Les dispositifs optoélectroniques organiques possèdent plusieurs avantages pour les applications dans le domaine du biomédical. Le photodétecteur organique (OPD) est un type de dispositif optoélectronique qui n’est pas encore utilisé pour la détection d’activité cérébrale. L’objectif de cette thèse a été d’explorer l’utilisation des OPD, constitués de différent matériaux donneur-accepteur d’électrons, dans le domaine des neurosciences. Nous avons présenté différent types d’OPD possédant une structure minimale, une excellente sensibilité et un grand potentiel d’intégration dans les méthodes de microfabrication existantes. Les détecteurs organiques ont été utilisés pour l’enregistrement de signaux optiques intrinsèques et de signaux fluorescents reflétant l’activité du calcium dans le cerveau. De plus, un autre aspect des OPD est présenté (en combinaison avec les transistors électrochimiques organiques (OECT)) : des systèmes électroniques biomimétiques basé sur une architecture électronique neuro-inspirée. Cette thèse démontre le potentiel des OPD pour enregistrer des activités cérébrales. Elle ouvre une nouvelle perspective, grâce à leur grande sensibilité, comme capteur optique en combinaison avec des dispositifs neuronaux implantables. Ceci élargira les frontières de l’électrophysiologie optique pour explorer les mécanismes complexes du cerveau et des maladies neurodégénératives. / Organic optoelectronic devices have many promising qualities for biomedical applications. Organic photodetectors (OPD), one type of such devices, have yet to be utilized for the detection of signals in the brain, to the best of our knowledge. The goal of this thesis was to explore the use of OPDs, based on different electron-donor and -acceptor materials in neuroscience applications. Different types of minimal-structure OPDs are presented, which have an excellent sensitivity and a high potential for incorporation into existing microfabrication methods. The organic sensors were utilized for monitoring the brain’s intrinsic optical signals and fluorescent calcium dynamics. Additionally, another aspect of these devices is presented (in combination with organic electrochemical transistors (OECT)): neuroinspired electronics, electronics that mimic biology. This thesis establishes the promise of OPDs for monitoring brain activities, which would lead to their integration, as high-sensitive micron-scale optical sensors in organic neural probes. Such device would result in exploring optical biological activities in the deep brain on the cellular level and would push the frontiers of optical-electrophysiology by giving a better understanding of complex mechanisms of the brain function and neurodegenerative diseases.

Pas de résumé en français seulement en anglais / The emergence of organic electronics – a technology that relies on carbon-based semiconductors to deliver devices with unique properties – represents one of the most dramatic developments of the past two decades. A rapidly emerging new direction in the field involves the interface with biology. The “soft” nature of organics offers better mechanical compatibility with tissue than traditional electronic materials, while their natural compatibility with mechanically flexible substrates suits the non-planar form factors often required for implants. More importantly, their ability to conduct ions in addition to electrons and holes opens up a new communication channel with biology. The coupling of electronics with living tissue holds the key to a variety of important life-enhancing technologies. One example is bioelectronic implants that record neural signals and/or electrically stimulate neurons. These devices offer unique opportunities to understand and treat conditions such as hearing and vision loss, epilepsy, brain degenerative diseases, and spinal cord injury.The engineering aspect of the work includes the development of a photolithographic process to integrate the conducting polymer poly(3,4-ethylenedioxythiophene: poly(styrene sulfonate) (PEDOT:PSS) with parylene C supports to make an active device. The technology is used to fabricate electrocorticography (ECoG) probes, high-speed transistors and wearable biosensors. The experimental work explores the fundamentals of communication at the interface between conducting polymers and the brain. It is shown that conducting polymers outperform conventional metallic electrodes for brain signals recording.Organic electrochemical transistors (OECTs) represent a step beyond conducting polymer electrodes. They consist of a conducting polymer channel in contact with an electrolyte. When a gate electrode excites an ionic current in the electrolyte, ions enter the polymer film and change its conductivity. Since a small amount of ions can effectively “block” the transistor channel, these devices offer significant amplification in ion-to-electron transduction. Using the developed technology a high-speed and high-density OECTs array is presented. The dense architecture of the array improves the resolution of the recording from neural networks and the transistors temporal response are 100 μs, significantly faster than the action potential. The experimental transistor responses are fit and modeled in order to optimize the gain of the transistor. Using the model, an OECT with two orders of magnitude higher normalized transconductance per channel width is fabricated as compared to Silicon-based field effect transistors. Furthermore, the OECTs are integrated to a highly conformable ECoG probe. This is the first time that a transistor is used to record brain activities in vivo. It shows a far superior signal-to-noise-ratio (SNR) compare to electrodes. The high SNR of the OECT recordings enables the observation of activities from the surface of the brain that only a perpetrating probe can record. Finally, the application of OECTs for biosensing is explored. The bulk of the currently available biosensors often require complex liquid handling, and thus suffer from problems associated with leakage and contamination. The use of an organic electrochemical transistor for detection of lactate by integration of a room temperature ionic liquid in a gel-format, as a solid-state electrolyte is demonstrated.

