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Label free urea biosensor based on organic electrochemical transistors
Univ Modena and Reggio Emilia, Italy.
Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering. RISE Acreo, Sweden.
Univ Modena and Reggio Emilia, Italy.
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2018 (English)In: FLEXIBLE AND PRINTED ELECTRONICS, ISSN 2058-8585, Vol. 3, no 2, article id 024001Article in journal (Refereed) Published
Abstract [en]

The quantification of urea is of the utmost importance not only in medical diagnosis, where it serves as a potential indicator of kidney and liver disfunction, but also in food safety and environmental control. Here, we describe a urea biosensor based on urease entrapped in a crosslinked gelatin hydrogel, deposited onto a fully printed PEDOT:PSS-based organic electrochemical transistor (OECT). The device response is based on the modulation of the channel conductivity by the ionic species produced upon urea hydrolysis catalyzed by the entrapped urease. The biosensor shows excellent reproducibility, a limit of detection as low as 1 mu M and a response time of a few minutes. The fabrication of the OECTs by screen-printing on flexible substrates ensures a significant reduction in manufacturing time and costs. The low dimensionality and operational voltages (0.5 V or below) of these devices contribute to make these enzymatic OECT-based biosensors as appealing candidates for high-throughput monitoring of urea levels at the point-of-care or in the field.

Place, publisher, year, edition, pages
IOP PUBLISHING LTD , 2018. Vol. 3, no 2, article id 024001
Keywords [en]
organic bioelectronics; urease; gelatin; OECT; screen-printing
National Category
Environmental Sciences
Identifiers
URN: urn:nbn:se:liu:diva-160143DOI: 10.1088/2058-8585/aac8a8ISI: 000435373100001OAI: oai:DiVA.org:liu-160143DiVA, id: diva2:1349348
Note

Funding Agencies|Swedish Foundation for Strategic Research [RIT15-0119]; BIORAPID project [643056]; Fondazione di Vignola

Available from: 2019-09-09 Created: 2019-09-09 Last updated: 2021-09-21
In thesis
1. Organic Bioelectronic Devices for Selective Biomarker Sensing: Towards Integration with Living Systems
Open this publication in new window or tab >>Organic Bioelectronic Devices for Selective Biomarker Sensing: Towards Integration with Living Systems
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inorganic materials have been the main players of the semiconductor industry for the past forty years. However, there has been a continuous interest and growth in the research and in the application of organic semiconductors (OSCs) as active materials in electronic devices, due to the possibility to process these materials at low temperature on flexible substrates, fabricate them on large-area, and upscale their fabrication using cost-effective strategies such as printing. Because of these features, organic electronic devices are rapidly emerging as biosensors for biomarkers, with a high potential for becoming a high-throughput tool even deployable at the point-of-care.  

One of the most used and studied platforms is the organic electrochemical transistor (OECT). OECTs have been largely used as biosensors in order to transduce and amplify electrical signals or detect biological analytes upon proper functionalization with specific biorecognition units. OECTs can operate at low voltages, are easy to fabricate on different substrates, and are compatible with the aqueous environment, and can therefore be interfaced with living systems, ranging from mammals to plants. The OECT device configuration includes a gate electrode that modulates the current in the channel through an electrolyte, which can be not only a buffered solution but even a complex biological fluid. When OECTs are operated as biosensors, the sensing mechanism relies on the current variation generated from specific reactions with the analyte of interest. These devices are paving the way to the development of point-of-care technologies and portable biosensors with fast and label-free detection. Moreover, OECTs can help to reveal new biological insight and allow a better understanding of physiological processes. 

During my PhD, I focused on design, fabrication, and validation of different OECT-based biosensors for the detection of biomarkers that are relevant for healthcare applications, thus showing their high potential as a proper sensing platform. We developed sensors towards different analytes, ranging from small molecules to proteins, with ad hoc designed materials strategies to endow the device with selectivity towards the species of interest. Most notably, I also demonstrated the possibility of integrating OECTs in plants, as an example of interfacing these biosensors with living systems. In the first two papers, we developed screen printed OECTs, presenting PEDOT:PSS as the semiconducting material on the channel. In the first case, the device also featured a PEDOT:PSS gate electrode which was further functionalized with biocompatible gelatin and the enzyme urease to ensure selectivity toward the analyte of interest, namely urea. The biosensor was able to monitor increasing urea concentrations with a limit of detection of 1 µM. In the second paper the screen-printed carbon gate electrode was first modified with platinum and then we ensured selectivity towards the analyte uric acid, a relevant biomarker for wound infection, by entrapping urate oxidase in a dual-ionic-layer hydrogel membrane to filter out charged interfering agents. The biosensor exhibited a 4.5 µM limit of detection and selectivity even in artificial wound exudate. In the third paper we designed an interleukin-6 (IL6) OECT based biosensor able to detect the cytokine down to the pM regime in PBS buffer. The mechanism of detection relied on the specific binding between an aptamer, used as sensing unit on the gate electrode, and the IL6 in solution, allowing for detection ranging from physiological to pathological levels. 

