanwhile, current nucleic acid vaccines must be stored in a frozen state that may hinder their application in developing countries. here, we report a separable microneedle (smn) patch to deliver polymer encapsulated spike (or nucleocapsid) protein encoding dna vaccines and immune adjuvant for efficient immunization. compared with intramuscular injection, smn patch can deliver nanovaccines into intradermal for inducing potent and durable adaptive immunity. ifn-γ+cd4/8+ and il-2+cd4/8+ t cells or virus specific igg are significantly increased after vaccination. moreover, in vivo results show the smn patches can be stored at room temperature for at least 30 days without decreases in immune responses. these features of nanovaccines-laden smn patch are important for developing advanced covid-19 vaccines with global accessibility.”

Lee, M. S., Pan, C. X., & Nambudiri, V. E.. (2021). Transdermal approaches to vaccinations in the COVID-19 pandemic era. Therapeutic Advances in Vaccines and Immunotherapy
Plain numerical DOI: 10.1177/25151355211039073
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“The covid-19 pandemic has necessitated rapid vaccine development for the control of the disease. most vaccinations, including those currently approved for covid-19 are administered intramuscularly and subcutaneously using hypodermic needles. however, there are several disadvantages including pain and fear of needlesticks, the need for two doses, the need for trained health care professionals for vaccine administration, and barriers to global distribution given the need for cold supply chain. recently, transdermal techniques have been under investigation for vaccines including covid-19. microneedle array technology utilizes multiple microscopic projections from a plate which delivers a vaccine in the form of a patch placed on the skin, allowing for painless antigen delivery with improved immune response. in this review, we discuss challenges of existing vaccines and review the literature on the science behind transdermal vaccines including microneedles, current evidence of application in infectious diseases including covid-19, and considerations for implementation and global access.”

Dixon, R. V., Skaria, E., Lau, W. M., Manning, P., Birch-Machin, M. A., Moghimi, S. M., & Ng, K. W.. (2021). Microneedle-based devices for point-of-care infectious disease diagnostics. Acta Pharmaceutica Sinica B
Plain numerical DOI: 10.1016/j.apsb.2021.02.010
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“Recent infectious disease outbreaks, such as covid-19 and ebola, have highlighted the need for rapid and accurate diagnosis to initiate treatment and curb transmission. successful diagnostic strategies critically depend on the efficiency of biological sampling and timely analysis. however, current diagnostic techniques are invasive/intrusive and present a severe bottleneck by requiring specialist equipment and trained personnel. moreover, centralised test facilities are poorly accessible and the requirement to travel may increase disease transmission. self-administrable, point-of-care (poc) microneedle diagnostic devices could provide a viable solution to these problems. these miniature needle arrays can detect biomarkers in/from the skin in a minimally invasive manner to provide (near-) real-time diagnosis. few microneedle devices have been developed specifically for infectious disease diagnosis, though similar technologies are well established in other fields and generally adaptable for infectious disease diagnosis. these include microneedles for biofluid extraction, microneedle sensors and analyte-capturing microneedles, or combinations thereof. analyte sampling/detection from both blood and dermal interstitial fluid is possible. these technologies are in their early stages of development for infectious disease diagnostics, and there is a vast scope for further development. in this review, we discuss the utility and future outlook of these microneedle technologies in infectious disease diagnosis.”

Kim, E., Erdos, G., Huang, S., Kenniston, T. W., Balmert, S. C., Carey, C. D., … Gambotto, A.. (2020). Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development. EBioMedicine
Plain numerical DOI: 10.1016/j.ebiom.2020.102743
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“Background: coronaviruses pose a serious threat to global health as evidenced by severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers), and covid-19. sars coronavirus (sars-cov), mers coronavirus (mers-cov), and the novel coronavirus, previously dubbed 2019-ncov, and now officially named sars-cov-2, are the causative agents of the sars, mers, and covid-19 disease outbreaks, respectively. safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. the coronavirus spike (s) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection. methods: we first generated codon optimized mers-s1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. in variant constructs, we engineered immune stimulants (rs09 or flagellin, as tlr4 or tlr5 agonists, respectively) into this trimeric design. we comprehensively tested the pre-clinical immunogenicity of mers-cov vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (mnas) by evaluating virus specific igg antibodies in the serum of vaccinated mice by elisa and using virus neutralization assays. driven by the urgent need for covid-19 vaccines, we utilized this strategy to rapidly develop mna sars-cov-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with mna mers-cov vaccines. findings: here we describe the development of mna delivered mers-cov vaccines and their pre-clinical immunogenicity. specifically, mna delivered mers-s1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. building on our ongoing efforts to develop mers-cov vaccines, promising immunogenicity of mna-delivered mers-cov vaccines, and our experience with mna fabrication and delivery, including clinical trials, we rapidly designed and produced clinically-translatable mna sars-cov-2 subunit vaccines within 4 weeks of the identification of the sars-cov-2 s1 sequence. most importantly, these mna delivered sars-cov-2 s1 subunit vaccines elicited potent antigen-specific antibody responses that were evident beginning 2 weeks after immunization. interpretation: mna delivery of coronaviruses-s1 subunit vaccines is a promising immunization strategy ag…”

Dixon, R. V., Lau, W. M., Moghimi, S. M., & Ng, K. W.. (2020). The diagnostic potential of microneedles in infectious diseases. Precision Nanomedicine
Plain numerical DOI: 10.33218/001c.13658
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“Graphical abstract point-of-care microneedle diagnostics abstract the coronavirus disease 2019 (covid-19) pandemic has taught us much about our weaknesses in the management of infectious disease outbreaks. a key lesson has been the need for more effective point-of-care diagnostic tools that produce not only rapid and reliable results but also facilitate decentralised testing to avoid overwhelming central test facilities when demand peaks in an outbreak. microneedle devices can be inserted painlessly into the skin to detect biomolecules in the epidermal and dermal layers. they have been used to identify biomarkers in both the interstitial fluid and capillary blood. importantly, they are amenable to self-administration. in this article, we provide an overview of existing microneedle-based diagnostic technologies and discuss how they may be built upon to provide effective diagnostic tools for infectious diseases.”

O’Shea, J., Prausnitz, M. R., & Rouphael, N.. (2021). Dissolvable microneedle patches to enable increased access to vaccines against SARS-CoV-2 and future pandemic outbreaks. Vaccines
Plain numerical DOI: 10.3390/vaccines9040320
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“Vaccines are an essential component of pandemic preparedness but can be limited due to challenges in production and logistical implementation. while vaccine candidates were rapidly developed against severe acute respiratory syndrome coronavirus 2 (sars-cov-2), immunization campaigns remain an obstacle to achieving herd immunity. dissolvable microneedle patches are advantageous for many possible reasons: improved immunogenicity; dose-sparing effects; expected low manufacturing cost; elimination of sharps; reduction of vaccine wastage; no need for reconstitution; simplified supply chain, with reduction of cold chain supply through increased thermostability; ease of use, reducing the need for healthcare providers; and greater acceptability compared to traditional hypodermic injections. when applied to coronavirus disease 2019 (covid-19) and future pandemic outbreaks, microneedle patches have great potential to improve vaccination globally and save many lives.”

Xia, D., Jin, R., Byagathvalli, G., Yu, H., Ye, L., Lu, C. Y., … Prausnitz, M. R.. (2021). An ultra-low-cost electroporator with microneedle electrodes (ePatch) for SARS-CoV-2 vaccination. Proceedings of the National Academy of Sciences of the United States of America
Plain numerical DOI: 10.1073/pnas.2110817118
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“Vaccination against severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and other pathogens with pandemic potential requires safe, protective, inexpensive, and easily accessible vaccines that can be developed and manufactured rapidly at a large scale. dna vaccines can achieve these criteria, but induction of strong immune responses has often required bulky, expensive electroporation devices. here, we report an ultra-low-cost (<1 usd), handheld (<50 g) electroporation system utilizing a microneedle electrode array (‘epatch’) for dna vaccination against sars-cov-2. the low cost and small size are achieved by combining a thumb-operated piezoelectric pulser derived from a common household stove lighter that emits microsecond, bipolar, oscillatory electric pulses and a microneedle electrode array that targets delivery of high electric field strength pulses to the skin’s epidermis. antibody responses against sars-cov-2 induced by this electroporation system in mice were strong and enabled at least 10-fold dose sparing compared to conventional intramuscular or intradermal injection of the dna vaccine. vaccination was well tolerated with mild, transient effects on the skin. this epatch system is easily portable, without any battery or other power source supply, offering an attractive, inexpensive approach for rapid and accessible dna vaccination to combat covid-19, as well as other epidemics.”

MA, A.. (2020). Evaluation of Microneedle Drug Delivery System and Nanoparticles Use in COVID-19 Patients. International Journal of Clinical Studies and Medical Case Reports
Plain numerical DOI: 10.46998/ijcmcr.2020.02.000037
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Flynn, O., Dillane, K., Lanza, J. S., Marshall, J. M., Jin, J., Silk, S. E., … Moore, A. C.. (2021). Low adenovirus vaccine doses administered to skin using microneedle patches induce better functional antibody immunogenicity as compared to systemic injection. Vaccines
Plain numerical DOI: 10.3390/vaccines9030299
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“Adenovirus-based vaccines are demonstrating promising clinical potential for multiple infectious diseases, including covid-19. however, the immunogenicity of the vector itself decreases its effectiveness as a boosting vaccine due to the induction of strong anti-vector neutralizing im-munity. here we determined how dissolvable microneedle patches (dmn) for skin immunization can overcome this issue, using a clinically-relevant adenovirus-based plasmodium falciparum malaria vaccine, adhu5–pfrh5, in mice. incorporation of vaccine into patches significantly enhanced its thermostability compared to the liquid form. conventional high dose repeated immunization by the intramuscular (im) route induced low antigen-specific igg titres and high anti-vector immunity. a low priming dose of vaccine, by the im route, but more so using dmn patches, induced the most efficacious immune responses, assessed by parasite growth inhibitory activity (gia) assays. administration of low dose adhu5–pfrh5 using patches to the skin, boosted by high dose im, induced the highest antigen-specific serum igg response after boosting, the greatest skewing of the antibody response towards the antigen and away from the vector, and the highest efficacy. this study therefore demonstrates that repeated use of the same adenovirus vaccine can be highly immunogenic towards the transgene if a low dose is used to prime the response. it also provides a method of stabilizing adenovirus vaccine, in easy-to-administer dissolvable microneedle patches, permitting storage and distribution out of cold chain.”

Wang, F. Y., Chen, Y., Huang, Y. Y., & Cheng, C. M.. (2021). Transdermal drug delivery systems for fighting common viral infectious diseases. Drug Delivery and Translational Research
Plain numerical DOI: 10.1007/s13346-021-01004-6
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“Transdermal drug delivery systems (tdds) have many advantages and represent an excellent alternative to oral delivery and hypodermic injections. tdds are more convenient and less invasive tools for disease and viral infection treatment, prevention, detection, and surveillance. the emerging development of microneedles for tdds has facilitated improved skin barrier penetration for the delivery of macromolecules or hydrophilic drugs. microneedle tdds patches can be fabricated to deliver virus vaccines and potentially provide a viable alternative vaccine modality that offers improved immunogenicity, thermostability, simplicity, safety, and compliance as well as sharp-waste reduction, increased cost-effectiveness, and the capacity for self-administration, which could improve vaccine distribution. these advantages make tdds-based vaccine delivery an especially well-suited option for treatment of widespread viral infectious diseases including pandemics. because microneedle-based bioassays employ transdermal extraction of interstitial fluid or blood, they can be used as a minimally invasive approach for surveying disease markers and providing point-of-care (poc) diagnostics. for cutaneous viral infections, tdds can provide localized treatment with high specificity and less systemic toxicity. in summary, tdds, especially those that employ microneedles, possess special attributes that can be leveraged to reduce morbidity and mortality from viral infectious diseases. in this regard, they may have considerable positive impact as a modality for improving global health. in this article, we introduce the possible role and summarize the current literature regarding tdds applications for fighting common cutaneous or systemic viral infectious diseases, including herpes simplex, varicella or herpes zoster, warts, influenza, measles, and covid-19. graphical abstract: [figure not available: see fulltext.].”

Kuwentrai, C., Yu, J., Rong, L., Zhang, B. Z., Hu, Y. F., Gong, H. R., … Xu, C.. (2021). Intradermal delivery of receptor-binding domain of SARS-CoV-2 spike protein with dissolvable microneedles to induce humoral and cellular responses in mice. Bioengineering and Translational Medicine
Plain numerical DOI: 10.1002/btm2.10202
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“The s1 subunit of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) spike protein contains an immunogenic receptor-binding domain (rbd), which is a promising candidate for the development of a potential vaccine. this study demonstrated that intradermal delivery of an s-rbd vaccine using a dissolvable microneedle skin patch can induce both significant b-cell and significant t-cell responses against s-rbd. importantly, the outcomes were comparable to that of conventional bolus injection.”

Ortega-Rivera, O. A., Shin, M. D., Chen, A., Beiss, V., Moreno-Gonzalez, M. A., Lopez-Ramirez, M. A., … Steinmetz, N. F.. (2021). Trivalent Subunit Vaccine Candidates for COVID-19 and Their Delivery Devices. Journal of the American Chemical Society
Plain numerical DOI: 10.1021/jacs.1c06600
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“The covid-19 pandemic highlights the need for platform technologies enabling rapid development of vaccines for emerging viral diseases. the current vaccines target the sars-cov-2 spike (s) protein and thus far have shown tremendous efficacy. however, the need for cold-chain distribution, a prime-boost administration schedule, and the emergence of variants of concern (vocs) call for diligence in novel sars-cov-2 vaccine approaches. we studied 13 peptide epitopes from sars-cov-2 and identified three neutralizing epitopes that are highly conserved among the vocs. monovalent and trivalent covid-19 vaccine candidates were formulated by chemical conjugation of the peptide epitopes to cowpea mosaic virus (cpmv) nanoparticles and virus-like particles (vlps) derived from bacteriophage qβ. efficacy of this approach was validated first using soluble vaccine candidates as solo or trivalent mixtures and subcutaneous prime-boost injection. the high thermal stability of our vaccine candidates allowed for formulation into single-dose injectable slow-release polymer implants, manufactured by melt extrusion, as well as microneedle (mn) patches, obtained through casting into micromolds, for prime-boost self-administration. immunization of mice yielded high titers of antibodies against the target epitope and s protein, and data confirms that antibodies block receptor binding and neutralize sars-cov and sars-cov-2 against infection of human cells. we present a nanotechnology vaccine platform that is stable outside the cold-chain and can be formulated into delivery devices enabling single administration or self-administration. cpmv or qβ vlps could be stockpiled, and epitopes exchanged to target new mutants or emergent diseases as the need arises.”

Zhang, T., Yang, L., Yang, X., Tan, R., Lu, H., & Shen, Y.. (2021). Millimeter‐Scale Soft Continuum Robots for Large‐Angle and High‐Precision Manipulation by Hybrid Actuation. Advanced Intelligent Systems
Plain numerical DOI: 10.1002/aisy.202000189
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“Developing small‐scale soft continuum robots with large‐angle steering capacity and high‐precision manipulation offers broad opportunities in various biomedical settings. however, existing continuum robots reach the bottleneck in actuation on account of the contradiction among small size, compliance actuation, large tender range, high precision, and small dynamic error. herein, a 3d‐printed millimeter‐scale soft continuum robot with an ultrathin hollow skeleton wall (300 μm) and a large inner‐to‐outer ratio (0.8) is reported. after coating a thin ferromagnetic elastomer layer (≈100–150 μm), the proposed soft continuum robot equipped with hybrid actuation (tendon‐ and magnetic‐driven mode) achieves large‐angle (up to 100°) steering and high‐precision (low to 2 μm for static positioning) micromanipulation simultaneously. specifically, the robot implements an ultralow dynamic tracking error of ≈10 μm, which is ≈30‐fold improved than the state of art. combined with a microneedle/knife or nasopharyngeal swab, the robot reveals the potential for versatile biomedical applications, such as drug injection on the target tissue, diseased tissue ablation, and covid‐19 nasopharyngeal sampling. the proposed millimeter‐scale soft continuum robot presents remarkable advances in large‐range and high‐precise actuation, which provides a new method for miniature continuum robot design and finds broad applications in biomedical engineering.”

Peng, K., Vora, L. K., Tekko, I. A., Permana, A. D., Domínguez-Robles, J., Ramadon, D., … Donnelly, R. F.. (2021). Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections. Journal of Controlled Release
Plain numerical DOI: 10.1016/j.jconrel.2021.10.001
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“Fungal infections affect millions of people globally and are often unreceptive to conventional topical or oral preparations because of low drug bioavailability at the infection site, lack of sustained therapeutic effect, and the development of drug resistance. amphotericin b (amb) is one of the most potent antifungal agents. it is increasingly important since fungal co-infections associated with covid-19 are frequently reported. amb is only administered via injections (iv) and restricted to life-threatening infections due to its nephrotoxicity and administration-related side effects. in this work, we introduce, for the first time, dissolving microneedle patches (dmp) loaded with micronised particles of amb to achieve localised and long-acting intradermal delivery of amb for treatment of cutaneous fungal infections. amb was pulverised with poly (vinyl alcohol) and poly (vinyl pyrrolidone) to form micronised particles-loaded gels, which were then cast into dmp moulds to form the tips. the mean particle size of amb in amb dmp tips after pulverisation was 1.67 ± 0.01 μm. this is an easy way to fabricate and load microparticles into dmp, as few steps are required, and no organic solvents are needed. amb had no covalent chemical interaction with the excipients, but the crystallinity of amb was reduced in the tips. amb was completely released from the tips within 4 days in vitro. amb dmp presented inhibition of candida albicans (ca) and the killing rate of amb dmp against ca biofilm inside porcine skin reached 100% within 24 h. amb dmp were able to pierce excised neonatal porcine skin at an insertion depth of 301.34 ± 46.86 μm. ex vivo dermatokinetic and drug deposition studies showed that amb was mainly deposited in the dermis. an in vivo dermatokinetic study revealed that the area under curve (auc0-inf) values of amb dmp and iv (fungizone® bolus injection 1 mg/kg) groups were 8823.0 d∙μg/g and 33.4 d∙μg/g, respectively (264-fold higher). amb remained at high levels (219.07 ± 102.81 μg/g or more) in the skin until 7 days after the application of amb dmp. pharmacokinetic and biodistribution studies showed that amb concentration in plasma, kidney, liver, and spleen in the amb dmp group was significantly lower than that in the iv group. accordingly, this system addressed the systemic side effects of intravenous injection of amb and localised the drug inside the skin for a week. this work establishes a novel, easy and effective method for long-acting and localise…”

Qin, M., Du, G., & Sun, X.. (2021). Recent Advances in the Noninvasive Delivery of mRNA. Accounts of Chemical Research
Plain numerical DOI: 10.1021/acs.accounts.1c00493
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“ConspectusOver the past two decades, research on mrna-based therapies has exploded, mainly because of the inherent advantages of mrna, including a low integration probability, transient expression, and simple and rapid in vitro transcription production approaches. in addition, thanks to improved stability and reduced immunogenicity by advanced strategies, the application of mrna has expanded from protein replacement therapy to vaccination, gene editing and other fields, showing great promise for clinical application. recently, with the successive launch of two mrna-based covid-19 vaccines, mrna technology has attracted an enormous amount of attention from scientific researchers as well as pharmaceutical companies. because of the large molecular weight, hydrophilicity, and highly negative charge densities of mrna, it is difficult to overcome the intracellular delivery barriers. therefore, various delivery vehicles have been developed to achieve more effective mrna delivery. in general, conventional mrna administration methods are based on injection strategies, including intravenous, intramuscular, intradermal, and subcutaneous injections. although these routes circumvent the absorption barriers to some extent, they bring about injection-related concerns such as safety issues, pain, low compliance, and difficulty in repeated dosing, increasing the need to explore alternative strategies for noninvasive delivery. the ideal noninvasive delivery systems are featured with easy to use, low risks of infection, and good patient compliance. at the same time, they allow patients to self-administer, reducing reliance on professional healthcare workers and interference with bodily functions and daily life. in particular, the noninvasive mucosal delivery of mrna vaccines can induce mucosal immune responses, which are important for resisting pathogens infected through mucosal routes.because of the potential clinical benefits mentioned above, we detailed the existing strategies for the noninvasive delivery of mrna in this review, including delivery via the nasal, pulmonary, vaginal, and transdermal routes. first, we discussed the unique strengths and biological hindrances of each route on the basis of physiology. next, we comprehensively summarized the research progress reported so far and analyzed the technologies and delivery vehicles used, hoping to provide some references for further explorations. among these noninvasive routes, nasal and pulmonary delivery are the …”

Mikronadeln, Mikronadelpflaster oder Mikroarray-Pflaster sind medizinische Geräte im Mikromaßstab, die zur Verabreichung von Impfstoffen, Arzneimitteln und anderen therapeutischen Wirkstoffen verwendet werden.[2] Während Mikronadeln ursprünglich für die transdermale Verabreichung von Arzneimitteln erforscht wurden, wurde ihre Verwendung auf die intraokulare, vaginale, transunguale, kardiale, vaskuläre, gastrointestinale und intracochleäre Verabreichung von Arzneimitteln ausgeweitet. [3] [4] [5] Mikronadeln werden mit verschiedenen Methoden hergestellt, in der Regel mit photolithografischen Verfahren oder durch Mikroformen[6], bei denen mikroskopische Strukturen in Harz oder Silizium geätzt werden, um Mikronadeln zu gießen. Mikronadeln werden aus verschiedenen Materialien wie Silizium, Titan, rostfreiem Stahl und Polymeren hergestellt.[7][1] Einige Mikronadeln bestehen aus einem Medikament, das dem Körper zugeführt werden soll, sind aber so geformt, dass sie die Haut durchdringen. Die Mikronadeln unterscheiden sich in Größe, Form und Funktion, werden aber alle als Alternative zu anderen Verabreichungsmethoden wie der herkömmlichen Injektionsnadel oder anderen Injektionsgeräten verwendet.

Mikronadeln werden in der Regel durch eine einzelne Nadel oder kleine Arrays appliziert. Bei den verwendeten Arrays handelt es sich um eine Ansammlung von Mikronadeln, die von einigen wenigen bis zu mehreren Hundert reichen und an einem Applikator, manchmal einem Pflaster oder einem anderen festen Stanzgerät, befestigt sind. Die Arrays werden auf die Haut des Patienten aufgebracht und erhalten Zeit, um die wirksame Verabreichung von Medikamenten zu ermöglichen. Mikronadeln stellen für Ärzte eine einfachere Methode dar, da ihre Anwendung weniger Schulung erfordert und sie nicht so gefährlich sind wie andere Nadeln. Dadurch wird die Verabreichung von Arzneimitteln an Patienten sicherer und weniger schmerzhaft, während gleichzeitig einige der Nachteile anderer Formen der Verabreichung von Arzneimitteln vermieden werden, wie z. B. das Infektionsrisiko, die Produktion von Sondermüll oder die Kosten.
Inhalt

1 Hintergrund
2 Arten von Mikronadeln
2.1 Fest
2.2 hohl
2.3 Beschichtet
2.4 Auflösbar
3 Vorteile
4 Benachteiligungen
5 Forschung und Anwendungen
5.1 Einsatz bei der COVID-19-Pandemie
6 Referenzen

Hintergrund
Hauptartikel: Mikroinjektion

Mikronadeln wurden erstmals 1998 in einer Arbeit der Forschergruppe um Mark Prausnitz am Georgia Institute of Technology erwähnt, in der nachgewiesen wurde, dass Mikronadeln die oberste Schicht (Stratum corneum) der menschlichen Haut durchdringen können und daher für die transdermale Verabreichung von therapeutischen Wirkstoffen geeignet sind.[8] Spätere Forschungen zur Verabreichung von Medikamenten über Mikronadeln haben die medizinischen und kosmetischen Anwendungen dieser Technologie durch ihr Design untersucht. In dieser frühen Arbeit wurde die Möglichkeit untersucht, Mikronadeln in Zukunft für Impfungen zu verwenden. Seitdem haben Forscher die Verabreichung von Insulin, Impfstoffen, entzündungshemmenden Mitteln und anderen Arzneimitteln über Mikronadeln untersucht. In der Dermatologie werden Mikronadeln zur Behandlung von Narben mit Hautrollern eingesetzt.

Das Hauptziel eines jeden Mikronadeldesigns ist es, die äußerste Schicht der Haut, das Stratum corneum (10-15μm), zu durchdringen.[9] Die Mikronadeln sind lang genug, um das Stratum corneum zu durchdringen, aber nicht so lang, dass sie Nerven stimulieren, die sich tiefer im Gewebe befinden und daher keine oder nur geringe Schmerzen verursachen.[8]

Die Forschung hat gezeigt, dass es eine Grenze für die Art von Medikamenten gibt, die durch intakte Haut verabreicht werden können. Nur Verbindungen mit einem relativ geringen Molekulargewicht, wie das häufige Allergen Nickel (130 Da),[10] können die Haut durchdringen. Verbindungen mit einem Gewicht von mehr als 500 Da können die Haut nicht durchdringen.[9]

Arten von Mikronadeln

Seit ihrer Entwicklung im Jahr 1998 wurden mehrere Fortschritte in Bezug auf die verschiedenen Arten von Mikronadeln gemacht, die hergestellt werden können. Die 4 Haupttypen von Mikronadeln sind fest, hohl, beschichtet und auflösbar/auflösend[2].
Festkörper

Diese Art von Array ist als zweiteiliges System konzipiert; das Mikronadel-Array wird zunächst auf die Haut aufgebracht, um mikroskopisch kleine Vertiefungen zu erzeugen, die gerade tief genug sind, um die äußerste Hautschicht zu durchdringen, und dann wird das Arzneimittel über ein transdermales Pflaster appliziert. Feste Mikronadeln werden von Dermatologen bereits in der Kollageninduktionstherapie eingesetzt, einer Methode, bei der durch wiederholtes Einstechen von Mikronadeln in die Haut die Expression und Ablagerung der Proteine Kollagen und Elastin in der Haut angeregt wird.[11]

Bei einer neueren Anpassung des Mikronadeldesigns kapseln auflösbare Mikronadeln das Arzneimittel in ein ungiftiges Polymer ein, das sich auflöst, sobald es sich in der Haut befindet.[1] Dieses Polymer würde es ermöglichen, das Arzneimittel in die Haut einzubringen, und könnte im Körper abgebaut werden. Pharmaunternehmen und Forscher haben begonnen, Polymere wie Fibroin zu untersuchen und einzusetzen, ein Protein auf Seidenbasis, das zu Strukturen wie Mikronadeln geformt und im Körper aufgelöst werden kann[12].
Vorteile

Die Verwendung von Mikronadeln hat viele Vorteile, von denen der größte der verbesserte Komfort für die Patienten ist. Nadelphobie kann sowohl Erwachsene als auch Kinder betreffen und manchmal zu Ohnmachtsanfällen führen. Der Vorteil von Mikronadel-Arrays ist, dass sie die Angst der Patienten vor einer Injektionsnadel verringern. Neben der Verbesserung des psychologischen und emotionalen Komforts sind Mikronadeln nachweislich wesentlich weniger schmerzhaft als herkömmliche Injektionen.[9] In einigen Studien wurden die Ansichten von Kindern zur Blutentnahme mit Mikronadeln aufgezeichnet, und es wurde festgestellt, dass die Patienten bereitwilliger waren, wenn sie mit einem weniger schmerzhaften Verfahren konfrontiert wurden als mit der herkömmlichen Blutentnahme mit Nadeln. Mikronadeln sind auch für Ärzte von Vorteil, da sie weniger gefährlichen Abfall produzieren als Nadeln und im Allgemeinen einfacher zu handhaben sind. Mikronadeln sind auch kostengünstiger als Nadeln, da sie weniger Material benötigen und das verwendete Material billiger ist als das Material von Injektionsnadeln.

Mikronadeln bieten eine neue Chance für die Gesundheitsversorgung zu Hause und in der Gemeinde. Einer der größten Nachteile herkömmlicher Nadeln ist der gefährliche Abfall, den sie produzieren, was die Entsorgung zu einem ernsten Problem für Ärzte und Krankenhäuser macht. Für Patienten, die sich regelmäßig Medikamente zu Hause verabreichen müssen, kann die Entsorgung zu einem Umweltproblem werden, wenn die Nadeln im Müll landen. Auflösbare oder schwellbare Mikronadeln würden denjenigen, die nur begrenzt in der Lage sind, ein Krankenhaus aufzusuchen, die Möglichkeit geben, sich bequem zu Hause Medikamente zu verabreichen, obwohl die Entsorgung von festen oder hohlen Mikronadeln immer noch ein Risiko für Nadelstichverletzungen oder durch Blut übertragbare Krankheitserreger darstellen könnte[1].

Ein weiterer Vorteil von Mikronadeln ist die geringere Invasion von Mikroorganismen in die Einstichstellen.[1][9] Bei herkömmlichen Injektionsmethoden können Einstichwunden bis zu 48 Stunden nach der Behandlung zurückbleiben. Damit bleibt ein großes Zeitfenster für das Eindringen schädlicher Bakterien in die Haut. Mikronadeln verletzen die Haut nur bis zu einer Tiefe von 10-15 μm, was es den Bakterien erschwert, in den Blutkreislauf einzudringen, und dem Körper eine kleinere Wunde zum Reparieren gibt.[6] Weitere Forschung ist erforderlich, um die Arten von Bakterien zu bestimmen, die in der Lage sind, die flache Einstichstelle von Mikronadeln zu überwinden.
Nachteile

Es gibt einige Bedenken darüber, wie Ärzte sicher sein können, dass das gesamte Medikament oder der Impfstoff in die Haut gelangt ist, wenn Mikronadeln eingesetzt werden. Sowohl bei hohlen als auch bei beschichteten Mikronadeln besteht das Risiko, dass das Medikament nicht richtig in die Haut eindringt und nicht wirksam ist. Beide Arten von Mikronadeln können entweder durch eine Beschädigung der Mikronadel oder durch eine unsachgemäße Anwendung durch den Arzt in die Haut einer Person eindringen[13][9]. Deshalb ist es wichtig, dass die Ärzte in der korrekten Anwendung der Arrays geschult werden.

Ein weiteres Problem besteht darin, dass bei unsachgemäßer Anwendung der Arrays Fremdmaterial im Körper zurückbleiben könnte. Obwohl bei Mikronadeln ein geringeres Infektionsrisiko besteht, sind die Arrays aufgrund ihrer geringen Größe zerbrechlicher als eine typische Injektionsnadel, so dass die Gefahr besteht, dass sie abbrechen und in der Haut verbleiben. Einige der für die Konstruktion der Mikronadeln verwendeten Materialien, wie z. B. Titan, können vom Körper nicht absorbiert werden, und Bruchstücke der Nadeln würden Reizungen verursachen.

Es gibt nur eine begrenzte Menge an Literatur zum Thema Medikamentenabgabe über Mikronadeln, da die aktuelle Forschung noch erforscht, wie man wirksame Nadeln herstellen kann.
Forschung und Anwendungen

Forscher am MIT unter der Leitung von Ana Jaklenec entwickeln eine Technologie zur Verabreichung von Impfstoffen und zur Hinterlassung eines unsichtbaren Impfpasses beim Patienten. Diese Forschungsarbeiten werden von zahlreichen Einrichtungen finanziert, darunter die Bill & Melinda Gates Foundation und das Koch-Institut[14].

Es wird sogar erwogen, die neue Technologie zur Überwachung der Impfungen von Reisenden einzusetzen, um die Ausbreitung von Infektionskrankheiten zu verhindern. Die unsichtbare Markierung würde an den Einreisehäfen gescannt werden, um den Personenverkehr zu ermöglichen und gleichzeitig die Verbreitung von Viren zu kontrollieren[15].

Einsatz bei der COVID-19-Pandemie

Mikronadeln bieten ein bequemes System zur Verabreichung von Impfstoffen an eine große Bevölkerungsgruppe, ohne dass eine ausgeklügelte Forschungsinfrastruktur erforderlich ist, und die Möglichkeit der Selbstverabreichung. Darüber hinaus sind auflösbare Mikronadelpflaster ein äußerst praktisches System für die Verabreichung von Impfstoffen, da sich die Nadeln in der Haut auflösen und keine scharfen biomedizinischen Abfälle hinterlassen (im Gegensatz zu herkömmlichen subkutanen/intramuskulären Impfsystemen), was die Entsorgung erleichtert.[16][17]

Mehrere Forschungsteams haben Mikronadeln für die Verabreichung verschiedener Arten von Impfstoffen gegen das SARS-CoV-2-Virus entwickelt oder sind dabei, diese zu entwickeln, um die COVID-19-Pandemie zu beenden[18].
https://en.wikipedia.org/wiki/Microneedle_drug_delivery
Übersetzt mit www.DeepL.com/Translator (kostenlose Version)
Dathathri, E., Lal, S., Mittal, M., Thakur, G., & De, S.. (2020). Fabrication of low-cost composite polymer-based micro needle patch for transdermal drug delivery. Applied Nanoscience (Switzerland)
Plain numerical DOI: 10.1007/s13204-019-01190-3
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“Microneedle delivery patches are an emerging technology to attain painless and sustained delivery through the epidermis of the skin. this study is unique in its attempt to develop polymeric microneedles embedded with drug. special polymer chitosan with hydrogel forming capability is cross-linked with pva, a water-soluble polymer with excellent film strengthening ability and loaded with model drug diclofenac sodium. the microneedle patch was fabricated by pouring the chitosan-pva solution (ratio 1:6) on negative replica of master mold, which upon drying was peeled off to result in the composite film. the film of chitosan-pva in the ratio 1:6 when tested for mechanical behavior exhibited improved mechanical strength owing to use of pva, the presence of effective cross-linking of pva with chitosan was further verified with ftir. the release from drug-loaded needles was promising, as cross-linking with pva enabled a sustained drug release of 20.17% at the end of 30 h. the release followed the higuchi model with fickian diffusion, indicating a swelling-dependent release. the microneedle prepared using a composite of chitosan-pva showed promising results indicating its potential to be used as a drug eluting transdermal patch.”

Yoon, H. S., Lee, S. J., Park, J. Y., Paik, S. J., & Allen, M. G.. (2014). A non-enzymatic micro-needle patch sensor for free-cholesterol continuous monitoring. In Proceedings of IEEE Sensors
Plain numerical DOI: 10.1109/ICSENS.2014.6985005
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“A patch type non-enzymatic free-cholesterol sensor was newly developed for continuous monitoring by using stainless steel based micro-needle patch and nanoporous platinum (npt) sensing electrodes. the formed micro-needle patch was coated with parylene/gold/parylene film and selectively dry-etched to form the gold electrodes at the tips of micro-needles. the bare gold tips were finally electroplated with nanoporous platinum. the sensor was then characterized and analyzed by using cyclic voltammetry and chronoamperometry measurement techniques. the fabricated sensor exhibited high sensitivity of 305na/mm•cm2 and correlation coefficient of 0.964 in 0.1m pbs (ph 7.4). in the recovery test, recovery rate was more than 89%.”

Srinivas, P., Shanthi, C. L., & Sadanandam, M.. (2010). Micro Needle Patches in Drug Delivery - A Review. International Journal of Pharmacy & Technology

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“Drugs are administered by using different drug delivery systems. a number of drug delivery systems have evolved over the years. in the last 20 years tdds (transdermal drug delivery system) has been growing at a rapid pace. now the micro needles are being developed as a novel drug delivery system. the micro needle skin patch system is also a drug delivery system, which will be used transdermally. the success of tdd has severely limited by the inability of most drugs to enter the skin at therapeutical useful rates. thus, the use of micro-needle patches in increasing skin permeability has been proposed and shown to dramatically increase in transdermal delivery, especially for macromolecules. using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. most drug delivery studies have emphasized microneedles, which have been shown to increase the skin permeability to a broad range of molecules and nanoparticles invitro. this review briefly deals with types, mode of drug delivery, coating and applications of microneedle patches. overall the microneedle skin patches are prone to be a very versatile drug delivery technology, allowing easy and reproducible delivery to skin.”

Mogusala, N. R., Devadasu, V. R., & Venisetty, R. K.. (2015). Fabrication of Microneedle Molds and Polymer Based Biodegradable Microneedle Patches: A Novel Method. American Journal of Drug Delivery and Therapeutics

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“Objective: microneedleis a micro sized needle-like structure which has the ability to pierce the skin in a non-invasive and painless way. the present research work aims to design microneedle molds in a novel way and fabricate and characterize biodegradable polymer based micro-needle patch utilizing polymer casting. methods: fabrication of polymer patch involved two steps, one is to fabricate microneedle array mold and the other is to prepare biodegradable polymeric microneedle patch using the molds. molds are prepared by manually piercing the mixture of resin and hydrate (emseal) using needles having micro tips and patches are prepared using polymer solution. characterization of microneedle patch was done using scanning electron microscope and skin piercing ability was understood from histological studies of the rat skin. results: the micro-needles on the patch were found to be uniform in size and shape, with concentric circular features, the size of the microneedle tip was found to be between 20-50 µm and base around 200 µm and the shape was found to be conical with sharp tip. the micro-needles showed good penetration in to the skin which was observed by the histological studies performed using rat skin. conclusion: the present study demonstrates that the microneedle molds can be prepared using resins and microneedles can be developed using polymer casting method. the developed microneedles showed comparable structural features with those reported in the literature. these microneedles possessed good mechanical strength and can pierce the rat skin.”