Grâce à leurs excellentes propriétés mécaniques, électriques et chimiques, les dispositifs organiques électroniques à base de polymères conducteurs peuvent résoudre l’incompatibilité entre les modules électroniques rigides en silicone et les exigences des tissus mous qui constituent l’environnement biologique. Les avancées en matière de semiconducteurs organiques et en microélectronique ont donné naissance à la bioélectronique. Cette discipline emploie des capteurs à des fins diagnostiques, telles que la détection des métabolites ou la mesure d’un potentiel d’action neuronal, et des actionneurs à des fins thérapeutiques, comme l’application locale d’un traitement à l’intérieur même du corps, ou la stimulation cérébrale profonde afin de guérir un trouble neurologique. En bioélectronique, l’utilisation de matériaux organiques, tels que le polymère conducteur poly(3,4-éthylènedioxythiophène) polystyrène sulfonate de sodium (PEDOT:PSS) a permis de développer des composants électroniques biomédicaux de qualité exceptionnelle, comme par exemple le transistor organique électrochimique (OECT), qui ont été testés in vitro et in vivo. Ce manuscrit explique en détail la fabrication, la fonctionnalisation et la caractérisation du OECT à base de PEDOT:PSS. Afin de pouvoir intégrer ce capteur à des systèmes de mesure biomédicaux déjà établis, l’OECT est intégré à des circuits simples, tels qu’un amplificateur de tension ou un pont de Wheatstone. Ces circuits sont mis à l’épreuve de la pratique clinique, dans le cas de mesures électrocardiographiques, ou de détection de métabolites dans des cellules cancéreuses. Cela permet d’apprécier à la fois leur applicabilité, et leurs limites. / Due to their outstanding mechanical, electrical and chemical properties, organic electronic devices based on conducting polymers can bridge the gap between the rigid silicon based read-out electronics and the soft biological environment and will have a huge impact on the medical healthcare sector. The recent advances in the field of organic semiconductors and microelectronics gave rise to a new discipline termed bioelectronics. This discipline deals with sensors for diagnostic purposes, ranging from metabolite detection and DNA recognition all the way to single neuronal firing events, and actuators for therapeutic purposes, through for example active local drug delivery inside the body or deep brain stimulation to cure neurological disorder. The use of organic materials such as the conducting polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) in the field of bioelectronics has brought about a variety of outstanding electronic biomedical devices, such as the organic electrochemical transistor (OECT), that have been implemented for both in vitro and in vivo applications. The present manuscript gives a detailed explanation of the fabrication, functionalization and characterization of OECTs based on PEDOT:PSS. To be able to intercept this sensor element with traditional biomedical recording systems, the OECT is implemented into simple circuit layouts such as a voltage amplifier or a Wheatstone bridge. These sensor circuits are then applied to real-life biomedical challenges, such as electrocardiographic recordings or metabolite detection in tumor cell cultures, to demonstrate their applicability as well as their limitations.