In the last two papers we developed OECT based biosensors to be interfaced with the plant world. In the fourth paper we presented a glucose sensor, based on the enzyme glucose oxidase (GOx) to detect glucose export from chloroplasts. In particular, we demonstrated real-time glucose monitoring with temporal resolution of 1 minute in complex media. In the fifth paper, we developed implantable OECT-based sugar sensors for in vivo real-time monitoring of sugar transport in poplar trees. The biosensors presented a multienzyme-functionalized gate endowing the device with specificity towards glucose and sucrose. Most notably, the OECT sensors did not cause a significant wound response in the plant, allowing us to demonstrate that OECT-based sensors are attractive tools for studying transport kinetics in plants, in vivo and real-time.

Abstract [sv]

Oorganiska material har varit huvudaktörerna i halvledarindustrin under de senaste fyrtio åren. Det har emellertid funnits ett kontinuerligt intresse och tillväxt inom forskning för tillämpningar av organiska halvledare (OSC) som aktiva material i elektroniska apparater, på grund av möjligheten att bearbeta dessa material vid låga temperaturer, på flexibla substrat, tillverka dem på stora ytor och skala med kostnadseffektiva strategier såsom tryckning. På grund av dessa funktioner växer organiska elektroniska enheter snabbt fram som biosensorer för biomarkörer, med hög potential att bli ett genomgående verktyg som även kan användas vid vårdplatsen. En av de mest använda och studerade plattformarna är den organiska elektrokemiska transistorn (OECT). OECT har i stor utsträckning använts som biosensorer för att transducera och förstärka elektriska signaler eller upptäcka biologiska analyter vid korrekt funktionalisering med specifika bio-igenkännande enheter. OECT kan fungera vid låga spänningar, de är lätta att tillverka på olika substrat och kompatibla med den vattenhaltiga miljöer, därför kan de kopplas till levande system, allt från däggdjur till växter. Dessa enheter banar väg för utvecklingen av point-of-care teknologier och portabla biosensorer med snabb och etikettfri detektering. Dessutom kan de hjälpa till att avslöja nya biologiska insikter och möjliggöra en bättre förståelse för fysiologiska processer.  OECT-enhetens konfiguration inkluderar en gate-elektrod som modulerar strömmen i kanalen genom en elektrolyt, som inte endast behöver vara en buffrad lösning utan till och med en komplex biologisk vätska. När OECT används som biosensorer är avkänningsmekanismen beroende av spänningsvariationen som genereras från specifika reaktioner med analyten av intresse. Under min doktorsexamen fokuserade jag på design, tillverkning och validering av olika OECT-baserade biosensorer för detektering av biomarkörer som är relevanta för tillämpningar inom vård och visar därmed deras höga potential som riktiga avkänningsplattformer. Vi utvecklade sensorer för olika analyter, allt från små molekyler till proteiner, med ad hoc-designad materialstrategi för att ge enheten selektivitet gentemot arten av intresse. Framför allt visade jag också möjligheten att integrera OECT i växter, som ett exempel på gränssnittet mellan dessa biosensorer och levande system. I de två första artiklarna utvecklade vi skärmtryckta OECT: er och presenterade PEDOT: PSS som halvledande material i kanalen. I det första fallet innehöll anordningen också en PEDOT:PSS gate-elektrod som ytterligare funktionaliserades med biokompatibelt gelatin och enzymet ureas för att säkerställa selektivitet mot analyten av intresse, nämligen urea. Biosensorn kunde övervaka ökande ureakoncentrationer med en detektionsgräns på 1 μM. I den andra artikeln modifierades först den skärmtryckta kol baserade gate-elektroden med platina och sedan säkerställde vi selektivitet mot analyten urinsyra, en relevant biomarkör för sårinfektion, genom att fånga upp uratoxidas i ett dubbelt jonskikt hydrogel-membran för att filtrera bort laddade störande medel. Biosensorn uppvisade en detektions- och selektivitetsgräns på 4.5 μM även i artificiell sårutsöndring. I den tredje artikeln designade vi en interleukin-6 (IL6) OECT-baserad biosensor som kunde detektera cytokinnivåer ner till pikomolar nivåer i PBS-buffert. Detektionsmekanismen är beroende av den specifika bindningen mellan en aptamer, som används som avkänningsenhet hos gate-elektroden, och IL6 i lösning, vilket möjliggör detektering som sträcker sig från fysiologiska till patologiska nivåer. 

I de två sista artiklarna utvecklade vi OECT-baserade biosensorer för att koppla samman med växtvärlden. I den fjärde artikeln uppvisade vi en glukossensor, baserad på enzymet glukosoxidas (GOx) för att detektera glukosexport från kloroplast. I synnerhet visade vi glukosövervakning i realtid med tidsmässig upplösning på 1 minut i komplexa medier. I den andra artikeln utvecklade vi implanterbara OECT-baserade sockersensorer för in vivo, realtidsövervakning av sockertransport i poppelträd. Biosensorerna presenterade en multienzymfunktionaliserad gate som ger enheten specificitet mot glukos och sackaros. Framför allt orsakade inte OECT-sensorerna signifikant sårrespons i växterna, vilket gjorde att vi kunde visa att OECT-baserade sensorer är attraktiva verktyg för att studera transportkinetik i växter, in vivo och realtid.     