Wang, J., & Pickwell-Macpherson, E.. (2020). Terahertz Imaging for Topical and Micro/Nano Needle Patch Drug Delivery. In International Conference on Infrared, Millimeter, and Terahertz Waves, IRMMW-THz
Plain numerical DOI: 10.1109/IRMMW-THz46771.2020.9370912
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Rapoport, A. M., & McAllister, P.. (2020). The Headache Pipeline: Excitement and Uncertainty. Headache
Plain numerical DOI: 10.1111/head.13728
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“There are many new treatment options available for migraine and more are coming. three calcitonin gene-related peptide (cgrp) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. small molecule cgrp receptor-blocking oral compounds, both for acute care and prevention, are also coming. four neurostimulators are available, with others on the way. new acute treatments coming soon include the 5ht1f agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. a new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxina. as always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.”

Kwon, S. Y.. (2004). In vitro evaluation of transdermal drug delivery by a micro-needle patch. Controlled Release Society 31st Annual Meeting …

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Ha, J. M., Lim, C. A., Han, K., Ha, J. C., Lee, H. E., Lee, Y., … Im, M.. (2017). The effect of micro-spicule containing epidermal growth factor on periocular wrinkles. Annals of Dermatology
Plain numerical DOI: 10.5021/ad.2017.29.2.187
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“Background: micro-needle patches have been recently used to increase skin permeability, which improves drug delivery, and for cosmetic purposes. however, these patches may often have limited efficacy due to insufficient skin penetration and reduced compliance caused by discomfort. objective: we evaluated the efficacy and the safety of soluble micro-spicule containing epidermal growth factor (ms-egf) for the treatment of periocular wrinkles. methods: twenty healthy volunteers aged 33 to 54 years were enrolled in a randomized, controlled, split-face study. for 4 weeks, a periocular wrinkle was treated daily with either a soluble ms-egf cream or a cream containing egf alone. all subjects underwent 8 weeks of follow-up. efficacy was assessed using an ultrasonic measurement of dermal depth and density, digital skin image analysis, 5-point photonumeric scale for periocular wrinkles and subjective satisfaction. results: ms-egf group showed statistically significant increase of dermal depth and density compared to egf alone group after 4 and 8 weeks. in addition, there was a marked improvement shown in clinical and 3-dimensional skin image in ms-egf group. the treatments were well-tolerated; no significant side-effect was noted. conclusion: the ms-egf formulation may represent an effective and biocompatible advance in the treatment of periocular wrinkles.”

Kwon, S. Y., & Oh, S.. (2005). Rapid Intradermal Drug Delivery by a Dissolvable Micro-Needle Patch. … Release Society 32 Nd Annual Meeting

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Jamaledin, R., Di Natale, C., Onesto, V., Taraghdari, Z. B., Zare, E. N., Makvandi, P., … Netti, P. A.. (2020). Progress in microneedle-mediated protein delivery. Journal of Clinical Medicine
Plain numerical DOI: 10.3390/jcm9020542
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“The growing demand for patient-compliance therapies in recent years has led to the development of transdermal drug delivery, which possesses several advantages compared with conventional methods. delivering protein through the skin by transdermal patches is extremely difficult due to the presence of the stratum corneum which restricts the application to lipophilic drugs with relatively low molecular weight. to overcome these limitations, microneedle (mn) patches, consisting of micro/miniature-sized needles, are a promising tool to perforate the stratum corneum and to release drugs and proteins into the dermis following a non-invasive route. this review investigates the fabrication methods, protein delivery, and translational considerations for the industrial scaling-up of polymeric mns for dermal protein delivery.”

Reddy Mogusala, N., Ratnam Devadasu, V., & Kumar Venisetty, R.. (2015). American Journal of Drug Delivery and Therapeutics Fabrication of Microneedle Molds and Polymer Based Biodegradable Microneedle Patches: A Novel Method. American Journal of Drug Delivery and Therapeutics

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Kwon, S. Y.. (2006). Acne Treatment by a Dissolvable Microneedle Patch. Controlled Release Society 33 St Annual Meeting

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Song, J. E., Jun, S. H., Park, S. G., & Kang, N. G.. (2020). A semi-dissolving microneedle patch incorporating TEMPO-oxidized bacterial cellulose nanofibers for enhanced transdermal delivery. Polymers
Plain numerical DOI: 10.3390/POLYM12091873
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“Although dissolving microneedles have garnered considerable attention as transdermal delivery tools, insufficient drug loading remains a challenge owing to their small dimension. herein, we report a one-step process of synthesizing semi-dissolving microneedle (sdmn) patches that enable effective transdermal drug delivery without loading drugs themselves by introducing tempo-oxidized bacterial cellulose nanofibers (tobcns), which are well dispersed, while retaining their unique properties in the aqueous phase. the sdmn patch fabricated by the micro-molding of a tobcn/hydrophilic biopolymer mixture had a two-layer structure comprising a water-soluble needle layer and a tobcn-containing insoluble backing layer. moreover, the sdmn patch, which had a hole in the backing layer where tobcns are distributed uniformly, could offer novel advantages for the delivery of large quantities of active ingredients. in vitro permeation analysis confirmed that tobcns with high water absorption capacity could serve as drug reservoirs. upon sdmn insertion and the application of drug aqueous solution through the drug inlet hole, the tobcns rapidly absorbed the solution and supplied it to the needle layer. simultaneously, the needle layer dissolved in body fluids and the drug solution to form micro-channels, which enabled the delivery of larger quantities of drugs to the skin compared to that enabled by solution application alone.”

Lee, S. J., Yoon, H. S., Xuan, X., Park, J. Y., Paik, S. J., & Allen, M. G.. (2016). A patch type non-enzymatic biosensor based on 3D SUS micro-needle electrode array for minimally invasive continuous glucose monitoring. Sensors and Actuators, B: Chemical
Plain numerical DOI: 10.1016/j.snb.2015.08.013
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“We developed a new patch-shaped enzyme free biosensor using a micro-needle array with pt black sensing electrode layer for painless continuous glucose monitoring applications. we fabricated the micro-needle array using a bulk micromachining technique and commercial stainless steel 316l grade substrate. pt black and ag/agcl were then electroplated on the tip of each micro-needle as working and counter/reference electrodes of the sensor, respectively. the fabricated micro-needle was 650 μm high and 150 μm wide. we used 48 and 24 micro-needles for the working electrode and counter/reference electrode, respectively. the measured sensitivity was 1.62 μa mm-1 with high linearity of 0.9939, and was obtained within 13 sec, in glucose concentrations ranging up to 36 mm. the biosensor also exhibited a low detection limit of 50 μm. we tested the sensor under pbs solution over a period of 6 days. then we partially inserted the sensor into a rabbit, to monitor the interstitial glucose level. we then induced change of interstitial glucose concentration by oral glucose tolerance test. although we expected the sensor to perform for more than 6 days, it performed for just 4 days as a sensor, due to bio fouling.”

Reddy Mogusala, N., Ratnam Devadasu, V., & Kumar Venisetty, R.. (2015). Fabrication of Microneedle Molds and Polymer Based Biodegradable Microneedle Patches: A Novel Method. American Journal of Drug Delivery and Therapeutics

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Alkhiro, A. R., & Ghareeb, M. M.. (2020). Formulation and evaluation of iornoxicam as dissolving microneedle patch. Iraqi Journal of Pharmaceutical Sciences
Plain numerical DOI: 10.31351/VOL29ISS1PP184-194
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“The objective of the study was to develop microneedle (mn) patch, with suitable properties to ensure the delivery of a therapeutic level of lornoxicam (lxm) in a period suitable to replace parenteral administration in patients, especially those who fear needles. the used polymers were cold water-soluble polyvinyl alcohol (pva) and polyvinylpyrrolidone (pvp) of low molecular weight with peg 400 as plasticizer and tween 80 (to enhance the release) using micro molding technique. patches were studied for needle morphology, drug content, axial fracture force measurement and drug release while the optimized formulas were further subjected to ph measurement, folding endurance, ex vivo permeation study, histopathology study, stability study and compatibility study. the patch with 11:1 ratio of pva to pvp, 30% solid content, 5% peg 400 and 3% tween 80 resulted in axial needle fracture force value of (1.35 n) which is suitable for skin penetration. the release was fast with almost 100% of drug released in 60 minutes. the permeation was enhanced significantly with a steady state flux of about 3.1 times that of the solution. the lag time of mn is shorter in comparison with ordinary patch. histopathology studies demonstrated the safety of the formulation, both stability studies and compatibility studies showed the suitability of the formulation. the results indicated that lxm microneedle patch could enhance drug permeation while achieving fast and painless administration. copyrights”

Lee, S., Lahiji, S. F., Jang, J., Jang, M., & Jung, H.. (2019). Micro-pillar integrated dissolving microneedles for enhanced transdermal drug delivery. Pharmaceutics
Plain numerical DOI: 10.3390/pharmaceutics11080402
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“The dissolving microneedle (dmn) patch is a transdermal delivery system, containing arrays of micro-sized polymeric needles capable of encapsulating therapeutic drugs within their matrix and releasing them into the skin. however, the elastic properties of the skin prevent dmns from complete insertion and accurate delivery of encapsulated compounds into the skin. moreover, the adhesive materials used in patches may cause skin irritation, inflammation, and redness. therefore, we developed a patchless, micro-pillar integrated dmn (p-dmn) that is simple to fabricate and enhances transdermal drug delivery compared with traditional dmn patches. the micro-pillars were made of poly methyl methacrylate at a height of 300 μm and a base diameter of 500 μm. to fabricate p-dmns, we employed hyaluronic acid, which is a widely used derma filler and plays a role in tissue re-epithelialization. we demonstrate that utilizing p-dmns significantly improves the delivery efficiency of an encapsulated drug surrogate (91.83% ± 7.75%) compared with traditional dmns (64.86% ± 8.17%). interestingly, p-dmns remarkably increase the skin penetration accuracy rate of encapsulated drugs, up to 97.78% ± 222%, compared with 44.44% ± 7.85% in traditional dmns. our findings suggest that p-dmns could serve as a highly accurate and efficient platform for transdermal delivery of various types of micro- and macro-biomolecules.”

Mazzara, J. M., Ochyl, L. J., Hong, J. K. Y., Moon, J. J., Prausnitz, M. R., & Schwendeman, S. P.. (2019). Self-healing encapsulation and controlled release of vaccine antigens from PLGA microparticles delivered by microneedle patches. Bioengineering & Translational Medicine
Plain numerical DOI: 10.1002/btm2.10103
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“There is an urgent need to reduce reliance on hypodermic injections for many vaccines to increase vaccination safety and coverage. alternative approaches include controlled release formulations , which reduce dosing frequencies, and utilizing alternative delivery devices such as microneedle patches (mnps). this work explores development of controlled release microparti-cles made of poly (lactic-co-glycolic acid) (plga) that stably encapsulate various antigens though aqueous active self-healing encapsulation (ase). these microparticles are incorporated into rapid-dissolving mnps for intradermal vaccination. plga microparticles containing alhydrogel are loaded with antigens separate from micro-particle fabrication using ase. this avoids antigen expsoure to many stressors. the microparti-cles demonstrate bi-phasic release, with initial burst of soluble antigen, followed by delayed release of alhydrogel-complexed antigen over approximately 2 months in vitro. for delivery, the microparticles are incorporated into mnps designed with pedestals to extend functional micro-needle length. these microneedles readily penetrate skin and rapidly dissolve to deposit micro-particles intradermally. microparticles remain in the tissue for extended residence, with mnp-induced micropores resealing readily. in animal models, these patches generate robust immune responses that are comparable to conventional administration techniques. this lays the framework for a versatile vaccine delivery system that could be self-applied with important logistical advantages over hypodermic injections.”

Corbett, H. J., Fernando, G. J. P., Chen, X., Frazer, I. H., & Kendall, M. A. F.. (2010). Skin vaccination against cervical cancer associated human papillomavirus with a novel micro-projection array in a mouse model. PLoS ONE
Plain numerical DOI: 10.1371/journal.pone.0013460
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“Background: better delivery systems are needed for routinely used vaccines, to improve vaccine uptake. many vaccines contain alum or alum based adjuvants. here we investigate a novel dry-coated densely-packed micro-projection array skin patch (nanopatchTM) as an alternate delivery system to intramuscular injection for delivering an alum adjuvanted human papillomavirus (hpv) vaccine (gardasil®) commonly used as a prophylactic vaccine against cervical cancer. methodology/principal findings: micro-projection arrays dry-coated with vaccine material (gardasil®) delivered to c57bl/6 mouse ear skin released vaccine within 5 minutes. to assess vaccine immunogenicity, doses of corresponding to hpv-16 component of the vaccine between 0.43±0.084 ng and 300±120 ng (mean ± sd) were administered to mice at day 0 and day 14. a dose of 55±6.0 ng delivered intracutaneously by micro-projection array was sufficient to produce a maximal virus neutralizing serum antibody response at day 28 post vaccination. neutralizing antibody titres were sustained out to 16 weeks post vaccination, and, for comparable doses of vaccine, somewhat higher titres were observed with intracutaneous patch delivery than with intramuscular delivery with the needle and syringe at this time point. conclusions/significance: use of dry micro-projection arrays (nanopatchTM) has the potential to overcome the need for a vaccine cold chain for common vaccines currently delivered by needle and syringe, and to reduce risk of needle-stick injury and vaccine avoidance due to the fear of the needle especially among children. © 2010 corbett et al.”

Hegarty, C., McConville, A., McGlynn, R. J., Mariotti, D., & Davis, J.. (2019). Design of composite microneedle sensor systems for the measurement of transdermal pH. Materials Chemistry and Physics
Plain numerical DOI: 10.1016/j.matchemphys.2019.01.052
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“Carbon loaded polystyrene microneedle patches have been prepared using silicone micro-moulding techniques and the ability of the needles to serve as viable transdermal sensors has been evaluated. the population of quinone groups at the interface of the embedded carbon nanoparticles was increased through anodisation and their ph dependent redox transitions exploited as the basis of a reagentless ph sensor. the peak position of the quinone oxidation process was found to shift in accordance with nernstian behaviour and the influence of penetration depth on response has been investigated. the analytical applicability of the microneedle electrode patch was critically evaluated through using tomato skin as model transdermal skin mimic. despite the increased complexity of the matrix, the microneedle sensor response was found to compare favourably with conventional/commercial ph probes.”

Li, W., Tang, J., Terry, R. N., Li, S., Brunie, A., Callahan, R. L., … Prausnitz, M. R.. (2019). H E A L T H A N D M E D I C I N E Long-acting reversible contraception by effervescent microneedle patch. Sci. Adv

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“To increase access to long-acting contraception, we developed a reversible contraceptive microneedle patch that is simple-to-administer, slowly releases contraceptive hormone (levonorgestrel) for >1 month, and generates no biohazardous sharps waste. after manually pressing the patch to skin for 1 min, microneedles rapidly separate from the patch within the skin due to effervescence triggered by contact with skin’s interstitial fluid, as demonstrated in rats and human participants. long-acting contraception is achieved by formulating microneedles with a biodegradable polymer [poly(lactic-co-glycolic) acid] that slowly releases levonorgestrel for ~1 month in vitro. in rats, the patch maintained levonorgestrel concentration above the human contraceptive threshold level for >1 month, and a placebo micro needle patch was well-tolerated in human participants. women of reproductive age in three continents demonstrated interest in and preference for long-acting contraception by microneedle patch. these studies indicate that an effervescent microneedle patch could facilitate greater access to long-acting contraception.”

Kesarwani, A., Yadav, A. K., Singh, S., Gautam, H., Singh, H. N., Sharma, A., & Yadav, C.. (2013). An Official Publication of Association of Pharmacy Professionals T HEORETICAL ASPECTS OF T RANSDERMAL D RUG D ELIVERY S YSTEM. Bulletin of Pharmaceutical Research

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“Transdermal patch is a medicated adhesive patch that is placed on the skin to deliver the drug through the skin in order to achieve systemic absorption of drug at a predetermined rate over a prolonged period of time. its main advantages includes controlled drug release with minimum side effects, improved bioavailability, bypass first pass metabolism and many more. there are factors such as physiochemical as well as biological which affect the bioavailability of transdermal medicament. due to technological advancement, many new techniques which have attained attention are iontophoresis, phonophoresis, electroporation micro needles etc. different types of transdermal patches can be prepared by varying methods. transdermal patches can be evaluated by interaction studies, folding endurance, thickness of the patch, weight uniformity, drug content and i n v i tr o studies. this review covers general aspects like advantages, methods of preparation of transdermal patches, evaluation, basic components of transdermal drug delivery system.”

Desale Rohan, S., Wagh Kalpesh, S., Akarte Anup, M., Baviskar Dheeraj, T., & Jain Dinesh, K.. (2012). Microneedle technology for advanced drug delivery: A review. International Journal of PharmTech Research

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“The objective of this review article is to summarize recent data, description results and basic functionality of silicon microneedles array through biodegradable instructions. in order to avoid the main troubles related to drug degradation by gastrointestinal track and their elimination through the liver, an easy solution can be fabrication of microneedles array with biodegradable instructions. transdermal drug delivery can avoid drug degradation, and it has a low diffusion coefficient so it is complicated to transport hydrophilic and high molecular weight drug (>500da) using passive patches. while, there is about 20 species of drug that relevant to former patches. micro-needle can convey hydrophilic and molecular weight, because it have valuable source of intellectual property. there are many studies in transdermal drug delivery, blood extraction, skin care fields with a micro-needle. existing micro-needle through using silicon, metal, and polymer materials. to make 3-d shape micro-needle mold, inclined uv lithography is used, but this process is complicated to control process condition and its process output ratio is so low. this review suggests the novel process using dicing progression with an inclined sharp edge to make the sharp shape of microneedle information. and the optical assessment module is made for evaluating the drug delivering ratio according to the needle length and insertion times. this estimation module has a water chamber and membrane to copy the drug delivery mechanism. we can discover that the drug delivering ratio can enlarge when use a longer needle as the surface area with drug sticking can be augmented.”

Hegarty, C., McKillop, S., McGlynn, R. J., Smith, R. B., Mathur, A., & Davis, J.. (2019). Microneedle array sensors based on carbon nanoparticle composites: interfacial chemistry and electroanalytical properties. Journal of Materials Science
Plain numerical DOI: 10.1007/s10853-019-03642-1
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“Conductive microneedle patches consisting of carbon nanoparticles embedded in a polystyrene matrix have been prepared using micro-moulding techniques. the interfacial properties of the structures before and after electrochemical etching have been characterised using x-ray photoelectron spectroscopy and contact angle. anodisation of the needles leads to a significant increase in oxygen functionality and is shown to dramatically improve the electroanalytical capabilities of the microneedle array. the detection of uric acid in horse blood was used as a model system through which to assess the performance of the system. the composite approach is shown to lead to viable carbon-based sensors and can offer a rapid prototype option for the development of tailored microneedle systems.”

Gardeniers, H. J. G. E., Luttge, R., Berenschot, E. J. W., De Boer, M. J., Yeshurun, S. Y., Hefetz, M., … Van Den Berg, A.. (2003). Silicon micromachined hollow microneedles for transdermal liquid transport. Journal of Microelectromechanical Systems
Plain numerical DOI: 10.1109/JMEMS.2003.820293
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“This paper presents a novel process for the fabrication of out-of-plane hollow micro needles in silicon. the fabrication method consists of a sequence of deep-reactive ion etching (drie), anisotropic wet etching and conformal thin film deposition, and allows needle shapes with different, lithography-defined tip curvature. in this study, the length of the needles varied between 150 and 350 micrometers. the widest dimension of the needle at its base was 250 μm. preliminary application tests of the needle arrays show that they are robust and permit skin penetration without breakage. transdermal water loss measurements before and after microneedle skin penetration are reported. drug delivery is increased approximately by a factor of 750 in microneedle patch applications with respect to diffusion alone. the feasibility of using the microneedle array as a blood sampler on a capillary electrophoresis chip is demonstrated.”

Dardano, P., Caliò, A., Politi, J., Rea, I., Rendina, I., & De Stefano, L.. (2016). Optically monitored drug delivery patch based on porous silicon and polymer microneedles. Biomedical Optics Express
Plain numerical DOI: 10.1364/boe.7.001645
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“© 2016 optical society of america. fabrication and characterization of an optically monitored hybrid patch for local administration of drugs, based on polymeric micro-needles and a porous silicon free-standing membrane, are reported. the microneedles are realized by an innovative photolithographic approach that allows fine tuning of geometrical parameters, using polyethylene glycol and a commercial photo-catalyzer. the porous silicon multilayer not only increases the storage of a relevant amount of the drug, but also offers a continuous, naked-eye monitoring of the drug delivery process. as a proofof- concept experiment, we report our results on the release of a dye molecule (fluorescein, 332 da) in a phosphate saline buffer.”

Tang, Y. H., Lin, Y. H., Huang, T. T., Wang, J. S., Hu, Y. C., & Shiao, M. H.. (2019). Development of micro-needle array for Tumor vaccine patch applications. In Proceedings of the IEEE Conference on Nanotechnology
Plain numerical DOI: 10.1109/NANO46743.2019.8993929
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“Microneedles have been given sufficient potential as a patch for transdermal drug delivery. however, very few product on the application of mems for the vaccine delivery is reported. the aim of this paper is to develop the vaccine coated solid microneedle patch by the use of micro-electromechanical systems (mems) technology, the fabrication of a silicon microneedle arrays made by uv lithography, inductively coupled plasma reactive ion etching (icp-rie) and wet chemical etching process. to solve the limitation of low vaccine volume carried, groove and pocket structure will be introduced. besides, through the control of formulation of surface tension, viscosity and hydrophilic/ hydrophobic properties by optimization of vaccine formulation composition, the vaccine carried volume can be achieved. moreover, bioactive of vaccine will be investigated by parameter of the osmotic pressure and phase-transformation. combination of vaccine formulation and microneedle to fabricate the delivery device, the release profile of the device will be evaluated in vitro, and will be further evaluated in the artificial human skin system to observe the immune response. the research will be included two parts: 1. vaccine coated solid microneedle patch device will be established; 2. design a microneedle patch having specific application, such as enterovirus 71 vaccines, and to realize a commercial available vaccine microneedle patch device. consequently, a microneedle array with biodegradable porous tips was further developed based on the fabricated microneedles patch.”

Lee, H., Jeon, H. Y., Park, S., Lee, H.-W., & Sungmin, B.. (2011). Micro needle array fabrication for drug delivery and drug delivery evaluation test using optical inspection module. International Conference on Nanotechnology and Biosensors

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“For drug delivery into the body, oral medication is primarily problematic due to drug degradation in the gastrointestinal tract and elimination through the liver. this method delivers a drug into a body at once and absorbed, so drug concentration in plasma increased rapidly and reaching the apex. then drug concentration is decreased gradually according to the body’s metabolism. this drug concentration profile shows that if drug concentration over the maximum desired level, it can give bad effect to the body and below the minimum desired level, it is difficult to expect drug effect. effective drug delivery profile is constant delivery of relevant drug concentration it can maintain plasma’s drug concentration. transdermal drug delivery can prevent drug degradation, and it can control release. stratum corneum (the outer layer of skin) is a major barrier for drug delivery, it has a low diffusion coefficient so it is difficult to transport hydrophilic and high molecular weight drug (>500da) using passive patches. since, there is about 20 species of drug that applicable to former patches. micro-needle can deliver hydrophilic and molecular weight, because it made micro scale holes in the skin. there are many studies in transdermal drug delivery, blood extraction, skin care fields using a micro-needle. existing micro-needle made using silicon, metal, polymer materials. to make 3-d shape micro-needle mold, inclined uv lithography is used, but this process is difficult to control process condition and its process output ratio is so low. this research suggests the novel process using dicing process with an inclined sharp edge to make the sharp shape of a micro- needle tips. and the optical inspection module is made for evaluating the drug delivering ratio according to the needle length and insertion times. this evaluation module has a water chamber and membrane to copy the drug delivery mechanism. we can find that the drug delivering ratio can increase when use a longer needle because the surface area with drug sticking can be increased”

Nguyen, T. T., Nguyen, T. T. D., Tran, N. M. A., & Vo, G. Van. (2022). Advances of microneedles in hormone delivery. Biomedicine and Pharmacotherapy
Plain numerical DOI: 10.1016/j.biopha.2021.112393
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“The skin is recognized as a potential target for local and systemic drug delivery and hormone. however, the transdermal route of drug administration seems to be limited by substantial barrier properties of the skin. recently, delivering hormone via the skin by transdermal patches is a big challenge because of the presence of the stratum corneum that prevents the application of hormone via this route. in order to overcome the limitations, microneedle (mn), consisting of micro-sized needles, are a promising approach to drill the stratum corneum and release hormone into the dermis via a minimal-invasive route. this review aimed to highlight advances in research on the development of mns-based therapeutics for their implications in hormone delivery. the challenges during clinical translation of mns from bench to bedside are also discussed.”

Ahn, B.. (2020). Optimal Microneedle Design for Drug Delivery Based on Insertion Force Experiments with Variable Geometry. International Journal of Control, Automation and Systems
Plain numerical DOI: 10.1007/s12555-019-0220-8
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“Microneedles, which prick micro holes in the stratum corneum (sc), are promising minimally invasive drug delivery devices alternating pills, conventional needles, or transdermal patches. however, the microneedle fabrication based on the optimal design has been studied rarely. in this paper, the forces required to insert microneedles into a skin model were measured over the various geometries in order to optimize the microneedle design. to measure the insertion force, the microneedles were fabricated with inclined uv lithography and hot embossing processes. the insertion force was measured with a custom-made dynamic displacement device which can measure and record the force of mn range loads. the insertion force is strongly related with tip angle and radius of tip’s curvature. the insertion forces increase with increasing width of shaft, but the relation is very week and the radius of fillet in the experimental range has no influence on the insertion force. this result can be used as an optimal design guide on the geometries of microneedle.”

Hu, H. W., Yi-Chun, D., & Ming-Jui, W.. (2019). FP555Multiple alert threshold of blood leakage detector in hemodialysis to increase the economic benefits of care. Nephrology Dialysis Transplantation
Plain numerical DOI: 10.1093/ndt/gfz106.fp555
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“INTRODUCTION: a puncture from body surface is commonly used in clinical treatment, such as hemodialysis or central venous catheters. needle dislodgement associated with higher leakage or risk of infection, although the probability is low, it can be fatal. at present, many existing leak detection devices have been used, but most of them have a single point and just determine whether there is blood leakage. it is impossible to accurately determine the difference of liquid leakage, and many micro-leakage causes trouble to the nursing staff.it increases the cumbersome nursing work. our team designed the patch which can sense the amount of liquid according to the area of blood leakage, and effectively classify the warning into micro-leakage and severe blood leakage. after the determination, different care modes can be provided. method(s): we designed a leak-sensing patch. by multi-channel circuit design and soft board process, we can determine the severity of the leak by sensing the amount of liquid absorbed by the patch to detect different impedance values. using a fake hand simulation experiment, different amounts of liquid wet the patch and confirm the distribution of blood leakage of 0.1 ml-1.5ml. we can set the customization threshold to reduce the gauze replacement cost and the burden of nursing staff, and also reach the warning effect nursing staff. result(s): a leak detection patch has been designed. after the prosthesis simulation experiment, a threshold can be set freely every 0.1-0.2 ml, and different levels of warnings can be designed according to the customized clinical requirements. it reduces the burden of nursing staff to achieve the effect of segmentation warning. conclusion(s): the research team developed a multi-threshold sensing patch that can determine the serious blood leak and slight blood leak, and provide accurate judgment of the nursing staff’s blood leakage care to achieve economic cost effectiveness.”

Dalvi, M., Kharat, P., Thakor, P., Bhavana, V., Singh, S. B., & Mehra, N. K.. (2021). Panorama of dissolving microneedles for transdermal drug delivery. Life Sciences
Plain numerical DOI: 10.1016/j.lfs.2021.119877
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“Recently, microfabrication technology has been developed to increase the permeability of drugs for transdermal delivery. microneedles are ultra-small needles usually in the micron size range (different dimensions in micron), generate pores, and allow for delivery of local medication in the systemic circulation via skin. the microneedles have been available in dissolving, solid, coated, hollow, and hydrogel-based microneedles. dissolving microneedles have been fabricated using micro-molding, photo-polymerization, drawing lithography and droplet blowing techniques. dissolving microneedles could be a valuable option for the delivery of low molecular weight drugs, peptides, enzymes, vaccines and bio-therapeutics. it consists of water-soluble materials including maltose, polyvinyl pyrrolidone, chondroitin sulfate, dextran, hyaluronic acid, and albumin. the microneedles have almost dissolved after patch removal, leaving only blunt stubs behind, which are easily removable. in this review, we summarize the major building blocks, classification, fabrication techniques, characterization, diffusion models and application of microneedles in diverse area. we also reviewed the regulatory aspects, computational studies, patents, clinical data, and market trends of microneedles.”

Yan, Q., Weng, J., Shen, S., Wang, Y., Fang, M., Zheng, G., … Yang, G.. (2021). Finite element analysis for biodegradable dissolving microneedle materials on skin puncture and mechanical performance evaluation. Polymers
Plain numerical DOI: 10.3390/polym13183043
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“In this study, a micro-molding technology was used to prepare the microneedles (mns), while a texture analyzer was used to measure its young’s modulus, poisson’s ratio and compression breaking force, to evaluate whether the mns can penetrate the skin. the effects of different materials were characterized by their ability to withstand stresses using the structural mechanics module of comsol multiphysics. carboxymethylcellulose (cmc) was chosen as the needle formulation material with varying quantities of polyvinyl pyrrolidone (pvp), polyvinyl alcohol (pva) and hyaluronic acid (ha) to adjust the viscosity, brittleness, hardness and solubility of the material. the results of both the experimental tests and the predictions indicated that the hardest tip material had a solids content of 15% (w/w ) with a 1:2 (w/w) cmc: ha ratio. furthermore, it was shown that a solid content of 10% (w/w) with a 1:5 (w/w) cmc: pva ratio is suitable for making patches. the correlation between the mechanical properties and the different materials was found using the simulation analysis as well as the force required for different dissolving microneedles (dmns) to penetrate the skin, which significantly promoted the research progress of microneedle transdermal drug delivery.”

Gala, R. P., Uz Zaman, R., D’souza, M. J., & Zughaier, S. M.. (2018). Novel whole-cell inactivated Neisseria gonorrhoeae microparticles as vaccine formulation in microneedle-based transdermal immunization. Vaccines
Plain numerical DOI: 10.3390/vaccines6030060
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“Neisseria gonorrhoeae is a strict human pathogen responsible for more than 100 million new sexually transmitted infections worldwide each year. due to the global emergence of antibiotic resistance, the center for disease control (cdc) recently listed n. gonorrhoeae as an urgent threat to public health. no vaccine is available in spite of the huge disease burden and the possibility of untreatable gonorrhea. the aim of this study is to investigate the immunogenicity of a novel whole-cell-based inactivated gonococcal microparticle vaccine formulation loaded in dissolvable microneedles for transdermal administration. the nanotechnology-based vaccine formulation consists of inactivated whole-cell gonococci strain cdc-f62, spray dried and encapsulated into biodegradable cross-linked albumin matrix with sustained slow antigen release. the dry vaccine nanoparticles were then loaded in a dissolvable microneedle skin patch for transdermal delivery. the efficacy of the whole-cell microparticles vaccine formulation loaded in microneedles was assessed in vitro using dendritic cells and macrophages as well as in vivo mouse model. antibody titers were measured using an enzyme immunosorbent assay (elisa) and antigen-specific t lymphocytes were assessed in spleens and lymph nodes. here we report that whole-cell-based gonococcal microparticle vaccine loaded in dissolvable microneedles for transdermal administration induced significant increase in antigen-specific igg antibody titers and antigen-specific cd4 and cd8 t lymphocytes in mice compared to gonococcal antigens in solution or empty microneedles. significant increase in antigen-specific igg antibody levels was observed at the end of week 2 in groups that received the vaccine compared to the group receiving empty nanoparticles. the advantages of using formalin-fixed whole-cell gonococci that all immunogenic epitopes are covered and preserved from degradation. the spherical shaped micro and nanoparticles are biological mimics of gonococci, therefore present to the immune system as invaders but without the ability to suppress adaptive immunity. in conclusion, the transdermal delivery of microparticles vaccine via a microneedle patch was shown to be an effective system for vaccine delivery. the novel gonorrhea nanovaccine is cheap to produce in a stable dry powder and can be delivered in microneedle skin patch obviating the need for needle use or the cold chain.”

Bozorgi, A., & Fahimnia, B.. (2021). Micro array patch (MAP) for the delivery of thermostable vaccines in Australia: A cost/benefit analysis. Vaccine
Plain numerical DOI: 10.1016/j.vaccine.2021.08.016
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“Background: it is anticipated that transforming the vaccine supply chain from syringe-and-needle to thermostable vaccines enabled by micro array patch (map) will result in reduced supply chain costs as well as reduced wastes (environmental impact) and improved safety. this paper provides a thorough cost comparison of the conventional syringe-and-needle vaccine supply chain versus the map vaccine supply chain for influenza vaccine delivery in australia. objective: to determine the potential cost implications and general benefits of replacing syringe-and-needle flu vaccine with map-enabled thermostable flu vaccine in australia. methods: we first provide a snapshot of the existing flu vaccine supply chain in australia including its limitations and opportunities for improvement. data/information is collected through interviewing the key stakeholders across vaccine supply chain including vaccine manufacturers, logistics providers, clinics, hospitals, and pharmacies. a cost/benefit analysis of the anticipated supply chain of the map-enabled vaccine will reveal the opportunities and challenges of supply chain transformation for flu vaccine delivery in australia. findings: our high-level practice-informed cost/benefit analysis identifies cold chain removal as an important source of cost saving, but administrative cost savings appear to be even more significant (e.g., time saving for nurses and those involved in cold chain management). our analysis also identifies the key benefits and limitations of vaccine supply chain transformation in australia. conclusion: we conclude that the benefits of moving from syringe-and-needle vaccines to thermostable map-delivered vaccines are beyond transportation and storage cost saving. potential benefits through cost saving, waste reduction, and service level improvement are discussed along with various safety and wellbeing consequences as well as directions for future research in this area.”

Koester, P. J., Tautorat, C., Beikirch, H., Gimsa, J., & Baumann, W.. (2010). Recording electric potentials from single adherent cells with 3D microelectrode arrays after local electroporation. Biosensors and Bioelectronics
Plain numerical DOI: 10.1016/j.bios.2010.08.003
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“This short communication reports on the innovative method of the local micro-invasive needle electroporation (lomine) of single adherent cells. the investigation of cellular reactions in living cell cultures represents a fundamental method, e.g. for drug development and environmental monitoring. existing classical methods for intracellular measurements using, e.g. patch clamp techniques are time-consuming and complex. present patch-on-chip systems are limited to the investigation of single cells in suspension. nevertheless, the most part of the cells of the human body is adherently growing. therefore, we develop a new chip system for the growth of adherent cells with 64 micro-structured needle electrodes as well as 128 dielectrophoretic electrodes, located within a measuring area of 1mm2. with this analytical chip, the intracellular investigation of electro-chemical changes and processes in adherently growing cells will become possible in the near future. here, we present first intracellular measurements with this chip system. © 2010 elsevier b.v.”

Nandedkar, T. D.. (2009). Nanovaccines: Recent developments in vaccination. Journal of Biosciences
Plain numerical DOI: 10.1007/s12038-009-0114-3
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“In the past 100 years, vaccination has contributed immensely to public health by preventing a number of infectious diseases. attenuated, killed or part of the microorganism is employed to stimulate the immune system against it. progress in biotechnology has provided protective immunity through dna vaccines. in recent years, nanovaccine is a novel approach to the methodology of vaccination. nanomaterials are delivered in the form of microspheres, nano-beads or micro-nanoprojections. painless, effective and safe needle-free routes such as the intranasal or the oral route, or patches of microprojections to the skin are some of the approaches which are in the experimental stage at present but may have a great future ahead in nanovaccination. © indian academy of sciences.”

