BioTIFS (2019 - 2022)

Grant support: ANR (Agence Nationale de la Recherche, France) and NIH (National Institutes of Health, USA)

To influence neural activity for desired outcomes, neural interface technology must access the appropriate peripheral nerve tissue, activate it in a focal targeted manner, and alter patterns of activity generated by the nervous system. The anatomical organization of peripheral nerves, which consists of multiple nerve fibers clustered into one or more fascicles, presents opportunities and challenges for precise control of spatiotemporal patterns. Systems that enable greater specificity are likely to achieve a higher degree of functionality with fewer side effects.

The BioTIFS project is directed at increasing the specificity that can be achieved with peripheral nerve stimulation in a manner that will enable a wide range of clinical and non-clinical applications. Longitudinal intrafascicular electrodes (LIFEs) allow access to nerve fibers within a fascicle and their mechanical properties are well-suited for chronic use. LIFEs enable activation with sub-fascicular specificity, but there is great potential for enhancing their specificity using advanced stimulation strategies. One of the impacts is an improved neurotechnology for restoring sensation to amputees and for treating diseases such as diabetes, inflammation, epilepsy, or depression..

Edifice (2016 - 2019)

Grant support: MENSR & CNRS (PEPS ingéniérie translationnelle)

Les dispositifs médicaux implantables jouent un rôle important dans le traitement des arythmies cardiaques. Pour cette application, il existe deux grandes catégories de dispositifs implantables : les pacemakers, ou stimulateurs cardiaques, et les défibrillateurs implantables. Environ 400000 dispositifs de ce genre sont implantés chaque année aux Etats-Unis ; en France 250000 patients en sont actuellement équipés et nécessitent un contrôle régulier de leur prothèse.

Un point faible majeur de tout dispositif implantable réside à l’interface implant-tissu en raison d’une réaction inflammatoire soutenue, en l’occurrence la fibrose cardiaque. L’organisme réagit finalement pour « isoler » l’implant du tissu cible, en l’encapsulant dans une gaine fibrotique, et cela a 2 types de conséquences : une conséquence électrique due à l’augmentation des seuils de stimulation et l’altération de la sensibilité des sondes, ce qui entraine sur le long terme une diminution de la durée de vie des batteries ; une conséquence médicale : les attachements tissulaires rendent délicate la procédure d’extraction des sondes.

Ce projet propose d’explorer une méthode de mesure électrique non-invasive, basée sur la spectroscopie d’impédance, pour caractériser la capsule fibrotique entourant les électrodes implantées. L’innovation visée consiste à adjoindre au signal thérapeutique de stimulation un algorithme d’impédance-métrie destiné à produire un diagnostic régulier de l’état de la fibrose induite par la sonde. Un tel cadre permettra également de tester de nouvelles solutions de biocompatibilité pour ces sondes.

Pour cela, ce projet exploratoire, en collaboration avec l'Institut Hospitalo-Universitaire de cardiologie LYRIC, se base sur trois grands objectifs : mieux comprendre les mécanismes de la fibrose cardiaque induite par l’implant au niveau cellulaire (IMS) et au niveau tissulaire (IHU LIRYC) ; développer une méthode robuste et non-invasive de caractérisation par spectroscopie d’impédance pour un suivi en temps réel de l’évolution de la fibrose autour des implants ; développer un circuit électronique qui permettra de faire du suivi en temps réel grâce à la modélisation des mesures précédemment effectuées in vivo et ex vivo.

Diablo (2018 - 2020)

Grant support: ANR (Agence Nationale de la Recherche, France)

Le PANCREAS ARTIFICIEL arrive. Il devrait améliorer la qualité de vie et éviter les complications chroniques des patients atteints de DIABETE DE TYPE 1 (DT1), maladie chronique qui concerne 5 à 10% des 371 millions de diabétiques dans le monde et se déclare généralement chez les enfants ou jeunes adultes. Dans le DT1, la destruction des cellules beta-pancréatiques provoque un déficit en insuline et nécessite une insulinothérapie dont le contrôle reste complexe : même avec les technologies récentes de mesure continue et de monitoring de la glycémie (CGM), les algorithmes d'insulinothérapie ne sont pas optimaux et ne peuvent totalement éliminer des risques vitaux comme l'hypoglycémie.

