Ultrasensitive and selective real-time detection of neurotransmitters for brain-on-a-chip applications

Samuel Rantataro

Ultrasensitive and selective real-time detection of neurotransmitters for brain-on-a-chip applications

Julkaisun otsikon käännös: Ultraherkät ja selektiiviset anturit hermovälittäjäaineiden reaaliaikaiseen mittaamiseen aivosiruteknologiassa

Samuel Rantataro

Tutkimustuotos: Doctoral Thesis › Collection of Articles

Abstrakti

Neurologiset sairaudet ovat vuosittain osallisena jopa 10 miljoonassa kuolemassa ja määrän odotetaan kasvavan ikääntyvän väestön lisääntyessä. Toistaiseksi saatavilla on ainoastaan oireita lievittäviä lääkkeitä, eikä sairauksia parantavia kohdennettuja lääkkeitä ole pystytty kehittämään. Vaikka eläinkokeissa onkin saatu lupaavia tuloksia kohdennettujen lääkkeiden käytöstä neurologisten sairauksien hoidossa, niiden tuloksia ei ole pystytty toistamaan ihmisissä. Haasteet kokeiden toistamisessa selittyvät muun muassa eroilla ihmisen ja koe-eläimen genomissa sekä hermostossa itsessään, minkä vuoksi tauti- ja lääketutkimuksessa olisi optimaalisinta käyttää ihmisen hermoston soluja. Aivo-organoidien ja muidenkin aivomallien käyttöön lääketutkimuksessa liittyy kuitenkin monia vaikeuksia, joista merkittävin kytkeytyy organoidien karakterisoimisen hitauteen. Mikäli organoidien vastetta eri lääkeaineille ei voida karakterisoida riittävän nopeasti tai monipuolisesti, lääkkeiden kehitys hidastuu merkittävästi. Sähkökemiallisia mittauksia voidaan hyödyntää organoidien olotilan tutkimisessa, erityisesti kun tavoitteena on tutkia tiettyä hermosolutyyppiä kaikkien solutyyppien joukosta. Sähkökemiallisia mittauksia kuitenkin vaikeuttaa elatusaineiden aiheuttama elektrodien likaantuminen, joka pienentää sensoreiden herkkyyttä merkittävästi. Tässä väitöskirjassa kehitettiin yksiseinämäisistä hiilinanoputkista valmistettuja sähkökemiallisia antureita hermovälittäjäaineiden reaaliaikaiseen mittaamiseen monimutkaisista aivo-malleista. Koska ihmisaivoja mahdollisimman tarkasti mallintavat aivomallit ovat erittäin herkkiä ympäristön vaikutuksille, sensorimateriaalien täytyy olla äärimmäisen bioyhteensopivia. Muutoin soluviljelmät muuttuvat epänormaaleiksi tai äärimmäisissä tapauksissa jopa tuhoutuvat kokonaan. Tässä väitöskirjassa havaittiin, että yksiseinämäisistä hiilinanoputkista tehdyt elektrodit mahdollistivat myös kaikkein herkimpienkin in vitro aivomallien selviytymisen elektrodin päällä. Biologisissa koejärjestelyissä käytetyistä karakterisointitekniikoista suurin osa perustuu käänteiseen mikroskopiaan, eli objektiivi sijaitsee näytteen alapuolella. Tämän vuoksi myös elektrodin olisi oltava läpinäkyvä, jotta sen päällä olevia aivomalleja voitaisiin tutkia mikroskopian menetelmin. Sähkökemiallisissa antureissa käytetyistä materiaaleista vain murto-osa on läpinäkyviä. Yksiseinämäisistä hiilinanoputkista voidaan kuitenkin valmistaa sähköisesti johtavia kalvoja yli 90 % läpinäkyvyydellä, kuten tässä väitöskirjassa on osoitettu. Yksiseinämäisistä hiilinanoputkista tehdyt ohutkalvot ovatkin siten hyvin ainutlaatuinen elektrodimateriaali, täyttäen kaikki aivosiru-teknologian vaatimukset.