Bozorgi, A., & Fahimnia, B.. (2021). Transforming the vaccine supply chain in Australia: Opportunities and challenges. Vaccine
Plain numerical DOI: 10.1016/j.vaccine.2021.08.033
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“Background: analyzing potential benefits of thermostable vaccines delivered through micro array patch (map) has received great attention in low and middle-income countries. the experience may or may not be the same in developed countries where the infrastructure is more developed. it is anticipated that transforming the vaccine supply chain from syringe-and-needle to thermostable map-delivered vaccines will result in reduced supply chain costs – including manufacturing/supply, logistics/distribution, and administration costs – as well as reduced wastes and improved safety. this paper provides an end-to-end supply chain analysis comparing the key aspects (cost, safety and environmental aspects) of the conventional syringe-and-needle vaccine supply chain with those of the map vaccine supply chain for influenza vaccine delivery in australia. directions for future research in this area will be provided. objective: to determine the potential supply chain impacts of replacing syringe-and-needle flu vaccine with map-enabled thermostable flu vaccine in australia. methods: we analyze the current flu vaccine supply chain in australia to identify practical limitations and opportunities for improvement. data/information is collected through interviewing the key stakeholders across vaccine supply chain including vaccine manufacturers, logistics providers, clinics, hospitals, and pharmacies. findings: a detailed practice-informed analysis is completed on the key operations of the flu vaccine supply chain. barriers and limitations of the conventional flu vaccine are discussed, along with potential improvements that can be achieved through the implementation of map-enabled flu vaccine delivery. we discuss how technology-driven innovations can help advance vaccine supply chains, improve vaccine visibility, reduce wastes, and enable informed decision-making. conclusion: we find that the benefits of moving from syringe-and-needle vaccines to thermostable map-delivered vaccines are beyond transportation and storage cost saving. potential benefits through cost saving, waste reduction, and service level improvement are discussed along with various safety and wellbeing consequences followed by directions for future research in this area.”

Yang, Y. C., Lin, Y. T., Yu, J., Chang, H. T., Lu, T. Y., Huang, T. Y., … Lin, T. E.. (2021). MXene Nanosheet-Based Microneedles for Monitoring Muscle Contraction and Electrostimulation Treatment. ACS Applied Nano Materials
Plain numerical DOI: 10.1021/acsanm.1c01237
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“MXenes belong to a large family of two-dimensional layered transition-metal carbides and nitrides. mxene nanosheets integrate the fascinating advantages of high electronic conductivity, excellent biocompatibility, and acid/base resistance. herein, we demonstrate a ‘hospital-on-a-chip’system with multifunctional microneedle electrodes for biosensing and electrostimulation using highly stable mxene nanosheets. this system consists of integrated microchip biosensors for an efficient diagnosis and medical treatment elements for therapies, thus resembling a miniaturized hospital. microneedles are composed of dozens of micron-sized needles that can be used as an effective and painless transdermal patch to puncture the dead skin barrier for drug delivery or biosensing purposes since they are directly in contact with the dermal layer inside the human body. the wearable mxene nanosheet-based microneedles can sense the tiny electric potential difference generated from the human eye movements or muscle contraction from the human arm. therefore, the diseases associated with neuromuscular abnormalities such as myasthenia gravis can be monitored. consequently, the transcutaneous electrical nerve stimulation treatment can be applied according to the feedback of the micro-biosensors. in addition, mxene microneedles can offer an electrically controlled drug delivery platform and the function of enhancing blood coagulation. finally, mxene nanosheet-based microneedles provide an interesting platform for wearable micro-biosensors and offer an essential part of the hospital-on-a-chip system.”

Chen, G., Hao, B., Ju, D., Liu, M., Zhao, H., Du, Z., & Xia, J.. (2015). Pharmacokinetic and pharmacodynamic study of triptolide-loaded liposome hydrogel patch under microneedles on rats with collagen-induced arthritis. Acta Pharmaceutica Sinica B
Plain numerical DOI: 10.1016/j.apsb.2015.09.006
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“Triptolide (tp), a major active component of tripterygium wilfordii hook.f. (twhf), is used to treat rheumatoid arthritis (ra). however, it has a narrow therapeutic window due to its serious toxicities. to increase the therapeutic index, a new triptolide-loaded transdermal delivery system, named triptolide-loaded liposome hydrogel patch (tp-lhp), has been developed. in this paper, we used a micro-needle array to deliver tp-lhp to promote transdermal absorption and evaluated this treatment on the pharmacokinetics and pharmacodynamics of tp-lhp in a rat model of collagen-induced arthritis (cia). the pharmacokinetic results showed that transdermal delivery of microneedle tp-lhp yielded plasma drug levels which fit a one-compartment open model. the relationship equation between plasma concentration and time was c=303.59×(e-0.064t-e-0.287t). the results of pharmacodynamic study demonstrated that tp-lhp treatment mitigated the degree of joint swelling and suppressed the expressions of fetal liver kinase-1, fetal liver tyrosine kinase-4 and hypoxia-inducible factor-1α in synovium. other indicators were also reduced by tp-lhp, including hyperfunction of immune, interleukin-1β and interleukin-6 levels in serum. the therapeutic mechanism of tp-lhp might be regulation of the balance between th1 and th2, as well as inhibition of the expression and biological effects of vascular endothelial growth factor.”

Yadav, J. D., Vaidya, K. A., Kulkarni, P. R., & Raut, R. A.. (2011). Microneedles: Promising technique for transdermal drug delivery. International Journal of Pharma and Bio Sciences

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“Transdermal drug delivery using microneedle is a novel method of drug delivery. microneedle is like conventional needles only fabricated in micro scale. the advantage of using microneedle is that it does not pass the stratum corneum. the dosing in microgram quantities can be done by this type of needle. the mechanism of action is based on temporary mechanical disruption of skin. the drug, in the form of biomolecules, is encapsulated within the microneedles, which are then inserted into the skin in the same way a drug like nitroglycerine is released into the bloodstream from a patch. the needles dissolve within minutes, releasing the trapped cargo at the intended delivery site. the review covers the various methods of drug delivery like poke with patch approach, coat and poke approach, biodegradable microneedles, hollow microneedles and dip and scrape. the various method of preparation of microneedles include molding, casting, laser cutting. the in vivo safety assessment and the evaluation of microneedle have shown that this technique can be used safely. there are various advantages of the microneedle trans dermal drug delivery methods over other techniques which helps to make it successful delivery system.”

Takai, K., & Taniguchi, M.. (2017). Targeted Epidural Blood Patch Under O-Arm–Guided Stereotactic Navigation in Patients with Intracranial Hypotension Associated with a Spinal Cerebrospinal Fluid Leak and Ventral Dural Defect. World Neurosurgery
Plain numerical DOI: 10.1016/j.wneu.2017.07.168
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“Objective targeted epidural blood patch (ebp) at the site of a presumed cerebrospinal fluid leak reportedly has better outcomes than non-targeted ebp; however, it is associated with a higher risk of wrong-site injection, such as iatrogenic subarachnoid or intramuscular injections, which lead to reintervention because of the insufficient coverage of injected blood. methods eight patients with intracranial hypotension owing to a csf leak diagnosed with myelographic computed tomography (ct) and thin-cut magnetic resonance imaging (mri) received an epidural blood patch under o-arm–guided stereotactic navigation. results the leak site was identified on the basis of myelographic ct findings of a micro-spur, epidural contrast medium extravasations, and mri findings of a ventral dural defect. during the ebp procedure, no iatrogenic dural puncture or subarachnoid injection occurred because o-arm–guided stereotactic navigation provided real-time feedback on the needle trajectory. o-arm ct revealed the sufficient coverage of injected blood following the first injection in 6 of 8 patients. in the 2 remaining patients, a second injection was performed during the same session because of insufficient coverage at the previous site. in all patients, complete recovery from orthostatic headaches was achieved after a single session. conclusions o-arm–guided navigation facilitated ebp by enabling real-time observations of the needle trajectory and distribution of injected blood while simultaneously avoiding major complications, such as wrong-site injections or reintervention.”

Söbbeler, F. J., & Kästner, S. B.. (2018). Effects of transdermal lidocaine or lidocaine with prilocaine or tetracaine on mechanical superficial sensation and nociceptive thermal thresholds in horses. Veterinary Anaesthesia and Analgesia
Plain numerical DOI: 10.1016/j.vaa.2017.10.003
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“Objective: to evaluate the transdermal local anaesthetic effect of lidocaine or lidocaine combined with prilocaine or tetracaine in horses. study design: experimental, randomized study. animals: a total of five healthy adult warmblood horses. methods: horses were clipped bilaterally at the withers, cranial saddle area and caudal saddle area. baseline measurements for mechanical superficial sensation via von frey filaments and nociceptive thermal thresholds were performed. a 5% lidocaine patch (12 hour exposure, treatment l), a lidocaine/prilocaine cream (each 2.5%, treatment lp) and a lidocaine/tetracaine cream (each 7%, treatment lt) were applied (both 2 hour exposure). the same product was applied at the same location bilaterally, but on the right side an epidermal micro-perforation (dermaroller, 1200 needles) was performed prior to application. a total of five more measurements were performed at each location, immediately at the end of exposure time followed by hourly measurements. thermal thresholds normalized to thermal excursion were analysed. one- or two-way anova and the wilcoxon signed-rank test were used for statistical analysis with p < 0.05 considered significant. results: epidermal micro-perforation had no enhancing effect. treatments l, lp, and lt resulted in increased thermal excursion (%) immediately (84.7 ± 12.9; 100.0 ± 0.0; 100.0 ± 0.0) and 1 hour (81.7 ± 66; 86.0 ± 17.7; 87.7 ± 14.4) after the removal of the respective product compared to baseline (66.1 ± 9.3; 69.9 ± 8.3; 76.5 ± 7.8). superficial mechanical sensation was decreased by the lidocaine-and-tetracaine cream at all time points, and by the lidocaine patch and lidocaine-and-prilocaine cream for three measurements. conclusions and clinical relevance: eutectic mixtures of lidocaine with either prilocaine or tetracaine led to a reduction in thermal nociception and mechanical sensation for up to 2 hours.”

Han, Z., Zeng, R., Zhou, P., Yang, L., Ren, Y., & Qu, Y.. (2021). Preparation and preliminary evaluation of insulin-loaded Bletilla striata polysaccharide dissolving microneedles with flexible patches. Chinese Traditional and Herbal Drugs
Plain numerical DOI: 10.7501/j.issn.0253-2670.2021.07.007
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“Objective: the insulin (ins)-loaded dissolving microneedles with flexible patches (ins-dmns) was prepared by bletilla striata polysaccharide (bsp) and polyvinyl alcohol (pva) for the first time, the physicochemical properties and transdermal delivery performance of ins-dmns were preliminarily evaluated. methods: ins-dmns were prepared by micro-molding technique. the concentration of bsp and pva was investigated with the hardness of needle bodies, flexibility of patches and formability of microneedles as the evaluation index. the morphological characteristics was observed by scanning electron microscopy. drug loading, solubility, skin irritation, mechanical strength and stability were tested. the transdermal release and diffusion of ins were observed by confocal microscopy. in vitro transdermal performance of ins-dmns was investigated by franz diffusion cell, and in vivo pharmacodynamics were studied to investigate their hypoglycemic effect on diabetic rats. results: the prepared ins-dmns were pyramidal in shape with uniform needle bodies and excellent mechanical strength. meanwhile, the needle bodies of ins-dmns could dissolve in 2 h, and the patches were flexible and flat. the dosage of ins was (0.25 ± 0.02) iu per patch, and the skin damage induced by ins-dmns was slight and recovered quickly. the stability was excellent and ins could reach 220 μm inside the skin. moreover, in vitro skin penetration results showed that the cumulative penetration of ins in ins-dmns reached 89.63% after 12 h, which proved that the bletilla striata polysaccharide dissolving microneedles with flexible patches could effectively improve the transdermal penetration of ins. the results of in vivo pharmacodynamics showed that ins-dmns exhibited a significant hypoglycemic effect, and compared with subcutaneous administration, microneedle administration was more sustainable. conclusion: ins-dmns realized the transdermal delivery of ins, where the needle bodies were mechanically robust enough to insert into the skin and continuously release drugs, while the flexible patches provided better skin adhesion.”

Friedmann, A., Cismak, A., Tautorat, C., Koester, P. J., Baumann, W., Held, J., … Heilmann, A.. (2012). FIB preparation and SEM investigations for three-dimensional analysis of cell cultures on microneedle arrays. Scanning
Plain numerical DOI: 10.1002/sca.20297
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“We report the investigation of the interfaces between microneedle arrays and cell cultures in patch-on-chip systems by using focused ion beam (fib) preparation and scanning electron microscopy (sem). first, fib preparations of micro chips are made to determine the size and shape of the designed microneedles. in this essay, we investigate the cell-substrate interaction, especially the cell adhesion, and the microneedle’s potential cell penetration. for this purpose, cross-sectional preparation of these hard/soft hybrid structures is performed by the fib technology. by applying the fib technology followed by high-resolution imaging with sem, new insights into the cell-substrate interface can be received. one can clearly distinguish between cells that are only in contact with microneedles and cells that are penetrated by microneedles. a stack of slice images is collected by the application of the slice-and-view setup during fib preparation and is used for threedimensional reconstruction of cells and micro-needles. © 2011 wiley periodicals, inc.”

Soltani-Arabshahi, R., Wong, J. W., Duffy, K. L., & Powell, D. L.. (2014). Facial allergic granulomatous reaction and systemic hypersensitivity associated with microneedle therapy for skin rejuvenation. JAMA Dermatology
Plain numerical DOI: 10.1001/jamadermatol.2013.6955
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“IMPORTANCE microneedle therapy includes skin puncture with multiple micro-sized needles to promote skin rejuvenation or increase transdermal delivery of topical medications. in cosmetic practices, various cosmeceuticals are applied before microneedling to enhance the therapeutic effects. this results in intradermal tattooing of the topical product. despite rapid increase in the use of microneedles in dermatology, there are few data about their safety. observations we describe 3 women, aged 40s to 60s, who developed facial granulomas following microneedle therapy for skin rejuvenation. two patients had undergone microinjection of the same branded topical moisturizer (vita c serum; sanítas skincare) during microneedle therapy. biopsy in all cases showed foreign body-type granulomas. results of tissue cultures were negative. chest radiography and serum angiotensinconverting enzyme findings were normal. the first 2 patients had a positive patch test reaction to vita c serum. initial treatment with topical and oral corticosteroids was ineffective. therapy with doxycycline hydrochloride and minocycline hydrochloride led to partial improvement in one case and resolution in another. conclusions and relevance application of topical products prior to microneedling can introduce immunogenic particles into the dermis and potentiate local or systemic hypersensitivity reactions. because the microneedle therapy system is accessible for home use, health care providers need to be aware of its potential consequences. copyright 2014 american medical association. all rights reserved.”

Desale, R. S., Wagh, K. S., Akarte, A. M., Baviskar, D. T., & Jain, D. K.. (2012). Microneedle Technology for Advanced Drug Delivery : A Review. International Journal of PharmTech Research

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“Th e o bj e c ti v e o f t h i s r e v i e w a r t i c l e i s t o s um m a r i z e re c e n t d a t a , d e s c r i p ti o n re s u l t s a n d b a s i c functionality of silicon microneedles array through biodegradable instructions. in order to avoid the main troubles related to drug degradation by gastrointestinal track and their elimination through the liver, an easy solution can be fabrication of microneedles array with biodegradable instructions. transdermal drug delivery can avoid drug degradation, and it has a low diffusion coefficient so it is complicated to transport hydrophilic and high molecular weight drug (>500da) using passive patches. while, there is about 20 species of drug that relevant to former patches. micro-needle can convey hydrophilic and molecular weight, because it have valuable source of intellectual property. there are many studies in transdermal drug delivery, blood extraction, skin care fields with a micro-needle. existing micro-needle through using silicon, metal, and polymer materials. to make 3-d shape micro-needle mold, inclined uv lithography is used, but this process is complicated to control process condition and its process output ratio is so low. this review suggests the novel process using dicing progression with an inclined sharp edge to make the sharp shape of microneedle information. and the optical assessment module is made for evaluating the drug delivering ratio according to the needle length and insertion times. this estimation module has a water chamber and membrane to copy the drug delivery mechanism. we can discover that the drug delivering ratio can enlarge when use a longer needle as the surface area with drug sticking can be augmented.”

Troensegaard Nielsen, K., Huss Eriksson, A., Funch Carlsen, M., Engell, K., Jansson, J., Petersson, K., … Kemp, P.. (2019). 387 Ex Vivo Visualization and Extended Drug Release from a Dissolvable Microarray. Journal of Investigative Dermatology
Plain numerical DOI: 10.1016/j.jid.2019.07.389
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“The aim of the study was to investigate a dissolvable microarray (ma) patch in terms of skin insertion and drug release in ex vivo human skin for 6 days and in vivo using minipigs for 4 days. the patches contain polymeric, microscopic arrays composed of a fast dissolving drug-free backing layer and slowly dissolving drug containing tips. the calcipotriol and betamethasone dipropionate (bdp) is encapsulated in the tip and delivered in a pain-free and minimally invasive manner by micro-perforation of the stratum corneum with 500 mum long microneedles. ma needles were visualized by scanning electron microscopy (sem) and skin penetration was studied using reflectance confocal microscopy (rcm). to study the extent and duration of drug release from the mas, a single application of a patch was compared both ex vivo and in vivo to daily application of a gel containing the same active pharmaceutical ingredients. drug release was assessed at several time points after application by quantifying target engagement (te) biomarkers and drug metabolism reflecting free drug available in the viable skin. thus, calcipotriol release was assessed by quantifying the vitamin d (vitd) te biomarkers cyp24a1 and cd14 by qpcr, and bdp release was assessed through quantification of a bdp metabolite. rcm showed efficient penetration of the ma patches into the upper dermis. the observed vitd te biomarkers and bdp metabolite levels were similar for a single applied ma patch compared to daily treatment with the comparator, daivobet gel for up to 6 days in ex vivo human skin and up to 4 days in minipigs. studies on calcipotriol and bdp containing ma patches in human skin explants and gottingen minipigs showed prolonged vitd target engagement and elevated bdp metabolite levels, on par with once daily application of the comparator daivobet gel. the ma patches are likely to offer a convenient treat-and-go approach with reduced dosing frequency and are currently in phase 1 clinical development in psoriasis.copyright © 2019”

Wu, L., Shrestha, P., Iapichino, M., Cai, Y., Kim, B., & Stoeber, B.. (2021). Characterization method for calculating diffusion coefficient of drug from polylactic acid (PLA) microneedles into the skin. Journal of Drug Delivery Science and Technology
Plain numerical DOI: 10.1016/j.jddst.2020.102192
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“Microneedles are designed for piercing the stratum corneum and delivering drugs into the epidermis and dermis layers of the skin. their micrometric dimension causes minor or negligible stimulations to sensory nerve fibers in the dermis layer of the skin, making drug administration through microneedles less painful compared to conventional hypodermic needle injection. with the advancement of microneedle related research, an increasing number of drugs are using microneedle-mediated drug delivery in the topical area of the skin, including localized delivery of some highly toxic drugs. it is essential to understand drug diffusion from microneedles to skin to avoid unwanted spread of toxic drugs in non-infected areas. this work aims to 1) deliver into the skin tissue fluorescent rhodamine b as a model drug from coated polylactic acid (pla) microneedles and dissolvable microneedles; 2) detect and depict the concentration distribution of the model drug from two types of microneedles into the skin tissue respectively; 3) determine a reliable diffusion coefficient of the model drug based on a constant source diffusion model and a limited source diffusion model for dissolvable microneedles and coated pla microneedles, respectively. dissolvable microneedles and coated pla microneedles were designed and fabricated by a novel methodology combining 3d printing, chemical etching, micro-molding and drop coating. rhodamine b was chosen as the model drug to enable fluorescent detection. two types of microneedles were mounted to a single patch and inserted into porcine skin to deliver the model drug. after microneedle removal, confocal microscopy was used to monitor the fluorescence intensity of rhodamine b in the skin tissue. based on an intensity-concentration calibration and two diffusion models, the diffusion coefficients of rhodamine b from the constant source (dissolvable microneedles) and limited source (coated pla microneedles) to the dermis layer of porcine skin were inferred to be from 3.1×10−8 to 3.6×10−8 cm2/s. this characterization method is expected to offer medical personnel a quantitative understanding of the diffusion process related to microneedle-mediated transdermal drug delivery.”

Griffin, P., Elliott, S., Krauer, K., Davies, C., Rachel Skinner, S., Anderson, C. D., & Forster, A.. (2017). Safety, acceptability and tolerability of uncoated and excipient-coated high density silicon micro-projection array patches in human subjects. Vaccine
Plain numerical DOI: 10.1016/j.vaccine.2017.10.021
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“Most vaccinations are performed by intramuscular injection with a needle and syringe. however, this method is not ideal due to limitations, such as the risk of needle-stick injury, the requirement for trained personnel to give injections and the need to reconstitute lyophilized vaccines. therefore, we tested an alternative delivery technology that overcomes the problems with needle and syringe. the nanopatchTM is an array of 10,000 silicon micro-projections per cm2 that can be dry-coated with vaccine for skin delivery. the high number and density of micro-projections means that high velocity application is required to achieve consistent skin penetration. before clinically testing a vaccine nanopatch, this study tests the safety, tolerability and acceptability/utility of uncoated and excipient-coated nanopatches in healthy adults. nanopatches were applied to skin of the upper arm and volar forearm and left in contact with the skin for two minutes before removal. the application sites were assessed for local skin response over 28 days. acceptability interviews were also performed. no unexpected adverse events directly related to the nanopatch application were reported. all applications of the nanopatch resulted in an expected erythema response which faded between days 3 and 7. in some subjects, some skin discolouration was visible for several days or up to 3 weeks after application. the majority (83%) of subjects reported a preference for the nanopatch compared to the needle and syringe and found the application process to be simple and acceptable. on a pain scale from 0 to 10, 78% of applications were scored ‘0’ (no pain) with the average scores for less than 1. the results from this study demonstrate the feasibility of the nanopatch to improve vaccination by showing that application of the product without vaccine to human skin is safe, tolerable and preferred to needle and syringe administration. clinical trial registry id: actrn1261500083549.”

Kesarwani, A., Yadav, A. K., Singh, S., Gautam, H., Singh, H. N., Sharma, A., & Yadav, C.. (2013). THEORETICAL ASPECTS OF TRANSDERMAL DRUG DELIVERY SYSTEM. Bulletin of Pharmaceutical Research

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“Transdermal patch is a medicated adhesive patch that is placed on the skin to deliver the drug through the skin in order to achieve systemic absorption of drug at a predetermined rate over a prolonged period of time. its main advantages includes controlled drug release with minimum side effects, improved bioavailability, bypass first pass metabolism and many more. there are factors such as physiochemical as well as biological which affect the bioavailability of transdermal medicament. due to technological advancement, many new techniques which have attained attention are iontophoresis, phonophoresis, electroporation micro needles etc. different types of transdermal patches can be prepared by varying methods. transdermal patches can be evaluated by interaction studies, folding endurance, thickness of the patch, weight uniformity, drug content and in vitro studies. this review covers general aspects like advantages, methods of preparation of transdermal patches, evaluation, basic components of transdermal drug delivery system.”

Rana, R., Saroha, K., Handa, U., Kumar, A., & Nanda, S.. (2016). Transdermal Patches as a tool for permeation of drug through skin. Journal of Chemical and Pharmaceutical Research

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“For many decades for the treatment of disease many of the dosage form are using which are including tablets, capsules, pills, creams, ointments, liquids, injectables. to maintain the concentration of drug it is necessary to take these types of dosage form several times of day. a novel drug delivery system thus aim at releasing one or more drug continuously at a predetermined pattern for a fixed period of time, either systematically or to a specific target organ. transdermal drug delivery system includes all topically administered drug formulations intended to deliver the active ingredients into the circulation. a patch contained high dose of drug which is retained on the skin for prolonged period of time. drug from patch enters into blood flow via diffusion process. skin contains 10-70 hair follicles and 200-250 sweat ducts per cm 2 of the skin so it is easily accessible by drugs. drug can penetrate through skin via three pathways-through hair follicles, sebaceous gland, and sweat ducts. its main advantages includes controlled drug release with minimum side effects, improved bioavailability, bypass first pass metabolism and many more. there are factors such as physiochemical as well as biological which affect the bioavailability of transdermal medicament. due to technological advancement, many new techniques which have attained attention are iontophoresis, phonophoresis, electroporation and micro needles etc. this review covers general aspects regarding transdermal patches like advantages, basic components of transdermal drug delivery system, methods of preparation of transdermal patches and evaluation.”

Museau, M., Butdee, S., Vignat, F., & others. (2011). Design and Manufacturing of Microneedles. Toward Sustainable Products?. Asian International Journal of Science and Technology in Production and Manufacturing Engineering

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“Microneedles can be used for drugs delivery instead of conventional hypodermic needles with some advantages: they cause less pain and skin irritation, the risk of transmitting infection is less important and they can be more economical to manufacture. a presentation of different families of microneedles and their advantages compared to conventional needles can be found in the first part of this paper. then, current manufacturing processes of microneedles are presented and discussed, followed by the proposition of an innovative manufacturing strategy to make a patch composed of hollow microneedles. this strategy combines micro machining processes to make an insert that will be use during injection moulding. at last, the concept of sustainability is presented with the aim to start discussion on the sustainable aspects of the designed microneedles, and then provide some answers”

Sun, F., Koh, K., Ryu, S. C., Han, D. W., & Lee, J.. (2012). Biocompatibility of nanoscale hydroxyapatite-embedded chitosan films. Bulletin of the Korean Chemical Society
Plain numerical DOI: 10.5012/bkcs.2012.33.12.3950
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“In order to improve the bioactivity and mechanical properties of hydroxyapatite (hap), chitosan (chi) was in situ combined into hap to fabricate a composite scaffold by a sublimation-assisted compression method. a highly porous film with sufficient mechanical strength was prepared and the bioactivity was investigated by examining the apatite formed on the scaffolds incubated in simulated body fluid. in addition, the cytotoxicity of the hap/chi composite was studied by evaluating the viability of murine fibroblasts (l-929 cells) exposed to diluted extracts of the composite films. the apatite layer was assessed using scanning electronic microscopy, inductively coupled plasma-optical emission spectrometry and weight measurement. composite analysis showed that a layer of micro-sized, needle-like crystals was formed on the surface of the composite film. additionally, the wst-8 assay after l-929 cells were exposed to diluted extracts of the composite indicated that the hap/chi scaffold has good in vitro cytocompatibility. the results indicated that hap/chi composites with porous structure are promising scaffolding materials for bone-patch engineering because their porous morphology can provide an environment conductive to attachment and growth of osteoblasts and osteogenic cells.”

Micro-Needle Drug Patch Uses Inkjet Technology. (2007). Biomedical Instrumentation & Technology
Plain numerical DOI: 10.2345/0899-8205(2007)41[431:mdpuit]2.0.co;2
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Sharquie, K. E., Noaimi, A. A., & Al-Khafaji, Z. N.. (2016). Direct Transplant of Melanocytes from Normal Donor Area into Vitiligenous Recipient Area by Intralesional Injection of Melanocytes Using Spade Like Needle Technique. Journal of Cosmetics, Dermatological Sciences and Applications
Plain numerical DOI: 10.4236/jcdsa.2016.64022
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“Background: vitiligo is a common autoimmune inflammatory skin disease, where there are different surgical techniques for treatment of stable patches of vitiligo .objective: to find non-costly, minimally invasive, simple technique by direct melanocytes transplant by spade needle technique in treatment of vitiligo. patients and methods: this interventional, therapeutic, comparative study was done in department of dermatology, baghdad teaching hospital, baghdad, iraq from april 2014-march 2015. twenty patients with localized, generalized and segmental vitiligo were included. full history and examination for each patient was done with 4 (20%) males and 16 (80%) females and their ages ranged from 9 - 40 (23.15 卤 11.44) years. forty one patches in 20 patients treated by spade grafting technique and the donor and recipient sites were demarcated and anesthesia done by xylocaine 2% with adrenalin 1:100,000. transplantation was started by using disposable needle gauge 18 (the sharp end of needle was cut by a scissor to make it a spade like) with medical syringe 5 ml supplied with normal saline. the micro-pieces were taken from donor site and transplanted directly, easily and rapidly into dermis of recipient site and followed by pushing normal saline and the procedure was repeated to cover all recipient sites with 5 mm distance between injection points. the surface area of the lesions was calculated and the reduction rate was estimated every month till the end of the 4th month period of the treatment. results: including 41 patches in 20 patients with the surface area of the patches ranged from 1.5 - 90 cm2 (13.78 卤 17.57) cm2. the mean 卤sd of surface area of lesions was decreased from 13.78 卤 17.57 cm2 at baseline visit to 13.61 卤 17.48 cm2 at the second visit (after 2 weeks ) which was statistically significant (p value 鈮?0.001). the mean surface area continued to be reduced till reaching 12.20 卤 15.68 cm2 at the third visit and 12.01 卤 15.55 cm2 at the fourth visit. all were statistically significant when compared to baseline visit. there was reduction in s”

Sun, Y., Chen, M., Yang, D., Qin, W., Quan, G., Wu, C., & Pan, X.. (2021). Self-assembly nanomicelle-microneedle patches with enhanced tumor penetration for superior chemo-photothermal therapy. Nano Research
Plain numerical DOI: 10.1007/s12274-021-3817-x
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“Nanomedicine with high specificity has been a promising tool for cancer diagnosis and therapy. however, the successful application of nanoparticle-based superficial cancer therapy is severely hindered by restricted deep tumor tissue accumulation and penetration. herein, a self-assembly nanomicelle dissolving microneedle (dmn) patch according to the ‘nano in micro’ strategy was conducted to co-deliver a first-line chemotherapeutic agent paclitaxel (ptx), and a photosensitizer ir780 (ptx/ir780-nms @dmns) for chemo-photothermal synergetic melanoma therapy. upon direct insertion into the tumor site, dmns created a regular and multipoint three-dimensional drug depot to maximize the tumor accumulation. accompanied by the dmn dissolution, the composition of the needle matrixes self-assembled into nanomicelles, which could efficiently penetrate deep tumor tissue. upon laser irradiation, the nanomicelles could not only ablate tumor cells directly by photothermal conversion but also trigger ptx release to induce tumor cell apoptosis. in vivo results showed that compared with intravenous injection, ir780 delivered by ptx/ir780-nms @dmns was almost completely accumulated at the tumor site. the antitumor results revealed that the ptx/ir780-nms @dmns could effectively eliminate tumors with an 88% curable rate without any damage to normal tissues. this work provides a versatile and generalizable framework for designing self-assembly dmn-mediated combination therapy to fight against superficial cancer. [figure not available: see fulltext.]”

Economidou, S. N., Pere, C. P. P., Reid, A., Uddin, M. J., Windmill, J. F. C., Lamprou, D. A., & Douroumis, D.. (2019). 3D printed microneedle patches using stereolithography (SLA)for intradermal insulin delivery. Materials Science and Engineering C
Plain numerical DOI: 10.1016/j.msec.2019.04.063
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“3D printed microneedle arrays were fabricated using a biocompatible resin through stereolithography (sla)for transdermal insulin delivery. microneedles were built by polymerising consecutive layers of a photopolymeric resin. thin layers of insulin and sugar alcohol or disaccharide carriers were formed on the needle surface by inkjet printing. the optimization of the printing process resulted in superior skin penetration capacity of the 3d printed microneedles compared to metal arrays with minimum applied forces varying within the range of 2 to 5 n. micro-ct analysis showed strong adhesion of the coated films on the microneedle surface even after penetration to the skin. in vivo animal trials revealed fast insulin action with excellent hypoglycaemia control and lower glucose levels achieved within 60 min, combined with steady state plasma glucose over 4 h compared to subcutaneous injections.”

Bora, P., Kumar, L., & Bansal, A. K.. (2008). Microneedle Technology for Advanced Drug Delivery : Evolving vistas. CRIPS

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“Transdermal patches are considered as a viable alternative to deliver the drugs having poor oral bioavailability. however, the success of transdermal patches is limited only to lipophilic and/or low molecular weight drugs. a number of advanced drug delivery systems including iontophoresis, sonophoresis, electroporation and microneedle technology have been developed for the penetration of even large molecular weight and/or hydrophilic compounds across the skin. micron scale needles assembled on a transdermal patch are proposed as a hybrid between hypodermic needles and transdermal patches to overcome the individual limitations of both the injections as well as patches. a variety of methods including poke with patch, coat and poke are possible for the fabrication of microneedle system. the technique has a promising future and is considered as a dosage form of interest for vaccines, peptides and genes.”

Ravi, S., Sharma, P. K., & Bansal, M.. (2011). A review: Transdermal drug delivery of nicotine. International Journal of Drug Development and Research

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“Cigarette smoking has been the leading cause of premature death and illness in many industrialized country in the world, while the u.s. alone registers more than 4,00,000 deaths each year. the nicotine patch serves to deliver a constant dose of nicotine across the skin that helps to relieve the symptoms which are associated with tobacco withdrawal. further, the use of carbon nanotube membranes and micro needle based transdermal drug delivery has lead to the great advancements. some of the main advantages of transdermal drug delivery are bypassing of hepatic first pass metabolism, maintenance of steady plasma level of the drug and enhancement of therapeutic efficiency. © 2010 ijddr.”

Shende, P., Sardesai, M., & Gaud, R. S.. (2018). Micro to nanoneedles: a trend of modernized transepidermal drug delivery system. Artificial Cells, Nanomedicine and Biotechnology
Plain numerical DOI: 10.1080/21691401.2017.1304409
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“The transdermal route of drug delivery is convenient, pain-free and follows controlled rate release pattern. however, many therapeutically active drugs cannot cross the stratum corneum effectively. lipophilic drugs like nifedipine cross the outer skin barrier easily and polar drugs, such as epinephrine are ineffective in showing the same effect. due to these reasons, advancements in drug delivery have taken place to deliver a wide range of drugs, especially macromolecules through the transdermal route and directly into systemic circulation bypassing hepatic metabolism and git degradation. so there is a need for advanced drug delivery systems like microneedles and nanoneedles through transdermal route. these tiny needles will also serve as non-toxic, safe and stable systems for advanced drug delivery. thus, macro to nanoformulation is the fast emerging fields nowadays. these have additional advantages to transdermal patches, such as better penetration, permeation, controlled release and direct delivery to the cytoplasm.”

Chen, X., Kositratna, G., Zhou, C., Manstein, D., & Wu, M. X.. (2014). Micro-fractional epidermal powder delivery for improved skin vaccination. Journal of Controlled Release
Plain numerical DOI: 10.1016/j.jconrel.2014.08.006
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“Skin vaccination has gained increasing attention in the last two decades due to its improved potency compared to intramuscular vaccination. yet, the technical difficulty and frequent local reactions hamper its broad application in the clinic. in the current study, micro-fractional epidermal powder delivery (epd) is developed to facilitate skin vaccination and minimize local adverse effects. epd is based on ablative fractional laser or microneedle treatment of the skin to generate microchannel (mc) arrays in the epidermis followed by topical application of powder drug/vaccine-coated array patches to deliver drug/vaccine into the skin. the novel epd delivered more than 80% sulforhodamine b (srb) and model antigen ovalbumin (ova) into murine, swine, and human skin within 1 h. epd of ova induced anti-ova antibody titer at a level comparable to intradermal (id) injection and was much more efficient than tape stripping in both delivery efficiency and immune responses. strikingly, the micro-fractional delivery significantly reduced local side effects of lps/cpg adjuvant and bcg vaccine, leading to complete skin recovery. in contrast, id injection induced severe local reactions that persisted for weeks. while reducing local reactogenicity, epd of ova/lps/cpg and bcg vaccine generated a comparable humoral immune response to id injection. epd of vaccinia virus encoding ova induced significantly higher and long-lasting interferon γ-secreting cd8 + t cells than id injection. in conclusion, epd represents a promising technology for needle-free, painless skin vaccination with reduced local reactogenicity and at least sustained immunogenicity. © 2014 elsevier b.v.”

Raghuraman, V., & Pandey, V. P.. (2014). Approaches and Significance of Transdermal Drug Delivery Systems: a Review. International Journal of Pharmaceutical Sciences and Research

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“Transdermal drug delivery system (tdds) is the most innovative and novel drug delivery systems by penetrating through the skin by increasing the scope of molecules that can be delivered. tdds that traditionally uses a patch containing loaded drug substances pressed on to the skin is convenient, painless and non-invasive, to avoid gastro intestinal (gi) tract toxicity (peptic ulcer disease). transdermal delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation which often causes undesirable side effect. the number of medications and the ways in which they can be administered have expanded dramatically over the years. one such advancement is the development of transdermal patch delivery systems. transdermal drug technology specialists are continuing to search for new methods that can effectively and painlessly deliver larger molecules in therapeutic quantities to overcome the difficulties associated with the oral route. various products of tdds are in use by applying approaches like micro needles, abrasion, micro scission, jet delivery, iontopher’s, electroportation, ultrasound and radiofrequency. the present drug delivery is highly significant if compared to oral route for less side effect, better bioavailability and longer duration of action.”

