Soft subdermal implant capable of wireless battery charging and programmable controls for applications in optogenetics

Optogenetics is a powerful technique that allows target-specific spatiotemporal manipulation of neuronal activity for dissection of neural circuits and therapeutic interventions. Recent advances in wireless optogenetics technologies have enabled investigation of brain circuits in more natural conditions by releasing animals from tethered optical fibers. However, current wireless implants, which are largely based on battery-powered or battery-free designs, still limit the full potential of in vivo optogenetics in freely moving animals by requiring intermittent battery replacement or a special, bulky wireless power transfer system for continuous device operation, respectively. To address these limitations, here we present a wirelessly rechargeable, fully implantable, soft optoelectronic system that can be remotely and selectively controlled using a smartphone. Combining advantageous features of both battery-powered and battery-free designs, this device system enables seamless full implantation into animals, reliable ubiquitous operation, and intervention-free wireless charging, all of which are desired for chronic in vivo optogenetics. Successful demonstration of the unique capabilities of this device in freely behaving rats forecasts its broad and practical utilities in various neuroscience research and clinical applications.ope

An efficient telemetry system for restoring sight

PhD ThesisThe human nervous system can be damaged as a result of disease or trauma, causing conditions such as Parkinson’s disease. Most people try pharmaceuticals as a primary method of treatment. However, drugs cannot restore some cases, such as visual disorder. Alternatively, this impairment can be treated with electronic neural prostheses. A retinal prosthesis is an example of that for restoring sight, but it is not efficient and only people with retinal pigmentosa benefit from it. In such treatments, stimulation of the nervous system can be achieved by electrical or optical means. In the latter case, the nerves need to be rendered light sensitive via genetic means (optogenetics). High radiance photonic devices are then required to deliver light to the target tissue. Such optical approaches hold the potential to be more effective while causing less harm to the brain tissue. As these devices are implanted in tissue, wireless means need to be used to communicate with them. For this, IEEE 802.15.6 or Bluetooth protocols at 2.4GHz are potentially compatible with most advanced electronic devices, and are also safe and secure. Also, wireless power delivery can operate the implanted device. In this thesis, a fully wireless and efficient visual cortical stimulator was designed to restore the sight of the blind. This system is likely to address 40% of the causes of blindness. In general, the system can be divided into two parts, hardware and software. Hardware parts include a wireless power transfer design, the communication device, power management, a processor and the control unit, and the 3D design for assembly. The software part contains the image simplification, image compression, data encoding, pulse modulation, and the control system. Real-time video streaming is processed and sent over Bluetooth, and data are received by the LPC4330 six layer implanted board. After retrieving the compressed data, the processed data are again sent to the implanted electrode/optrode to stimulate the brain’s nerve cells

Beyond solid-state lighting: Miniaturization, hybrid integration, and applications og GaN nano- and micro-LEDs

Gallium Nitride (GaN) light-emitting-diode (LED) technology has been the revolution in modern lighting. In the last decade, a huge global market of efficient, long-lasting and ubiquitous white light sources has developed around the inception of the Nobel-price-winning blue GaN LEDs. Today GaN optoelectronics is developing beyond lighting, leading to new and innovative devices, e.g. for micro-displays, being the core technology for future augmented reality and visualization, as well as point light sources for optical excitation in communications, imaging, and sensing. This explosion of applications is driven by two main directions: the ability to produce very small GaN LEDs (microLEDs and nanoLEDs) with high efficiency and across large areas, in combination with the possibility to merge optoelectronic-grade GaN microLEDs with silicon microelectronics in a fully hybrid approach. GaN LED technology today is even spreading into the realm of display technology, which has been occupied by organic LED (OLED) and liquid crystal display (LCD) for decades. In this review, the technological transition towards GaN micro- and nanodevices beyond lighting is discussed including an up-to-date overview on the state of the art

Optogenetics in striated muscle: defibrillation of the heart and direct stimulation of skeletal muscles with light