Julkaisun otsikon käännös	Ultraherkät ja selektiiviset anturit hermovälittäjäaineiden reaaliaikaiseen mittaamiseen aivosiruteknologiassa
Alkuperäiskieli	Englanti
Pätevyys	Tohtorintutkinto
Myöntävä instituutio	Aalto-yliopisto
Valvoja/neuvonantaja	Laurila, Tomi, Vastuuprofessori Airavaara, Mikko, Ohjaaja, Ulkoinen henkilö
Kustantaja	Aalto University
Painoksen ISBN	978-952-64-1854-4
Sähköinen ISBN	978-952-64-1855-1
Tila	Julkaistu - 2024
OKM-julkaisutyyppi	G5 Artikkeliväitöskirja

Tutkimusalat

aivosiru
hermovälittäjäaine
sähkökemia
anturi
läpinäkyvä
dopamiini

YK:n kestävän kehityksen tavoitteet

Tämä tuotos edistää seuraavia kestävän kehityksen tavoitteita:

Pääsy asiakirjaan

http://urn.fi/URN:ISBN:978-952-64-1855-1

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Rissanen, A. (Manager)
Aalto-yliopisto
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Repo, P. (Manager) & Rissanen, A. (Other)
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@phdthesis{d3ac32054f47493fb885a02597933f9c,

title = "Ultrasensitive and selective real-time detection of neurotransmitters for brain-on-a-chip applications",

abstract = "Neurological diseases account annually up to 10 million deaths and the number is expected to increase as the population ages. Up to date, drug discovery has had 0% success rate to find disease modifying treatment for central nervous system diseases, mainly arising from extremely poor translation of results from animal studies to us humans. To overcome this limitation, human cellbased brain models are being rapidly adopted into academic neuroscientific research but also in the pharmaceutical industry. Unfortunately, the use of these brain models is limited by lack of highthroughput characterization methods. Electrochemical measurements can be used to examine the condition of specific cell types in the brain models, however this is severely complicated by the highly-fouling nature of cell culture medium. As complex in vitro brain models are extremely delicate, electrochemical recordings must be performed in the culture medium instead of highly clean electrolytes. By using electrochemical sensors prepared from single-walled carbon nanotube (SWCNT) films, real-time detection of neurotransmitters at nanomolar sensitivity was demonstrated in culture medium for the first time. Arising from the sensitivity of brain model cultures, biocompatibility of the sensor materials is essential because otherwise the brain-on-a-chip will lack the {"}brain{"} component. Healthy development of all the most-sensitive and complex in vitro brain models were observed with the SWCNT electrodes, including primary dopaminergic neurons, induced human pluripotent stem cell-derived neurons, but also human brain organoids. Lastly, many biological characterization techniques are based on inverse microscopy and thus, optical transparency is necessary. While transparent substrates could be used to obtain partial visibility for non-transparent microelectrode array, the electrode areas and electrical wiring remain out of sight. Contrasting that, the SWCNT films are highly conductive and can be made with 90% transparency to obtain complete visibility. While many materials are claimed to meet the requirements of brain-on-a-chip devices, more thorough investigation reveals that such claims are mistakenly made and actually only concern individual components from the ensemble of strict specifications. Furthermore, these earlier claims have been made based on highly simplified and misleading experimental settings. SWCNTs are thus a very unique electrode material, as they are currently the only material fulfilling all the requirements of brain-on-a-chip devices, paving way for broader adoption of the technology.",

keywords = "brain-on-a-chip, neurotransmitter, electrochemistry, sensor, transparent, dopamine, aivosiru, hermov{\"a}litt{\"a}j{\"a}aine, s{\"a}hk{\"o}kemia, anturi, l{\"a}pin{\"a}kyv{\"a}, dopamiini, brain-on-a-chip, neurotransmitter, electrochemistry, sensor, transparent, dopamine",

author = "Samuel Rantataro",

year = "2024",

language = "English",

isbn = "978-952-64-1854-4",

series = "Aalto University publication series DOCTORAL THESES",

publisher = "Aalto University",

number = "117",

address = "Finland",

school = "Aalto University",

}

TY - BOOK

T1 - Ultrasensitive and selective real-time detection of neurotransmitters for brain-on-a-chip applications