En effet, se baser sur un capteur du glucose seul revient à négliger la mesure des lipides et les signaux hormonaux dont les variations se reflètent sur le besoin d'insuline en cas de stress, activité physique, cycle menstruel, etc… Les pancréas artificiels basés sur les CGM reposent donc encore sur les ajustements du patient/médecin et leur contrôle en boucle fermée est loin d'être aussi robuste que celui d'un pancréas sain.

 DIABLO contribue à l'émergence d'un nouveau paradigme de pancréas artificiel basé sur des CAPTEURS MULTI-PARAMETRIQUES A BASE D'ILOTS PANCREATIQUES. Il s'agit : (i) de décoder les ALGORITHMES ENDOGENES des îlots, qui ont été façonnés par l'évolution depuis 500 millions d'années pour maintenir l'homéostasie glucidique, (ii) de traduire ces algorithmes dans un MODELE, et y associer un CONTROLEUR ad hoc pour gérer une thérapie en continu et boucle fermée, (iii) de développer des ARCHITECTURES MATERIELLES d'implantation des BIOCAPTEURS et des algorithmes de commande dans un futur dispositif médical, (iv) de tester l'ensemble lors d'un ESSAI CLINIQUE en hôpital.

 Le projet rassemble des chercheurs académiques (biologie, microélectronique, automatique) et des cliniciens diabétologues; le consortium a déjà développé et breveté une technologie de capteur bio-électronique qui enregistre et traite en TEMPS REEL l'activité électrique d'îlots pancréatiques.

Dans DIABLO seront réalisés:

 - un MODELE IN SILICO et en conditions physiologiques (réponse au glucose et aux hormones) d'un biocapteur à base d'îlots, technologie propriétaire du consortium du projet. A base de données expérimentales et développé grâce à des méthodes d'identification paramétriques/non-paramétriques, ce modèle permettra d'évaluer les performances du biocapteur mais aussi d'explorer systématiquement les mécanismes des îlots.

 - une version améliorée du SIMULATEUR T1DMS (approuvé par la FDA) de patient DT1, intégrant: a)  le biocapteur modélisé ci-dessus; b) un nouveau CONTROLEUR de régulation de la glycémie, contrôleur muti-paramétrique ROBUSTE aux variations physiologiques chroniques du patient.

 - un prototype de BIOCAPTEUR BIO-ELECTRONIQUE intégré de façon optimale, portable et relié au patient par microdialyse, qui sera testé lors d'un essai clinique en CHU sur 10 PATIENTS ATTEINTS DE DT1.  Lors de scenarios quotidiens variés, les réponses du biocapteur et les commandes du contrôleur DIABLO seront comparées aux mesures et commandes des systèmes de CGM standards.

 L'impact de DIABLO sera marquant à plusieurs titres : RECHERCHE EN BIOLOGIE DES ILOTS, TECHNOLOGIES DES DISPOSITIFS MEDICAUX, THERAPIE DU DT1.

Plus précisément, de DIABLO pourront émerger : 1) le décodage des algorithmes endogènes des îlots ; 2) des techniques de synthèse haut niveau de composants électroniques embarqués pour le traitement modulaire de signaux biologiques ; 3) un nouveau capteur bio-électronique qualifié pour la régulation de la glycémie chez l'humain ; 4) des algorithmes de contrôle robustes aux variations physiologiques pour des applications de pancréas artificiel ; 5) des techniques de réalisation et de modélisation d'organes sur puces, pour l'étude des effets génétiques et pharmacologiques sur les îlots et la glycémie.