In the past decades, there has been a noticeable growth in the deployment of wireless sensor networks. These sensors/stimulators are typically powered by a battery which has limited life span. Power harvesting is one of the solutions to this problem. According to a medical-care experiment, the recovery process of an injured nerve has been boosted with the help of electrical stimulator. The latter is not only preferable to be portable but to be implantable as well in order to make medical treatment easier on the patient. This work has implemented two prototype versions of rectification circuitry used to harvest RF signal to power an electrical stimulator for peripheral nerve regeneration. The system consists an efficient rectifier, DC-limiter, biasing circuitry and modest regulator. In order to gain higher rectification efficiency, ON-OFF offset methodology is reviewed. Moreover, a mixed-signal design is proposed to construct a delay compensation mechanism. It is designed with 0.35 um AMS technology and it is assumed to read 13.56 MHz NFC signal from loop antennas. Schematic and layout levels are introduced with corresponding simulation findings. Moreover, tape-out is made for both architectures along with comparative results/discussions.

Cancer progression and physiological changes within the cells are accompanied by alterations in the biophysical properties. Therefore, the cell biophysical properties can serve as promising markers for cancer detection and physiological activities. To aid in the investigation of the biophysical markers of cells, a microfluidic chip has been developed which consists of a constriction channel and embedded microelectrodes. Single-cell impedance magnitudes at four frequencies and entry and travel times are measured simultaneously during their transit through the constriction channel. This microchip provides a high-throughput, label-free, automated assay to define biophysical signatures of malignant cells and monitor the therapeutic efficacy of drugs. Here, we monitored the dynamic cellular biophysical markers in response to sphingosine kinase inhibitors (SphKIs), and compared the effectiveness of drug delivery using Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with SphKIs versus conventional delivery. Cells treated with SphKIs showed significantly higher impedance magnitudes at all four frequencies. The bioelectrical parameters extracted using a model also revealed that the highly aggressive breast cells treated with SphKIs shifted electrically towards that of a less malignant phenotype; SphKI-treated cells exhibited an increase in cell-channel interface resistance and a significant decrease in specific membrane capacitance. Furthermore, SphKI-treated cells became slightly more deformable as measured by a decrease in their channel entry and travel times. We observed no significant difference in the bioelectrical changes produced by SphKI delivered conventionally or with NPs. However, NPs-packaged delivery of SphKI decreased the cell deformability. In summary, the results showed that while the bioelectrical properties of the cells were dominantly affected by SphKIs, the biomechanical properties were mainly changed by the NPs. / Master of Science

L’enregistrement et la stimulation in vivo de l’activité neuronale peuvent aussi bien servir pour la recherche médicale que pour les interfaces cerveau-machine. Les dispositifs à base d’électronique organique sont de prometteurs candidats pour ce faire, grâce à leur flexibilité et leur biocompatibilité. Le contrôle local de l’activité neuronale est la clé de nombreuses stratégies thérapeutiques visant à traiter les troubles neurologiques. Une solution idéale serait donc de fabriquer un dispositif capable de détecter l’activité neuronale et, en réponse, d’injecter des molécules endogènes. L’un des objectifs de cette thèse est de s’attaquer à cette problématique à l’aide d’un dispositif permettant à la fois de stimuler les cellules, et de mesurer l’activité neuronale, au même endroit, à l’échelle cellulaire. Nous présentons un dispositif organique capable de délivrer précisément des neurotransmetteurs in vitro et in vivo. En convertissant un signal électrique en la délivrance de neurotransmetteurs, le dispositif mime le fonctionnement d’une synapse. Le neurotransmetteur inhibiteur, l’acide γ- aminobutyrique (GABA), est relargué au niveau des électrodes d’enregistrement par l’activation d’une pompe ionique électronique. L’injection du GABA engendre l’arrêt de l’activité épileptique qui a été enregistré au niveau des électrodes. Des dispositifs multifonctionnels ouvrent de nombreuses possibilités, incluant des dispositifs thérapeutiques avec des boucles de retour, avec lesquels l’enregistrement local de signaux régule la délivrance d’agents thérapeutiques. De plus, nous avons également réalisé pendant cette thèse l’intégration de transistors organiques sur un film organique ultra fin, pour mesurer les signaux électrophysiologiques in vivo à la surface d’un cerveau de rat. Le dispositif, implanté de façon épidurale, montre des résultats surpassant certains dispositifs subduraux de taille similaire, permettant ainsi une approche moins invasive et efficace pour mesurer l’activité neuronale. / Recordings and stimulation of in vivo neural activity are necessary for diagnostic purposes and for brain-machine interfaces. Organic electronic devices constitute a promising candidate due to their mechanical flexibility and biocompatibility. Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules simultaneously to achieve the most efficient feedback regulation. Thus, there is a need for novel devices to specifically interface nerve cells. Here, we demonstrate an organic electronic device capable of precisely delivering neurotransmit- ters in vitro and in vivo. In converting electronic addressing into delivery of neurotransmit- ters, the device mimics the nerve synapse. The inhibitory neurotransmitter, -aminobutyric acid (GABA), was actively delivered and stopped epileptiform activity, recorded simultaneously and colocally. These multifunctional devices create a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents. In addition, we demonstrate the engineering of an organic electrochemical transistor embedded in an ultrathin organic film designed to record electrophysiological signals on the surface of the brain. The device was applied in vivo and epidurally implanted could reach capabilities beyond similar sized electrodes allowing minimally invasive monitoring of brain activity.

Les fibres amyloïdes sont des biomatériaux prometteurs pour la bioélectronique, en particulier pour l’interfaçage avec les systèmes biologiques. Ces fibres, formées par l’auto-assemblage de protéines, sont aisément synthétisables et modifiables/fonctionnalisables. Elles possèdent de surcroît des propriétés physiques remarquables notamment en termes de stabilité et de résistance mécanique. Nous avons étudié les mécanismes de conductions de charges dans les fibres formées par la protéine HET-s(218-289), seules fibres amyloïdes dont la structure atomique soit connue. Les échantillons ont été caractérisés électriquement et électrochimiquement sous la forme de films « secs ». L’influence de plusieurs paramètres sur la conductivité, entre autres la température, l’humidité ou encore la lumière, a été investiguée. Nous avons montré que l’organisation de la protéine en fibres permet la mise en place de processus de transport de charges intrinsèques. De plus, l’eau joue un rôle essentiel dans ces mécanismes et les principaux porteurs de charges sont certainement des protons. En parallèle, une simulation de dynamique moléculaire appuyée notamment par des expériences de diffusions des neutrons, a mis en évidence une forte interaction entre l’eau et les fibres. Deux canaux d’eau stabilisés par liaisons hydrogènes se formeraient le long des fibres. Ces derniers peuvent permettre le transport de protons par un mécanisme de type Grotthuss. Des réactions électrochimiques, en particulier l’électrolyse de l’eau, seraient la source des protons transportés grâce aux fibres. Cela conduit à l’instauration d’un courant catalytique à partir d’un seuil de tension de polarisation. Enfin, deux effets photo-électriques ont été observés lorsque les fibres sont irradiées entre 200 et 400 nm. Le premier est un photo-courant qui serait dû à la photolyse de l’eau adsorbée dans les échantillons. Le second, qualifié de « photo-courant inverse », se produit plus spécifiquement à la longueur d’onde de 280nm et seulement en présence de dioxygène. Il engendre une diminution de la conductivité. Cela serait dû à une réaction entre l’état triplet des tryptophanes des fibres et le dioxygène, captant in fine des protons. / Amyloid fibers are very promising biomaterials for bioelectronics, especially for interfacing with biological systems. These self-assembled proteins fibers are easy to synthetize, to tune and to functionalize. Their physical properties such as stability and mechanical strength are noticeable. We studied charge transport processes in HET-s(218-289), the only amyloid fibers we know the atomic structure. The samples were characterized as “dried” films by electrical measurement and electrochemistry. The influence of several parameters such as temperature, humidity or light was investigated. We demonstrated that the fiber organization allows intrinsic charge transport mechanisms in which water plays a crucial role. Furthermore, the dominant charge carriers would be protons. Molecular dynamic simulation and neutron diffusion experiments run in parallel show strong water-fibers interactions. In particular, H-bonded water wires can be formed along the fibers and support proton transport according to a Grotthuss-like mechanism. Proton production would result from electrochemical reactions, especially from water electrolysis. Therefore a catalytic current is detected when the bias exceeds a certain threshold. In addition, two photoelectric phenomena were observed when the fibers are irradiated with near UV light (200-400nm). The first one is a photocurrent probably due to water photo-splitting. The other occurs specifically at 280nm wavelength and in the presence of molecular oxygen. It leads to a decrease of the sample conductivity. This likely results from chemical reaction(s) between triplet-state tryptophan and oxygen that consumes protons.