AU - Rantataro, Samuel

PY - 2024

Y1 - 2024

N2 - Neurological diseases account annually up to 10 million deaths and the number is expected to increase as the population ages. Up to date, drug discovery has had 0% success rate to find disease modifying treatment for central nervous system diseases, mainly arising from extremely poor translation of results from animal studies to us humans. To overcome this limitation, human cellbased brain models are being rapidly adopted into academic neuroscientific research but also in the pharmaceutical industry. Unfortunately, the use of these brain models is limited by lack of highthroughput characterization methods. Electrochemical measurements can be used to examine the condition of specific cell types in the brain models, however this is severely complicated by the highly-fouling nature of cell culture medium. As complex in vitro brain models are extremely delicate, electrochemical recordings must be performed in the culture medium instead of highly clean electrolytes. By using electrochemical sensors prepared from single-walled carbon nanotube (SWCNT) films, real-time detection of neurotransmitters at nanomolar sensitivity was demonstrated in culture medium for the first time. Arising from the sensitivity of brain model cultures, biocompatibility of the sensor materials is essential because otherwise the brain-on-a-chip will lack the "brain" component. Healthy development of all the most-sensitive and complex in vitro brain models were observed with the SWCNT electrodes, including primary dopaminergic neurons, induced human pluripotent stem cell-derived neurons, but also human brain organoids. Lastly, many biological characterization techniques are based on inverse microscopy and thus, optical transparency is necessary. While transparent substrates could be used to obtain partial visibility for non-transparent microelectrode array, the electrode areas and electrical wiring remain out of sight. Contrasting that, the SWCNT films are highly conductive and can be made with 90% transparency to obtain complete visibility. While many materials are claimed to meet the requirements of brain-on-a-chip devices, more thorough investigation reveals that such claims are mistakenly made and actually only concern individual components from the ensemble of strict specifications. Furthermore, these earlier claims have been made based on highly simplified and misleading experimental settings. SWCNTs are thus a very unique electrode material, as they are currently the only material fulfilling all the requirements of brain-on-a-chip devices, paving way for broader adoption of the technology.

AB - Neurological diseases account annually up to 10 million deaths and the number is expected to increase as the population ages. Up to date, drug discovery has had 0% success rate to find disease modifying treatment for central nervous system diseases, mainly arising from extremely poor translation of results from animal studies to us humans. To overcome this limitation, human cellbased brain models are being rapidly adopted into academic neuroscientific research but also in the pharmaceutical industry. Unfortunately, the use of these brain models is limited by lack of highthroughput characterization methods. Electrochemical measurements can be used to examine the condition of specific cell types in the brain models, however this is severely complicated by the highly-fouling nature of cell culture medium. As complex in vitro brain models are extremely delicate, electrochemical recordings must be performed in the culture medium instead of highly clean electrolytes. By using electrochemical sensors prepared from single-walled carbon nanotube (SWCNT) films, real-time detection of neurotransmitters at nanomolar sensitivity was demonstrated in culture medium for the first time. Arising from the sensitivity of brain model cultures, biocompatibility of the sensor materials is essential because otherwise the brain-on-a-chip will lack the "brain" component. Healthy development of all the most-sensitive and complex in vitro brain models were observed with the SWCNT electrodes, including primary dopaminergic neurons, induced human pluripotent stem cell-derived neurons, but also human brain organoids. Lastly, many biological characterization techniques are based on inverse microscopy and thus, optical transparency is necessary. While transparent substrates could be used to obtain partial visibility for non-transparent microelectrode array, the electrode areas and electrical wiring remain out of sight. Contrasting that, the SWCNT films are highly conductive and can be made with 90% transparency to obtain complete visibility. While many materials are claimed to meet the requirements of brain-on-a-chip devices, more thorough investigation reveals that such claims are mistakenly made and actually only concern individual components from the ensemble of strict specifications. Furthermore, these earlier claims have been made based on highly simplified and misleading experimental settings. SWCNTs are thus a very unique electrode material, as they are currently the only material fulfilling all the requirements of brain-on-a-chip devices, paving way for broader adoption of the technology.

KW - brain-on-a-chip

KW - neurotransmitter

KW - electrochemistry

KW - sensor

KW - transparent

KW - dopamine

KW - aivosiru

KW - hermovälittäjäaine

KW - sähkökemia

KW - anturi

KW - läpinäkyvä

KW - dopamiini

KW - brain-on-a-chip

KW - neurotransmitter

KW - electrochemistry

KW - sensor

KW - transparent

KW - dopamine

M3 - Doctoral Thesis

SN - 978-952-64-1854-4

T3 - Aalto University publication series DOCTORAL THESES

PB - Aalto University

ER -

Ultrasensitive and selective real-time detection of neurotransmitters for brain-on-a-chip applications

Abstrakti

Tutkimusalat

YK:n kestävän kehityksen tavoitteet

Pääsy asiakirjaan

Sormenjälki

Laitteet

OtaNano

OtaNano Nanofab

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