Diaglyc (2018 - 2020)

Grant support: ANR (Agence Nationale de la Recherche, France) and FEDER

IsletChip (2014 - 2017)

Grant support: ANR (Agence Nationale de la Recherche, France) and DGOS (Direction Générale de l'Offre de Soins, France)

Type 1 diabetes concerns some 30 million patients. Transplantation represents one therapeutic choice in patients with serious progressive complications. Currently no method has been established to evaluate the quality of donor islets within the short time span prior to transplantation. IsletChip bridges this important gap in a multidisciplinary approach (diabetology-transplantation medicine/biology-electrophys./microelectronics) from CNRS research groups, clinical groups in France (Grenoble, Montpellier) and in Switzerland (Geneva). The project develops a novel bio-sensing approach (extracellular recordings of islets on MEAs), real-time data filtering and time-frequency analysis. The project addresses technological, biological and signal processing challenges that will be of benefit for other applications (e.g. rehabilitation of neuronal motor control, control of stem cell differentiation). Our approach may ultimately also serve as sensor in an artificial pancreas. 

CEnAVex (2013-2016)

Grant support: ANR (Agence Nationale de la Recherche, France) and NIH (National Institutes of Health, USA)

Approximately 270,000 Americans and 20,000 French are survivors of traumatic spinal cord injury (SCI). The cervical cord is the most common site of injury (54%) and people with cervical SCI can have partial or complete loss of ventilatory control. Most people with SCI that require ventilation management are initially supported with positive pressure-mechanical ventilation, which is associated with significant discomfort and can lead to respiratory diseases and prevent optimal recovery. Alternatively, ventilation can be achieved by diaphragmatic pacing by electrical phrenic nerve stimulation. More recently, intramuscular stimulation of multiple respiratory muscles has been proposed as a viable less surgically invasive approach. The open-loop stimulation strategy currently utilized for pacing has major limitations including the need for manual stimulation parameter tuning, and inability to alter stimulation parameters on muscle fatigue or changing metabolic demand. 

The CENAVEX project proposes the design, development and prototype realization of a novel closed-loop control system that utilizes the computational power of spike-based neuromorphic hardware to adaptively control dynamic processes in biological systems. It will specifically address the challenge of simultaneously adapting the rhythm and pattern of oscillatory drive to achieve effective and efficient control of complex biological functions. The work will focus on the specific problem of controlling ventilation in individuals with high-level SCI by electrically stimulating the motoneurons that drive respiratory musculature. 

To accomplish our objectives we will develop a lung-respiratory muscles computational model and test the abilities of the CENAVEX system, implement the control scheme in software for real-time computer-based control of ventilation in anesthetized intact rodents and those with chronic cervical incomplete SCI, and implement the scheme in neuromorphic hardware with spiking networks, synaptic learning and bio-interface hardware for standalone system assessment in rodents. Successful completion of the proposed project will pave the path for translation to an innovative respiratory pacing system capable of allowing adequate ventilation in people with SCI with impaired respiratory control, taking into account non-linear properties of muscle activation, muscle fatigue, and metabolic demand of the individual.

The Human Brain Project (2013-2023)

Grant support: European Union (Flagship projects - Future Emerging Technologies)

Understanding the human brain is one of the greatest scientific challenges of our time. Such an understanding will lead to fundamentally new computing technologies, transform the diagnosis and treatment of brain diseases, and provide profound insights into our humanity. Today, for the first time, exponential improvements in the capabilities of modern ICT open up new opportunities to investigate the complexity of the brain. The goal of the Human Brain Project (HBP) is thus to build an integrated ICT infrastructure enabling a global collaborative effort to address this grand challenge, and ultimately to emulate the computational capabilities of the brain. The infrastructure will consist of a tightly linked network of six ICT platforms, which, like current large-scale physics facilities, will operate as a resource both for core HBP research and for external projects, chosen by competitive call. The HBP will drive innovation in ICT, creating new technologies for i) interactive supercomputing, visualisation and big data analytics; ii) federated analysis of globally distributed data; iii) simulation of the brain and other complex systems; iv) objective classification of disease; v) scalable and configurable neuromorphic computing systems, based on the brain’s principles of computation and cognition and its architectures. Expected outputs include simulations of the brain that reveal the chains of events leading from genes to cognition; simulations of diseases and the effects of drugs; early diagnoses and personalised treatments; and a computing paradigm that overcomes bottlenecks in power, reliability and programmability, captures the brain’s cognitive capabilities, and goes beyond Moore’s Law. Overall, the HBP will help to reach a unified understanding of the brain, reduce the economic and social burden of brain disease, and empower the European pharmaceutical and computing industries to lead world markets with enormous potential for growth. 