Abstract [it]

I materiali inorganici sono stati i protagonisti dell'industria dei semiconduttori negli ultimi quarant'anni. Tuttavia, c'è un continuo interesse e crescita nella ricerca e nell'applicazione di semiconduttori organici (OSC) come materiali per dispositivi elettronici, grazie alla possibilità di processarli a bassa temperatura, su substrati flessibili e di fabbricarli utilizzando diverse strategie come lo stampaggio. Grazie a queste caratteristiche, i dispositivi elettronici organici stanno rapidamente emergendo come piattaforme per biosensori di biomarcatori, con un forte potenziale di diventare uno strumento utilizzabile come point-of-care. 

Una delle piattaforme più utilizzate e studiate è il Transistor Elettrochimico Organico (OECT). Gli OECT sono stati ampiamente utilizzati come biosensori per trasdurre e amplificare segnali elettrici o rilevare analiti biologici previa funzionalizzazione con specifiche unità di bioriconoscimento. Gli OECT possono operare a basso voltaggio, sono facili da fabbricare su diversi substrati e compatibili con l'ambiente acquoso, quindi possono essere interfacciati con sistemi viventi, dai mammiferi al mondo vegetale. La configurazione degli OECT include un elettrodo di gate che modula la corrente nel canale attraverso un elettrolita, che può essere non solo una soluzione tampone ma anche un fluido biologico complesso. Quando gli OECT vengono utilizzati come biosensori, il meccanismo di rilevamento si basa sulla variazione di corrente generata da reazioni specifiche con l'analita di interesse. 

Durante il mio dottorato di ricerca, mi sono concentrata sulla progettazione, fabbricazione e validazione di biosensori basati su OECT per il rilevamento di biomarcatori per applicazioni cliniche e ambientali, mostrando il loro potenziale come piattaforma di rilevamento. Abbiamo sviluppato sensori verso diversi tipi di analiti, dalle piccole molecole alle proteine, usando materiali progettati ad hoc per dotare i dispositivi di selettività verso le specie di interesse. In particolare, abbiamo anche dimostrato la possibilità di integrare gli OECT nelle piante, per dimostrare la loro compatibilita´ con sistemi viventi. Nei primi due articoli, abbiamo sviluppato OECT stampati, che presentano PEDOT:PSS come materiale semiconduttore sul canale. Nel primo caso, il dispositivo presenta anche un elettrodo di gate di PEDOT:PSS che è stato ulteriormente funzionalizzato con gelatina biocompatibile e l'enzima ureasi per garantire la selettività verso l'analita di interesse, ovvero l'urea. Il biosensore è in grado di monitorare varie concentrazioni di urea con un limite di detection di 1µM. Nel secondo articolo l'elettrodo di gate di carbonio stampato è stato prima modificato con platino e succesivamente abbiamo assicurato la selettività del biosensore verso l'acido urico, un biomarcatore rilevante per l'infezione di ferite, intrappolando l'urato ossidasi in una membrana a doppio strato ionico per filtrare gli interferenti. Il biosensore ha un limite di rilevamento di 4,5 µM anche in essudato artificiale ed e´selettivo per l´analita di interesse. Nel terzo articolo abbiamo progettato un biosensore per la detection di interleuchina-6 (IL6) in grado di rilevare livelli di citochina in concentrazioni pM in PBS. Il meccanismo di rilevamento si basa sul legame specifico tra un aptamero, utilizzato come unità di rilevamento sull'elettrodo di gate, e l'IL6 in soluzione, consentendo il rilevamento da livelli fisiologici a patologici. 

Negli ultimi due articoli abbiamo sviluppato biosensori basati su OECT per interfacciare il mondo vegetale. Nel quarto articolo abbiamo presentato un sensore, basato sull'enzima glucosio ossidasi (GOx) per rilevare l'esportazione di glucosio da cloroplasti. In particolare, abbiamo dimostrato il monitoraggio di glucosio in tempo reale con una risoluzione temporale di 1 minuto. Nel secondo articolo, abbiamo sviluppato sensori impiantabili basati su OECT per il monitoraggio in vivo e in tempo reale del trasporto di zuccheri negli alberi di pioppo. I biosensori presentano un elettrodo di gate funzionalizzato con diversi enzimi in modo da conferire al dispositivo una specificità nei confronti di glucosio e saccarosio. In particolare, i dispositivi non hanno causato singificativi danni al tessuto, consentendoci di dimostrare che i sensori basati su OECT possono rappresentatere soluzioni alternative per studiare la cinetica di trasporto nelle piante, in vivo e in tempo reale.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2021. p. 55
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 2176
National Category
Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:liu:diva-179471 (URN)10.3384/diss.diva-179471 (DOI)9789179290399 (ISBN)
Public defence
2021-11-05, K1, Kåkenhus, Campus Norrköping, Norrköping, 10:00 (English)
Opponent
Supervisors
Available from: 2021-09-21 Created: 2021-09-21 Last updated: 2021-11-11Bibliographically approved

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