Sriperumbudur, K. K., Koester, P. J., Stubbe, M., Tautorat, C., Held, J., & Gimsa, J.. (2009). Local Electroporation of Single Adherent Cells by Micro-Structured Needle Electrodes. In proceedings of the comsol

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“In spite of its low throughput, patch-clamp is the established method for intracellular measurements of the transmembrane potential. to address this problem, we have developed new biosensor-chips with micro-structured needle electrodes (mnes). mne-penetration of single cells growing on the mne-tips leads to a situation comparable to the whole-cell mode in classical patch clamp. mne-penetration was accomplished by local micro-invasive needle electroporation (lomine; koester et al., 2008; baumann et al., 1998a and b). in this paper, we simulate the field and potential distributions around the mne before lomine assuming reasonable cell and medium parameters for a cell being in contact with the needle via focal adhesion points.”

Szymura, T. H., Dunajski, A., Aman, I., Makowski, M., & Szymura, M.. (2007). The spatial pattern and microsites requirements of Abies alba natural regeneration in the Karkonosze Mountains. Dendrobiology

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“Progeny of four adult silver firs, which were an admixture in norway spruce (picea abies) stand was, analyzed. the study was done in lower mountain zone of the karkonosze (giant mts.) national park (sw poland). the seedlings occurred in two clumps related to the position of adult trees, whereas spatial pattern of the seedlings inside each clump was random. the seedlings were spaced mainly in distances 5-25 from the nearest adult tree. the maximal distance was up to 50 m. most seedlings were established in accordance with main wind directions. also, in these directions seedlings were more distant from adult trees than in other directions. the seedlings grew in better light environment (12% of ppfd) than average (9,6% ppfd). this effect was statistically significant. the height increment of the seedlings was low and was not correlated with light conditions. similarly, there was not any correlation between the apical dominance ratio and light. the lack of this correspondence we attributed to browsing. the silver fir seedlings were significantly underrepresented in patches of vaccinium myrtillus, on raw needles, under crown of adult trees and in concave micro-relief form. the underrepresentation in the places covered by canopy and in patches of bilberry we related to the indirect effect of continuous browsing, which leads to higher seedlings mortality in more shaded places and sites of stronger competition between forest floor vegetation and silver fir seedlings.”

Nazari, K., Mehta, P., Arshad, M. S., Ahmed, S., Andriotis, E. G., Singh, N., … Ahmad, Z.. (2020). Quality by design micro-engineering optimisation of NSAID-loaded electrospun fibrous patches. Pharmaceutics
Plain numerical DOI: 10.3390/pharmaceutics12010002
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“The purpose of this study was to apply the quality by design (qbd) approach to the electrospinning of fibres loaded with the nonsteroidal anti-inflammatory drugs (nsaids) indomethacin (indo) and diclofenac sodium (diclo). a quality target product profile (qtpp) was made, and risk assessments (preliminary hazard analysis) were conducted to identify the impact of material attributes and process parameters on the critical quality attributes (cqas) of the fibres. a full factorial design of experiments (doe) of 20 runs was built, which was used to carry out experiments. the following factors were assessed: drugs, voltage, flow rate, and the distance between the processing needle and collector. release studies exhibited indo fibres had greater total release of active drug compared to diclo fibres. voltage and distance were found to be the most significant factors of the experiment. multivariate statistical analytical software helped to build six feasible design spaces and two flexible, universal design spaces for both drugs, at distances of 5 cm and 12.5 cm, along with a flexible control strategy. the current findings and their analysis confirm that qbd is a viable and invaluable tool to enhance product and process understanding of electrospinning for the assurance of high-quality fibres.”

Kündig, T. M., Bot, A., & Senti, G.. (2012). Intralymphatic vaccination. In Gene Vaccines
Plain numerical DOI: 10.1007/978-3-7091-0439-2_10
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“The immune response is initiated by dendritic cells and other antigen-presenting cells. these cells are present in nearly all organs and tissues of the body, so that theoretically any organ or tissue could serve as a route for vaccine administration. the choice of route is therefore mainly based on practical aspects. using conventional needle and syringe the subcutaneous or intramuscular route are standard. the dermis and especially the epidermis are technically more difficult to target, but are likely to gain more interest due to the recent development of micro-needle patches and needle free injection devices. vaccine administration via mucosal surfaces such as nasal or oral vaccination represents another option for needle free vaccine administration. while all the above mentioned routes of administration have been proven to work and protect against childhood diseases, influenza and many other infectious agents, the discussion and comparison of these different routes usually focuses on patient convenience, reduction of pain and distress for children, cost and on the possibility for mass vaccination. in this review, however, we would like to focus on how the route of administration can enhance the efficacy of vaccination, in clinical indications that are benefiting to a much lesser extent from conventional vaccination. especially in therapeutic vaccination, i.e., in a smaller patient number that already suffers from a disease, vaccination efficiency rather than convenience is the main issue. this is particularly the case in therapeutic cancer vaccines and in allergen specific immunotherapy. intralymphatic vaccination is a strategy to maximize immunogenicity and therefore vaccine efficacy. the main part of this review will discuss this long known vaccination route and its clinical applicability in therapeutic vaccination, with a special focus on gene vaccines.”

Kang, G., Kim, S., Yang, H., Jang, M., Chiang, L., Baek, J. H., … Jung, H.. (2019). Combinatorial application of dissolving microneedle patch and cream for improvement of skin wrinkles, dermal density, elasticity, and hydration. Journal of Cosmetic Dermatology
Plain numerical DOI: 10.1111/jocd.12807
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“Background: dissolving microneedles (dmns), microscale needles with a biodegradable polymer matrix, have been widely investigated for transdermal drug delivery. however, the restricted drug loading space of dmns limited the delivery of the desired quantity of active compounds. in this study, we developed novel combinatorial therapies involving sequential application of adenosine-loaded dmn (ad-dmn) patches and a topical adenosine-loaded cream (ad-cream). the application of dmns created skin channels, which delivered encapsulated drugs from both the dmns and cream. the use of combinatorial therapies can maximize drug delivery. methods: to compare the efficacy of combinatorial therapies and ad-cream application, a double-blind clinical test was conducted over 10 weeks on 21 females with wrinkles around their eyes, and the skin parameters such as wrinkles, dermal density, elasticity, and hydration were analyzed. the skin irritation test was assessed by expert interviewers to elucidate undesirable side effects. results: the combinatorial therapies showed statistically significant efficacy for the improvement of average depth of wrinkles, dermal density, elasticity, and hydration after an 8-week application (p < 0.001). adverse effects on the skin were not observed in any subject during the test period. conclusion: the efficacy and safety results showed that the combinatorial therapies were a safe and outstanding innovation for the optimization of transdermal therapy.”

Chitra, K. P., Bhimavarapu, R., Rani.B, S., Priyadarshini, I., & Reddy, A. B.. (2011). MICRONEEDLES: AN EFFECTIVE TECHNIQUE FOR TRANSDERMAL DRUG DELIVERY. International Journal of Biomedical Research
Plain numerical DOI: 10.7439/ijbr.v2i8.127
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“Optimization of drug delivery through human skin is important in modern therapy. with limitations of oral drug delivery, pain and needle phobias associated with traditional injections drug delivery research has focused on transdermal delivery route. a new approach to transdermal delivery that acts as a bridge between the user friendless of patches and the broad effectiveness of hypodermic needles has recently received attention.by using needles of micron dimensions, termed microneedles, skin can be pierced to effectively deliver the drugs, the mechanism of action is based on temporary mechanical disruption of skin. the drug, in the form of biomolecules, is encapsulated within the micro needles, which are then inserted into the skin in the same way a drug like nitroglycerine is released into the bloodstream from a patch. the needles dissolve within minutes, releasing the trapped cargo at the intended delivery site. the present review focus on various studies related to micro needles for transdermal drug delivery and technology applications in various fields.”

Severe systemic reaction associated with skin microneedling therapy in 2 sisters: A previously unrecognized potential for complications?. (2013). Journal of the American Academy of Dermatology
Plain numerical DOI: 10.1016/j.jaad.2012.12.904
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“Skin microneedling creates microconduits through the epidermis, resulting in neocollagenesis and neovascularization in the papillary dermis, used to treat acne scars, stretch marks and for facial rejuvenation. two sisters, aged 34 and 44 years, underwent facial skin microneedling by a trained practitioner in a criss-cross manner, following skin cleansing and topical anesthetic cream application. a separate sealed single-use, presterilized, ce marked, fda registered drum-shaped roller (192 stainless steel microneedles; 8 rows, 1.5 mm long, 0.25 mm wide) was used on each woman. both developed marked neck lymphadenopathy within 24 hours of the procedure. in addition, the older sister experienced immediate intense localized erythema and prolonged pinpoint bleeding, malaise, and headache. systemic antibiotic treatment was unhelpful. she deteriorated further in the following 2 weeks, developing a florid erythematous papular rash on the face, with progression to the trunk and limbs and associated facial edema. hospitalization with oral and topical corticosteroid treatment led to gradual improvement over 2 weeks. infective and autoimmune screens were negative. incisional biopsy revealed a non-specific, chronic inflammatory infiltrate. patch testing to british standard series, topical anesthetic cream, aftercare products and sunblock used, showed reaction to nickel sulphate (d4++), already known to the patient. on manufacturer inquiry, the roller microneedles were found to contain up to 0.006% sulphur and 8% nickel bound to surgical grade stainless steel alloy. skin microneedling is considered a safe alternative to more invasive cosmetic procedures, with no down time and minimal side effects of mild transient erythema and bruising. rarer adverse effects have been attributed to: nonsterilized devices or roller reuse (microbial infections); nickel-plated microneedles (allergic contact dermatitis); inexpensive metal micro-needles (needle breakage); enhanced needle penetration caused by microneedle length >2 mm or excessive operator force (trauma). low sulphur stainless steel alloys containing nickel are thought to pose little or no risk in short term contact with nickel-sensitive individuals. to our knowledge, this is the first report of serious systemic reaction to treatment with a ce marked, fda registered microneedle roller in 2 sisters, highlighting the need for caution in offering microneedling as a risk-free option in cosmetic practice.”

M., B., E., D., M., C., E., F., A., G., & F., G.. (2009). An innovative transdermal drug delivery device for the treatment of chronic diseases. Experimental Dermatology

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“In chronic disease, such as in type 1 diabetes (t1d), the final goal indicated by physicians is to maintain an adequate blood level of glucose by utilizing a continuous and modulated administration of insulin, over time. it is essential to find an effective and personalised drug administration since the usual pharmaceutical formulations are unable, at the same time, to achieve these goals. an appealing alternative to hypodermic injections could be transdermal drug delivery (tdd) using patches, although the limitation for insulin is represented by its high molecular weight. tdd seems to be an attractive option but the bioavailability of insulin will have to be optimized compared with that achieved by subcutaneous injection. we designed an innovative biomedical micro-structured device for controlled, painless, tdd, based on a matrix of hollow micro-needles in order to insert the drug just below the epidermal layers and let it diffuse into of papillary dermis blood vessels. in the complete device drug flux rate will be controlled by the help of a tuneable, micro-structured pump. an existing non-miniaturised prototype has been produced and some preliminary skin piercing and infusion tests have already been performed on human skin biopsies. in particular we delivered a green fluorochrome- labelled insulin, monitoring the drug diffusion in the skin. samples were immediately frozen in liquid nitrogen and cryostate sections were obtained. skin sections demonstrated piercing of the epidermis and infusion of insulin within epidermis and dermis reaching the dermal capillaries.”

Faraji Rad, Z., Prewett, P. D., & Davies, G. J.. (2021). Rapid prototyping and customizable microneedle design: Ultra-sharp microneedle fabrication using two-photon polymerization and low-cost micromolding techniques. Manufacturing Letters
Plain numerical DOI: 10.1016/j.mfglet.2021.10.007
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“In recent years, interest in microneedle devices for drug and vaccine delivery and point-of-care diagnostics has grown due to low cost, convenience and minimal invasiveness. a cluster of miniature needles on a small patch could enhance the quality of human health care, revolutionizing test and drug and vaccine delivery systems. however, current fabrication methods are not viable for cost-effective large-scale manufacture. this study reports fabrication of ultra-sharp microneedles with microfluidic channels using two-photon polymerization (2pp) which enables flexible designs with resolution down to 100 nm. the technique is ideally suited to prototyping and the fabrication of master molds from which elastomeric negative-molds have been used in a rapid micromolding technique to make batches of ultra-sharp microneedles. this micromolding process has mass manufacturing potential.”

Olatunji, O., & Das, D. B.. (2019). Drug delivery using microneedles. In Comprehensive Biotechnology
Plain numerical DOI: 10.1016/B978-0-444-64046-8.00311-6
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“This article aims to review various aspects of the technique of using microneedles for drug delivery. drug delivery using microneedles is a relatively new form of transdermal drug delivery that not only permits painless drug delivery but also increases the range of drugs that can be delivered through the skin. they are also likely to improve neural, ocular, and intravascular drug delivery in addition to their other benefits outside drug delivery. microneedles were first applied to transdermal drug delivery in the late 1990s, making this a novel idea at that time. different techniques can be applied for drug delivery while using microneedles. these are the poke with patch, coat and poke, and dip and scrape approaches, encapsulating the drugs within the dissolving microneedles and flowing through the lumen of hollow microneedles. a range of materials have been used to fabricate microneedles such as silicon, metal, glass, and polymer using the microelectromechanical systems (mems) fabrication methods. a micro-dip coating method has been introduced for coating of solid microneedles, and this has been shown to be an efficient method as the drugs adhere well to the needle surface and do not rub off on insertion into the skin, rather they dissolve within the epidermis as desired. vaccines, proteins, dna, vitamins, and calcein have been successfully coated on solid microneedles, and experiments on rats have shown that drugs delivered using coated microneedles do reach the bloodstream and have the expected pharmacologic effects.”

Waghulde, S., Naik, P. P., Gorde, N., Juvatkar, P., Shirodkar, P. Y., & Kale, M. K.. (2013). Development, recent inventions and evaluation techniques of transdermal drug delivery system - A review. International Journal of Pharmaceutical and Phytopharmacological Research

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“Patch-based transdermal drug delivery offers a convenient way to administer drugs without the drawbacks of standard hypodermic injections relating to issues such as patient acceptability and injection safety. however, conventional transdermal drug delivery is limited to therapeutics where the drug can diffuse across the skin barrier. by using miniaturized needles, a pathway into the human body can be established which allow transport of macromolecular drugs such as insulin or vaccines. the human skin is a readily accessible surface for drug delivery. skin of an average adult body covers a surface of approximately 2 m 2 and receives about one-third of the blood circulating through the body. over the past three decades, developing controlled drug delivery has become increasingly important in the pharmaceutical industry. the human skin surface is known to contain, on an average, 10-70 hair follicles and 200-250 sweat ducts on every square centimeters of the skin area. it is one of the most readily accessible organs of the human body. the potential of using the intact skin as the port of drug administration to the human body has been recognized for several decades, but skin is a very difficult barrier to the ingress of materials allowing only small quantities of a drug to penetrate over a period of time. during the past decade, the number of drugs formulated in the patches has hardly increased, and there has been little change in the composition of the patch systems. modifications have been mostly limited to refinements of the materials used. the present article development, recent inventions and evaluation techniques of transdermal drug delivery system.”

S., X., H., Z., H., Z., A.S., P., X., Z., J., Z., & J.A., R.. (2018). A wearable, flexible, conformable and depth-modulated phototherapy device: Initial application in morphea. Journal of Investigative Dermatology

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“Morphea is a localized, sclerosing skin condition that can extend deep into muscle and fascia. while uva-1 (340-400 nm) phototherapy is often effective, these units are not widely available, expose unaffected skin to uva-1, and require several weeks until treatment response. thus, there is a need for new uva-1 systems that offer faster response times, greater efficacy, targeted therapy and increased convenience. in morphea, uva-1 leads to the upregulation of collagenase and ifnγ, leading to decreased collagen i, collagen iii, and tgfβ expression. however, the intensity of uva-1 attenuates to 1% at 190 μm in human skin, which is more superficial than the depth of disease in many morphea cases. thus, we hypothesize that deeper uva-1 delivery will improve efficacy and response time. using advanced techniques in flexible electronics, we have developed a soft, conformable, and depth-modulated uva-1 phototherapy device. the devices top layer has an array of uva-1 light emitting diodes (spectral peak output: 360-nm) fully embedded within a flexible silicone substrate. the power intensity output is 35 mw/cm2 with uniform distribution across the entire patch as confirmed by a uva light meter. the bottom layer includes a dense array of microneedles from poly-lactic-co-glycolic-acid (plga), a polymer enabling 99% of uva transmittance, which create micro-channels 700 μm for deeper uva-1 delivery into the skin. optical modeling, confirmed by confocal microscopy in agarose, demonstrates that the plga microneedle waveguides increase light transmission by 250% along the z-axis along the length of the needles. the system can conform to any curvilinear body surface and be cut to any shape or size. future clinical testing will validate the safety and efficacy of the system compared to standard uva-1 phototherapy.”

Nishimura, M., Akai, T., Hotta, A., Ishida, M., & Kamon, M.. (2018). Development of gas-permeable/waterproof sheet and its application as a cover sheet of putrefactive-radioactive contaminated waste. In 11th International Conference on Geosynthetics 2018, ICG 2018

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“We have newly developed a gas-permeable/waterproof sheet (gpws), comprising a micro-porous sheet which is waterproof and with gas permeability, coated with nonwovens to protect and reinforce this center sheet, and have conducted many kinds of experiments in both laboratories and fields. gpws has been widely applied as a cover sheet for temporary storage sites of putrefactive-radioactive contaminated waste due to the accident of fukushima dai-ichi nuclear power station. although gpws itself has waterproofness based on micro-porous sheet, it is quite difficult to achieve sufficient waterproofness in seams of gpwss because gpws has needle-punched nonwoven layers that intrinsically have (in-plane) hydraulic transmissivity. in this paper, we first show representative characteristics of gpws, such as waterproofness, gas permeability, and tensile strength. special seaming method of gpwss we developed is also presented. in addition, we developed patch repairing method that is useful for repairing damaged point of gpws by external factor such as birds’ pecking and abrasion by excessive stepping. these seaming and patch repairing methods are actually applied to real temporary storage sites of putrefactive- radioactive contaminated waste in which gpws is used as a cover sheet at fukushima site.”

G., C., B., H., D., J., M., L., H., Z., Z., D., … Xia, J.. (2015). Pharmacokinetic and pharmacodynamic study of triptolide-loaded liposome hydrogel patch under microneedles on rats with collagen-induced arthritis. Acta Pharmaceutica Sinica B

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Volchatova, E. V., Bezrukova, E. V., Kulagina, N. V., Kerber, E. V., Reshetova, S. A., Shchetnikov, A. A., & Filinov, I. A.. (2021). Vegetation history in the lake ilchir basin (East sayan mountains) for the last 8500 years. Geosfernye Issledovaniya
Plain numerical DOI: 10.17223/25421379/18/4
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“Holocene climate is more complex both temporally and spatially than is commonly recognized. pollen records from inland regions are important for understanding past changes in landscapes, assessing the sensitivity of ecosystems to future climatic variations that affect the composition of vegetation and its change over time. high-mountain boreal ecosystems are very vulnerable to climate change, and even minor fluctuations in it can lead to serious natural changes. we carried out analysis of pollen, spores, micro-charcoal particles, conifer stomata, and lithology of an ams 14c-dated core from high-mountain lake ilchir situated in the eastern sayan mountains, in order to reveal changes in vegetation and climate since 8490 cal yr bp. the sediments of 133 cm long core consists of gray silty clay and shows no signs of sedimentary hiatuses. fife bulk sediment samples were dated with an accelerator mass spectrometry (ams) system. the modern vegetation of the lake ilchir basin is ranges from moist forb-grass meadow around the lake to small patches of open larch stands and shrubby birch on the basin slopes. the pollen record presented here is the first continuous and well-dated records from lake ilchir covering the last 8490 cal years, allowing detailed reconstruction of vegetation and environmental dynamics in the region. the results of the pollen analysis and pollen-based vegetation and climate reconstruction suggest that grass-dominated meadow communities prevailed in the lake basin from 8490 to 6000 kyr bp. the absence of larch and fir stomata in the sediments suggests the growth of trees rather far from the lake shore. probably, the climate in the basin was moderately cold with insufficient moisture. the high scots pine pollen percentage in comparison with surface pollen spectra suggests a higher than today position of the upper boundary of the pine in response of higher-than-present summer insolation. between 6000–3700 kyr bp the climate was characterized by warmer than modern winter seasons and high snow cover, which did not allow the soils to freeze and supported the development of fir in the ilchir lake basin. however, the increased abundance of larch pollen and stomatal cells of its needles in sediments suggest an increased role of larch in the composition of local vegetation and/or its approach to the lake shoreline. expansion of the areas of larch means that climate gradually became sharply continental, more arid. the last 3700 years was characterized …”

Chen, G., Xu, K., Dou, J. J., Yan, J. H., Ju, D. H., Zhao, H. Y., … Hao, B. H.. (2012). Effects of different triptolide formulations given by MEMS micro-needles on skin injury of rheumatoid arthritis rats. Chinese Pharmaceutical Journal

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“OBJECTIVE: to study the effects of different triptolide formulations given by micro electro mechanical systems (mems) micro-needles on skin injury of rheumatoid arthritis rats . methods: three formulations of triptolide were prepared including the aqueous solution of 20% propylene glycol, liposomes, and liposomes hydrogel patch. rats with rheumatoid arthritis induced by collagen ii were used, and 100 and 200 μm mems micro-needles treatment was performed on left and right sides of rat skin. the lactate dehydrogenase (ldh) activities were measured by ultraviolet spectro-photometric method. results: after processed by mems micro-needle, the ldh activities of ra rat skin did not change obviously (p > 0.05). all triptolide formulations increased ldh activities (p < 0.05), and the increasement of solution group was largest (p < 0.001), followed by lipsomes group (p < 0.01) and liposomes hydrogel patch (p < 0.05). nevertheless, there was no significant difference between left and right sides of rat skin (p > 0.05). conclusion: both 100 and 200 μm mems micro-needles were safe for enhancement of transdermal delivery in rheumatoid arthritis rats. the skin injury was observably relieved when triptolide was prepared as liposomes hydrogel patch which is a perfect formulation for transdermal delivery of triptolide. copyright 2012 by the chinese pharmaceutical association.”

S., W., P.P., N., N., G., P., J., P.Y., S., & M.K., K.. (2013). Development, recent inventions and evaluation techniques of transdermal drug delivery system - A review. International Journal of Pharmaceutical and Phytopharmacological Research

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Ma, B., Gan, Z., & Liu, S.. (2005). Flexible silicon microneedles array for micro fluid transfer. In 2005 6th International Conference on Electronics Packaging Technology
Plain numerical DOI: 10.1109/ICEPT.2005.1564615
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“This paper will report on a new method of using silicon micro needle in bio-medical application. the hollow micro needle array have been designed and fabricated from single crystal silicon for transdermal delivery. the machined micro needles are shank height of 150μm with 250μm center-tocenter spacing. the needle size, density and shape are controlled by independent processing steps. packaging technology incorporates a micro needles array affixed to a polymeric adhesive base. the maximal adhesive patch size is 2 cm2. flow rate test is proved that the polymeric base construction is important to function of micro needles array. glucose solution tests show that surface tension is the dominant force to affect the characters of flow in micro needles channel. © 2005 ieee.”

Newswire, P. R.. (2015). Microneedles for Transdermal and Intradermal Drug Delivery, 2014-2030. Lon-Reportbuyer

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; “; LONDON, july 30, 2015 /prnewswire/ -- introductiontransdermal delivery via microneedles is increasingly gaining traction as one of the more promising drug delivery technologies. microneedles are of a few hundred microns in size, capable of creating transient pores across the skin by penetrating the stratum corneum layer to deliver molecules. these needles are not big enough to reach the nerve-rich regions of the skin; as a result, the drug delivery is perceived as completely painless and devoid of bleeding. drugs, vaccines, proteins, peptides and other biomolecules are suitable for delivery using the microneedle technology.the market is still in its infancy. so far, only one microneedle based delivery device, soluvia prefilled microinjection system, has reached the market. the vaccine-device combination product was fda approved in may 2011 for intradermal delivery of fluzone influenza vaccine. we have identified more than 25 companies, with proprietary microneedle technology, actively working towards the development of microneedle-based drug or vaccine products. clearside biomedical, nanopass technologies, corium international, circassia, radius health and zosano pharma are examples of companies which are evaluating microneedle based drug/vaccine – device combination products (referred to as products hereafter) in clinical trials.during the course of our research, we came across 22 products currently in different stages of development. we expect around ten products to be launched by the end of this decade, providing the much needed push to this market. technological advancements will ensure the development of microneedle systems with improved safety and efficacy profile. as more products move from pipeline to the market, we expect to see an increase in the investment in this area from various quarters. scope of the reportthe ‘Microneedles for transdermal and intradermal drug delivery, 2014-2030’ report provides an extensive study in the field of microneedle based delivery systems for therapeutic use. the report covers various aspects, such as, benefits of microneedle assisted drug delivery over conventional needle-syringe system, key industry stakeholders, manufacturing challenges and upcoming opportunities.one of the key objectives of this report is to understand the current and future state of the microneedles market. this is done by analysing - products currently available in the market and those under development (both clinical / pre-clinical)- re…”

Tayyaba, S., Ashraf, M. W., Afzulpurkar, N., & Khaleeq Ur Rahman, M.. (2013). Design, simulation and development of gold microneedles patch. In ASME International Mechanical Engineering Congress and Exposition, Proceedings (IMECE)
Plain numerical DOI: 10.1115/IMECE2013-64443
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“Technological advancements are essential for all fields of life particularly in health discipline to test and analyze the biological and biomedical samples. biological micro electromechanical system (bio-mems) based healthcare technologies are handy to make human life comfortable and snug by ease of use, eradicating pain, reducing risk of diseases, improving diagnosis process and treatments techniques. in this study the design, simulation and development of piezoelectricaly actuated microfluidic device (gold needle patch) has been presented. the simulation of skin insertion using gold needle into skin to study the effects of skin piercing and optimize the design of needle has been conducted in ansys autodyne by making 3d model with applied force 0.4 to 0.9 n at the tip area of needle. the microfluidic analysis of 3×3 microneedle patch has been carry out in ansys workbench using computational fluid dynamic (cfx) environment. the maximum velocity 2.015 e4 m/sec has been achieved. after the successful development of gold needles patch, the fluid transport and insertion test of piezoelectricaly actuated patch also has been conducted using chicken skin. copyright © 2013 by asme.”

Chong, W., Teodorescu, M., Martini, A., & Rahnejat, H.. (2012). Mechanisms of entrapment and release of fluid droplets from nano-scale surface features. In American Society of Mechanical Engineers, Tribology Division, TRIB
Plain numerical DOI: 10.1115/IJTC2012-61201
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“Engineering surfaces are never perfectly flat. they contain micro and nano-scale features on multiple length scales. predicting the amount of fluid trapped in these minute surface crevices and its controlled release could benefit a variety of practical applications. in a sliding contact, the released fluid could create an ultra-thin film, reducing the direct contact and consequently the boundary friction. transdermal patches are the least invasive of available subcutaneous drug delivery techniques. the drug is stored in a micro-reservoir and it is released to the skin either through a permeable membrane or through a series of micro needles. the aim of the current paper represents the first attempt to investigate whether a modeling approach encompassing two complementary simulation techniques in an integrated framework can be used to predict the volume of fluid stored in a nano-scale surface feature. molecular dynamics (md) simulation could provide accurate modeling of fluid behavior at nano-scale, and statistical mechanics (sm) could provide a fast prediction. copyright © 2012 by asme.”

Chen, P. C., & Hsieh, S. J.. (2014). 3-D biocompatible microneedle arrays with nanoporous surface. In FAIM 2014 - Proceedings of the 24th International Conference on Flexible Automation and Intelligent Manufacturing: Capturing Competitive Advantage via Advanced Manufacturing and Enterprise Transformation
Plain numerical DOI: 10.14809/faim.2014.0977
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“During the past few years, developing painless needles or patches to replace traditional hypodermic needles has been investigated. since micromachining can be used to construct a high density metallic micropillar array, we propose to use a biocompatible metal oxide, such as al2o3 and tio2, as an alternative material for fabricating arrays of microneedles. in this study, we fabricated an anodic aluminum oxide (aao) covered al micro-indent array using electrochemical and mechanical micromachining. we demonstrate use of a nanoindenter to make pyramidal indentions on al surface in order to produce a female microneedle array mold. we also performed melting injection to fill aao template with ultra-high molecular weight polyethylene (uhmwpe) to produce uhmwpe nanotubes. the microneedle array provides a 3-d structure that possesses several hundred times more surface area than a traditional nanotube template. this suggests that a medical-grade polymer microneedle array can potentially be formed for more applications. this 3-d microneedle array device can be used not only for painless injection or extraction, but also for storage, highly sensitive detection, drug delivery, and microelectrodes.”

Tautorat, C., Koester, P. J., Held, J., Gaspar, J., Ruther, P., Paul, O., … Baumann, W.. (2008). Intracellular potential measurements of adherently growing cells using micro-needle arrays. In 12th International Conference on Miniaturized Systems for Chemistry and Life Sciences - The Proceedings of MicroTAS 2008 Conference

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“We present a new sensor chip system for intracellular potential measurements of adherently growing cells using micro-structured needle electrode (mne) arrays. existing methods for intracellular investigations are time-consuming, tedious or limited to the analysis of suspended cells. however, most biological cells grow adherently. to overcome these methodological limitations a novel technique, local micro-invasive needle electroporation (lomine) in mne arrays, has been developed. lomine opens the cell membrane for introducing a mne into the cytoplasm. this paper describes the fabrication process of the mne-array chips and first cell electroporation experiments.”

Held, J., Gaspar, J., Ruther, P., & Paul, O.. (2008). Microneedle Arrays Electrode With Dielectrophoretic Electrodes For Intracellular Recording Applications. In 6th International Meeting on Substrate-Integrated Micro Electrode Arrays

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“This paper reports on the fabrication of microneedle electrodes for thenelectroporation of adherent cells and intracellular recording applicationsnwith focus on the influence of external factors in cell metabolism.nclassical methods such as the patch-clamp method have been applied mostlynto single cells in suspension. however, in the human body the majority ofncells are adherent cells, which motivated the development of the newnmicroneedle-based chip design. the chip comprises an array of 64nmicroneedles with each needle combined with two dielectrophoresis (dep)nelectrodes to attract cells towards the needle electrodes. the arraynoccupies a total area of approximately 1 mm2. the microneedles arenfabricated using dry etching of silicon, followed by insulation, twonmetallization and two passivation layers. the passivation layer is openednat the tip of the needles in order to expose the metal for cell positioningnvia dielectrophoresis, electroporation, and intracellular recording.nvarious needles with diameters as small as 1 µm and a height smaller thann10 µm were fabricated. preliminary investigations have shown that heartnmuscle cells, fibroblasts, and also primary cells of mice and rats grow onnthese structures [1].nthe available classical patch-clamp methods for intracellular measurementsnof cells in suspension are time-consuming and require experienced laborn[2]. absolute values of the transmembrane potential vm are between 20 mvnand 200 mv in living cells, depending on organism and cell type [3].nhowever, the absolute measurement of vm is not possible with planarnelectrodes. patch-on-chip systems are presently limited to theninvestigation of suspended single cells [4]. however, adherent cells need anbiological matrix or artificial biocompatible attaching materials on whichnthey can firmly grow. all above-mentioned methods, with exception of thenwhole-cell patch-clamp are limited to the investigation of ion channels. nthe fabrication process of the microneedle electrodes is schematicallynshown in fig. 1. the three-dimensional definition of the microneedlesncomprises three dry etching steps, namely: isotropic, anisotropic andnisotropic silicon etching. the first step realizes the tip of the needle,nthe anisotropic etching step adjusts its height, and the final isotropicnstep thins the needle and sharpens its tip, see fig. 1 (b). by varying thenetch mask diameter and process parameters, different needle profiles can be…”

Lee, J., Jung, J., Shin, D., & Kim, Y. T.. (2012). Patch type sensor module for diagnosis of acute myocardial infarction. In Proceedings of IEEE Sensors
Plain numerical DOI: 10.1109/ICSENS.2012.6411371
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“Myocardial infarction is getting more attention in human health care system by the busy daily activity and prolonged human life span. myocardial infarction is not easy to detect in early stage. whether it is acute or not, it can be chronically fatal without proper detection and treatment in early stage of warning signs. our research is focused on the wearable device that detects myocardial infarction by monitoring cardiac markers from tiny amount of blood sample. our device consist with three parts, blood sampling part, electrochemical sensor part and signal processing part. blood sampling part extracts about 10ul of blood sample with micro-needles, then the blood is transported to electrochemical sensor through polymer parylene coated microfluidic channels. electrochemical sensor detects electro-chemical current generated by oxidation-reduction cycle at the three dimensional integrated micro-electrodes. signal processing part includes traditional signal conditioners such as i-v converter, amplifier and filter, and data processing units such as a/d, d/a convertors and micro-processor. the usefulness of out device is extended by providing combined on line communication capability with bluetooth local area communication and wifi and/or 3g wireless networks. every realtime sensor data and status information from the sensor modules are collected by centralized server located in hospital. with our myocardial infarction diagnosis device, the patients’ unexpected heart attacks can be prevented and the hospital may provide controllable risk caring for the disease without hospitalization of the patients. © 2012 ieee.”

Bavi, N., Cox, C. D., Perozo, E., Martinac, B., Mbengue, M., Navaud, O., … Davis, R. W.. (2015). Special Paper 373. BMC Plant Biology

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“Mechanical stimulations play a significant role in the day to day existence of plants. plants exhibit varied responses depending on the nature and intensity of these stimuli. in this review, we present recent literature on the responses of plants to mechanical stimuli, focusing primarily on those exerted during plant-microbe interactions. we discuss how microbes are able to apply mechanical stimuli on plants and how some plant responses to pathogenic and symbiotic microbes present striking similarities with responses to mechanical stimuli applied, for instance, using micro-needles. we hypothesize that appropriate responses of plants to pathogenic and symbiotic microbes may require a tight integration of both chemical and mechanical stimulations exerted by these microbes. © 2014 elsevier ltd.”

Trada, H., Walsh, K., Isham, A., & Cambron, S.. (2007). Out-of-plane micro-needle arrays using silicon micromachining. In Conference Proceedings - IEEE SOUTHEASTCON
Plain numerical DOI: 10.1109/SECON.2007.342933
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“An array of out-of-plane silicon processed micro-needles has been successfully fabricated using relatively simple fabrication techniques. this abstract describes the methods explored to produce 100-element needle arrays (10×10) on a single die. applications of the micro-needles include transdermal drug delivery and tissue delivery (during surgery). two types of needles were fabricated: solid electrode and hollow through-hole. the solid-core micro-needles can be used for painless perforation of the skin layer to increase absorption of drugs through patches. these types are fabricated using only oxidation, dicing and isotropic etching. the hollow versions have more applications for direct delivery of drugs through the skin and require additional steps of lithography and deep reactive ion etch (drie). in both cases, the fabrication process starts with thermal oxidation of a 〈100〉 orientation, p-type, 500ums thick silicon wafer. wet oxidation of the wafer at 1000°c yields an oxide layer of ∼ 0.5μms thickness. the wafer is then diced with a diamond blade along the x and y directions. the cuts are spaced 250μms apart and approximately 350-400μms deep. this results in square pillar-like structures which are 250μms in size (on a side) and 350-400 μms tall. the cuts are made to yield an array of 100 (10×10) pillars following which, another series of cuts is made to separate the arrays into individual die samples each containing 100 elements. to obtain the hollow needle structures, a drie step is required to create holes in the wafer. this etch step is performed prior to dicing the wafer. the wafer is spin-coated with microchem corporation’s negative photoresist su-8 50. this epoxy-based resist gives a layer thickness of about 100 μms, which is essential to protect the silicon during this etch. the wafer is patterned using a photomask of arrays of 50μm hole openings. the relatively small lumen size of 50μms and the etch depth of 500μms requires a 10-12 hour etch which necessitates the thick protective layer. after the holes are etched, the pillars are cut around the holes such that the hole openings are centered in the x direction and 10μms off-centered in the y direction. this yields a micro-needle with an off-centered lumen opening. the off-centered opening prevents blockage of the passage during delivery. we explored both wet chemical and dry gas etching approaches to isotropically etch the standing pillars. the wet etch involves the use of a mixture of 5% hyd…”

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Dr. Robert W. Malone: Massenpsychose

Robert Wallace Malone ist ein US-amerikanischer Virologe, Immunologe und Molekularbiologe. Er ist Ko-Autor von Pionierstudien zur Entwicklung der Lipofektion mit mRNA, einer wesentlichen Technik bei späteren RNA-Impfstoffen.

Zitat Wikipeadia: "Seit der Covid-19-Pandemie 2020 verbreitet er Falschinformationen über die Sicherheit und Wirksamkeit von SARS-CoV-2-Impfstoffen."
https://de.wikipedia.org/wiki/Robert_W._Malone
Eine Massenpsychose ist definiert als eine Epidemie von Wahnsinn, die auftritt, wenn ein großer Teil der Gesellschaft den Bezug zur Realität verliert und in Wahnvorstellungen versinkt.