IMS Bordeaux is in charge of organizing over HBP consortium workshops, schools, on-line training and conferences:

• Multidisciplinary workshops on HBP-related research topics
• Platform training workshops
• Summer Schools
• Annual student conference

Partners: 
87 institutions (EU and non-EU)

Diaβetachip (2013-2015)

Hybrid Bioelectronics Sensors as Novel Devices for Use in Diabetology

Based on our expertise and proof of concept (see below), we propose to develop stepwise a new cell based-technology combining primary islet cells cultured on multi-electrode arrays (MEAs) and digital on-chip computation for real-time analysis (providing smart MEAs). This ensures rapid diagnostics and avoids storage of extremely large amounts of data generated by high-frequency recordings. Microelectrode arrays and extracellular recordings allow long-term measurements (in our hands for more than a week) in contrast to other techniques (optical, patch) and such set-ups are per se relatively easy to miniaturize. Our arrangement of smart MEAs will serve:

• First as a device for automated functional islet screening within the granting period for pre-transplantation quality tests, drug and toxicology tests, real-time analysis during regeneration of islet cells from stem cells: the Diaßchip device.
• In the long-term we plan to extend this device to a bio-microelectronic hybrid sensor of insulin demand: the Diaßsensor product.

Partners: 
University hospital of Bordeaux 
CBMN (UMR 5248)

BIODIA (2012-2014)

Biotechnologies for diabetes therapy

Using cultured pancreatic islets (or islet cells) as sensor, microelectrodes to record the sensor signal and active microelectronic devices to decode on-line the sensor signal, BIODIA aims now to provide the following two items:

• An external sensor for automatic screening of glucose responses and the effect of drugs and toxic compounds hereon (to be used in screening for compounds or during stem cell differentiation).
• An external sensor detecting the demand in insulin as the base for the further development of a sensor commanding an insulin pump and functioning in a closed loop configuration.

Beyond the granting period, the closed loop will be developed further to provide a sensor for continuous on-line monitoring and automated signal interpretation (drug/toxicology screening) in animals (48 months) and finally an implantable sensor operating in a closed-loop with a delivery device in man. 

Partners: 
J. Lang, CBMN (UMR 5248) 
V. Ravaine, ISM (UMR 5255)

HYRENE (2011-2014)

HYRENE is a fundamental research project aiming at the development of innovative technologies : hybrid systems connecting artificial and biological neural networks. 