Delivery of biologically relevant ions such as drugs, neurotransmitters and hormones have been recognized as powerful a tool to control physiology of animals and plants for research purposes and practical applications. In the plant research community, ions are most commonly delivered as part of a solvent by soaking, spraying, pipetting or by adding to the soil. These methods have low control of the delivery dynamics and quantity of ion uptake. These issues motivated the development of the Organic Electronic Ion Pump (OEIP), which delivers only ions of interest by applying an external electric field through a polyelectrolyte membrane of high fixed charge concentration. A miniaturized, implantable version of the OEIP based on capillary fibres (c-OEIP), where the polyelectrolyte is enclosed in a capillary, enabled even higher precision of the delivery. In this master thesis, c-OEIP has been applied in the tropical plant Kalanchoe Blossfeldiana, chosen due to its characteristic skill to gradually learn to save water: while maturing it shifts to night time photosynthesis and transpiration, called Constitutive Crassulacean Acid Metabolism. A better understanding of this metabolism and water saving ability could guide engineering of enhanced drought tolerance in crop plants, which is motivated by the increasing global warming. One of the biologically relevant ions that is potentially involved in this water-saving learning process is the malate ions. The aim of this thesis is to test the hypothesis that c-OEIP is able to deliver malate ions to cause a reduction in stomatal conductance and transpiration of intact leaves of Kalanchoe Blossfeldiana. To test this hypothesis, firstly, the capillary-based OEIP were fabricated using polyimide coated glass capillaries filled with AETMAC polyelectrolyte. The ability of these devices to deliver malic acid (MA) was verified by using current-voltage characterisation during loading and delivery of MA. Secondly, the setup for MA delivery with c-OEIP to intact kalanchoe leaf was developed, optimising the insertion method to minimize the wounding of the plant and increase assay reproducibility. Finally, the MA was delivered to intact kalanchoe leaves via c-OEIP, where the plant transpiration response was evaluated using standard gas exchange porometer and also novel infrared camera, as plant temperature can be correlated with plant transpiration status. The results indicate that c-OEIP can deliver MA and trigger reduction of transpiration of young kalanchoe leaves, supporting the hypothesis that malate ions act to reduce stomatal conductance, potentially conveying a feedback message from the mesophyll to the guard cells. / <p>Examensarbetet är utfört vid Institutionen för teknik och naturvetenskap (ITN) vid Tekniska fakulteten, Linköpings universitet</p>

No description available.