MASSENBILDUNGSPSYCHOSE
oder... Massenhypnose - der Wahnsinn der Menschenmassen

Robert W. Malone MD, MS

Wie viele von Ihnen wissen, habe ich viel Zeit damit verbracht, über die Theorie der Massenpsychose zu forschen und zu sprechen. Das meiste von dem, was ich gelernt habe, stammt von Dr. Mattias Desmet, der erkannte, dass diese Form der Massenhypnose, der Wahnsinn der Massen, das seltsame Phänomen erklären kann, dass etwa 20-30% der Bevölkerung in der westlichen Welt von den edlen Lügen und der vorherrschenden Erzählung über die Sicherheit und Wirksamkeit der genetischen Impfstoffe, die von Politikern, Wissenschaftsbürokraten, Pharmafirmen und den alten Medien propagiert und durchgesetzt werden, hingerissen sind.

Was man bei der Massenhypnose beobachten kann, ist, dass ein großer Teil der Bevölkerung völlig unfähig ist, neue wissenschaftliche Daten und Fakten zu verarbeiten, die zeigen, dass sie über die Wirksamkeit und die nachteiligen Auswirkungen der obligatorischen Maskenverwendung, der Aussperrungen und der genetischen Impfstoffe, die den Körper der Menschen dazu bringen, große Mengen an biologisch aktivem Coronavirus-Spike-Protein herzustellen, getäuscht wurden.

Diejenigen, die durch diesen Prozess hypnotisiert wurden, sind nicht in der Lage, die Lügen und Falschdarstellungen zu erkennen, mit denen sie täglich bombardiert werden, und greifen aktiv jeden an, der die Frechheit besitzt, ihnen Informationen mitzuteilen, die der Propaganda widersprechen, die sie übernommen haben. Und für diejenigen, deren Familien und soziale Netze durch diesen Prozess auseinandergerissen wurden und die feststellen, dass enge Verwandte und Freunde sie gegeistert haben, weil sie die offiziell bestätigte "Wahrheit" in Frage stellen und tatsächlich der wissenschaftlichen Literatur folgen, kann dies eine Quelle tiefer Ängste, Sorgen und psychologischer Schmerzen sein.

Mit diesen Seelen im Hinterkopf habe ich während eines Vortrags, den ich kürzlich in Tampa, Florida, vor etwa 2.000 Zuhörern gehalten habe, auch die Massenbildungstheorie von Dr. Mattias Desmet diskutiert. Als ich in das Publikum blickte und sprach, konnte ich auf vielen Gesichtern Erleichterung sehen, und sogar Tränen liefen aus den Augen stoischer Männer.

Ohne dass ich es wusste, nahm jemand die Rede auf und fügte die Gesangsspur zu einer Reihe beruhigender Bilder von Naturlandschaften hinzu, woraus ein Video entstand, das sich weltweit verbreitet hat. Im Folgenden finden Sie einen Link zu dem Video sowie einige Anmerkungen, die den Vortrag verdeutlichen und ergänzen. Viele haben mir gesagt, dass sie es als sehr heilsam empfinden. Ich hoffe, es kann auch Ihnen helfen.

Ein kurzer Überblick über Mass Formation, die von Dr. Mattias Desmet entwickelt wurde. Er ist Psychologe und Statistiker. Er ist an der Universität von Gent in Belgien tätig. Ich glaube, Dr. Mattias ist dem, was passiert, auf der Spur, und er nennt dieses Phänomen:

MASSENBILDUNGSPSYCHOSE

Wenn er also von "Massenbildung" spricht, kann man sich dies als Äquivalent zur "Massenbildung" vorstellen. Man kann sich das vorstellen als:

MASSENPSYCHOSE

Zu den Bedingungen für die Entstehung einer Massenbildungspsychose gehören ein Mangel an sozialer Verbundenheit und Sinnstiftung sowie große Mengen latenter Angst und passiver Aggression. Wenn Menschen mit einer Erzählung überschwemmt werden, die ein plausibles "Angstobjekt" und eine Strategie zu dessen Bewältigung präsentiert, schließen sich viele Menschen zusammen, um das Objekt mit kollektiver Zielstrebigkeit zu bekämpfen. Auf diese Weise können die Menschen aufhören, sich auf ihre eigenen Probleme zu konzentrieren, und vermeiden persönliche seelische Ängste. Stattdessen konzentrieren sie all ihre Gedanken und Energie auf dieses neue Objekt.

Mit fortschreitender Massenbildung wird die Gruppe immer enger zusammengeschweißt und verbunden. Ihr Aufmerksamkeitsfeld wird eingeengt, und sie werden unfähig, alternative Standpunkte in Betracht zu ziehen. Die Anführer der Bewegung werden verehrt und können nichts falsch machen.

Eine Gesellschaft, die unter dem Bann der Massenbildung steht, wird eine totalitäre Regierungsstruktur unterstützen, die zu sonst unvorstellbaren Grausamkeiten fähig ist, um die Konformität aufrechtzuerhalten. Ein Hinweis: Massenbildung ist etwas anderes als Gruppendenken. Das Gruppendenken lässt sich leicht beheben, indem man einfach abweichende Stimmen einbringt und ihnen eine Plattform bietet. Bei der Massenbildung ist das nicht so einfach. Selbst wenn das Narrativ auseinanderfällt, wenn Risse in der Strategie das Problem nicht lösen, kann sich die hypnotisierte Menge nicht von dem Narrativ lösen. Genau das scheint jetzt mit COVID-19 zu geschehen. Die Lösung für diejenigen, die das Narrativ kontrollieren, besteht darin, immer größere Lügen zu produzieren, um die Lösung zu stützen. Diejenigen, die von der Massenbildung kontrolliert werden, sind nicht mehr in der Lage, die Vernunft zu gebrauchen, um sich von der Gruppenerzählung zu befreien.

Das offensichtliche Beispiel für Massenbildung ist natürlich Deutschland in den 1930er und 40er Jahren. Wie konnten die Deutschen, die hochgebildet und im klassischen Sinne sehr liberal waren, westlich denkende Menschen, wie konnten sie so verrückt werden und den Juden das antun? Wie konnte das geschehen?
Einem zivilisierten Volk? Ein Anführer einer Massenbildungsbewegung wird die Plattform nutzen, um die Gruppe weiterhin mit neuen Informationen zu versorgen, auf die sie sich konzentrieren kann. Im Fall von COVID-19 verwende ich gerne den Begriff "Angstporno". Die Anführer füttern die "Bestie" über die Mainstream-Medien und die Regierungskanäle kontinuierlich mit weiteren Botschaften, die ihre Anhänger fokussieren und weiter hypnotisieren.

Studien legen nahe, dass die Massenbildung einer allgemeinen Verteilung folgt:

30 % werden durch das Gruppennarrativ einer Gehirnwäsche unterzogen, hypnotisiert und indoktriniert.

40 % in der Mitte sind überredbar und können sich anschließen, wenn keine würdige Alternative gesehen wird.

30% kämpfen gegen das Narrativ.

Diejenigen, die rebellieren und gegen das Narrativ ankämpfen, werden zum Feind der Gehirngewaschenen und zum primären Ziel von Aggressionen.

Eine der besten Möglichkeiten, der Massenbildung entgegenzuwirken, besteht darin, dass diejenigen, die sich gegen das Narrativ auflehnen, sich weiterhin dagegen aussprechen, was dazu beiträgt, die Hypnose einiger Mitglieder der gehirngewaschenen Gruppe zu durchbrechen und die überzeugbare Mitte davon zu überzeugen, die Vernunft der Gedankenlosigkeit vorzuziehen.

Dr. Desmet ist der Meinung, dass bei einem so großen Ereignis wie COVID-19 die einzige Möglichkeit, die Psychose der Massenbildung zu durchbrechen, darin besteht, der Menge etwas Größeres zu geben, auf das sie sich konzentrieren kann. Er glaubt, dass der Totalitarismus dieses größere Thema sein könnte. Natürlich könnte nach COVID-19 der globale Totalitarismus das größte Problem unserer Zeit sein.

Original: https://rwmalonemd.substack.com/p/mass-formation-psychosis

https://www.youtube.com/watch?v=EWWvk2SaMS4

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Prof. Dr. Arne Burkhardt

Im pathologischen Institut in Reutlingen werden am Montag, den 20.09.2021, die Ergebnisse der Obduktionen von acht nach COVID19-Impfung Verstorbenen vorgestellt. Die feingeweblichen Analysen wurden von den Pathologen Prof. Dr. Arne Burkhardt und Prof. Dr. Walter Lang durchgeführt. Die Erkenntnisse bestätigen die Feststellung von Prof. Dr. Peter Schirmacher, dass bei mehr als 40 von ihm obduzierten Leichnamen, die binnen zwei Wochen nach der CVID-19-Impfung gestorben sind, circa ein Drittel kausal an der Impfung verstorben sind. Im Rahmen der live gestreamten Pressekonferenz werden mikroskopische Details der Gewebeveränderungen gezeigt. Prof. Dr. Werner Bergholz berichtet über die aktuellen Parameter der statistischen Erfassung des Impfgeschehens.
Auf der Pressekonferenz wird zudem das Ergebnis der Analyse von COVID-19-Impfstoffproben einer österreichische Forschergruppe vorgestellt, das sich mit den Erkenntnissen von Wissenschaftlern aus Japan und den USA deckt. Es haben sich im Impfstoff undeklarierte metallhaltige Bestandteile feststellen lassen. Optisch fallen Impfstoffelemente durch ihre ungewöhnliche Form auf.
Aus den Untersuchungsergebnissen resultieren rechtliche und politische Forderungen so zum Beispiel nach unverzüglicher Informationssammlung durch die Behörden, um die gesundheitliche Gefährdungslage der Bevölkerung durch die COVID-109-Impfstoffe bewerten zu können. Z.B. können durch Einsichtnahme in die IVF-Register frühe Signale eingeschränkter Fruchtbarkeit der Geimpften geprüft werden. Über das Krebsregister können Erkenntnisse über das Entstehen von Krebs durch die gentechnischen Veränderungen der Virus-RNA gewonnen werden. Eine Aussetzung der COVID-19-Impfungen ist zu erwägen.

Prof. Dr. Arne Burkhardt

Prof. Dr. Arne Burkhardt blickt auf langjährige Lehrtätigkeit an den Universitäten Hamburg, Bern und Tübingen zurück sowie auf Gastprofessuren/Studienaufenthalte in Japan (Nihon Universität), USA (Brookhaven National Institut), Korea, Schweden, Malaysia und der Türkei. Er hat 18 Jahre lang das Pathologische Institut in Reutlingen geleitet, war danach als niedergelassener Pathologe tätig. Prof. Burkhardt hat über 150 Artikel in Fachzeitschriften und als Beiträge in Handbüchern veröffentlicht. Er hat zudem pathologische Institute zertifiziert.

Prof. Dr. Walter Lang

Prof. Dr. Walter Lang hat 27 Jahre ein vom gegründetes Privatinstitut für Pathologie mit den Schwerpunkten Transplantationspathologie, extragynäkologische Cytologie, Schilddrüsentumore, Lungen/Pleurapathologie geleitet. Er führte Konsultations-Diagnostik für 12 große Lungen-Kliniken und erbrachte Leberpathologie-Leistungen für zahlreiche Kliniken. Im Zeitraum 2010-2020 betreute er die Pathologie der Lungenklinik in Herner.

Prof. Dr. Werner Bergholz

Prof. Dr. Werner Bergholz ist ehemaliger Professor für Elektrotechnik mit Schwerpunkt Qualitäts- und Risikomanagement an der Jakobs-University Bremen. Vor seiner Berufung war Prof. Bergholz 17 Jahre im Management der Chip-Produktion bei der Firma Siemens tätig.

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Dr. Carrie Madej

https://www.bitchute.com/video/qKNJa2Zvu7c8/

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Kybernetische Kriesenoptimierung

Die Etymologie der Kybernetik
Im Altgriechischen heißt das Wort für "lenken" "kybernan", was wiederum die Wurzel des Begriffs "Kybernetik" bildet, der 1948 von dem US-Mathematiker Norbert Wiener geprägt wurde. Die Konstruktion basiert möglicherweise auf der französischen cybernétique aus den 1830er Jahren, der "Kunst des Regierens". Im akademischen Kontext ist Kybernetik die Theorie oder das Studium der Kommunikation und Steuerung. Im Allgemeinen ist die Kybernetik ein transdisziplinärer Ansatz zur Erforschung von Regelungssystemen - ihren Strukturen, Beschränkungen und Möglichkeiten.

Der lateinische Begriff "gubernare" (lenken, regieren, leiten, lenken, regieren) hat dieselbe etymologische Wurzel. Das Wort 'governor' und 'goverment' sind beide verwandt.

Norbert Wiener
Wiener gilt als Begründer der Kybernetik, einer Formalisierung des Begriffs der Rückkopplung mit Auswirkungen auf Technik, Systemsteuerung, Informatik, Biologie, Neurowissenschaften, Philosophie und die Organisation der Gesellschaft.

Norbert Wiener gilt als einer der ersten, der die Theorie aufstellte, dass alles intelligente Verhalten das Ergebnis von Rückkopplungsmechanismen ist, die möglicherweise von Maschinen simuliert werden können, und war ein wichtiger früher Schritt zur Entwicklung der modernen künstlichen Intelligenz.

https://youtu.be/_nAn-QH6syM

https://youtu.be/wx26zpPg884

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Luciferase in der Neurowissenschaft

https://www.youtube.com/watch?v=UJ4AN_4gPdM

Trimmer, C., Snyder, L. L., & Mainland, J. D.. (2014). High-throughput analysis of mammalian olfactory receptors: Measurement of receptor activation via luciferase activity. Journal of Visualized Experiments
Plain numerical DOI: 10.3791/51640
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“Odorants create unique and overlapping patterns of olfactory receptor activation, allowing a family of approximately 1, 000 murine and 400 human receptors to recognize thousands of odorants. odorant ligands have been published for fewer than 6% of human receptors1-11. this lack of data is due in part to difficulties functionally expressing these receptors in heterologous systems. here, we describe a method for expressing the majority of the olfactory receptor family in hana3a cells, followed by high-throughput assessment of olfactory receptor activation using a luciferase reporter assay. this assay can be used to (1) screen panels of odorants against panels of olfactory receptors; (2) confirm odorant/receptor interaction via dose response curves; and (3) compare receptor activation levels among receptor variants. in our sample data, 328 olfactory receptors were screened against 26 odorants. odorant/receptor pairs with varying response scores were selected and tested in dose response. these data indicate that a screen is an effective method to enrich for odorant/receptor pairs that will pass a dose response experiment, i.e. receptors that have a bona fide response to an odorant. therefore, this high-throughput luciferase assay is an effective method to characterize olfactory receptors-an essential step toward a model of odor coding in the mammalian olfactory system.”

Crespo, E. L., Bjorefeldt, A., Prakash, M., & Hochgeschwender, U.. (2021). Bioluminescent Optogenetics 2.0: Harnessing Bioluminescence to Activate Photosensory Proteins In Vitro and In Vivo. Journal of Visualized Experiments
Plain numerical DOI: 10.3791/62850
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“Bioluminescence - light emitted by a luciferase enzyme oxidizing a small molecule substrate, a luciferin - has been used in vitro and in vivo to activate light-gated ion channels and pumps in neurons. while this bioluminescent optogenetics (bl-og) approach confers a chemogenetic component to optogenetic tools, it is not limited to use in neuroscience. rather, bioluminescence can be harnessed to activate any photosensory protein, thus enabling the manipulation of a multitude of light-mediated functions in cells. a variety of luciferase-luciferin pairs can be matched with photosensory proteins requiring different wavelengths of light and light intensities. depending on the specific application, efficient light delivery can be achieved by using luciferase-photoreceptor fusion proteins or by simple co-transfection. photosensory proteins based on light-dependent dimerization or conformational changes can be driven by bioluminescence to effect cellular processes from protein localization, regulation of intracellular signaling pathways to transcription. the protocol below details the experimental execution of bioluminescence activation in cells and organisms and describes the results using bioluminescence-driven recombinases and transcription factors. the protocol provides investigators with the basic procedures for carrying out bioluminescent optogenetics in vitro and in vivo. the described approaches can be further extended and individualized to a multitude of different experimental paradigms.”

Srinivasan, P., Griffin, N. M., Joshi, P., Thakur, D., Nguyen-Le, A., McCotter, S., … Theogarajan, L.. (2019). An Autonomous Molecular Bioluminescent Reporter (AMBER) for voltage imaging in freely moving animals. BioRxiv
Plain numerical DOI: 10.1101/845198
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“Genetically encoded reporters have greatly increased our understanding of biology, especially in neuroscience. while fluorescent reporters have been widely used, light delivery and phototoxicity have hindered their utility. bioluminescence overcomes some of these challenges but requires the addition of an exogenous luciferin limiting its use. using a modular approach we have engineered autonomous molecular bioluminescent reporter (amber), an indicator of membrane potential. unlike other luciferase-luciferin bioluminescent systems amber encodes the genes to express both the luciferase and luciferin. amber is a voltage-gated luciferase coupling the functionalities of the ciona voltage sensing domain (vsd) and bacterial luciferase, luxab. when amber is co-expressed with the luciferin producing genes it reversibly switches the bioluminescent intensity as a function of membrane potential. utilizing both biophysical and biochemical methods we show that unlike other voltage indicators amber modulates its enzymatic activity as a function of the membrane potential. amber shows a several fold increase in the luminescent (δl/l) output upon switching from off to on state when the cell is depolarized. in vivo expression of amber in c. elegans allowed detecting pharyngeal pumping action and mechanosensory neural activity from multiple worms simultaneously. since we are able to report neural activity of multiple animals at the same time, we believe amber can be used in social behavior assays to elucidate the role of membrane potential underlying the behaviors.”

Carullo, N. V. N., Hinds, J. E., Revanna, J. S., Tuscher, J. J., Bauman, A. J., & Day, J. J.. (2021). A cre-dependent crispr/dcas9 system for gene expression regulation in neurons. ENeuro
Plain numerical DOI: 10.1523/ENEURO.0188-21.2021
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“Site-specific genetic and epigenetic targeting of distinct cell populations is a central goal in molecular neuroscience and is crucial to understand the gene regulatory mechanisms that underlie complex phenotypes and behaviors. while recent technological advances have enabled unprecedented control over gene expression, many of these approaches are focused on selected model organisms and/or require labor-intensive customization for different applications. the simplicity and modularity of clustered regularly interspaced short palindromic repeats (crispr)-based systems have transformed genome editing and expanded the gene regulatory toolbox. however, there are few available tools for cell-selective crispr regulation in neurons. we designed, validated, and optimized crispr activation (crispra) and crispr interference (crispri) systems for cre recombinase-dependent gene regulation. unexpectedly, crispra systems based on a traditional double-floxed inverted open reading frame (dio) strategy exhibited leaky target gene induction even without cre. therefore, we developed an intron-containing cre-dependent crispra system (svi-dio-dcas9-vpr) that alleviated leaky gene induction and outperformed the traditional dio system at endogenous genes in hek293t cells and rat primary neuron cultures. using gene-specific crispr sgrnas, we demonstrate that svi-dio-dcas9-vpr can activate numerous rat or human genes (grm2, tent5b, fos, sstr2, andgadd45b) in a cre-specific manner. to illustrate the versatility of this tool, we created a parallel crispri construct that successfully inhibited expression from a luciferase reporter in hek293t cells only in the presence of cre. these results provide a robust framework for cre-dependent crispr-dcas9 approaches across different model systems, and enable cell-specific targeting when combined with common cre driver lines or cre delivery via viral vectors.”

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Hydrogel in der Neurowissenschaft

https://www.youtube.com/watch?v=cL3e8tC8TwE

Eigel, D., Werner, C., & Newland, B.. (2021). Cryogel biomaterials for neuroscience applications. Neurochemistry International
Plain numerical DOI: 10.1016/j.neuint.2021.105012
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“Biomaterials in the form of 3d polymeric scaffolds have been used to create structurally and functionally biomimetic constructs of nervous system tissue. such constructs can be used to model defects and disease or can be used to supplement neuronal tissue regeneration and repair. one such group of biomaterial scaffolds are hydrogels, which have been widely investigated for cell/tissue culture and as cell or molecule delivery systems in the field of neurosciences. however, a subset of hydrogels called cryogels, have shown to possess several distinct structural advantages over conventional hydrogel networks. their macroporous structure, created via the time and resource efficient fabrication process (cryogelation) not only allows mass fluid transport throughout the structure, but also creates a high surface area to volume ratio for cell growth or drug loading. in addition, the macroporous structure of cryogels is ideal for applications in the central nervous system as they are very soft and spongey, yet also robust, which makes them a user-friendly and reproducible tool to address neuroscience challenges. in this review, we aim to provide the neuroscience community, who may not be familiar with the fundamental concepts of cryogels, an accessible summary of the basic information that pertain to their use in the brain and nervous tissue. we hope that this review shall initiate creative ways that cryogels could be further adapted and employed to tackle unsolved neuroscience challenges.”

Aurand, E. R., Lampe, K. J., & Bjugstad, K. B.. (2012). Defining and designing polymers and hydrogels for neural tissue engineering. Neuroscience Research
Plain numerical DOI: 10.1016/j.neures.2011.12.005
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“The use of biomaterials, such as hydrogels, as neural cell delivery devices is becoming more common in areas of research such as stroke, traumatic brain injury, and spinal cord injury. when reviewing the available research there is some ambiguity in the type of materials used and results are often at odds. this review aims to provide the neuroscience community who may not be familiar with fundamental concepts of hydrogel construction, with basic information that would pertain to neural tissue applications, and to describe the use of hydrogels as cell and drug delivery devices. we will illustrate some of the many tunable properties of hydrogels and the importance of these properties in obtaining reliable and consistent results. it is our hope that this review promotes creative ideas for ways that hydrogels could be adapted and employed for the treatment of a broad range of neurological disorders. © 2011 elsevier ireland ltd and the japan neuroscience society.”

Wu, X., He, L., Li, W., Li, H., Wong, W. M., Ramakrishna, S., & Wu, W.. (2017). Functional self-assembling peptide nanofiber hydrogel for peripheral nerve regeneration. Regenerative Biomaterials
Plain numerical DOI: 10.1093/rb/rbw034
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“Peripheral nerves are fragile and easily damaged, usually resulting in nervous tissue loss, motor and sensory function loss. advances in neuroscience and engineering have been significantly contributing to bridge the damage nerve and create permissive environment for axonal regrowth across lesions. we have successfully designed two self-assembling peptides by modifying rada 16-i with two functional motifs ikvav and rgd. nanofiber hydrogel formed when combing the two neutral solutions together, defined as rada 16-mix that overcomes the main drawback of rada16-i associated with low ph. in the present study, we transplanted the rada 16-mix hydrogel into the transected rat sciatic nerve gap and effect on axonal regeneration was examined and compared with the traditional rada16-i hydrogel. the regenerated nerves were found to grow along the walls of the large cavities formed in the graft of rada16-i hydrogel, while the nerves grew into the rada 16-mix hydrogel toward distal position. rada 16-mix hydrogel induced more axons regeneration and schwann cells immigration than rada16-i hydrogel, resulting in better functional recovery as determined by the gait-stance duration percentage and the formation of new neuromuscular junction structures. therefore, our results indicated that the functional sap rada16-mix nanofibrous hydrogel provided a better environment for peripheral nerve regeneration than rada16-i hydrogel and could be potentially used in peripheral nerve injury repair.”

Sunwoo, S. H., Han, S. I., Joo, H., Cha, G. D., Kim, D., Choi, S. H., … Kim, D. H.. (2020). Advances in Soft Bioelectronics for Brain Research and Clinical Neuroengineering. Matter
Plain numerical DOI: 10.1016/j.matt.2020.10.020
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“Recent advances in bioelectronics, such as skin-mounted electroencephalography sensors, multi-channel neural probes, and closed-loop deep brain stimulators, have enabled electrophysiological brain activities to be both monitored and modulated. despite this remarkable progress, major challenges remain, which stem from the inherent mechanical, chemical, and electrical differences that exist between brain tissues and bioelectronics. new approaches are therefore required to address these mismatches between biotic and abiotic systems. here, we review recent technological advances that minimize such mismatches by using unconventional soft materials, such as silicon/metal nanowires, functionalized hydrogels, and stretchable conductive nanocomposites, as well as customized fabrication processes and novel device designs. the resulting novel, soft bioelectronic devices provide new opportunities for brain research and clinical neuroengineering. advances in bioelectronics for neuroscience and neuroengineering have enabled continuous monitoring of electrophysiological signals and feedback modulation of abnormal brain activities. despite such progress, there remain issues in terms of long-term high-quality neural interfacing, mainly owing to inherent mechanical, chemical, and electrical mismatches between the device and the brain tissue. new approaches, therefore, are required to address these discrepancies between the biotic and abiotic system. this review introduces technological advances that potentially solve such issues by using soft materials and devices. specifically, we summarize recent progress in soft materials, such as nanoscale materials, conductive polymers, functionalized hydrogels, and stretchable conductive nanocomposites. these unconventional materials, combined with customized processing techniques and device designs, provide novel soft device solutions for brain science and clinical neuroengineering. techniques for recording and modulating neural activities are essential for brain science and clinical neuroengineering. this review introduces recent progress on unconventional soft materials and their processing techniques for the fabrication of soft bioelectronic devices. such approaches could reduce the inherence discrepancies, including mechanical, chemical, and electrical mismatches, between the bioelectronic device and the brain tissue. as a result, the soft bioelectronic devices have successfully enabled high-quality neural interfacing in vivo …”

Liu, S., Zhao, Y., Hao, W., Zhang, X. D., & Ming, D.. (2020). Micro- and nanotechnology for neural electrode-tissue interfaces. Biosensors and Bioelectronics
Plain numerical DOI: 10.1016/j.bios.2020.112645
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“Implantable neural electrodes can record and regulate neural activities with high spatial resolution of single-neuron and high time resolution of sub-millisecond, which are the most extensive window in neuroscience research. however, the mechanical mismatch between conventional stiff electrodes and soft neural tissue can lead to inflammatory responses and degradation of signals in chronic recordings. although remarkable breakthroughs have been made in sensing and regulation of neural signals, the long-term stability and chronic inflammatory response of the neural electrode-tissue interfaces still needs further development. in this review, we focus on the latest developments for the optimization of neural electrode-tissue interfaces, including electrode materials (graphene fiber-based and cnt fiber-based), electrode structures (flexible electrodes), nano-coatings and hydrogel-based neural interfaces. the parameters of impedance, charge injection limit, signal-to-noise ratio and neuron lost zone are used to evaluate the electrochemical performance of the devices, the recording performance of biosignals and the stability of the neural interfaces, respectively. these optimization methods can effectively improve the long-term stability and the chronic inflammatory response of neural interfaces during the recording and modulation of biosignals.”

Millet, L. J., & Gillette, M. U.. (2012). Over a century of neuron culture: From the hanging drop to microfluidic devices. Yale Journal of Biology and Medicine

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“The brain is the most intricate, energetically active, and plastic organ in the body. these features extend to its cellular elements, the neurons and glia. understanding neurons, or nerve cells, at the cellular and molecular levels is the cornerstone of modern neuroscience. the complexities of neuron structure and function require unusual methods of culture to determine how aberrations in or between cells give rise to brain dysfunction and disease. here we review the methods that have emerged over the past century for culturing neurons in vitro, from the landmark finding by harrison (1910) - that neurons can be cultured outside the body - to studies utilizing culture vessels, micro-islands, campenot and brain slice chambers, and microfluidic technologies. we conclude with future prospects for neuronal culture and considerations for advancement. we anticipate that continued innovation in culture methods will enhance design capabilities for temporal control of media and reagents (chemotemporal control) within sub-cellular environments of three-dimensional fluidic spaces (microfluidic devices) and materials (e.g., hydrogels). they will enable new insights into the complexities of neuronal development and pathology. © 2012.”

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Zuckerberg über Zensur

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Genetische Manipulation und Patentrecht: Eine extrem wichtige Frage!

https://www.youtube.com/watch?v=QHIocNOHd7A

https://www.youtube.com/watch?v=QC6HFEIgvDM

Als Craig Venter et al. den ersten synthetischen Organismus erschufen kodierten Sie Ihre Namen und weitere Informationen in den DNA Kode um den Nachweis zweifelohne führen zu können das Sie der Erschaffer dieses Genkomplexes sind.

https://www.spiegel.de/wissenschaft/natur/erster-kuenstlicher-organismus-sie-sollen-tun-was-wir-wollen-a-696057.html

Genetisch Manipulierte Organismen (GMOs) können patentiert werden - nicht-GMOs können nicht patentiert werden. Die extrem wichtige Frage ist: Wem gehören die veränderten Gensequenzen die den Menschen momentan unter falscehm Vorwand der "Impfung" injeziert werden? Wie seiht das Ganze patentrechtlich aus?
--

Jiang, L.. (2020). Commercialization of the gene-edited crop and morality: challenges from the liberal patent law and the strict GMO law in the EU. New Genetics and Society
Plain numerical DOI: 10.1080/14636778.2019.1686968
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“The eu aspires to utilize the economic advantages of gene-editing technology on one hand and ensure human health and environmental safety on the other. surrounding the fierce debates over emerging gene-edited plant, the current debate focused on the issue of whether the gene-edited crop should be within or outside the gmo law and its implication for innovation. it should not be forgotten that it is also involved in the complex patentability issues pertaining to the legal interpretation of the patent law. the gene-edited crop is governed by gmo regulations due to its potential risk to human health and environmental safety. but it is heavily patented, as patent regulations ignore its potential risk. this article examines the discrepancy of the gene-edited crop between the existing gmo law and the patent law and reveals the challenges to current eu jurisdiction, including the international trade impediment challenge, the patent monopoly challenge, the market confusion challenge, and the agricultural economy suspension challenge. in the end, this article argues that eu gmo regulations should be bridged with a patent system in facing the regulatory challenges from the gene-edited crop.”

Medvedieva, M. O., & Blume, Y. B.. (2018). Legal Regulation of Plant Genome Editing with the CRISPR/Cas9 Technology as an Example. Cytology and Genetics
Plain numerical DOI: 10.3103/S0095452718030106
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“The product-oriented and the process-oriented legal approaches to the regulation of genome editing technologies, crispr/cas9 in particular, are considered. the relevant legislation of the united states and the european union and some international treaties are analyzed. the issue of genome editing that is within the scope of gmo legislation and general legislation on risk assessment and regulation is addressed. the issue of patenting of gene editing technologies in the legislation of the united states and the european union and under international law is considered. ‘patent wars’ between research teams that developed the crispr/cas9 technology are described. the possibilities of obtaining patent protection for plants produced by genome editing are considered.”

Crespi, R. S.. (2000). An Analysis of Moral Issues Affecting Patenting Inventions in the Life Sciences: A European Perspective. Science and Engineering Ethics
Plain numerical DOI: 10.1007/s11948-000-0045-8
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“Following the 1980 us supreme court decision to allow a patent on a living organism, debate has continued on the moral issues involved in biotechnology patents of many kinds and remains a contentious issue for those opposed to the use of biotechnology in industry and agriculture. attitudes to patenting in the life sciences, including those of the research scientists themselves, are analysed. the relevance of morality to patent law is discussed here in an international context with particular reference to the law of the european patent convention administered by the european patent office (epo). the epo has been the principal forum for opposition to such patents and the few cases under dispute in the epo are reviewed, including patents for the onco-mouse, human relaxin gene, and the pgs herbicidally resistant plant (gmo). morality provisions in the european parliament and council directive 98/44/ec are also summarised.”

Carpenter, C.. (2010). Seeds of Doubt: The European Court of Justice’s Decision in Monsanto v. Cefetra and the Effect on European Biotechnology Patent Law. International Lawyer

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“Monsanto technology llc v. cefetra bv" was the first european court of justice (ecj) interpretation of the twelve-year-old european union biotechnology directive (directive 98/44/eg), which established the foundation for patenting genetic material in member countries. 2 the ecj’s decision effectively limited the scope of the directive, and conse- quently, european biotechnology patent protection by determining that genetic patents are only effective when the patented gene ‘perform[s] the function for which it is pat- ented[.]’ 3 the first part of this paper will discuss the history of the parties in dispute and the industry that is becoming familiar to this kind of dispute. the second and third parts will focus on the specific case that is the focus of this paper, and the final portion will analyze the effect this case had and will continue to have on patent law, particularly in the european union and argentina.”

Zimny, T.. (2015). Recent changes to EU law on GMOs and their potential influence on the patentability of GM plants. Some remarks on possible side effects of directive 2015/412/EU. Biotechnologia
Plain numerical DOI: 10.5114/bta.2015.54185
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“In this article i present recent changes in eu legislation on the cultivation of gm plants and i attempt to answer the question as to whether the new laws continue to follow the precautionary principle approach and the case by case approach that characterized the european union’s gmo legislation until recently. also, given the nature of the newly introduced grounds for restricting the cultivation of gmos, i try to find out if the new legislation could influence the patentability of transgenic plants or methods of their production. while growing in popularity around the world, transgenic plants face strong opposition within the european union. recent changes to eu legislation governing the cultivation of gm plants are just another example of the said opposition. directive (eu) 2015/412 of the european parliament and of the council amending directive 2001/18/ec provided member states with means to restrict or effectively prohibit cultivation of genetically engineered plants in their territories, even if such plants have already been authorized for cultivation in the eu. the reasons countries can currently invoke in order to introduce limitations are no longer restricted to bio-safety, but rather encompass a set of political and social issues such as socioeconomic impacts, avoidance of gmo presence in other products, agricultural policy objectives, public policy etc. they are to a much lesser extent (than up till now) based on the precautionary principle, as possible restrictions will also concern already examined and authorized gmos. restrictions no longer need to target particular transformation events, they can now encompass certain traits or crops. when it comes to the patentability of gm plants or methods of their production, the recent changes seem to have limited influence, given the european patent office’s stance on the application of morality and ‘ordre public’ exclusions and its relative independence from eu law. the possibility cannot be excluded that local laws adopted on the basis of the newly introduced changes could influence procedures before local patent office, should those offices decide to apply the morality or ‘ordre public’ exception to patentability. the newly adopted laws have a rather different effect, though. the profitability of developing gm plants in the eu (and their patenting) may become questionable, should the exploitation of such inventions be prohibited in several eu member states.”

Beslac, M., & Coric, G.. (2017). Financial and production aspects of genetically modified organisms. Ekonomika Poljoprivrede
Plain numerical DOI: 10.5937/ekopolj1704583b
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“The purpose and goal of this research is to familiarize the general community, especially agricultural producers with the problem of financing the cultivation and trade of gmo and the problems serbia is facing in the process of joining the eu. the paper uses an experimental method, the method of analysis, synthesis, induction and deduction, and presents the results which have been obtained by surveying 163 farmers from vojvodina. the main results of this study show that, if the law so regulates, most agricultural producers agree to produce gmos, but only if the conditions for the traditional production do not provide acceptable yield and income. the contribution of this paper is that it has shown that gmos are such organisms that would never have been created in nature and that they actually represent a patent for certain organizations. it has also shown that there is a need for informing and educating farmers in the field of gmos as well as the need for further research on this topic.”

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Speicherung von medizinischen Informationen unter der Hautoberfläche

McHugh, K. J., Jing, L., Severt, S. Y., Cruz, M., Sarmadi, M., Jayawardena, H. S. N., … Jaklenec, A.. (2019). Biocompatible near-infrared quantum dots delivered to the skin by microneedle patches record vaccination. Science Translational Medicine, 11(523)
Plain numerical DOI: 10.1126/scitranslmed.aay7162
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“Accurate medical recordkeeping is a major challenge in many low-resource settings where well-maintained centralized databases do not exist, contributing to 1.5 million vaccine-preventable deaths annually. here, we present an approach to encode medical history on a patient using the spatial distribution of biocompatible, near-infrared quantum dots (nir qds) in the dermis. qds are invisible to the naked eye yet detectable when exposed to nir light. qds with a copper indium selenide core and aluminum-doped zinc sulfide shell were tuned to emit in the nir spectrum by controlling stoichiometry and shelling time. the formulation showing the greatest resistance to photobleaching after simulated sunlight exposure (5-year equivalence) through pigmented human skin was encapsulated in microparticles for use in vivo. in parallel, microneedle geometry was optimized in silico and validated ex vivo using porcine and synthetic human skin. qd-containing microparticles were then embedded in dissolvable microneedles and administered to rats with or without a vaccine. longitudinal in vivo imaging using a smartphone adapted to detect nir light demonstrated that microneedle-delivered qd patterns remained bright and could be accurately identified using a machine learning algorithm 9 months after application. in addition, codelivery with inactivated poliovirus vaccine produced neutralizing antibody titers above the threshold considered protective. these findings suggest that intradermal qds can be used to reliably encode information and can be delivered with a vaccine, which may be particularly valuable in the developing world and open up new avenues for decentralized data storage and biosensing.”

Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532118/?report=reader

URL: https://news.mit.edu/2019/storing-vaccine-history-skin-1218

Auto translated:

Ein spezieller unsichtbarer Farbstoff, der zusammen mit einem Impfstoff verabreicht wird, könnte die Speicherung der Impfhistorie am Patienten ermöglichen und so Leben in Regionen retten, in denen weder Papier noch digitale Aufzeichnungen zur Verfügung stehen.
Anne Trafton | MIT-Nachrichtenbüro
Veröffentlicht am:
Dezember 18, 2019
Presseanfragen
Illustration eines Pflasters mit Mikronadeln, das auf die Haut aufgetragen wird.
Bildunterschrift:
Eine große Herausforderung für Impfkampagnen in einigen Entwicklungsregionen besteht darin, dass es nur wenig Infrastruktur für die Speicherung medizinischer Daten gibt, so dass es oft keine einfache Möglichkeit gibt, festzustellen, wer einen bestimmten Impfstoff oder eine Auffrischungsimpfung benötigt. MIT-Ingenieure haben eine Möglichkeit entwickelt, Informationen über den Impfstoffverlauf eines Patienten unter der Haut zu speichern. Dazu wird ein unsichtbarer Quantenpunkt-Farbstoff verwendet, der zusammen mit einem Impfstoff über ein Mikronadelpflaster verabreicht wird.
Credits:
Bild: Second Bay Studios

Anmerkung des Herausgebers: Dieser Artikel wurde aktualisiert, um klarzustellen, dass diese Forschung entwickelt wurde, um vermeidbare Todesfälle in Teilen der Welt zu verhindern, in denen es keine Papier- oder digitalen Systeme zur Speicherung der Impfdaten von Patienten gibt. Viele Impfstoffe erfordern mehrere Dosen in bestimmten Abständen; ohne genaue Aufzeichnungen erhalten die Menschen möglicherweise nicht alle erforderlichen Dosen. Die Methode befindet sich noch im Versuchsstadium und wird für keine der aktuellen Impfungen, einschließlich der Covid-19-Impfstoffe, verwendet.

Jedes Jahr führt ein Mangel an Impfungen zu etwa 1,5 Millionen vermeidbaren Todesfällen, vor allem in Entwicklungsländern. Ein Faktor, der Impfkampagnen in diesen Ländern erschwert, ist die geringe Infrastruktur für die Speicherung medizinischer Daten, so dass es oft keine einfache Möglichkeit gibt, festzustellen, wer einen bestimmten Impfstoff benötigt.

MIT-Forscher haben nun eine neue Methode entwickelt, um die Impfhistorie eines Patienten zu erfassen: Sie speichern die Daten in einem für das bloße Auge unsichtbaren Farbmuster, das gleichzeitig mit dem Impfstoff unter die Haut verabreicht wird.

"In Gebieten, in denen Impfausweise in Papierform oft verloren gehen oder gar nicht existieren und elektronische Datenbanken unbekannt sind, könnte diese Technologie eine schnelle und anonyme Erfassung der Impfhistorie von Patienten ermöglichen, um sicherzustellen, dass jedes Kind geimpft wird", sagt Kevin McHugh, ein ehemaliger Postdoc am MIT, der jetzt Assistenzprofessor für Bioengineering an der Rice University ist.

Die Forscher haben gezeigt, dass ihr neuer Farbstoff, der aus Nanokristallen, so genannten Quantenpunkten, besteht, mindestens fünf Jahre lang unter der Haut verbleiben kann, wo er Nahinfrarotlicht aussendet, das von einem speziell ausgerüsteten Smartphone erkannt werden kann.

McHugh und der ehemalige Gastwissenschaftler Lihong Jing sind die Hauptautoren der Studie, die heute in Science Translational Medicine erscheint. Ana Jaklenec, wissenschaftliche Mitarbeiterin am Koch Institute for Integrative Cancer Research des MIT, und Robert Langer, Professor am David H. Koch Institute des MIT, sind die Hauptautoren der Studie.

Ein unsichtbarer Rekord

Vor einigen Jahren machte sich das MIT-Team daran, eine Methode zur Aufzeichnung von Impfinformationen zu entwickeln, die keine zentrale Datenbank oder andere Infrastruktur erfordert. Viele Impfstoffe, wie z. B. der Impfstoff gegen Masern, Mumps und Röteln (MMR), erfordern mehrere Dosen, die in bestimmten Abständen verabreicht werden müssen; ohne genaue Aufzeichnungen erhalten Kinder möglicherweise nicht alle erforderlichen Dosen.

"Um gegen die meisten Krankheitserreger geschützt zu sein, braucht man mehrere Impfungen", sagt Jaklenec. "In einigen Gebieten in den Entwicklungsländern kann dies sehr schwierig sein, da es an Daten darüber mangelt, wer geimpft wurde und ob zusätzliche Impfungen erforderlich sind oder nicht".

Um eine dezentralisierte Patientenakte zu erstellen, entwickelten die Forscher eine neue Art von Quantenpunkten auf Kupferbasis, die Licht im nahen Infrarotspektrum aussenden. Die Dots haben nur einen Durchmesser von etwa 4 Nanometern, sind aber in biokompatible Mikropartikel eingekapselt, die Kugeln mit einem Durchmesser von etwa 20 Mikrometern bilden. Durch diese Verkapselung kann der Farbstoff nach der Injektion unter der Haut verbleiben.

Die Forscher haben ihren Farbstoff so konzipiert, dass er nicht mit einer herkömmlichen Spritze und Nadel, sondern mit einem Mikronadelpflaster verabreicht wird. Solche Pflaster werden derzeit entwickelt, um Impfstoffe gegen Masern, Röteln und andere Krankheiten zu verabreichen, und die Forscher zeigten, dass ihr Farbstoff problemlos in diese Pflaster eingearbeitet werden kann.

Die in dieser Studie verwendeten Mikronadeln bestehen aus einer Mischung aus auflösbarem Zucker und einem Polymer namens PVA sowie aus dem Quantenpunkt-Farbstoff und dem Impfstoff. Wenn das Pflaster auf die Haut geklebt wird, lösen sich die 1,5 Millimeter langen Mikronadeln teilweise auf und geben ihre Ladung innerhalb von etwa zwei Minuten frei.

Durch das selektive Einbringen von Mikropartikeln in die Mikronadeln erzeugen die Pflaster ein Muster in der Haut, das mit bloßem Auge nicht sichtbar ist, aber mit einem Smartphone ohne Infrarotfilter gescannt werden kann. Das Pflaster kann so angepasst werden, dass je nach Art des verabreichten Impfstoffs unterschiedliche Muster aufgedruckt werden.

"Es ist denkbar, dass dieser 'unsichtbare' Ansatz eines Tages neue Möglichkeiten für die Datenspeicherung, die Biosensorik und die Impfung schaffen könnte."

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Etymologie des Terminus “Pandemie”

Das Adjektiv griech. epidḗmios (ἐπιδήμιος) 'im ganzen Volk, über das ganze Volk verbreitet', zu griech. dḗmos (δῆμος) 'Volk', wird schon von griechischen Ärzten auf eine sich rasch ausbreitende ansteckende Krankheit bezogen; dazu gehört das Abstraktum epidēmía (ἐπιδημία) 'Verbreitung' (einer Krankheit).
Der Begriff "Pandemie", aus dem Griechischen pandēmos, was "alle Menschen" bedeutet, geht zusammen mit dem Wort "Panik" auf den griechischen Naturgott Pan zurück (cf. Panflöte).

Freud schreibt in Massenpsychologie und Ich-Analyse:
Man wird nicht erwarten dürfen, daß der Gebrauch des Wortes »Panik« scha rf und eindeutig bes timmt sei. Manchmal bezeichnet man so jede Massenangst, andere Male auch die Angst eines Einzelnen, wenn sie über jedes Maß hinausgeht, häufig scheint der Name für den Fall reserviert, daß der Angstausbruch durch den Anlaß nich t gerechtfertigt wird. Nehmen wir das Wort »Panik« im Sinne der Massenangst, so können wir eine weitgehende Analogie be- haupten. Die Angst des Individuums wird her vorgerufen entweder durch die Größe der Gefahr oder durch das Auflassen von Gefühl sbindungen (Libidobesetzungen); der letz- tere Fall ist der der neurotischen Angst.24 Ebenso entsteht die Panik durch die Steige- rung der alle betreffenden Gefahr oder durch das Aufhören der die Masse zusammen- haltenden Gefühlsbindungen, und dieser letzte Fall ist der neurot ischen Angst analog. (Vgl. hiezu den gedankenreichen, etwas phantastischen Aufsatz von Béla v. Felszeghy: PANIK UND PANKOMPLEX, Imago, VI, 1920.)

Wenn man die Panik wie Mc Dougall (1.c.) als eine der de utlichsten Leistungen der »group mind« beschreibt, gelangt man zum Para doxon, daß sich diese Massenseele in einer ihrer auffälligsten Äußerungen selbst aufhebt. Es ist kein Zweifel möglich, daß die Panik die Zersetzung der Masse bedeutet, si e hat das Aufhören aller Rücksichten zur Folge, welche sonst die Einzelnen der Masse füreinander zeigen. Der typische Anlaß für den Ausbruch einer Pa nik ist so ähnlich, wi e er in der Nestroy- schen Parodie des Hebbelschen Dramas von J udith und Holofernes dargestellt wird. Da schreit ein Krieger: »Der Feldherr hat den Kopf verloren«, und darauf ergreifen alle As- syrer die Flucht. Der Verlust des Führers in irgendeinem Si nne, das Irrewerden an ihm, bringt die Panik bei gleich bleibender Gefahr zum Ausbruch; mit der Bindung an den Führer schwinden – in der Regel – auch die gegenseitigen Bindungen der Massenindi- viduen. Die Masse zerstiebt wie ein Bolognes er Fläschchen, dem man die Spitze abge- brochen hat

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Psychiatrie und die dunkle Seite: Eugenik, nationalsozialistische und sowjetische Psychiatrie

Luty, J.. (2014). Psychiatry and the dark side: eugenics, Nazi and Soviet psychiatry. Advances in Psychiatric Treatment, 20(1), 52–60. Plain numerical DOI: 10.1192/apt.bp.112.010330DOI URLdirectSciHub download

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“Psychiatrist thomas szasz fought coercion (compulsory detention) and denied that mental illness existed. although he was regarded as a maverick, his ideas are much more plausible when one discovers that between 1939 and 1941, up to 100 000 mentally ill people, including 5000 children, were killed in nazi germany. in the course of the nazi regime, over 400 000 forced sterilisations took place, mainly of people with mental illnesses. other countries, including denmark, norway, sweden and switzerland, had active forced sterilisation programmes and eugenics laws. similar laws were implemented in the usa, with up to 25 000 forced sterilisations. these atrocities were enabled and facilitated by psychiatrists of the time and are only one example of the dark side of the profession. this article reviews some of these aspects of the history of psychiatry, including germany’s eugenics programme and the former ussr’s detention of dissidents under the guise of psychiatric treatment.”

Zusammenfassung

Der Psychiater Thomas Szasz bekämpfte den Zwang (Zwangsinternierung) und leugnete die Existenz psychischer Krankheiten. Obwohl er als Außenseiter galt, werden seine Ideen viel plausibler, wenn man bedenkt, dass zwischen 1939 und 1941 in Nazideutschland bis zu 100 000 psychisch kranke Menschen, darunter 5000 Kinder, getötet wurden. Im Laufe des Naziregimes wurden über 400 000 Zwangssterilisationen durchgeführt, vor allem an Menschen mit psychischen Erkrankungen. In anderen Ländern, darunter Dänemark, Norwegen, Schweden und die Schweiz, gab es aktive Zwangssterilisationsprogramme und Eugenikgesetze. Ähnliche Gesetze wurden in den USA umgesetzt, wo bis zu 25 000 Zwangssterilisationen durchgeführt wurden. Diese Gräueltaten wurden von den damaligen Psychiatern ermöglicht und gefördert und sind nur ein Beispiel für die dunkle Seite des Berufsstandes. Dieser Artikel gibt einen Überblick über einige dieser Aspekte der Geschichte der Psychiatrie, einschließlich des deutschen Eugenikprogramms und der Inhaftierung von Dissidenten in der ehemaligen UdSSR unter dem Deckmantel der psychiatrischen Behandlung.

Weitere Infos: https://cognitive-liberty.online/psychiatry-and-the-dark-side-eugenics-nazi-and-soviet-psychiatry-cambridge-university-press/

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Mullis versus Fauci

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Hydrogels & Biosensors

Manickam, P., Vashist, A., Madhu, S., Sadasivam, M., Sakthivel, A., Kaushik, A., & Nair, M. (2020). Gold nanocubes embedded biocompatible hybrid hydrogels for electrochemical detection of H2O2. Bioelectrochemistry. https://doi.org/10.1016/j.bioelechem.2019.107373
Tavakoli, J., & Tang, Y. (2017). Hydrogel based sensors for biomedical applications: An updated review. In Polymers. https://doi.org/10.3390/polym9080364
Erfkamp, J., Guenther, M., & Gerlach, G. (2019). Enzyme-functionalized piezoresistive hydrogel biosensors for the detection of urea. Sensors (Switzerland). https://doi.org/10.3390/s19132858
Wang, K., Hao, Y., Wang, Y., Chen, J., Mao, L., Deng, Y., Chen, J., Yuan, S., Zhang, T., Ren, J., & Liao, W. (2019). Functional Hydrogels and Their Application in Drug Delivery, Biosensors, and Tissue Engineering. In International Journal of Polymer Science. https://doi.org/10.1155/2019/3160732
Distler, T., & Boccaccini, A. R. (2020). 3D printing of electrically conductive hydrogels for tissue engineering and biosensors – A review. In Acta Biomaterialia. https://doi.org/10.1016/j.actbio.2019.08.044
Miao, X., Pan, J., Zhu, Q., Zhu, H., & Wei, T. (2021). Synthesis of enzymatic hydrogels and their application in biosensors. Scientia Sinica Chimica. https://doi.org/10.1360/SSC-2020-0231

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Prof. Daniel Kahneman über die Manipulation des Denkens

https://www.youtube.com/watch?v=_fPdSEnLxvg

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Dr. Mike Yeadon

Abschluss in Biochemie, Toxikologie und Atempharmakologie
Arbeitete 17 Jahre lang bei Pfizer als Vice President und Chefwissenschaftler

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Netzwerkanalyse Corona Komplex

Home

In monatelanger Recherche-Arbeit hat ein IT-Spezialist, der anonym bleiben möchte, eine komplexe Netzwerkanalyse zu Beziehungsgeflechten, Verbindungen und Geldflüssen zwischen zahlreichen einflussreichen Stiftungen, NGOs, Unternehmen, Personen, Organisationen, Öffentlich-privaten Partnerschaften (ÖPP) etc. erstellt, welche nach seinen Worten komplett auf öffentlich zugängliche Quellen beruhe.

Original PDF: http://corona-propaganda.de/wp-content/uploads/Netzwerkanalyse-Corona-Komplex.pdf
Podcast: https://apolut.net/covid-19-die-netzwerke-die-die-pandemie-erschaffen-haben-von-thomas-roeper/

Netzwerkanalyse-Corona-Komplex

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Sir Bertrand Russel: The impact of science on society

Nehmen wir zunächst die Frage der Ernährung und der Bevölkerung. Gegenwärtig wächst die Weltbevölkerung mit einer Rate von etwa 20 Millionen pro Jahr. Der größte Teil dieses Anstiegs findet in Russland und Südostasien. Die Bevölkerung in Westeuropa und den den Vereinigten Staaten bleibt nahezu unverändert. Unterdessen droht die Nahrungsmittel die Nahrungsmittelversorgung der Welt als Ganzes zu schrumpfen droht. durch unkluge Anbaumethoden und die Zerstörung der Wälder. Dies ist eine explosive Situation. Sich selbst überlassen, muss sie zu einer Nahrungsmittelknappheit und in der Folge zu einem Weltkrieg führen. Die Technik, macht jedoch andere Dinge möglich.

Die Lebensstatistiken im Westen werden von der Medizin und Geburtenkontrolle: die eine verringert die Todesfälle, die andere die Geburten. Die Folge ist, dass das Durchschnittsalter im Westen ansteigt: Es gibt einen geringeren Prozentsatz an jungen Menschen und einen größeren Prozentsatz an alten Menschen. Manche Leute meinen, dass dies unglückliche Folgen haben muss, aber als alter Mensch Person bin ich mir da nicht sicher.

Die Gefahr einer weltweiten Nahrungsmittelknappheit kann eine Zeit lang durch Verbesserungen in der Technik der Landwirtschaft abgewendet werden. Aber wenn die Bevölkerung weiterhin so schnell wächst wie bisher, können solche Verbesserungen nicht lange ausreichen. Es wird dann zwei Gruppen geben zwei Gruppen geben, eine arme mit einer wachsenden Bevölkerung, die die andere reich mit einer gleichbleibenden Bevölkerung. Eine solche Situation kann nicht zu einem Weltkrieg führen. Wenn es nicht zu einer endlose Reihe von Kriegen geben soll, muss die Bevölkerung Bevölkerung in der ganzen Welt stationär werden, und dies wird wahrscheinlich in vielen Ländern als Ergebnis staatlicher Maßnahmen geschehen Maßnahmen. Dies wird eine Ausweitung der wissenschaftlichen Technik nik auf sehr intime Angelegenheiten. Es gibt jedoch zwei andere Möglichkeiten. Der Krieg kann so zerstörerisch werden, dass zumindest dass zumindest für eine gewisse Zeit keine Überbevölkerung zu befürchten ist; oder die wissenschaftlichen Nationen können besiegt werden und die Anarchie kann die die wissenschaftliche Technik zerstören.

Die Biologie wird das menschliche Leben durch das Studium der Vererbung. Ohne Wissenschaft haben die Menschen Haustiere Nutztiere und Nahrungspflanzen auf vorteilhafte Weise verändert. Es ist anzunehmen, dass er sie noch viel mehr verändern wird, und viel schneller verändern wird, wenn er die Wissenschaft der Genetik zum Tragen kommt. Vielleicht wird es sogar möglich sein, auf künstliche Weise erwünschte Mutationen in den Genen herbeizuführen. (Bislang sind die einzigen Muta Mutationen künstlich herbeigeführt werden können, sind neutral oder schädlich.) In jedem Fall ist es ziemlich sicher, dass die wissenschaftliche Technik sehr bald große Verbesserungen bei den Tieren und Pflanzen, die für den Menschen nützlich sind.

Wenn solche Methoden zur Veränderung des angeborenen Charakters von Tieren und Pflanzen lange genug verfolgt worden sind, um ihren Erfolg offensichtlich wird, ist es wahrscheinlich, dass es eine eine starke Bewegung zur Anwendung wissenschaftlicher Methoden auf die menschliche Fortpflanzung. Es gäbe zunächst starke religiöse und religiöse und emotionale Hindernisse für die Annahme einer solchen Politik. Aber angenommen nehmen wir an, Russland wäre in der Lage, diese Hindernisse zu überwinden und eine Rasse zu züchten, die stärker, intelligenter und und widerstandsfähiger gegen Krankheiten zu züchten als jede andere Rasse, die bisher und angenommen, die anderen Nationen würden erkennen, dass sie, wenn sie dass sie im Krieg besiegt werden würden, wenn sie nicht nachziehen, dann würden entweder die anderen Nationen freiwillig ihre Vorurteile aufgeben, oder, oder sie würden nach einer Niederlage gezwungen sein, sie aufzugeben. Jede wissenschaftliche Technik, wie bestialisch sie auch sein mag, muss sich verbreiten, wenn wenn sie im Krieg nützlich ist - bis zu dem Zeitpunkt, an dem die Menschen beschließen, dass sie genug vom Krieg haben und von nun an in Frieden leben wollen. Wie dieser Tag nicht gekommen zu sein scheint, muss die wissenschaftliche Züchtung von des Menschen zu erwarten. Ich werde diesem Thema in einem späteren Kapitel zurückkommen.

Die Physiologie und die Psychologie bieten Felder für die wissenschaftliche Technik. nik, die noch der Entwicklung harren. Zwei große Männer, Pawlow und Freud, haben den Grundstein gelegt. Ich akzeptiere nicht die Ansicht Ich bin nicht der Ansicht, dass sie in einem wesentlichen Konflikt stehen, aber auf ihren Fundamenten aufgebaut werden soll, ist noch ungewiss.

Ich denke, das Thema, das politisch am wichtigsten sein wird, ist die Massenpsychologie. ist die Massenpsychologie. Die Massenpsychologie ist, wissenschaftlich Massenpsychologie ist, wissenschaftlich gesehen, nicht sehr weit fortgeschritten, und nicht an Universitäten, sondern in der Werbung, Politiker und vor allem Diktatoren. Diese Studie ist ungemein nützlich für praktische Menschen, ob sie nun reich werden oder die Regierung übernehmen wollen. Sie ist natürlich eine Wissenschaft, auf der Psychologie des Individuums gegründet, aber bisher hat sie Methoden verwendet, die auf einer Art intuitivem eine Art intuitiven gesunden Menschenverstand. Ihre Bedeutung hat sich durch die Entwicklung moderner Propagandamethoden enorm gesteigert Propaganda. Die einflussreichste davon ist das, was man als "Erziehung". Die Religion spielt eine Rolle, wenn auch eine abnehmende; die Presse, das Kino und das Radio spielen eine immer größere Rolle.

Das Wesentliche in der Massenpsychologie ist die Kunst der Per- sussion. Überredungskunst.

https://docs.google.com/viewerng/viewer?url=https://ia800300.us.archive.org/0/items/TheImpactOfScienceOnSociety-B.Russell/TheImpactOfScienceOnSociety-B.Russell.pdf

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Relatierte Studien

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Sir Graham Wilson: The Hazards of Immunization (1967)

Sir Graham Wilson The Hazards of Immunization (1967)

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Dr. Klaus Hartmann: Wie sicher sind Impfstoffe?

https://www.youtube.com/watch?v=yIAp4dRRJR0

https://www.youtube.com/watch?v=TmOMFnxi-i4

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Dr. Suzanne Humphries: Die Impf-Illusion

https://academic.oup.com/cid/article/54/12/1778/455098
https://www.pnas.org/content/early/2013/11/20/1314688110.abstract
https://www.bmj.com/content/333/7560/174.full
https://drsuzanne.net/wp-content/uploads/2018/02/Mawson-2017-final-report-in-print-pilotS-1.pdf
https://drsuzanne.net/wp-content/uploads/2018/02/STeinhoff-12-influenza-vax-preg.pdf
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Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity
https://pubmed.ncbi.nlm.nih.gov/23609067/
Full-text: https://siksik.org/wp-content/uploads/vaccins/14-2013-Immunol-Res-Shaw.pdf

Zusammenfassung

Wir haben die Neurotoxizität von Aluminium bei Menschen und Tieren unter verschiedenen Bedingungen und nach verschiedenen Verabreichungswegen untersucht und geben einen Überblick über die verschiedenen damit verbundenen Krankheitszustände. Die Literatur zeigt eindeutig negative Auswirkungen von Aluminium auf das Nervensystem über die gesamte Altersspanne hinweg. Bei Erwachsenen kann die Aluminiumexposition zu scheinbar altersbedingten neurologischen Defiziten führen, die der Alzheimer-Krankheit ähneln, und wurde mit dieser Krankheit sowie mit der guamanischen Variante ALS-PDC in Verbindung gebracht. Ähnliche Ergebnisse wurden in Tiermodellen gefunden. Darüber hinaus führt die Injektion von Aluminiumadjuvantien in einem Versuch, das Golfkriegssyndrom und die damit verbundenen neurologischen Defizite zu modellieren, bei jungen männlichen Mäusen zu einem ALS-Phänotyp. Bei Kleinkindern besteht ein hochsignifikanter Zusammenhang zwischen der Anzahl der verabreichten Impfstoffe mit Aluminiumadjuvanzien und der Häufigkeit von Autismus-Spektrum-Störungen. Viele der Merkmale der aluminiuminduzierten Neurotoxizität könnten zum Teil auf Autoimmunreaktionen zurückzuführen sein, die Teil des ASIA-Syndroms sind.

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[PMID]24277828[/PMID]

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Aphorismen, Analogien & Metaphern

"Viele Menschen sind stolz auf Ihr Vaterland
Doch regiert werden Sie von böser Hand"
~ Christopher B. Germann

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Prof. Mausfeld: Gesundheit nur Vorwand

prof-rainer-mausfeld-corona-covid

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Graphene neuroscience literature

Lin, H. Y., Nurunnabi, M., Chen, W. H., & Huang, C. H.. (2019). Graphene in neuroscience. In Biomedical Applications of Graphene and 2D Nanomaterials Plain numerical DOI: 10.1016/B978-0-12-815889-0.00016-7DOI URLdirectSciHub download

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“Graphene and graphene-derived materials have been widely applied in various biomedical fields. in neuroscience, graphene and its derivatives can be applied as nanocarriers for drug delivery, as compelling biocompatible substrates for tissue engineering, as conductive electrodes for obtaining the stimulation response in studying neural networks, as low photobleaching nanocomposite tags in bioimaging, as enhancers for guiding neural growth and differentiation as regenerative medicine, and so forth. among these applications, the material composition, functionalization, and dimension of graphene are considerably important. in this chapter, we provide a brief review to address the accomplishments and further perspective of graphene and its related materials applied in neuroscience.”

Perini, G., Palmieri, V., Ciasca, G., De Spirito, M., & Papi, M.. (2020). Unravelling the potential of graphene quantum dots in biomedicine and neuroscience. International Journal of Molecular Sciences Plain numerical DOI: 10.3390/ijms21103712DOI URLdirectSciHub download

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“Quantum dots (qds) are semiconducting nanoparticles that have been gaining ground in various applications, including the biomedical field, thanks to their unique optical properties. recently, graphene quantum dots (gqds) have earned attention in biomedicine and nanomedicine, thanks to their higher biocompatibility and low cytotoxicity compared to other qds. gqds share the optical properties of qd and have proven ability to cross the blood-brain barrier (bbb). for this reason, gqds are now being employed to deepen our knowledge in neuroscience diagnostics and therapeutics. their size and surface chemistry that ease the loading of chemotherapeutic drugs, makes them ideal drug delivery systems through the bloodstream, across the bbb, up to the brain. gqds-based neuroimaging techniques and theranostic applications, such as photothermal and photodynamic therapy alone or in combination with chemotherapy, have been designed. in this review, optical properties and biocompatibility of gqds will be described. then, the ability of gqds to overtake the bbb and reach the brain will be discussed. at last, applications of gqds in bioimaging, photophysical therapies and drug delivery to the central nervous system will be considered, unraveling their potential in the neuroscientific field.”

Orecchioni, M., Bordoni, V., Fuoco, C., Reina, G., Lin, H., Zoccheddu, M., … Delogu, L. G.. (2020). Toward High-Dimensional Single-Cell Analysis of Graphene Oxide Biological Impact: Tracking on Immune Cells by Single-Cell Mass Cytometry. Small Plain numerical DOI: 10.1002/smll.202000123DOI URLdirectSciHub download

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“Considering the potential exposure to graphene, the most investigated nanomaterial, the assessment of the impact on human health has become an urgent need. the deep understanding of nanomaterial safety is today possible by high-throughput single-cell technologies. single-cell mass cytometry (cytometry by time-of flight, cytof) shows an unparalleled ability to phenotypically and functionally profile complex cellular systems, in particular related to the immune system, as recently also proved for graphene impact. the next challenge is to track the graphene distribution at the single-cell level. therefore, graphene oxide (go) is functionalized with agins2 nanocrystals (go–in), allowing to trace go immune–cell interactions via the indium (115in) channel. indium is specifically chosen to avoid overlaps with the commercial panels (>30 immune markers). as a proof of concept, the go–in cytof tracking is performed at the single-cell level on blood immune subpopulations, showing the go interaction with monocytes and b cells, therefore guiding future immune studies. the proposed approach can be applied not only to the immune safety assessment of the multitude of graphene physical and chemical parameters, but also for graphene applications in neuroscience. moreover, this approach can be translated to other 2d emerging materials and will likely advance the understanding of their toxicology.”

Song, Q., Jiang, Z., Li, N., Liu, P., Liu, L., Tang, M., & Cheng, G.. (2014). Anti-inflammatory effects of three-dimensional graphene foams cultured with microglial cells. Biomaterials Plain numerical DOI: 10.1016/j.biomaterials.2014.05.002DOI URLdirectSciHub download

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“One of the key goals in nerve tissue engineering is to develop new materials which cause less or no neuroinflammation. despite the rapid advances of using graphene as a neural interface material, it still remains unknown whether graphene could provoke neuroinflammation or not, and whether and how the topographical features of graphene influence the neuroinflammation induction. by immunofluorescence, elisa technique, western blot, scanning electron microscope (sem) methods, we investigated the pro- and/or anti-inflammatory responses of microglia in the graphene films (2d-graphene) or graphene foams (3d-graphene) culturing systems. furthermore, the growth situations of the neural stem cells (nscs) in the conditioned culture medium produced in the graphene substrates were evaluated. the results show that: 1) neither 2d nor 3d graphene induced distinct neuroinflammation when compared to the tissue culture polystyrene (tcps) substrates; 2) the topographical structures of the graphene might affect the material/cell interactions, leading to disparate effects on lipopolysaccharide (lps)-induced neuroinflammation; 3) 3d graphene exhibited a remarkable capability of rescuing lps-induced neuroinflammation probably through the restriction of microglia morphological transformation by the unique topographical features on the surface, showing the ability of anti-inflammation against external insults, while 2d graphene failed to. these results provide insights into the diverse biological effects of the material’s topographical structures and open new opportunity for the applications of graphene in neuroscience. © 2014 elsevier ltd.”

Kitko, K. E., & Zhang, Q.. (2019). Graphene-based nanomaterials: From production to integration with modern tools in neuroscience. Frontiers in Systems Neuroscience Plain numerical DOI: 10.3389/fnsys.2019.00026DOI URLdirectSciHub download

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“Graphene, a two-dimensional carbon crystal, has emerged as a promising material for sensing and modulating neuronal activity in vitro and in vivo. in this review, we provide a primer for how manufacturing processes to produce graphene and graphene oxide result in materials properties that may be tailored for a variety of applications. we further discuss how graphene may be composited with other bio-compatible materials of interest to make novel hybrid complexes with desired characteristics for bio-interfacing. we then highlight graphene’s ever-widen utility and unique properties that may in the future be multiplexed for cross-modal modulation or interrogation of neuronal network. as the biological effects of graphene are still an area of active investigation, we discuss recent development, with special focus on how surface coatings and surface properties of graphene are relevant to its biological effects. we discuss studies conducted in both non-murine and murine systems, and emphasize the preclinical aspect of graphene’s potential without undermining its tangible clinical implementation.”

Garcia-Cortadella, R., Schwesig, G., Jeschke, C., Illa, X., Gray, A. L., Savage, S., … Garrido, J. A.. (2021). Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity. Nature Communications Plain numerical DOI: 10.1038/s41467-020-20546-wDOI URLdirectSciHub download

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“Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. however, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.”

Cherian, R. S., Sandeman, S., Ray, S., Savina, I. N., Ashtami, J., & Mohanan, P. V.. (2019). Green synthesis of Pluronic stabilized reduced graphene oxide: Chemical and biological characterization. Colloids and Surfaces B: Biointerfaces Plain numerical DOI: 10.1016/j.colsurfb.2019.03.043DOI URLdirectSciHub download

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“The wonder material graphene has numerous potential applications in nanoelectronics, biomedicine, storage devices, etc. synthesis of graphene is highly challenging due to the toxic chemicals used and its low yield. in the present study, a facile green route for synthesis of reduced graphene oxide (rgo) was carried out using ascorbic acid as reducing agent. rgo was stabilized using pluronic p123 polymer to give pluronic stabilized reduced graphene oxide (rgo-p) and gave superior yield (15 mg graphene oxide yielded ˜13 mg rgo-p). despite the potential neuroscience applications of graphene, the impending toxicological outcome upon interaction with neurons is not well understood. here, differentiated pc-12 neuron-like cells exposed to rgo-p showed a dose-dependent cytotoxicity. membrane disruption and cytoskeletal integrity remained uncompromised after 24 h exposure. oxidative stress in pc-12 was evident due to an increase in ros generation in dose and time-dependent manner. in vivo acute toxicity was assessed in mice administered with 10 mg/kg body weight of rgo-p. there were no evident changes in behaviour, motor function or other morphological changes. in conclusion, rgo-p was successfully synthesized and provided superior yield. even though in vitro toxicity testing showed dose-dependent toxicity, in vivo toxic effect was not apparent.”

Bramini, M., Alberini, G., Colombo, E., Chiacchiaretta, M., DiFrancesco, M. L., Maya-Vetencourt, J. F., … Cesca, F.. (2018). Interfacing graphene-based materials with neural cells. Frontiers in Systems Neuroscience Plain numerical DOI: 10.3389/fnsys.2018.00012DOI URLdirectSciHub download

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“The scientific community has witnessed an exponential increase in the applications of graphene and graphene-based materials in a wide range of fields, from engineering to electronics to biotechnologies and biomedical applications. for what concerns neuroscience, the interest raised by these materials is two-fold. on one side, nanosheets made of graphene or graphene derivatives (graphene oxide, or its reduced form) can be used as carriers for drug delivery. here, an important aspect is to evaluate their toxicity, which strongly depends on flake composition, chemical functionalization and dimensions. on the other side, graphene can be exploited as a substrate for tissue engineering. in this case, conductivity is probably the most relevant amongst the various properties of the different graphene materials, as it may allow to instruct and interrogate neural networks, as well as to drive neural growth and differentiation, which holds a great potential in regenerative medicine. in this review, we try to give a comprehensive view of the accomplishments and new challenges of the field, as well as which in our view are the most exciting directions to take in the immediate future. these include the need to engineer multifunctional nanoparticles (nps) able to cross the blood-brain-barrier to reach neural cells, and to achieve on-demand delivery of specific drugs. we describe the state-of-the-art in the use of graphene materials to engineer three-dimensional scaffolds to drive neuronal growth and regeneration in vivo, and the possibility of using graphene as a component of hybrid composites/multi-layer organic electronics devices. last but not least, we address the need of an accurate theoretical modeling of the interface between graphene and biological material, by modeling the interaction of graphene with proteins and cell membranes at the nanoscale, and describing the physical mechanism(s) of charge transfer by which the various graphene materials can influence the excitability and physiology of neural cells.”

Capasso, A., Rodrigues, J., Moschetta, M., Buonocore, F., Faggio, G., Messina, G., … Lisi, N.. (2021). Interactions between Primary Neurons and Graphene Films with Different Structure and Electrical Conductivity. Advanced Functional Materials Plain numerical DOI: 10.1002/adfm.202005300DOI URLdirectSciHub download

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“Graphene-based materials represent a useful tool for the realization of novel neural interfaces. several studies have demonstrated the biocompatibility of graphene-based supports, but the biological interactions between graphene and neurons still pose open questions. in this work, the influence of graphene films with different characteristics on the growth and maturation of primary cortical neurons is investigated. graphene films are grown by chemical vapor deposition progressively lowering the temperature range from 1070 to 650 °c to change the lattice structure and corresponding electrical conductivity. two graphene-based films with different electrical properties are selected and used as substrate for growing primary cortical neurons: i) highly crystalline and conductive (grown at 1070 °c) and ii) highly disordered and 140-times less conductive (grown at 790 °c). electron and fluorescence microscopy imaging reveal an excellent neuronal viability and the development of a mature, structured, and excitable network onto both substrates, regardless of their microstructure and electrical conductivity. the results underline that high electrical conductivity by itself is not fundamental for graphene-based neuronal interfaces, while other physico–chemical characteristics, including the atomic structure, should be also considered in the design of functional, bio-friendly templates. this finding widens the spectrum of carbon-based materials suitable for neuroscience applications.”

Rauti, R., Secomandi, N., Martín, C., Bosi, S., Severino, F. P. U., Scaini, D., … Ballerini, L.. (2020). Tuning Neuronal Circuit Formation in 3D Polymeric Scaffolds by Introducing Graphene at the Bio/Material Interface. Advanced Biosystems Plain numerical DOI: 10.1002/adbi.201900233DOI URLdirectSciHub download

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“2D cultures are useful platforms allowing studies of the fundamental mechanisms governing neuron and synapse functions. yet, such models are limited when exploring changes in network dynamics due to 3d-space topologies. 3d platforms fill this gap and favor investigating topologies closer to the real brain organization. graphene, an atom-thick layer of carbon, possesses remarkable properties and since its discovery is considered a highly promising material in neuroscience developments. here, elastomeric 3d platforms endowed with graphene cues are exploited to modulate neuronal circuits when interfaced to graphene in 3d topology. ex vivo neuronal networks are successfully reconstructed within 3d scaffolds, with and without graphene, characterized by comparable size and morphology. by confocal microscopy and live imaging, the 3d architecture of synaptic networks is documented to sustain a high rate of bursting in 3d scaffolds, an activity further increased by graphene interfacing. changes are reported in the excitation/inhibition ratio, potentially following 3d-graphene interfacing. a hypothesis is thus proposed, where the combination of synapse formation under 3d architecture and graphene interfaces affects the maturation of gabaergic inhibition. this will tune the balance between hyperpolarizing and depolarizing responses, potentially contributing to network synchronization in the absence of changes in gabaergic phenotype expression.”