Optogenetic depolarization of cells using the non-selective cation channel Channelrhodopsin-2 (ChR2) enables precise control over the membrane potential of cells within a specific area of intact organs. Furthermore, the selective overexpression of light-gated proteins allows cell type-specific and pain-free stimulation which could be of great benefit for future scientific and therapeutic approaches. In my thesis, I explored two potential applications of optogenetic methods in striated muscle: optogenetic defibrillation to terminate ventricular arrhythmia in intact mouse hearts and direct optogenetic stimulation of skeletal muscles. These new approaches could lead in the future to the development of optogenetic defibrillators and laryngeal pacemakers. Most experiments were performed with explanted hearts, isolated skeletal fibers and muscles or larynges from transgenic ChR2 expressing mice. To add translational perspectives, we also explored optogenetic defibrillation and intralaryngeal muscles stimulation after ChR2 gene transfer to wild type mice using adeno-associated virus (AAV). Optogenetic defibrillation by epicardial illumination was highly efficient in terminating ventricular arrhythmia in transgenic hearts and the success rate of optogenetic defibrillation was depending on the pulse duration, the size of illumination and the light intensity. Importantly, we were also able to terminate ventricular arrhythmia in non-transgenic hearts even one year after AAV mediated gene transfer. The potential applicability of optogenetic defibrillation in the human heart was assessed in experimentally-calibrated computer simulations of a patient’s heart with infarct-related ventricular tachycardia. Because optogenetic stimulation would be in principle pain-free in patients, the proof for its feasibility could lay the foundation for the development of a new treatment option for patients at high risk for ventricular arrhythmia. Direct optogenetic stimulation of skeletal muscle was first proven in isolated Flexor digitorum brevis fibers and in intact soleus muscles, which could both be stimulated using brief light pulses. The force of light-induced single twitches could be precisely controlled by varying the pulse duration and light intensity. Optogenetic stimulation was most efficient with 10 ms long pulses at a repetition rate of 40 Hz reaching ~84% of the maximum force generated by electrical stimulation with 100 Hz. Recurrent nerve paralysis is a severe complication of neck surgery, malignant processes or central neurological diseases and results in a fixed paramedian position of the vocal cords as well as life-threatening dyspnea in the case of bilateral paralysis. Current treatment options consist only of destructive surgery. Unfortunately the use of local electrical stimulation to restore laryngeal function faces severe technical limitations. Therefore I sought to explore direct optogenetic stimulation of intralaryngeal muscles in explanted larynges from ChR2 transgenic mice. Specific illumination of the individual intralaryngeal muscle groups led to an opening or closing of the vocal cords depending on the site of illumination. This proves the sufficient spatial resolution of light for selective stimulation of the intralaryngeal muscles groups. In addition, we were able to induce opening of the vocal cords in wild type mice after AAV-based gene transfer of ChR2 with light. Thus optogenetic stimulation could become a new treatment option for patients suffering from bilateral laryngeal paralysis. In conclusion, optogenetic stimulation can overcome the severe limitations of electrical stimulation of the heart and skeletal muscles. The new technologies, I have developed and characterized in this thesis, allow for the design of completely new stimulation patterns to address open questions in muscle physiology. Furthermore, optogenetic stimulation of striated muscles could become a new treatment option for patients enabling selective and pain-free stimulation with few side effects