One goal of this project is to couple a whole organ (mouse spinal cord) with a hardware networks in order to restore the organ functional activity after a lesion. Further perspectives are the development of smart “neuroelectronic” interfaces for functional rehabilitation. Population aging all around the world raises a societal issue due to the associated increase in neurodegenerative diseases. 
One therapeutic approach to treat resulting functional deficiencies is to propose neural prosthesis based on neuro-electronic implants. In recent years, technological advances in the field of micro- and nano-electronics has led to the development of new instrumentation tools for the exploration of the central nervous system, making use of dedicated interfaces between microelectronics and live neural networks. This field of research has strongly developed since 2000, especially with the emergence of brain-machine interfaces. These interfaces, which are now tested in humans, process brain signals recorded with microelectrode arrays to turn them into command signals for the control of external devices (robotic arms, computers…). 
However, to date, such interfaces remain mainly monodirectional, with no information delivered back to the network. The current challenge is to achieve bidirectional neuro-electronic interfaces, establishing a true dynamic communication between live neural networks and electronic systems. Especially, electronic systems connected to neural networks with existing technologies do not include embedded intelligence. 
The technical approach defined for HYRENE is to couple live large-scale neural networks and artificial neural networks embedded in analog and mixed integrated electronics and endowed with adaptive capabilities (synaptic plasticity). This hybrid coupling will use dedicated microelectrode arrays to record and electrically stimulate live neural networks, with a specific emphasis on stimulation localization. The system including the artificial and living neural networks will form a closed loop with a regulated feedback. The artificial neural networks will implement conductance-based neuron and synapse models, controlled by plasticity rules like STDP (spike-timing dependent plasticity). 
Dedicated integrated electronics will be designed to implement the communication channels between the living and artificial networks: signal conditioning for the biological signals (from living to artificial) and adapted coding of the artificial neurons events (from artificial to living). In this project, integration between physics (electronic engineering, Microsystems) and biology (integrative neuroscience) is mandatory. 

All 3 partners rely on their large experience in multi-disciplinary collaborative projects at national and international levels. This project is expected to generate scientific advances:

• in the field of information science: by the design of embedded self-organized artificial neural networks, able to communicate in real time with entire biological networks.
• in the field of life science : a tool to develop and test efficient strategies for spinal cord rehabilitation.

SHIVA

Date : 2014 Designer : Florian Kölbl Technology : CMOS AMS 0.35μm HV Size : 2100*1550μm without pads Description : SHIVA (Stimulator with High voltage compliance for In Vivo/vitro Applications) is an ASIC designed to provide current mode electrical stimulation of biological tissues in different contexts. The design principle is based on a scale effect on electrode impedances, so that one chip can provide from 1 to 8 channels that can stimulate micro or macro electrode(s). These chip can also be combined to provide stimulation on more than 8 channels setups.

SEPIA

Date : 2013 Designer : Florian Kölbl Size : 14*30 mm Description : SEPIA is an embedded stimulator for chronic Deep Brain Stimulation on small rodents. The circuit is placed on a plastic support implanted over the rodent's skull by surgery. The circuit, its batteries and packaging weight less than 14 g and can be implanted on the animal letting him free to move in the experimental area. Stimulation waveform can also be changed by physiologists to test different stimulation strategies, study the involved mechanisms and evaluate DBS sides effects.

MultiMed

Date : 2012 Designer : Jean-Baptiste Floderer Description : MultiMed is a digital platform dedicated to bioelectric signal treatments. This FPGA based system is able to amplify, register and treat in real time 64 channels of a Multi-Electrode Array. Spike detection and slow wave analysis can be executed for multiple application fields like in vitro neural network recording, ex-vivo spinal cord monitoring and pancreatic cell activity analysis. The graphical user interface (VGA) allows the real time display of the data and the modification of the configuration parameters of this system.

OSLO

Process : CMOS AMS 0.35μm Date : 07/2011 Size : 1600*1600μm2 without pads Designer : Guillaume Arnaud Description : The ASIC "OSLO" is dedicated to the on-line detection of neural action potential (spikes) that convey information for in vitro excitable cells. OSLO computes in analog mode a detection threshold of the spikes; this threshold is servoed to the standard deviation of the input signal (neural signal). OSLO output stage encodes spike events in asynchronous binary mode. OSLO is a test device; further prototypes should be embedded in microsystems or implants.

MINUS

Process : AMS 0.35um 2P4M CMOS process Date : 07/2010 Size : 3000 * 3000 μm2 without pads Designer : Adeline Zbrzeski Description :M edicalI nterface forN eU ronalS timulation is dedicated to acquisition of low-amplitude neuronal signals, and adapted stimulation. The device includes different amplifiers and filters for test and characterization.