Thunemann, M., Lu, Y., Liu, X., Klllç, K., Desjardins, M., Vandenberghe, M., … Kuzum, D.. (2018). Deep 2-photon imaging and artifact-free optogenetics through transparent graphene microelectrode arrays. Nature Communications Plain numerical DOI: 10.1038/s41467-018-04457-5DOI URLdirectSciHub download

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“Recent advances in optical technologies such as multi-photon microscopy and optogenetics have revolutionized our ability to record and manipulate neuronal activity. combining optical techniques with electrical recordings is of critical importance to connect the large body of neuroscience knowledge obtained from animal models to human studies mainly relying on electrophysiological recordings of brain-scale activity. however, integration of optical modalities with electrical recordings is challenging due to generation of light-induced artifacts. here we report a transparent graphene microelectrode technology that eliminates light-induced artifacts to enable crosstalk-free integration of 2-photon microscopy, optogenetic stimulation, and cortical recordings in the same in vivo experiment. we achieve fabrication of crack- and residue-free graphene electrode surfaces yielding high optical transmittance for 2-photon imaging down to ~ 1 mm below the cortical surface. transparent graphene microelectrode technology offers a practical pathway to investigate neuronal activity over multiple spatial scales extending from single neurons to large neuronal populations.”

Garcia-Cortadella, R., Schäfer, N., Cisneros-Fernandez, J., Ré, L., Illa, X., Schwesig, G., … Guimerà-Brunet, A.. (2020). Switchless multiplexing of graphene active sensor arrays for brain mapping. Nano Letters Plain numerical DOI: 10.1021/acs.nanolett.0c00467DOI URLdirectSciHub download

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“Sensor arrays used to detect electrophysiological signals from the brain are paramount in neuroscience. however, the number of sensors that can be interfaced with macroscopic data acquisition systems currently limits their bandwidth. this bottleneck originates in the fact that, typically, sensors are addressed individually, requiring a connection for each of them. herein, we present the concept of frequency-division multiplexing (fdm) of neural signals by graphene sensors. we demonstrate the high performance of graphene transistors as mixers to perform amplitude modulation (am) of neural signals in situ, which is used to transmit multiple signals through a shared metal line. this technology eliminates the need for switches, remarkably simplifying the technical complexity of state-of-the-art multiplexed neural probes. besides, the scalability of fdm graphene neural probes has been thoroughly evaluated and their sensitivity demonstrated in vivo. using this technology, we envision a new generation of high-count conformal neural probes for high bandwidth brain machine interfaces.”

Liu, X., Lu, Y., Iseri, E., Shi, Y., & Kuzum, D.. (2018). A compact closed-loop optogenetics system based on artifact-free transparent graphene electrodes. Frontiers in Neuroscience Plain numerical DOI: 10.3389/fnins.2018.00132DOI URLdirectSciHub download

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“Electrophysiology is a decades-old technique widely used for monitoring activity of individual neurons and local field potentials. optogenetics has revolutionized neuroscience studies by offering selective and fast control of targeted neurons and neuron populations. the combination of these two techniques is crucial for causal investigation of neural circuits and understanding their functional connectivity. however, electrical artifacts generated by light stimulation interfere with neural recordings and hinder the development of compact closed-loop systems for precise control of neural activity. here, we demonstrate that transparent graphene micro-electrodes fabricated on a clear polyethylene terephthalate film eliminate the light-induced artifact problem and allow development of a compact battery-powered closed-loop optogenetics system. we extensively investigate light-induced artifacts for graphene electrodes in comparison to metal control electrodes. we then design optical stimulation module using micro-led chips coupled to optical fibers to deliver light to intended depth for optogenetic stimulation. for artifact-free integration of graphene micro-electrode recordings with optogenetic stimulation, we design and develop a compact closed-loop system and validate it for different frequencies of interest for neural recordings. this compact closed-loop optogenetics system can be used for various applications involving optogenetic stimulation and electrophysiological recordings.”

Lu, Y., Lyu, H., Richardson, A. G., Lucas, T. H., & Kuzum, D.. (2016). Flexible Neural Electrode Array Based-on Porous Graphene for Cortical Microstimulation and Sensing. Scientific Reports Plain numerical DOI: 10.1038/srep33526DOI URLdirectSciHub download

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“Neural sensing and stimulation have been the backbone of neuroscience research, brain-machine interfaces and clinical neuromodulation therapies for decades. to-date, most of the neural stimulation systems have relied on sharp metal microelectrodes with poor electrochemical properties that induce extensive damage to the tissue and significantly degrade the long-term stability of implantable systems. here, we demonstrate a flexible cortical microelectrode array based on porous graphene, which is capable of efficient electrophysiological sensing and stimulation from the brain surface, without penetrating into the tissue. porous graphene electrodes show superior impedance and charge injection characteristics making them ideal for high efficiency cortical sensing and stimulation. they exhibit no physical delamination or degradation even after 1 million biphasic stimulation cycles, confirming high endurance. in in vivo experiments with rodents, same array is used to sense brain activity patterns with high spatio-temporal resolution and to control leg muscles with high-precision electrical stimulation from the cortical surface. flexible porous graphene array offers a minimally invasive but high efficiency neuromodulation scheme with potential applications in cortical mapping, brain-computer interfaces, treatment of neurological disorders, where high resolution and simultaneous recording and stimulation of neural activity are crucial.”

Chen, J., Yu, Q., Fu, W., Chen, X., Zhang, Q., Dong, S., … Zhang, S.. (2020). A highly sensitive amperometric glutamate oxidase microbiosensor based on a reduced graphene oxide/prussian blue nanocube/gold nanoparticle composite film-modified pt electrode. Sensors (Switzerland) Plain numerical DOI: 10.3390/s20102924DOI URLdirectSciHub download

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“A simple method that relies only on an electrochemical workstation has been investigated to fabricate a highly sensitive glutamate microbiosensor for potential neuroscience applications. in this study, in order to develop the highly sensitive glutamate electrode, a 100 µm platinum wire was modified by the electrochemical deposition of gold nanoparticles, prussian blue nanocubes, and reduced graphene oxide sheets, which increased the electroactive surface area; and the chitosan layer, which provided a suitable environment to bond the glutamate oxidase. the optimization of the fabrication procedure and analytical conditions is described. the modified electrode was characterized using field emission scanning electron microscopy, impedance spectroscopy, and cyclic voltammetry. the results exhibited its excellent sensitivity for glutamate detection (lod = 41.33 nm), adequate linearity (50 nm–40 µm), ascendant reproducibility (rsd = 4.44%), and prolonged stability (more than 30 repetitive potential sweeps, two-week lifespan). because of the important role of glutamate in neurotransmission and brain function, this small-dimension, high-sensitivity glutamate electrode is a promising tool in neuroscience research.”

Park, D. W., Ness, J. P., Brodnick, S. K., Esquibel, C., Novello, J., Atry, F., … Ma, Z.. (2018). Electrical Neural Stimulation and Simultaneous in Vivo Monitoring with Transparent Graphene Electrode Arrays Implanted in GCaMP6f Mice. ACS Nano Plain numerical DOI: 10.1021/acsnano.7b04321DOI URLdirectSciHub download

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“Electrical stimulation using implantable electrodes is widely used to treat various neuronal disorders such as parkinson’s disease and epilepsy and is a widely used research tool in neuroscience studies. however, to date, devices that help better understand the mechanisms of electrical stimulation in neural tissues have been limited to opaque neural electrodes. imaging spatiotemporal neural responses to electrical stimulation with minimal artifact could allow for various studies that are impossible with existing opaque electrodes. here, we demonstrate electrical brain stimulation and simultaneous optical monitoring of the underlying neural tissues using carbon-based, fully transparent graphene electrodes implanted in gcamp6f mice. fluorescence imaging of neural activity for varying electrical stimulation parameters was conducted with minimal image artifact through transparent graphene electrodes. in addition, full-field imaging of electrical stimulation verified more efficient neural activation with cathode leading stimulation compared to anode leading stimulation. we have characterized the charge density limitation of capacitive four-layer graphene electrodes as 116.07-174.10 μc/cm2 based on electrochemical impedance spectroscopy, cyclic voltammetry, failure bench testing, and in vivo testing. this study demonstrates the transparent ability of graphene neural electrodes and provides a method to further increase understanding and potentially improve therapeutic electrical stimulation in the central and peripheral nervous systems.”

John, A. A., Subramanian, A. P., Vellayappan, M. V., Balaji, A., Mohandas, H., & Jaganathan, S. K.. (2015). Carbon nanotubes and graphene as emerging candidates in neuroregeneration and neurodrug delivery. International Journal of Nanomedicine Plain numerical DOI: 10.2147/IJN.S83777DOI URLdirectSciHub download

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“Neuroregeneration is the regrowth or repair of nervous tissues, cells, or cell products involved in neurodegeneration and inflammatory diseases of the nervous system like alzheimer’s disease and parkinson’s disease. nowadays, application of nanotechnology is commonly used in developing nanomedicines to advance pharmacokinetics and drug delivery exclusively for central nervous system pathologies. in addition, nanomedical advances are leading to therapies that disrupt disarranged protein aggregation in the central nervous system, deliver functional neuroprotective growth factors, and change the oxidative stress and excitotoxicity of affected neural tissues to regenerate the damaged neurons. carbon nanotubes and graphene are allotropes of carbon that have been exploited by researchers because of their excellent physical properties and their ability to interface with neurons and neuronal circuits. this review describes the role of carbon nanotubes and graphene in neuroregeneration. in the future, it is hoped that the benefits of nanotechnologies will outweigh their risks, and that the next decade will present huge scope for developing and delivering technologies in the field of neuroscience.”

Rauti, R., Musto, M., Bosi, S., Prato, M., & Ballerini, L.. (2019). Properties and behavior of carbon nanomaterials when interfacing neuronal cells: How far have we come?. Carbon Plain numerical DOI: 10.1016/j.carbon.2018.11.026DOI URLdirectSciHub download

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“In the last two decades, an increasing amount of studies have investigated the use of components based on carbon-(nano)materials in the engineering of neural interfaces, to improve the performance of current state of the art devices. carbon is an extremely versatile element, characterized by a variety of allotropes and structures with different properties due to their sp, sp2 or sp3 hybridization. among the diverse carbon nanomaterials, carbon nanotubes and graphene are naturally excellent electrical conductors, thus representing ideal candidates for interfacing electrical-excitable tissues. in addition, their dimensional range holds the potential to enhance the material interactions with bio-systems. successful interfacing of the nervous system with devices that record or modulate neuronal electrical activity requires their stable electrical coupling with neurons. the efficiency of this coupling can be improved significantly by the use of conductive, ad hoc designed, nanomaterials. here we review different carbon-based nanomaterials currently under investigation in basic and applied neuroscience, and the recent developments in this research field, with a special focus on in vitro studies.”

Zheng, Z., Huang, L., Yan, L., Yuan, F., Wang, L., Wang, K., … Liu, Y.. (2019). Polyaniline functionalized graphene nanoelectrodes for the regeneration of PC12 cells via electrical stimulation. International Journal of Molecular Sciences Plain numerical DOI: 10.3390/ijms20082013DOI URLdirectSciHub download

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“The regeneration of neurons is an important goal of neuroscience and clinical medicine. the electrical stimulation of cells is a promising technique to meet this goal. however, its efficiency highly depends on the electrochemical properties of the stimulation electrodes used. this work reports on the preparation and use of a highly electroactive and biocompatible nanoelectrode made from a novel polyaniline functionalized graphene composite. this nanocomposite was prepared using a facile and efficient polymerization-enhanced ball-milling method. it was used to stimulate the growth of pc12 cells under various electrical fields. the enhanced growth of axons and improved wound regeneration of pc12 cells were observed after this treatment, suggesting a promising strategy for neuro traumatology.”

Guan, S., Wang, J., & Fang, Y.. (2019). Transparent graphene bioelectronics as a new tool for multimodal neural interfaces. Nano Today Plain numerical DOI: 10.1016/j.nantod.2019.01.003DOI URLdirectSciHub download

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“A central challenge of neuroscience is to monitor the coordinated activity of neural circuits underlying information processing and behavior. combining the advantages of electrical and optical modalities can provide unprecedented access to the spatiotemporal dynamics of neural activity. transparent graphene bioelectronics has emerged as a suitable tool for the seamless integration of electrophysiological recording with optical imaging and optogenetic stimulation, opening up a variety of new opportunities in both neuroscience research and clinical applications.”

Lu, Y., Liu, X., & Kuzum, D.. (2018). Graphene-based neurotechnologies for advanced neural interfaces. Current Opinion in Biomedical Engineering Plain numerical DOI: 10.1016/j.cobme.2018.06.001DOI URLdirectSciHub download

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“Understanding how neuron populations transform activities of individual neurons into complex behaviors is one of the biggest challenges of neuroscience research. however, current neural monitoring and controlling technologies provide insufficient spatiotemporal resolution to unravel neural circuit functions. to this end, multifunctional neurotechnologies combining electrical, optical and chemical sensing and stimulation modalities have been proposed to overcome resolution limits. research in multifunctional probes has fueled the demand for new materials to build minimally invasive chronic interfaces to the brain. graphene has recently emerged as a neural interface material offering several outstanding properties, such as optical transparency, flexibility, high conductivity, functionalization and biocompatibility. the unique combination of these properties in a single material system makes graphene an attractive choice for multi-modal probing of neural activity. in this review, we discuss recent advances in graphene-based neurotechnologies, highlight different approaches and consider emerging directions inspired by unique characteristics of graphene.”

Fischer, R. A., Zhang, Y., Risner, M. L., Li, D., Xu, Y., & Sappington, R. M.. (2018). Impact of Graphene on the Efficacy of Neuron Culture Substrates. Advanced Healthcare Materials Plain numerical DOI: 10.1002/adhm.201701290DOI URLdirectSciHub download

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“How graphene influences the behavior of living cells or tissues remains a critical issue for its application in biomedical studies, despite the general acceptance that graphene is biocompatible. while direct contact between cells and graphene is not a requirement for all biomedical applications, it is often mandatory for biosensing. therefore, it is important to clarify whether graphene impedes the ability of cells to interact with biological elements in their environment. here, a systematic study is reported to determine whether applying graphene on top of matrix substrates masks interactions between these substrates and retinal ganglion cells (rgcs). six different platforms are tested for primary rgc cultures with three platforms comprised of matrix substrates compatible with these neurons, and another three having a layer of graphene placed on top of the matrix substrates. the results demonstrate that graphene does not impede interactions between rgcs and underlying substrate matrix, such that their positive or negative effects on neuron viability and vitality are retained. however, direct contact between rgcs and graphene reduces the number, but increases basal activity, of functional cation channels. the data indicate that, when proper baselines are established, graphene is a promising biosensing material for in vitro applications in neuroscience.”

Wang, R., Shi, M., Brewer, B., Yang, L., Zhang, Y., Webb, D. J., … Xu, Y. Q.. (2018). Ultrasensitive Graphene Optoelectronic Probes for Recording Electrical Activities of Individual Synapses. Nano Letters Plain numerical DOI: 10.1021/acs.nanolett.8b02298DOI URLdirectSciHub download

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“The complex neuronal circuitry connected by submicron synapses in our brain calls for technologies that can map neural networks with ultrahigh spatiotemporal resolution to decipher the underlying mechanisms for multiple aspects of neuroscience. here we show that, through combining graphene transistor arrays with scanning photocurrent microscopy, we can detect the electrical activities of individual synapses of primary hippocampal neurons. through measuring the local conductance change of graphene optoelectronic probes directly underneath neuronal processes, we are able to estimate millivolt extracellular potential variations of individual synapses during depolarization. the ultrafast nature of graphene photocurrent response allows for decoding of activity patterns of individual synapses with a sub-millisecond temporal resolution. this new neurotechnology provides promising potentials for recording of electrophysiological outcomes of individual synapses in neural networks.”

Bourrier, A., Shkorbatova, P., Bonizzato, M., Rey, E., Barraud, Q., Courtine, G., … Delacour, C.. (2019). Monolayer Graphene Coating of Intracortical Probes for Long-Lasting Neural Activity Monitoring. Advanced Healthcare Materials Plain numerical DOI: 10.1002/adhm.201801331DOI URLdirectSciHub download

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“The invasiveness of intracortical interfaces currently used today is responsible for the formation of an intense immunoresponse and inflammatory reaction from neural cells and tissues. this leads to a high concentration of reactive glial cells around the implant site, creating a physical barrier between the neurons and the recording channels. such a rejection of foreign analog interfaces causes neural signals to fade from recordings which become flooded by background noise after a few weeks. despite their invasiveness, those devices are required to track single neuron activity and decode fine sensory or motor commands. in particular, such quantitative and long-lasting recordings of individual neurons are crucial during a long time period (several months) to restore essential functions of the cortex, disrupted after injuries, stroke, or neurodegenerative diseases. to overcome this limitation, graphene and related materials have attracted numerous interests, as they gather in the same material many suitable properties for interfacing living matter, such as an exceptionally high neural affinity, diffusion barrier, and high physical robustness. in this work, the neural affinity of a graphene monolayer with numerous materials commonly used in neuroprostheses is compared, and its impact on the performance and durability of intracortical probes is investigated. for that purpose, an innovative coating method to wrap 3d intracortical probes with a continuous monolayer graphene is developed. experimental evidence demonstrate the positive impact of graphene on the bioacceptance of conventional intracortical probes, in terms of detection efficiency and tissues responses, allowing real-time samplings of motor neuron activity during 5 weeks. since continuous graphene coatings can easily be implemented on a wide range of 3d surfaces, this study further motivates the use of graphene and related materials as it could significantly contribute to reduce the current rejection of neural probes currently used in many research areas, from fundamental neurosciences to medicine and neuroprostheses.”

Moschetta, M., Lee, J. Y., Rodrigues, J., Podestà, A., Varvicchio, O., Son, J., … Capasso, A.. (2021). Hydrogenated Graphene Improves Neuronal Network Maturation and Excitatory Transmission. Advanced Biology Plain numerical DOI: 10.1002/adbi.202000177DOI URLdirectSciHub download

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“Graphene is regarded as a viable bio-interface for neuroscience due to its biocompatibility and electrical conductivity, which would contribute to efficient neuronal network signaling. here, monolayer graphene grown via chemical vapor deposition is treated with remote hydrogen plasma to demonstrate that hydrogenated graphene (hgr) fosters improved cell-to-cell communication with respect to pristine graphene in primary cortical neurons. when transferred to polyethylene terephthalate, hgr exhibits higher wettability than graphene (water contact angle of 83.7° vs 40.7°), while preserving electrical conductivity (≈3 kω □-1). a rich and mature network is observed to develop onto hgr. the intrinsic excitability and firing properties of neurons plated onto hgr appears unaltered, while the basic passive and active membrane properties are fully preserved. the formation of excitatory synaptic connections increases in hgr with respect to pristine graphene, leading to a doubled miniature excitatory postsynaptic current frequency. this study supports the use of hydrogenation for tailoring graphene into an improved neuronal interface, indicating that wettability, more than electrical conductivity, is the key parameter to be controlled. the use of hgr can bring about a deeper understanding of neuronal behavior on artificial bio-interfaces and provide new insight for graphene-based biomedical applications.”

Liu, X., Lu, Y., & Kuzum, D.. (2018). High-Density Porous Graphene Arrays Enable Detection and Analysis of Propagating Cortical Waves and Spirals. Scientific Reports Plain numerical DOI: 10.1038/s41598-018-35613-yDOI URLdirectSciHub download

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“Cortical propagating waves have recently attracted significant attention by the neuroscience community. these travelling waves have been suggested to coordinate different brain areas and play roles in assisting neural plasticity and learning. however, it is extremely challenging to record them with very fine spatial scales over large areas to investigate their effect on neural dynamics or network connectivity changes. in this work, we employ high-density porous graphene microelectrode arrays fabricated using laser pyrolysis on flexible substrates to study the functional network connectivity during cortical propagating waves. the low-impedance porous graphene arrays are used to record cortical potentials during theta oscillations and drug-induced seizures in vivo. spatiotemporal analysis on the neural recordings reveal that theta oscillations and epileptiform activities have distinct characteristics in terms of both synchronization and resulting propagating wave patterns. to investigate the network connectivity during the propagating waves, we perform network analysis. the results show that the propagating waves are consistent with the functional connectivity changes in the neural circuits, suggesting that the underlying network states are reflected by the cortical potential propagation patterns.”

Ye, S., Yang, P., Cheng, K., Zhou, T., Wang, Y., Hou, Z., … Ren, L.. (2016). Drp1-Dependent Mitochondrial Fission Mediates Toxicity of Positively Charged Graphene in Microglia. ACS Biomaterials Science and Engineering Plain numerical DOI: 10.1021/acsbiomaterials.5b00465DOI URLdirectSciHub download

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“The unique physicochemical properties of graphene and its derivatives enable their application in the diagnostics and therapy of central nervous system (cns) diseases. however, the potential impacts of surface properties of functionalized graphene on microglia remain poorly understood. herein, we used graphene oxides (go), polyethylene glycol (peg)- and polyethylenimine (pei)-functionalized go, which possess different surface charges, to investigate their effects on microglia by focusing on mitochondrial dynamics. the positively charged go-pei was found to promote mitochondrial fission as observed in bv-2 cells with mitochondria labeled by dsred2-mito, indicating that alterations in mitochondrial dynamics depend on the surface properties of graphene. concurrent to mitochondrial fragmentation, treatment with positively charged go-pei induced an increase in mitochondrial recruitment of dynamin-related protein (drp1). additionally, go-pei treatment also led to apoptotic and autophagic cell death. however, drp1 silencing by small interfering rna (sirna) could effectively attenuate go-pei-induced apoptotic and autophagic cell death, indicating that mitochondrial fragmentation occurs upstream of go-pei-mediated toxicity in microglia. overall, our study indicated that positively charged go-pei might cause deleterious influence on the central immune homeostasis by drp1-dependent mitochondrial fragmentation, and provide the strategies for the rational design of graphene-based materials in neuroscience.”

Balch, H. B., McGuire, A. F., Horng, J., Tsai, H. Z., Qi, K. K., Duh, Y. S., … Wang, F.. (2021). Graphene Electric Field Sensor Enables Single Shot Label-Free Imaging of Bioelectric Potentials. Nano Letters Plain numerical DOI: 10.1021/acs.nanolett.1c00543DOI URLdirectSciHub download

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“The measurement of electrical activity across systems of excitable cells underlies current progress in neuroscience, cardiac pharmacology, and neurotechnology. however, bioelectricity spans orders of magnitude in intensity, space, and time, posing substantial technological challenges. the development of methods permitting network-scale recordings with high spatial resolution remains key to studies of electrogenic cells, emergent networks, and bioelectric computation. here, we demonstrate single-shot and label-free imaging of extracellular potentials with high resolution across a wide field-of-view. the critically coupled waveguide-amplified graphene electric field (cage) sensor leverages the field-sensitive optical transitions in graphene to convert electric potentials into the optical regime. as a proof-of-concept, we use the cage sensor to detect native electrical activity from cardiac action potentials with tens-of-microns resolution, simultaneously map the propagation of these potentials at tissue-scale, and monitor their modification by pharmacological agents. this platform is robust, scalable, and compatible with existing microscopy techniques for multimodal correlative imaging.”

Shokoueinejad, M., Park, D. W., Jung, Y. H., Brodnick, S. K., Novello, J., Dingle, A., … Williams, J.. (2019). Progress in the field of micro-electrocorticography. Micromachines Plain numerical DOI: 10.3390/mi10010062DOI URLdirectSciHub download

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“Since the 1940s electrocorticography (ecog) devices and, more recently, in the last decade, micro-electrocorticography (μecog) cortical electrode arrays were used for a wide set of experimental and clinical applications, such as epilepsy localization and brain-computer interface (bci) technologies. miniaturized implantable μecog devices have the advantage of providing greater-density neural signal acquisition and stimulation capabilities in a minimally invasive fashion. an increased spatial resolution of the μecog array will be useful for greater specificity diagnosis and treatment of neuronal diseases and the advancement of basic neuroscience and bci research. in this review, recent achievements of ecog and μecog are discussed. the electrode configurations and varying material choices used to design μecog arrays are discussed, including advantages and disadvantages of μecog technology compared to electroencephalography (eeg), ecog, and intracortical electrode arrays. electrode materials that are the primary focus include platinum, iridium oxide, poly(3,4-ethylenedioxythiophene) (pedot), indium tin oxide (ito), and graphene. we discuss the biological immune response to μecog devices compared to other electrode array types, the role of μecog in clinical pathology, and brain-computer interface technology. the information presented in this review will be helpful to understand the current status, organize available knowledge, and guide future clinical and research applications of μecog technologies.”

Monaco, A. M., & Giugliano, M.. (2014). Carbon-based smart nanomaterials in biomedicine and neuroengineering. Beilstein Journal of Nanotechnology Plain numerical DOI: 10.3762/bjnano.5.196DOI URLdirectSciHub download

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“The search for advanced biomimetic materials that are capable of offering a scaffold for biological tissues during regeneration or of electrically connecting artificial devices with cellular structures to restore damaged brain functions is at the forefront of interdisciplinary research in materials science. bioactive nanoparticles for drug delivery, substrates for nerve regeneration and active guidance, as well as supramolecular architectures mimicking the extracellular environment to reduce inflammatory responses in brain implants, are within reach thanks to the advancements in nanotechnology. in particular, carbon-based nanostructured materials, such as graphene, carbon nanotubes (cnts) and nanodiamonds (nds), have demonstrated to be highly promising materials for designing and fabricating nanoelectrodes and substrates for cell growth, by virtue of their peerless optical, electrical, thermal, and mechanical properties. in this review we discuss the state-of-the-art in the applications of nanomaterials in biological and biomedical fields, with a particular emphasis on neuroengineering.”

Zhao, S., Liu, X., Xu, Z., Ren, H., Deng, B., Tang, M., … Duan, X.. (2016). Graphene Encapsulated Copper Microwires as Highly MRI Compatible Neural Electrodes. Nano Letters Plain numerical DOI: 10.1021/acs.nanolett.6b03829DOI URLdirectSciHub download

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“Magnetic resonance imaging (mri) compatible neural electrodes are important for combining high-resolution electrophysiological measurements with more global mri mapping of brain activity, which is critical for fundamental neuroscience studies, as well as clinical evaluation and monitoring. copper is a favorable material to use in mri because it has magnetic susceptibility close to water and tissues. however, the cytotoxicity of copper precludes its direct implantation for neural recording. here, we overcome this limitation by developing a graphene encapsulated copper (g-cu) microelectrode. the toxicity of copper is largely eliminated, as evidenced by the in vitro cell tests and in vivo histology studies. local field potentials and single-unit spikes were recorded from rodent brains with the g-cu microelectrodes. notably, the g-cu microelectrodes show no image artifacts in a 7.0 t mri scanner, indicating minimal magnetic field distortion in their vicinity. this high mri compatibility of our g-cu probes would open up new opportunities for fundamental brain activity studies and clinical applications requiring continuous mri and electrophysiological recordings.”

Li, G., Yang, J., Yang, W., Wang, F., Wang, Y., Wang, W., & Liu, L.. (2018). Label-free multidimensional information acquisition from optogenetically engineered cells using a graphene transistor. Nanoscale Plain numerical DOI: 10.1039/c7nr07264cDOI URLdirectSciHub download

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“The optogenetic technique, which allows the manipulation of cellular activity patterns in space and time by light, has transformed the field of neuroscience. however, acquiring multidimensional optogenetic information remains challenging despite the fact that several cellular information detection methods have been proposed. herein, we present a new method to acquire label-free multidimensional information from optogenetically engineered cells using a graphene transistor. using a graphene film to form a strong densely packed layer with cells, the cellular action potentials were characterized as light-activated transistor conductance signals, which quantified the multidimensional optogenetic information. based on this approach, some important cellular optogenetic information, including electrophysiological state, cell concentration, expression levels of opsin and response to variable light intensity, were also precisely detected. furthermore, the graphene transistor was also used to distinguish cells expressing different channelrhodopsin-2 variants. our study offers a general detection method of multidimensional optogenetic information for extending the applications of the optogenetic technique and provides a novel sensor for the development of future biological prosthetic devices.”

Liu, S., Zhao, Y., Hao, W., Zhang, X. D., & Ming, D.. (2020). Micro- and nanotechnology for neural electrode-tissue interfaces. Biosensors and Bioelectronics Plain numerical DOI: 10.1016/j.bios.2020.112645DOI URLdirectSciHub download

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Wu, T., Li, Y., Liang, X., Liu, X., & Tang, M.. (2021). Identification of potential circRNA-miRNA-mRNA regulatory networks in response to graphene quantum dots in microglia by microarray analysis. Ecotoxicology and Environmental Safety Plain numerical DOI: 10.1016/j.ecoenv.2020.111672DOI URLdirectSciHub download

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“Along with the increasing application of graphene quantum dots (gqds) in the fields of biomedicine and neuroscience, it is important to assess the probably adverse effects of gqds in the central nervous system (cns) but their underlying toxic mechanisms is still unclear. in this study, we evaluate the molecular mechanisms associated with circular rnas (circrnas) of nitrogen-doped gqds (n-gqds) and amino-functionalized gqds (a-gqds) damaging the cell viability and cellular structure in microglia by an integrative analysis of rna microarray. the differentially expressed circrna (decircrnas)-mirna- differentially expressed mrna (demrnas) regulatory networks were conducted in bv2 microglial cells treated with 25 µg/ml n-gqds, 100 µg/ml n-gqds and 100 µg/ml a-gqds. based on that, the protein-coding genes in each cerna network were collected to do bio-functional analysis to evaluate signaling pathways that were indirectly mediated by circrnas. some pathways that could play indispensable roles in the neurotoxicity of n-gqds or both two kinds of gqds were found. low-dosed n-gqds exposure mainly induced inflammatory action in microglia, while high-dosed n-gqds and a-gqds exposure both affect olfactory transduction and gabaergic synapse. meanwhile, several classical signaling pathways, including mtor, erbb and mapk, could make diverse contributions to the neurotoxicity of both two kinds of gqds. these circrnas could be toxic biomarkers or protective targets in neurotoxicity of gqds. more importantly, they emphasized the necessity of comprehensive analysis of latent molecular mechanisms through epigenetics approaches in biosafety assessment of graphene-based nanomaterials.”

Guo, C. X., Ng, S. R., Khoo, S. Y., Zheng, X., Chen, P., & Li, C. M.. (2012). RGD-peptide functionalized graphene biomimetic live-cell sensor for real-time detection of nitric oxide molecules. ACS Nano Plain numerical DOI: 10.1021/nn301974uDOI URLdirectSciHub download

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“It is always challenging to construct a smart functional nanostructure with specific physicochemical properties to real time detect biointeresting molecules released from live-cells. we report here a new approach to build a free-standing biomimetic sensor by covalently bonding rgd-peptide on the surface of pyrenebutyric acid functionalized graphene film. the resulted graphene biofilm sensor comprises a well-packed layered nanostructure, in which the rgd-peptide component provides desired biomimetic properties for superior human cell attachment and growth on the film surface to allow real-time detection of nitric oxide, an important signal yet short-life molecule released from the attached human endothelial cells under drug stimulations. the film sensor exhibits good flexibility and stability by retaining its original response after 45 bending/relaxing cycles and high reproducibility from its almost unchanged current responses after 15 repeated measurements, while possessing high sensitivity, good selectivity against interferences often existing in biological systems, and demonstrating real time quantitative detection capability toward nitric oxide molecule released from living cells. this study not only demonstrates a facial approach to fabricate a smart nanostructured graphene-based functional biofilm, but also provides a powerful and reliable platform to the real-time study of biointeresting molecules released from living cells, thus rendering potential broad applications in neuroscience, screening drug therapy effect, and live-cell assays. © 2012 american chemical society.”

Liu, & Speranza. (2019). Functionalization of Carbon Nanomaterials for Biomedical Applications. C — Journal of Carbon Research Plain numerical DOI: 10.3390/c5040072DOI URLdirectSciHub download

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“Over the past decade, carbon nanostructures (cnss) have been widely used in a variety of biomedical applications. examples are the use of cnss for drug and protein delivery or in tools to locally dispense nucleic acids to fight tumor affections. cnss were successfully utilized in diagnostics and in noninvasive and highly sensitive imaging devices thanks to their optical properties in the near infrared region. however, biomedical applications require a complete biocompatibility to avoid adverse reactions of the immune system and cnss potentials for biodegradability. water is one of the main constituents of the living matter. unfortunately, one of the disadvantages of cnss is their poor solubility. surface functionalization of cnss is commonly utilized as an efficient solution to both tune the surface wettability of cnss and impart biocompatible properties. grafting functional groups onto the cnss surface consists in bonding the desired chemical species on the carbon nanoparticles via wet or dry processes leading to the formation of a stable interaction. this latter may be of different nature as the van der waals, the electrostatic or the covalent, the π-π interaction, the hydrogen bond etc. depending on the process and on the functional molecule at play. grafting is utilized for multiple purposes including bonding mimetic agents such as polyethylene glycol, drug/protein adsorption, attaching nanostructures to increase the cnss opacity to selected wavelengths or provide magnetic properties. this makes the cnss a very versatile tool for a broad selection of applications as medicinal biochips, new high-performance platforms for magnetic resonance (mr), photothermal therapy, molecular imaging, tissue engineering, and neuroscience. the scope of this work is to highlight up-to-date using of the functionalized carbon materials such as graphene, carbon fibers, carbon nanotubes, fullerene and nanodiamonds in biomedical applications.”

Crowe, M., Lai, Y., Wang, Y., Lu, J., Zhao, M., Tian, Z., … Diao, J.. (2017). A Proteoliposome Method for Assessing Nanotoxicity on Synaptic Fusion and Membrane Integrity. Small Methods Plain numerical DOI: 10.1002/smtd.201700207DOI URLdirectSciHub download

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“Nanoparticles have received significant research interest for potential biomedical applications. before nanomaterials are administered to patients, their biocompatibility should be thoroughly evaluated through in vitro experiments and other preclinical procedures. many studies have sought to assess the toxicity of nanomaterials on synaptic transmission for neuroscience applications. however, it may be hard to perform such experiments because of the difficulty associated with delivering synthesized nanomaterials across cell membranes. here, an in vitro method is demonstrated that mimics neuronal exocytosis, which features protein-reconstituted liposomes for nanotoxicity testing; the effects of graphene oxide and pristine graphene on fusogenic activity and membrane integrity are examined. these results demonstrate the potential of this system as a novel in vitro platform for assessing the biocompatibility of nanomaterials, drug molecules, and other substances.”

Liu, Y., & Duan, X.. (2020). Carbon-based nanomaterials for neural electrode technology. Wuli Huaxue Xuebao/ Acta Physico - Chimica Sinica Plain numerical DOI: 10.3866/PKU.WHXB202007066DOI URLdirectSciHub download

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“As a powerful tool for monitoring and modulating neural activities, implantable neural electrodes constitute the basis for a wide range of applications, including fundamental studies of brain circuits and functions, treatment of various neurological diseases, and realization of brain-machine interfaces. however, conventional neural electrodes have the issue of mechanical mismatch with soft neural tissues, which can result in tissue inflammation and gliosis, thus causing degradation of function over chronic implantation. furthermore, implantable neural electrodes, especially depth electrodes, can only carry out limited data sampling within predefined anatomical regions, making it challenging to perform large-area brain mapping. with excellent electrical, mechanical, and chemical properties, carbonbased nanomaterials, including graphene and carbon nanotubes (cnts), have been used as materials of implantable neural electrodes in recent years. electrodes made from graphene and cnt fibers exhibit low electrochemical impedance, benefiting from the porous microstructure of the fibers. this enables a much smaller size of neural electrode. together with the low young’s modulus of the fibers, this small size results in very soft electrodes. soft neural electrodes made from graphene and cnt fibers show a much-reduced inflammatory response and enable stable chronic in vivo action potential recording for 4-5 months. combining different modalities of neural interfacing, including electrophysiological measurement, optical imaging/stimulation, and magnetic resonance imaging (mri), could leverage the spatial and temporal resolution advantages of different techniques, thus providing new insights into how neural circuits process information. transparent neural electrode arrays made from graphene or cnts enable simultaneous calcium imaging through the transparent electrodes, from which concurrent electrical recording is taken, thus providing complementary cellular information in addition to high-temporal-resolution electrical recording. transparent neural electrodes from carbon-based nanomaterials can record well-defined neuronal response signals with negligible light-induced artifacts from cortical surfaces under optogenetic stimulation. graphene and cnt-based materials were used to fabricate mri-compatible neural electrodes with negligible artifacts under high field mri. simultaneous deep brain stimulation (dbs) and functional magnetic resonance imaging (fmri) with graph…”

Bramini, M., Rocchi, A., Benfenati, F., & Cesca, F.. (2019). Neuronal Cultures and Nanomaterials. In Advances in Neurobiology Plain numerical DOI: 10.1007/978-3-030-11135-9_3DOI URLdirectSciHub download

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“In recent years, the scientific community has witnessed an exponential increase in the use of nanomaterials for biomedical applications. in particular, the interest of graphene and graphene-based materials has rapidly risen in the neuroscience field due to the properties of this material, such as high conductivity, transparency and flexibility. as for any new material that aims to play a role in the biomedical area, a fundamental aspect is the evaluation of its toxicity, which strongly depends on material composition, chemical functionalization and dimensions. furthermore, a wide variety of three-dimensional scaffolds have also started to be exploited as a substrate for tissue engineering. in this application, the topography is probably the most relevant amongst the various properties of the different materials, as it may allow to instruct and interrogate neural networks, as well as to drive neural growth and differentiation. this chapter discusses the in vitro approaches, ranging from microscopy analysis to physiology measurements, to investigate the interaction of graphene with the central nervous system. moreover, the in vitro use of three-dimensional scaffolds is described and commented.”