High-precision fluorescence photometry for real-time biomarkers detection

Les derniers évènements planétaires et plus particulièrement l'avènement sans précédent du nouveau coronavirus augmente la demande pour des appareils de test à proximité du patient. Ceux-ci fonctionnent avec une batterie et peuvent identifier rapidement des biomarqueurs cibles. Pareils systèmes permettent aux utilisateurs, disposant de connaissances limitées en la matière, de réagir rapidement, par exemple dans la détection d'un cas positif de COVID-19. La mise en œuvre de l'élaboration d'un tel instrument est un projet multidisciplinaire impliquant notamment la conception de circuits intégrés, la programmation, la conception optique et la biologie, demandant tous une maîtrise pointue des détails. De plus, l'établissement des spécifications et des exigences pour mesurer avec précision les interactions lumière-échantillon s'additionnent au besoin d'expérience dans la conception et la fabrication de tels systèmes microélectriques personnalisés et nécessitent en elles-mêmes, une connaissance approfondie de la physique et des mathématiques. Ce projet vise donc à concevoir et à mettre en œuvre un appareil sans fil pour détecter rapidement des biomarqueurs impliqués dans des maladies infectieuses telles que le COVID-19 ou des types de cancers en milieu ambulatoire. Cette détection se fait grâce à des méthodes basées sur la fluorescence. La spectrophotométrie de fluorescence permet aux médecins d'identifier la présence de matériel génétique viral ou bactérien tel que l'ADN ou l'ARN et de les caractériser. Les appareils de paillasse sont énormes et gourmand énergétiquement tandis que les spectrophotomètres à fluorescence miniatuarisés disponibles dans le commerce sont confrontés à de nombreux défis. Ces appareils miniaturisés ont été découverts en tirant parti des diodes électroluminescentes (DEL) à semi-conducteurs peu coûteuses et de la technologie des circuits intégrés. Ces avantages aident les scientifiques à réduire les erreurs possibles, la consommation d'énergie et le coût du produit final utilisé par la population. Cependant, comme leurs homologues de paillasse, ces appareils POC doivent quantifier les concentrations en micro-volume d'analytes sur une large gamme de longueurs d'onde suivant le cadre d'une économie en ressources. Le microsystème envisagé bénéficie d'une approche de haute précision pour fabriquer une puce microélectronique CMOS. Ce procédé se fait de concert avec un boîtier personnalisé imprimé en 3D pour réaliser le spectrophotomètre à la fluorescence nécessaire à la détection quantitative d'analytes en microvolume. En ce qui a trait à la conception de circuits, une nouvelle technique de mise à auto-zeroing est appliquée à l'amplificateur central, celui-ci étant linéarisé avec des techniques de recyclage et de polarisation adaptative. Cet amplificateur central est entièrement différentiel et est utilisé dans un amplificateur à verrouillage pour récupérer le signal d'intérêt éclipsé par le bruit. De plus, l'augmentation de la sensibilité de l'appareil permet des mesures quantitatives avec des concentrations en micro-volume d'analytes ayant moins d'erreurs de prédiction de concentration. Cet avantage cumulé à une faible consommation d'énergie, un faible coût, de petites dimensions et un poids léger font de notre appareil une solution POC prometteuse dans le domaine de la spectrophotométrie de fluorescence. La validation de ce projet s'est fait en concevant, fabriquant et testant un prototype discret et sans fil. Son article de référence a été publié dans IEEE LSC 2018. Quant à la caractérisation et l'interprétation du prototype d'expériences in vitro à l'aide d'une interface MATLAB personnalisée, cet article a été publié dans IEEE Sensors journal (2021). Les circuits intégrés et les photodétecteurs ont été fabriqués ont été conçus et fabriqués par Cadence en 2019. Relativement aux solutions de circuit proposées, elles ont été fabriquées avec la technologie CMOS 180 nm et publiées lors de la conférence IEEE MWSCAS 2020. Tout comme cette dernière contribution, les expériences in vitro avec le dispositif proposé incluant la puce personnalisée et le boîtier imprimé en 3D ont été réalisés et les résultats électriques et optiques ont été soumis au IEEE Journal of Solid-State Circuits (JSSC 2022).The most recent and unprecedented experience of the novel coronavirus increases the demand for battery-operated near-patient testing devices that can rapidly identify the target biomarkers. Such systems enable end-users with limited resources to quickly get feedback on various medical tests, such as detecting positive COVID-19 cases. Implementing such a device is a multidisciplinary project dealing with multiple areas of expertise, including integrated circuit design, programming, optical design, and biology, each of which needs a firm grasp of details. Alongside the need for experience in designing and manufacturing custom microelectronic systems, establishing the specifications and requirements to precisely measure the light-sample interactions requires an in-depth knowledge of physics and mathematics. This project aims to design and implement a wireless point-of-care (POC) device to rapidly detect biomarkers involved in infectious diseases such as COVID-19 or different types of cancers in an ambulatory setting using fluorescence-based methods. Fluorescence spectrophotometry allows physicians to identify and characterize viral or bacterial genetic materials such as DNAs or RNAs. The benchtop devices that are currently available are bulky and power-hungry, whereas the commercially available miniaturized fluorescence spectrophotometers are facing many challenges. Many of these difficulties have been resolved in literature thanks to inexpensive semiconductor light-emitting diodes (LEDs) and integrated circuits technology. Such advantages aid scientists in decreasing the size, power consumption, and cost of the final product for end-users. However, like the benchtop counterparts, such POC devices must quantify micro-volume concentrations of analytes across a wide wave length range under an economy of resources. The envisioned microsystem benefits from a high-precision approach to fabricating a CMOS microelectronic chip combined with a custom 3D-printed housing. This implementation results in a fluorescence spectrophotometer for qualitative and quantitative detection of micro-volume analytes. In terms of circuit design, a novel switched-biasing ping-pong auto-zeroed technique is applied to the core amplifier, linearized with recycling and adaptive biasing techniques. The fully differential core amplifier is utilized within a lock-in amplifier to retrieve the signal of interest overshadowed by noise. Increasing the device's sensitivity allows quantitative measurements down to micro-volume concentrations of analytes with less concentration prediction error. Such an advantage, along with low-power consumption, low cost, low weight, and small dimensions, make our device a promising POC solution in the fluorescence spectrophotometry area. The approach of this project was validated by designing, fabricating, and testing a discrete and wireless prototype. Its conference paper was published in IEEE LSC 2018, and the prototype characterization and interpretation of in vitro experiments using a custom MATLAB interface were published in IEEE Sensors Journal (2021). The integrated circuits and photodetectors were designed and fabricated by the Cadence circuit design toolbox (2019). The proposed circuit solutions were fabricated with 180-nm CMOS technology and published at IEEE MWSCAS 2020 conference. As the last contribution, the in vitro experiments with the proposed device, including the custom chip and 3D-printed housing, were performed, and the electrical and optical results were submitted to the IEEE Journal of Solid-State Circuits (JSSC 2022)