In the realm of neuroelectronics, the challenge lies in achieving finer observations of physiological processes to comprehend neuronal interactions and computations. This necessitates the development of more compliant and biomimetic interfaces for improved integration with biological tissues, enabling finer physiological process observations. Commonly used flat and static electrode interfaces contrast sharply with the dynamic, complex, and three dimensional (3D) extracellular matrix (ECM) in which cells reside. Introducing 3D patterns on electrode surfaces enhances cell-chip coupling, improving the signal recording. Moreover, inorganic electrodes are stiff and rigid, creating mechanical mismatches with softer biological tissues, and they fail to fully capture ionic conduction.This thesis addresses these challenges by focusing on designing and engineering a multi-layer dynamic and stimuli-responsive bioelectronic interface. The system combines light-responsive, deformable polymers like Poly(Disperse Red 1-methacrylate) (pDR1m) with conductive polymers such as Poly(3,4-ethylenedioxythiophene): poly(stirensulfonate) (PEDOT:PSS). pDR1m responds to light, exhibiting 3D surface topography deformation, while PEDOT:PSS facilitates electrical recording and stimulation of cells, offering mixed electronic and ionic conduction as well as good mechanical properties. The potential use of an intermediate Polydimethylsiloxane (PDMS) film to improve layer adhesion is also explored. The individual and multi-layer samples were first optimized for spin coating manufacturing, and then thoroughly characterized to investigate their thickness, morphology, optical and electrochemical properties. Patterning of pDR1m-based samples was carried out using laser scanning confocal microscopy and a Lloyd’s mirror interferometer.The pDR1m\PEDOT:PSS sample demonstrates promising morphological and conductive properties, and the presence of PEDOT:PSS does not alter the absorption spectra of pDR1m. The multi-layer approach also supports efficient inscription of 3D surface reliefs without damaging the conductive layer. In conclusion, this work successfully designs conductive and dynamic light-driven films, which showcase good potential for bioelectronics and neuroelectronic interfaces. These interfaces could lead to enhanced investigations into combined electromechanical stimulation on cells and provide a more biomimetic coupling with biological tissues. / Inom neuroelektronikens område ligger utmaningen i att uppnå finare observationer av fysiologiska processer för att förstå neuronala interaktioner och beräkningar. Detta kräver utveckling av mer följsamma och biomimetiska gränssnitt för förbättrad integration med biologiska vävnader, vilket möjliggör finare fysiologiska processobservationer. Vanligt använda platta och statiska elektrodgränssnitt står i skarp kontrast till den dynamiska, komplexa och tredimensionella (3D) extracellulära matrisen (ECM) i vilken celler finns. Att introducera 3D-mönster på elektrodytor förbättrar cell-chip-kopplingen, vilket förbättrar signalinspelningen. Dessutom är oorganiska elektroder styva och stela, vilket skapar mekaniska felmatchningar med mjukare biologiska vävnader, och de lyckas inte helt fånga jonledning.Den här avhandlingen tar upp dessa utmaningar genom att fokusera på att designa och konstruera ett flerlagers dynamiskt och stimuli-responsivt bioelektroniskt gränssnitt. Systemet kombinerar ljuskänsliga, deformerbara polymerer som Poly(Disperse Red 1-methacrylate) (pDR1m) med ledande polymerer som Poly(3,4-etylendioxitiofen): poly(stirensulfonat) (PEDOT:PSS). pDR1m reagerar på ljus och uppvisar 3D-yttopografideformation, medan PEDOT:PSS underlättar elektrisk inspelning och stimulering av celler, erbjuder blandad elektronisk och jonledning samt goda mekaniska egenskaper. Den potentiella användningen av en mellanliggande polydimetylsiloxan (PDMS) film för att förbättra skiktvidhäftningen undersöks också. De individuella och flerskiktiga proverna optimerades först för spinnbeläggningstillverkning och karakteriserades sedan grundligt för att undersöka deras tjocklek, morfologi, optiska och elektrokemiska egenskaper. Mönster av pDR1m-baserade prover utfördes med laserskanning konfokalmikroskopi och en Lloyds spegelinterferometer.pDR1m\PEDOT:PSS-provet visar lovande morfologiska och ledande egenskaper, och närvaron av PEDOT:PSS förändrar inte absorptionsspektra för pDR1m. Flerskiktsmetoden stöder också effektiv inskription av 3D-ytreliefer utan att skada det ledande lagret. Sammanfattningsvis designar detta arbete framgångsrikt ledande och dynamiska ljusdrivna filmer, som visar upp god potential för bioelektronik och neuroelektroniska gränssnitt. Dessa gränssnitt kan leda till förbättrade undersökningar av kombinerad elektromekanisk stimulering på celler och ge en mer biomimetisk koppling med biologiska vävnader.