Govindhan, M., Liu, Z., & Chen, A.. (2016). Design and electrochemical study of platinum-based nanomaterials for sensitive detection of nitric oxide in biomedical applications. Nanomaterials Plain numerical DOI: 10.3390/nano6110211DOI URLdirectSciHub download

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“The extensive physiological and regulatory roles of nitric oxide (no) have spurred the development of no sensors, which are of critical importance in neuroscience and various medical applications. the development of electrochemical no sensors is of significant importance, and has garnered a tremendous amount of attention due to their high sensitivity and selectivity, rapid response, low cost, miniaturization, and the possibility of real-time monitoring. nanostructured platinum (pt)-based materials have attracted considerable interest regarding their use in the design of electrochemical sensors for the detection of no, due to their unique properties and the potential for new and innovative applications. this review focuses primarily on advances and insights into the utilization of nanostructured pt-based electrode materials, such as nanoporous pt, pt and ptau nanoparticles, ptau nanoparticle/reduced graphene oxide (rgo), and ptw nanoparticle/rgo-ionic liquid (il) nanocomposites, for the detection of no. the design, fabrication, characterization, and integration of electrochemical no sensing performance, selectivity, and durability are addressed. the attractive electrochemical properties of pt-based nanomaterials have great potential for increasing the competitiveness of these new sensors and open up new opportunities in the creation of novel no-sensing technologies for biological and medical applications.”

Kostarelos, K., Vincent, M., Hebert, C., & Garrido, J. A.. (2017). Graphene in the Design and Engineering of Next-Generation Neural Interfaces. Advanced Materials Plain numerical DOI: 10.1002/adma.201700909DOI URLdirectSciHub download

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“Neural interfaces are becoming a powerful toolkit for clinical interventions requiring stimulation and/or recording of the electrical activity of the nervous system. active implantable devices offer a promising approach for the treatment of various diseases affecting the central or peripheral nervous systems by electrically stimulating different neuronal structures. all currently used neural interface devices are designed to perform a single function: either record activity or electrically stimulate tissue. because of their electrical and electrochemical performance and their suitability for integration into flexible devices, graphene-based materials constitute a versatile platform that could help address many of the current challenges in neural interface design. here, how graphene and other 2d materials possess an array of properties that can enable enhanced functional capabilities for neural interfaces is illustrated. it is emphasized that the technological challenges are similar for all alternative types of materials used in the engineering of neural interface devices, each offering a unique set of advantages and limitations. graphene and 2d materials can indeed play a commanding role in the efforts toward wider clinical adoption of bioelectronics and electroceuticals.”

Pampaloni, N. P., Giugliano, M., Scaini, D., Ballerini, L., & Rauti, R.. (2019). Advances in nano neuroscience: From nanomaterials to nanotools. Frontiers in Neuroscience Plain numerical DOI: 10.3389/fnins.2018.00953DOI URLdirectSciHub download

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“During the last decades, neuroscientists have increasingly exploited a variety of artificial, de-novo synthesized materials with controlled nano-sized features. for instance, a renewed interest in the development of prostheses or neural interfaces was driven by the availability of novel nanomaterials that enabled the fabrication of implantable bioelectronics interfaces with reduced side effects and increased integration with the target biological tissue. the peculiar physical-chemical properties of nanomaterials have also contributed to the engineering of novel imaging devices toward sophisticated experimental settings, to smart fabricated scaffolds and microelectrodes, or other tools ultimately aimed at a better understanding of neural tissue functions. in this review, we focus on nanomaterials and specifically on carbon-based nanomaterials, such as carbon nanotubes (cnts) and graphene. while these materials raise potential safety concerns, they represent a tremendous technological opportunity for the restoration of neuronal functions. we then describe nanotools such as nanowires and nano-modified mea for high-performance electrophysiological recording and stimulation of neuronal electrical activity. we finally focus on the fabrication of three-dimensional synthetic nanostructures, used as substrates to interface biological cells and tissues in vitro and in vivo.”

Liu, X., Ren, C., Lu, Y., Hattori, R., Shi, Y., Zhao, R., … Kuzum, D.. (2019). Decoding ECoG High Gamma Power from Cellular Calcium Response using Transparent Graphene Microelectrodes. In International IEEE/EMBS Conference on Neural Engineering, NER Plain numerical DOI: 10.1109/NER.2019.8717147DOI URLdirectSciHub download

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“The ecog has been widely used in human brain research, while 2-photon microscopy has been broadly applied to basic neuroscience studies using animal models. bridging the gap between the 2-photon microscopy and the ecog is critical for transferring the vast amount of neuroscience knowledge obtained from animal models to human brain studies. here we develop an lstm recurrent neural network model to decode the ecog high gamma power from the cellular calcium activities obtained by multimodal ecog recordings and 2-photon calcium imaging enabled by transparent graphene microelectrode arrays. in both awake and anesthetized states, our model can successfully decode the stimulus-induced ecog high gamma power increases and its spontaneous fluctuations in the absence of stimulus.”

Lee, J. H., Shin, Y. C., Jin, O. S., Han, D. W., Kang, S. H., Hong, S. W., & Kim, J. M.. (2012). Enhanced neurite outgrowth of PC-12 cells on graphene-monolayer-coated substrates as biomimetic cues. Journal of the Korean Physical Society Plain numerical DOI: 10.3938/jkps.61.1696DOI URLdirectSciHub download

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“Neurons are electrically excitable cells that transmit and process information in the nervous system. recently, the differentiation of human neural stem cells to neurons has been shown to be enhanced on graphene substrates, and differentiated neurons have been shown to be able to still carry electrical signals when stimulated by graphene electrodes. graphene films grown by using chemical vapor deposition were transferred onto glass coverslips by using the scooping method and were then coated with fetal bovine serum for a neuronal cell culture. the graphene substrates as biomimetic cues have been shown to enhance the neurite outgrowth of pc-12 cells. our findings suggest that graphene has a unique surface property that can promote neuronal cells, which should open tremendous opportunities in neuroscience, neural engineering and regenerative medicine. © 2012 the korean physical society.”

Gutruf, P., Good, C. H., & Rogers, J. A.. (2018). Perspective: Implantable optical systems for neuroscience research in behaving animal models—Current approaches and future directions. APL Photonics Plain numerical DOI: 10.1063/1.5040256DOI URLdirectSciHub download

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“Perspective: biomedical sensing and imaging with optical fibers-innovation through convergence of science disciplines apl photonics 3, 100902 (2018); https://doi.org/10.1063/1.5040861 invited article: enhanced four-wave mixing in waveguides integrated with graphene oxide apl photonics 3, 120803 (2018); https://doi.org/10.1063/1.5045509 single crystal diamond micro-disk resonators by focused ion beam milling apl photonics 3, 126101 (2018); https://doi.”

Geracitano, L. A., Fagan, S. B., & Monserrat, J. M.. (2021). Analysis of global and Latin-American trends in nanotoxicology with a focus on carbon nanomaterials: a scientometric approach. Journal of Chemical Technology and Biotechnology Plain numerical DOI: 10.1002/jctb.6729DOI URLdirectSciHub download

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“BACKGROUND: the scientific trends and developments in the field of nanotoxicology were analyzed through a scientometric approach. this study aimed to describe and unravel the main topics on nanomaterials concerning their potential toxicity. it was generated four databases: two for global nanotoxicological papers (ds1 and ds2) and two with a latin-american focus (la1 and la2). ds2 and la2 databases were constructed with studies dealing with the toxic effects of carbon nanomaterials. scientometric analyses were performed using citespace software. the following items were evaluated: frequencies, burst, centrality for co-citations of web of science categories, keywords, references, authors, and countries. results: global analysis resulted in a total of 29 798 papers for ds1 and 3835 for ds2. latin-american papers resulted in 1397 articles for la1 and 148 for la2. scientometric analyses indicated a specialization of the topics covered over time, ranging from general categories (such as chemistry) to more specialized ones (such as genetics or neurosciences). nano-silver prevailed in the nanotoxicological studies and graphene dominated in the field of carbon nanomaterials. in the last 5 years, a prominent growth has been observed in the number of studies that focus on the potential impact of nanomaterials on the environment. conclusion: the research efforts in nanotoxicology have been mainly concentrated on assays that use nano-silver; meanwhile, in carbon nanomaterials, the focus has been concentrated on toxicological tests with graphene. overall, we stress the importance of nanotoxicology as a strategy to obtain scientific information that can aid in the environmental sustainability of nanotechnologies.”

Abbasi, R.. (2018). Interpretable Machine Learning with Applications in Neuroscience. UC Berkeley Electronic Theses and Dissertations

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“This thesis is divided into two parts. in part i, we examine the properties of thin sheets of carbon and boron nitride. we begin with an introduction to the theory of elastic sheets, where the stretching and bending modes are considered in detail. the coupling between stretching and bending modes is thought to play a crucial role in the thermodynamic stability of atomically-thin 2d sheets such as graphene.”

Wang, L., Jiang, T., Song, Y., Shi, W., & Cai, X.. (2014). Dopamine detection using a patch-clamp system on a planar microeletrode array electrodeposited by polypyrrole/graphene nanocomposites. Science China Technological Sciences Plain numerical DOI: 10.1007/s11431-014-5465-9DOI URLdirectSciHub download

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“To achieve a dopamine (da) response with high sensitivity and high signal-to-noise ratio (s/n) with a patch-clamp system, polypyrrole/graphene (ppy/gr) nanocomposites were steadily electrodeposited by an electrochemical method on a planar microelectrode array (pmea) fabricated by a standard micromachining process. the electrodeposition process was carried out by chronopotentimetry measurement scanning from 0.1 to 0.8 c/cm2 at the current of 2 ma; 0.5 c/cm2 was found to be optimal. the pmea modified by ppy/gr at the 0.5 c/cm2 exhibits remarkable properties; for instance, the standard deviation (sd) decreases from 8.4614×10 -11 to 5.62×10-11 a, reduced by 33.52%, and the sensitivity increases from 2566.88 to 76114.65 μammcm-2, 29.65 times higher than the bare pt (platinum). a good linear relationship between the current and da concentration in the range of 0.30 to 61.71 μm was obtained, with a correlation coefficient of 0.997. the sensor is meaningful for neuroscience research and the treatment of neurological diseases. © 2014 science china press and springer-verlag berlin heidelberg.”

Golparvar, A. J., & Yapici, M. K.. (2018). Graphene-coated wearable textiles for EOG-based human-computer interaction. In 2018 IEEE 15th International Conference on Wearable and Implantable Body Sensor Networks, BSN 2018 Plain numerical DOI: 10.1109/BSN.2018.8329690DOI URLdirectSciHub download

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“Electrooculography (eog) is a well-known approach to analyze eye movement features. applications of eog can be found in various areas including medical diagnosis, neurosciences, control systems, sensors and interfaces for human-computer interaction (hci). however, standard gel-based electrodes limit wearability and portability which hinder the development of long-term eog monitoring applications. to overcome these limitations, we have employed graphene-coated fabric electrodes as suitable alternatives for the currently used silver/silver chloride (ag/agcl) ‘wet’ electrodes. proof of the concept is provided by side by side comparison of conventional electrodes and fabric electrodes in automatic blink detection with sequential multi-step thresholding algorithm. additionally, the eog biopotentials are converted into real-time digital signals which could be used as clock signals to facilitate the development of hci applications.”

Govindhan, M., & Chen, A.. (2016). Enhanced electrochemical sensing of nitric oxide using a nanocomposite consisting of platinum-tungsten nanoparticles, reduced graphene oxide and an ionic liquid. Microchimica Acta Plain numerical DOI: 10.1007/s00604-016-1936-yDOI URLdirectSciHub download

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“We describe a high-performance nitric oxide (no) sensor by using a nanocomposite consisting of platinum-tungsten alloy nanoparticles, sheets of reduced graphene oxide and an ionic liquid (ptw/rgo-il) that was deposited onto the surface of a glassy carbon (gc) electrode. the modified gc electrode exhibits excellent electrocatalytic activity toward the oxidation of no with a strong peak at 0.78 v vs. ag/agcl due to the synergistic effects of bimetallic ptw nanoparticles, reduced graphene oxide nanosheets and an ionic liquid. the sensor possesses a detection limit as low as 0.13 nm, high sensitivity (3.01 μa μm−1 cm2), and good selectivity over electroactive interferents that may exist in biological systems. the sensor was tested to selectively distinguish no in actual human serum and urine samples, confirming potential practical applications. in our perception, the approach described here may be extended to the fabrication of various kind of composites made from metal nanostructures, graphene and ionic liquids for medical and environmental analysis. [figure not available: see fulltext.]”

Monaco, A. M., & Giugliano, M.. (2015). Correction to Carbon-based smart nanomaterials in biomedicine and neuroengineering [Beilstein J. Nanotechnol. 5, (2014) 1849-1863] doi:10.3762/bjnano.5.196. Beilstein Journal of Nanotechnology Plain numerical DOI: 10.3762/bjnano.6.51DOI URLdirectSciHub download
Vázquez-Guardado, A., Yang, Y., Bandodkar, A. J., & Rogers, J. A.. (2021). Author Correction: Recent advances in neurotechnologies with broad potential for neuroscience research (Nature Neuroscience, (2020), 23, 12, (1522-1536), 10.1038/s41593-020-00739-8). Nature Neuroscience Plain numerical DOI: 10.1038/s41593-021-00813-9DOI URLdirectSciHub download

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“In the version of this article initially published, errors occurred in the text and fig. 2 legend. in the paragraph beginning ‘advances in materials science are essential attempts…’ the platinum–silicone composites should have been described as ‘300 µm electrode diameter, 35 nm thickness, 1.4 ocm2 impedance, 57 µc/cm2 cics.’ in the paragraph beginning ‘microand nanofabrication techniques …’ the array of 360 recording sites for fast addressing should have been described as having sampling rates of ~277 hz. in the paragraph beginning ‘another area of progress …’ single- or few-layer sheets of graphene should have been described as having impedances of 1.6 ocm2 and 91 ocm2, respectively, while structures defined by colloidal sphere lithography and traditional photolithography should have been described as having impedances of 1.63 ocm2 and 0.14 oµm2, respectively. in the paragraph beginning ‘incorporating lenses and imaging …’ the phrase ‘at high sampling rates (16 hz) and fine resolution (~15 µm)’ should have cited ref. 74. in the fig. 2 legend, panel f should read ‘flexible array of 360 gold electrodes (300 × 300 µm2, spaced by 500 µm) supported by a backplane of active matrix electronics on a thin (25 µm) polyimide substrate for micro-electrocorticography (10 × 9 mm2) from the auditory cortex at a density of 400 electrodes cm–2.’ the references for panels g and h were swapped; they should read ‘g, ref. 34, springer nature; h, ref. 29, aaas.’ the errors have been corrected in the pdf and html versions of this article.”

Nasri, B., Wu, T., Alharbi, A., Gupta, M., Ranjitkumar, R., Sebastian, S., … Shahrjerdi, D.. (2017). Heterogeneous integrated CMOS-graphene sensor array for dopamine detection. In Digest of Technical Papers - IEEE International Solid-State Circuits Conference Plain numerical DOI: 10.1109/ISSCC.2017.7870364DOI URLdirectSciHub download

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“Understanding dopamine (da) signaling in the brain is essential for advancing our knowledge of pathological disorders such as drug addiction, parkinson’s disease, and schizophrenia. currently, fast-scan cyclic voltammetry (fscv) with carbon microfiber (cmf) electrodes is the method of choice in neuroscience labs for monitoring the concentration of phasic (transient) da release. this method offers sub-second temporal resolution and high specificity because the signal of interest occurs at a known potential. however, existing cmf electrodes are bulky, limiting the spatial resolution to single-site measurements. further, they are produced through manual processes (e.g. cutting cmfs under optical microscope), thus introducing significant device variability [1]. lastly, when long probes (3-to-5cm) are used to monitor da release in deep brain structures of large animals, environmental noise severely diminishes the detection limit [1]. to address these problems, we combine advances in nanofabrication with silicon chip manufacturing to create a heterogeneous integrated cmos-graphene sensor for accurate measurement of da with high spatiotemporal resolution (fig. 15.7.1).”

Tasnim, N.. (2018). An Integrated Study Towards Curing Neurodegenerative Disorders Using Materials Science and Stem Cell-based Tissue Engineering Approaches. ProQuest Dissertations and Theses

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“Neurodegenerative diseases affect around one billion people globally that are characterized by irreversible degeneration of brain tissues. these diseases cause serious effects on patients degrading their brain functions and causing enormous physical and mental health issues. parkinson’s disease (pd) is one of the most common neurodegenerative disorder affecting millions of people worldwide which results from loss of dopaminergic (da) neurons in the mid-brain. unfortunately, no medical treatment is effective to date for these significant brain disorders, except some symptomatic therapies only focusing on improving the quality of patient’s life. two current approaches hold great promise in targeting pd as well as other neurodegenerative diseases, by surgically implanting electrodes for deep brain stimulation (dbs) and transplanting healthy neuronal cells at the site of tissue loss, due to disease in the brain. however, cells for transplantation need to be delivered via a scaffold. nerve regeneration in a scaffold of appropriate biomaterial is of great importance while being implanted inside the animal body for further clinical applications. in this dissertation, both approaches for treating pd were incorporated by in vitro studies using surface-engineering and tissue-engineering techniques. for the first approach, graphene oxide (go) coatings on commercially available 316l stainless steel (ss) surfaces was done to reduce the neurotoxicity of ss and modified surfaces showed hydrophilicity, biocompatibility, cell proliferation, and decreased reactive oxygen species (ros) expression with shsy-5y neuroblastoma cell lines. transplantation of stem cells in vivo is another approach for reducing the progression of pd by reversing the loss of affected da neurons. so, our second approach included differentiation of mesenchymal stem cells into da neurons using sonic hedgehog, fibroblast growth factor, basic fibroblast growth factor and brain-derived neurotrophic factor, while they were cultured within collagen coated three-dimensional (3d) graphene foams. 3d multilayer graphene scaffold could mimic the actual brain tissue environment and more closely exhibit morphologies, functions and other necessary characteristics compared to 2d culture on tissue culture plastic. the graphene-based scaffolds were not cytotoxic as cells seemed to retain viability and proliferated substantially during in vitro culture. these results suggest the utility of graphene-based mater…”

Rastogi, S. K., & Cohen-Karni, T.. (2019). Nanoelectronics for neuroscience. In Encyclopedia of Biomedical Engineering Plain numerical DOI: 10.1016/B978-0-12-801238-3.99893-3DOI URLdirectSciHub download

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“Characterizing the electrical activity between neuronal cells is crucial in understanding the complex processes in the brain, both in healthy and diseased tissue. neural interface technology that enables recording of the neuronal electrical activity as well as stimulation of the neurons has attracted great attention for both experimental and clinical applications. in this article, we discuss the fundamentals of the bioelectrical signals recording, and the advancements in the field of nano-bioelectronics, that is, the different kinds of materials and designs used to improve the cellular-device interface to enable recording and stimulation of the neuronal cells. furthermore, we discuss the development of synthetic biomaterials that enable fusion of electronics and bioactive scaffolds which are essential to regenerative engineering. we also discuss the technical and scientific challenges associated with these technologies, and the future prospects and opportunities.”

Salazar, P., Martín, M., Ford, R., O’Neill, R. D., & González-Mora, J. L.. (2018). Neurotransmitter microsensors for neuroscience. In Encyclopedia of Interfacial Chemistry: Surface Science and Electrochemistry Plain numerical DOI: 10.1016/B978-0-12-409547-2.13917-4DOI URLdirectSciHub download

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“Brain communication is mediated by exocytosis release of neurotransmitters into the synaptic cleft. over the last four decades researchers have explored diverse electrochemical techniques for sensing different oxidizable catecholamines such as dopamine, serotonin, and norepinephrine and their metabolites in individual cells, culture cells, and in in vivo applications. nowadays, carbon fiber microelectrodes are still the gold standard in neurochemical and neurophysiological studies although new materials, such as carbon nanotubes, polymers, graphene, and nanoparticles, have been introduced to improve their sensitivity, selectivity, and long-term stability. this article reviews the main issues involved in the design and application of such electrochemical microsensors for in vivo monitoring of key electroactive neurotransmitters.”

CHAPTER 4. Nanosensing the Brain. (2013) Plain numerical DOI: 10.1039/9781849735414-00130DOI URLdirectSciHub download

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“This chapter provides an overview of the features and application of emerging nanomaterials and miniaturized electronic circuits for in vitro neuroscience research. innovative detection methods and sensors based on nanomaterials offer unprecedented spatial and temporal resolution to elucidate patterns of neuronal firings less invasively and with better signal-to-noise ratio. the chapter begins with a brief discussion of nanoparticles and quantum dots{,} and their application in sensor technology. incorporation of one-dimensional nanostructures in cell cultures can be used to induce superior and directed neuronal adhesion and growth. possibilities for the use of nanowires as probes{,} nanoelectrodes{,} optical enhancers and electrical detectors are explored and the use of the amazing two-dimensional nanostructure graphene in the field of neuroscience is examined{,} including some of the challenges with incorporating graphene in sensing field effect transistors for detection of neural cells activity. example applications of nanotechnologies in neuroscience{,} ranging from sensing of structural deformation of cells to stimulation of neuroregeneration{,} are described. the chapter concludes with a perspective on the challenges and developments anticipated with the application of nanotechnologies in neuroscience.”

Liu, X., Lu, Y., & Kuzum, D.. (2018). Investigation of Propagating Cortical Waves and Spirals Recorded by High Density Porous Graphene Arrays. In Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS Plain numerical DOI: 10.1109/EMBC.2018.8512428DOI URLdirectSciHub download

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“Propagating waves along the cortical surface have recently attracted significant attention by the neuroscience community. however, whether these propagating waves imply network connectivity changes for the neural circuits is not known. in this work, we employ a high density porous graphene microelectrode array and perform in vivo experiments with rodents to investigate network connectivity during cortical propagating waves. the spatial-temporal analysis of the cortical recordings reveals various types of propagating waves across the recording area. network analysis results show that these propagating waves are consistent with the functional connectivity changes in the neural circuits, suggesting that the underlying network states are reflected by the cortical potential propagation patterns.”

Du, L., Hu, L., & Wu, C.. (2016). Micro/nano neuronal network cell biosensors. In Micro/Nano Cell and Molecular Sensors Plain numerical DOI: 10.1007/978-981-10-1658-5_6DOI URLdirectSciHub download

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“Neuronal network cell biosensors were developed by coupling the neuronal network with multisite detection devices. in this chapter, we will mainly focus on three major issues, including the patterned growth of neuronal networks, principles of various detection devices, and the application of neuronal network-based biosensors in the field of neuroscience and biomedicine. in the culture of neuronal networks, several neuronal patterning techniques will be discussed in detail, such as photolithography, micro-contact printing, microfluidics, etc. the transfection methods were employed in the bioengineering of neuronal networks in order to modify the function of neuronal network. in the field of neuronal network-based biosensor, there are two kinds of multisite detection devices: microelectrode array (mea) and field-effect transistor (fet). the basic working principle of fet and its advantages will be presented. based on this knowledge, two other emerging fetsutilized nanomaterials (graphene fet and nanowire fet) will also be introduced. at the end, some examples of neuronal network-based biosensors will be presented by discussing their application in the neuroscience research and drug detection.”

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Infektions”schutzgesetz” § 21 – Impfstoffe

§ 21 Impfstoffe
URL: https://www.gesetze-im-internet.de/ifsg/__21.html
Bei einer auf Grund dieses Gesetzes angeordneten oder einer von der obersten Landesgesundheitsbehörde öffentlich empfohlenen Schutzimpfung oder einer Impfung nach § 17a Absatz 2 des Soldatengesetzes dürfen Impfstoffe verwendet werden, die Mikroorganismen enthalten, welche von den Geimpften ausgeschieden und von anderen Personen aufgenommen werden können. Das Grundrecht der körperlichen Unversehrtheit (Artikel 2 Abs. 2 Satz 1 Grundgesetz) wird insoweit eingeschränkt.
Wie bei dem Begriff "Verteidigungsministerin" (cf. "United States Department of Defense" - welches in Wirklichkeit nicht verteidigt sondern brutale und unbegründete Angriffe ausführt) handelt es sich bei dem Begriff "Infektionsschutzgesetz" um einen psycholinguistisch strategisch eingesetzten Euphemismus. Die semantische Bedeutung wird invertiert (Bedeutungsumkehrung zu Zwecken der psychologischen Manipulation; sprich: Gehirnwäsche über Sprache).
Ein Euphemismus, auch: Glimpfwort, Beschönigung, Hehlwort, Hüllwort oder Verbrämung ist ein sprachlicher Ausdruck, der eine Person, eine Personengruppe, einen Gegenstand oder einen Sachverhalt beschönigend, mildernd oder in verschleiernder Absicht benennt. Das semantische Gegenstück zum Euphemismus ist der Dysphemismus. Dieser wertet das Bezeichnete ab und versieht es mit negativen Konnotationen. Beide, Euphemismus und Dysphemismus, gelten als rhetorische Figuren.
https://www.youtube.com/watch?v=QL4GmixjoB0

Am 1. Juli 1969 erschien ein hochrangiger Beamter des Pentagons für biologische Kriegsführung, Dr. Donald MacArthur, vor dem Unterausschuss für Bewilligungen des Verteidigungsministeriums des US-Repräsentantenhauses. Dr. MacArthur erklärte den versammelten Abgeordneten, dass es innerhalb der nächsten 5 bis 10 Jahre wahrscheinlich möglich sein würde, einen neuen infektiösen Mikroorganismus herzustellen, der sich in bestimmten wichtigen Aspekten von allen bekannten krankheitsverursachenden Organismen unterscheiden könnte. Der wichtigste davon ist, dass er widerspenstig gegenüber den immunologischen und therapeutischen Prozessen sein könnte, von denen wir abhängen, um unsere relative Freiheit von Infektionskrankheiten aufrechtzuerhalten ... [Er] informierte den Unterausschuss, dass ein Forschungsprogramm zur Erforschung der Durchführbarkeit der Entwicklung einer solchen Krankheit, "ein synthetischer biologischer Erreger, ein Erreger, der nicht natürlich existiert und gegen den keine natürliche Immunität erworben werden könnte", nur etwa 5 Jahre in Anspruch nehmen würde und 10 Millionen Dollar kosten würde.

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US Vollspektrum-Dominanz

Joint Vision 2020 war ein Dokument, das am 30. Mai 2000 vom Verteidigungsministerium der Vereinigten Staaten veröffentlicht wurde und die Notwendigkeit einer "Vollspektrum-Dominanz" auf dem Schlachtfeld proklamierte. Die Konzepte der Joint Vision 2020 bildeten in der Folge die Grundlage der Militärdoktrin der Vereinigten Staaten.

Das Dokument beschreibt die militärischen Bedrohungen, mit denen die Vereinigten Staaten im Jahr 2020 konfrontiert sein könnten, sowie mögliche Antworten auf diese Bedrohungen.

Original Text (PDF)

http://pentagonus.ru/doc/JV2020.pdf

Vollspektrum-Dominanz, auch bekannt als Vollspektrum-Überlegenheit, ist die Erlangung der Kontrolle über alle Dimensionen des Kampfraums durch eine militärische Einheit, die effektiv über eine überwältigende Vielfalt von Ressourcen in Bereichen wie terrestrische, luftgestützte, maritime, unterirdische, extraterrestrische, psychologische und bio- oder cyber-technologische Kriegsführung verfügt.

Die Beherrschung des gesamten Spektrums umfasst den physischen Kampfraum; Luft, Oberfläche und Unterwasser sowie das elektromagnetische Spektrum und den Informationsraum. Kontrolle bedeutet, dass die Freiheit der gegnerischen Streitkräfte, den Kampfraum zu nutzen, vollständig eingeschränkt ist.

Das Verteidigungsministerium der Vereinigten Staaten definiert "Vollspektrum-Überlegenheit" wie folgt:

Der kumulative Effekt der Dominanz in der Luft-, Land-, See- und Weltraumdomäne und der Informationsumgebung, die den Cyberspace einschließt, der die Durchführung gemeinsamer Operationen ohne wirksame Opposition oder unzulässige Störungen ermöglicht."[1]

Die Doktrin des US-Militärs vertritt die strategische Absicht, diesen Zustand in einem Konflikt entweder allein oder mit Verbündeten[2] zu erreichen, indem jeder Gegner besiegt und jede Situation im gesamten Bereich der militärischen Operationen kontrolliert wird.

Die erklärte Absicht impliziert erhebliche Investitionen in eine Reihe von Fähigkeiten: dominantes Manövrieren, Präzisionseinsatz, fokussierte Logistik und volldimensionaler Schutz.

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Hacking DNA

Bill Gates sagte kürzlich in einem Interview zu einem Reporter, dass er, wenn er heute ein Kind wäre, Computer hacken würde: Er würde Biologie hacken.

Exzerpt aus dem Buch „Storing Digital Binary Data in Cellular DNA: The New Paradigm“ (2020)

p.28

Looking at the bright side, biologists of the near future will figure out how to program viruses andbacteria to deliver custom-made cures that shrink cancerous tumors or reverse the tide of dementia.However, in the superscary scenario, bioterrorists could engineer deadly superbugs that target humanson a genetic level. In a 2012 article inThe Atlantic, a technologically plausible scheme was presentedin which the president of the United States is assassinated by a highly contagious cold, designed totarget a weak link in his specific genetic code.

Die Biologen der nahen Zukunft werden herausfinden, wie man Viren und Bakterien so programmieren kann, dass sie maßgeschneiderte Heilmittel liefern, die Krebstumore schrumpfen lassen oder die Flut von Demenzerkrankungen umkehren. In einem Artikel aus dem Jahr 2012 inThe Atlantic wurde ein technologisch plausibles Schema vorgestellt, in dem der Präsident der Vereinigten Staaten durch eine hochansteckende Erkältung ermordet wird, die auf eine Schwachstelle in seinem spezifischen genetischen Code abzielt.

https://www.theatlantic.com/magazine/archive/2012/11/hacking-the-presidents-dna/309147/
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Hacking der DNA des Präsidenten

Die US-Regierung sammelt heimlich die DNA von Staatsoberhäuptern der Welt, und schützt angeblich die von Barack Obama. Entschlüsselt könnten diese genetischen Blaupausen kompromittierende Informationen liefern. In nicht allzu ferner Zukunft könnten sie sogar noch mehr bieten - die Grundlage für die Entwicklung personalisierter Biowaffen, die einen Präsidenten ausschalten und keine Spuren hinterlassen könnten.
Von Andrew Hessel, Marc Goodman und Steven Kotler
Ausgabe November 2012

So ist die Zukunft angekommen. Es begann ganz harmlos, in den frühen 2000er Jahren, als Unternehmen zu erkennen begannen, dass hochqualifizierte Aufgaben, die zuvor intern von einem einzigen Mitarbeiter ausgeführt wurden, effizienter über das Internet an eine größere Gruppe von Menschen ausgelagert werden konnten. Zunächst wurde das Design von T-Shirts (Threadless.com) und das Schreiben von Enzyklopädien (Wikipedia.com) per Crowd-Sourcing vergeben, doch schon bald hielt der Trend Einzug in die härteren Wissenschaften. Schon bald wurden die Suche nach außerirdischem Leben, die Entwicklung von selbstfahrenden Autos und die Faltung von Enzymen zu neuartigen Proteinen auf diese Weise durchgeführt. Da die grundlegenden Werkzeuge der genetischen Manipulation - die keine zehn Jahre zuvor noch Millionen von Dollar gekostet hatten - rapide im Preis fielen, war das Design biologischer Wirkstoffe durch die Masse nur der nächste logische Schritt.

Im Jahr 2008 entstanden gelegentliche DNA-Design-Wettbewerbe mit kleinen Preisen; 2011, mit dem Start des 100-Millionen-Dollar-Wettbewerbs von GE zur Bekämpfung von Brustkrebs, entwickelte sich das Feld zu ernsthaften Wettbewerben. Anfang 2015, als personalisierte Gentherapien für Krebs im Endstadium zu einem Trend in der Medizin wurden, tauchten Websites für das Design von Viren auf, auf denen Menschen Informationen über ihre Krankheit hochladen und Virologen Entwürfe für eine individuelle Heilung veröffentlichen konnten. Aus medizinischer Sicht machte das alles durchaus Sinn: Die Natur hatte Äonen lang hervorragende Designarbeit an Viren geleistet. Mit ein wenig Umrüstung waren sie ideale Vehikel für die Übertragung von Genen.

Bald schon wurden diese Seiten mit Anfragen überschwemmt, die weit über Krebs hinausgingen. Diagnostika, Impfstoffe, antimikrobielle Mittel und sogar Designer-Psychopharmaka - alles stand auf der Speisekarte. Was die Menschen mit diesen Bio-Designs anstellten, war jedem selbst überlassen. Es gab noch kein internationales Gremium, das über sie wachte.

Als also im November 2016 ein Besucher mit dem Namen Cap'n Capsid zum ersten Mal eine Herausforderung auf der Viral-Design-Website 99Virions postete, schlug niemand Alarm; seine Anfrage war nur eine von etwa 100, die an diesem Tag eingereicht wurden. Cap'n Capsid war vielleicht ein Berater der pharmazeutischen Industrie und seine Aufgabe nur ein weiterer Versuch, die sich radikal verändernde Forschungs- und Entwicklungslandschaft zu verstehen - eigentlich hätte er jeder sein können -, aber das Problem war trotzdem interessant. Außerdem bot Capsid 500 Dollar für den Siegerentwurf, keine schlechte Summe für ein paar Stunden Arbeit.
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Später zeigten die Logdateien von 99Virions, dass die IP-Adresse von Cap'n Capsid aus Panama stammte, obwohl dies wahrscheinlich eine Fälschung war. Die Design-Spezifikation selbst ließ keine roten Fahnen aufkommen. Geschrieben in SBOL, einer Open-Source-Sprache, die in der synthetischen Biologie sehr beliebt ist, schien es sich um eine Standard-Impfstoffanforderung zu handeln. Also machten sich die Leute einfach an die Arbeit, ebenso wie die automatischen Computerprogramme, die für die "Auto-Evolution" neuer Designs geschrieben worden waren. Diese Algorithmen wurden ziemlich gut und gewannen nun fast ein Drittel der Herausforderungen.

Innerhalb von 12 Stunden wurden 243 Designs eingereicht, die meisten von diesen computerisierten Expertensystemen. Doch dieses Mal war der Gewinner, GeneGenie27, tatsächlich ein Mensch - ein 20-jähriger Student der Columbia University mit einem Händchen für Virologie. Sein Entwurf wurde schnell an einen florierenden Online-Biomarktplatz in Shanghai weitergeleitet. Weniger als eine Minute später erhielt ein isländisches Synthese-Start-up den Auftrag, den 5.984-Basen-Paar-Bauplan in tatsächliches genetisches Material zu verwandeln. Drei Tage später wurde ein Paket mit 10-Milligramm-Mikrotabletten, die sich schnell auflösen, in einen FedEx-Umschlag gesteckt und an einen Kurier übergeben.

Zwei Tage später erhielt Samantha, eine Studentin im zweiten Semester an der Harvard University, das Paket. In dem Glauben, es enthalte ein neues synthetisches Psychedelikum, das sie online bestellt hatte, schob sie sich am Abend eine Tablette in ihr linkes Nasenloch und ging dann zu ihrem Kleiderschrank. Als Samantha mit dem Anziehen fertig war, hatte die Tablette begonnen, sich aufzulösen, und ein paar Stränge des fremden genetischen Materials waren in die Zellen ihrer Nasenschleimhaut eingedrungen.

Irgendeine Partydroge - alles, was sie bekam, schien eine Grippe zu sein. Später in der Nacht hatte Samantha leichtes Fieber und schüttete Milliarden von Viruspartikeln aus. Diese Partikel verbreiteten sich um...
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