Light technology for efficient and effective photodynamic therapy: A critical review

Photodynamic therapy (PDT) is a cancer treatment with strong potential over well-established standard therapies in certain cases. Non-ionising radiation, localisation, possible repeated treatments, and stimulation of immunological response are some of the main beneficial features of PDT. Despite the great potential, its application remains challenging. Limited light penetration depth, non-ideal photosensitisers, complex dosimetry, and complicated implementations in the clinic are some limiting factors hindering the extended use of PDT. To surpass actual technological paradigms, radically new sources, light-based devices, advanced photosensitisers, measurement devices, and innovative application strategies are under extensive investigation. The main aim of this review is to highlight the advantages/pitfalls, technical challenges and opportunities of PDT, with a focus on technologies for light activation of photosensitisers, such as light sources, delivery devices, and systems. In this vein, a broad overview of the current status of superficial, interstitial, and deep PDT modalities - and a critical review of light sources and their effects on the PDT process - are presented. Insight into the technical advancements and remaining challenges of optical sources and light devices is provided from a physical and bioengineering perspective.This work was supported by Ministerio de Ciencia e Innovación and Agencia Estatal de Investigación (PID2019-107270RB-C21/AIE/10.13039/501100011033

Microfluidics for Biosensing

There are 12 papers published with 8 research articles, 3 review articles and 1 perspective. The topics cover: Biomedical microfluidics Lab-on-a-chip Miniaturized systems for chemistry and life science (MicroTAS) Biosensor development and characteristics Imaging and other detection technologies Imaging and signal processing Point-of-care testing microdevices Food and water quality testing and control We hope this collection could promote the development of microfluidics and point-of-care testing (POCT) devices for biosensing

Novel Electrochemical Biosensors for Clinical Assays

Biosensors, i.e., devices where biological molecules or bio(mimetic)structures are intimately coupled to a chemo/physical transducer for converting a biorecognition event into a measurable signal, have recently gained a wide (if not huge) academic and practical interest for the multitude of their applications in analysis, especially in the field of bioanalysis, medical diagnostics, and clinical assays. Indeed, thanks to their very simple use (permitting sometimes their application at home), the minimal sample pretreatment requirement, the higher selectivity, and sensitivity, biosensors are an essential tool in the detection and monitoring of a wide range of medical conditions from glycemia to Alzheimer’s disease as well as in the monitoring of drug responses. Soon, we expect that their importance and use in clinical diagnostics will expand rapidly so as to be of critical importance to public health in the coming years. This Special Issue would like to focus on recent research and development in the field of biosensors as analytical tools for clinical assays and medical diagnostics