Cerebrovascular stroke or trauma lead to an important loss of neuronal tissue, leading to strong disability. A current challenge in the field of tissue engineering is to make implants which first ensure a good survival of implanted neuronal cells and furthermore, which allow to direct growth of these neuronal cells in a preferential direction, in order to organize the tissue reconstruction and to reconnect the two parts separated by the lesion. The objective of the project is to prepare and to inject in vivo biocompatible oriented gels charged with human neural stem cells. The aim is to demonstrate that these gels will guide the growth of neurons in a preferential direction and that they can improve the motor functional recovery and quality. For this purpose, a first step is to design and prepare new hydrogels for 3D cell culture, based on "Low Molecular Weight" (LMW) supramolecular hydrogelators. These gelators tend to form by self-assembly entangled fibers in water which support the formation of viscoelastic hydrogels. Their mechanical and rheological properties differ from polymer based hydrogels and can better mimic the properties of the extracellular matrix. In some cases, they also display fast gel recovery after shear as can do "self-healing" materials. For this reason, they could better fulfill the rheological requirements in their application as injectable matrices and could be more suitable for 3D cell cultures compared with polymer gels. Compared with few other LMW hydrogels already traded for 3D cell culture and injectability, based on quite expensive peptides, the objective is to design and synthetize of biocompatible "Low Molecular Weight" supramolecular hydrogelators belonging to other families of molecules. We will determine their biocompatibility and their rheological properties in relation with their use as in vitro 3D cell culture matrix and as injectable matrix for in vivo applications. In order to induce the oriented growth of neuronal cells, different methods for orienting the supramolecular fibers will be implemented. The objective is to better control the self-assembly of the "dissociated molecules" to fibers to get well-defined and well-organized fibrillar aggregates, and to get more particularly oriented fibers. The design of specific devices for controlling the alignment and the gelation triggers will be implemented. Finally, 3D in vitro neural cell cultures, including human neural stem cells, will be performed on the hydrogels, with or without orientation. Cytotoxicity, growth, adhesion and cell differentiation will be studied. Finally, the ability of hydrogels oriented to guide the growth of neurites in one preferred direction will be assessed. The final achievement will be to test, with the gels giving the best results in vitro, whether they can be injected and oriented in vivo. The results will be studied from the point of view of functional recovery and tissue reconstruction.

Invasive biopsy is still today the reference diagnostic technique of a lot of skin pathologies (inflammation, tumors). Nevertheless, several situations of diagnosis should be kept as conservative as possible. Consequently, non-invasive imaging methods (ultrasounds, computed tomography, magnetic resonance imaging) have been developed for clinical use. In particular, existing optical coherence tomography (OCT) systems can perform non-invasive 3D optical biopsies of skin, improving patient’s quality of life. Nevertheless, these bulk systems are expensive (100 k€), essentially only affordable at the hospital and hence not sufficiently employed by physicians or dermatologists as an early diagnosis tool. MEMS-VCSEL technology offers a novel combination of high compactness, high speed, record coherence length, and flexibility for wavelength-tuned OCT systems. The use of optically pumped MEMS-VCSELs sources for SS-OCT at 1.3 µm for ophthalmology was first demonstrated in 2011 but since that time, the threshold towards the use of 850nm low-cost electrically-pumped tunable devices in a compact system is still not crossed. DOCT-VCSEL project aims at demonstrating a portable SS-OCT imaging system based on novel electrically-pumped MEMS-VCSEL light-source technology operating at 850 nm and taking advantage of polymers and semiconductors-based collective micro-nanotechnologies. These new compact and low cost sources can be arranged in arrays and will be completing an adapted architecture of array-type active Mirau interferometers developed within the European collaborative project VIAMOS (2012-2015). Thanks to this combination, we will develop a miniature (< 20 cm3), low cost SS-OCT imager (15 k€) providing cross-sectional 3-D tomograms with a depth greater than 0.5 mm, axial and transverse resolutions of 6 µm (corresponding to a laser tunability of 35 nm) and imaging field of 8x8 mm2, enabling doctors to perform painless and earlier detection of skin pathologies, including intra-operatively for the delimitation of gesture. For this purpose, DOCT-VCSEL brings together an experienced consortium made of 2 research institutes (LAAS/Toulouse and FEMTO-ST/Besançon) and 2 medical groups (Service de Dermatologie and Inserm CIC1431/CHU de Besançon). Partner’s expertise includes MEMS, MOEMS, VCSELs, OCT microscopy and dermatology. A unique team of transverse expertise is thus gathered in DOCT-VCSEL to design and demonstrate a miniature solution for in vivo 3D skin imaging to further address the early diagnosis of cutaneous pathologies that will potentially benefit millions of people worldwide. To validate the technical and functional performances of DOCT-VCSEL microsystem, translational trials will be performed at the UHB in the department of Dermatology by the end of the project. For an easy and rapid analysis, a specific imaging processing tool will be developed with the help of the company Pixience specialized in skin measurements tools.

Low cost strain sensors based on electron tunneling in assemblies of metallic nanoparticles (MNPs) are proposed as a new touch technology for flexible displays, but their sensitivity and stability are still impacted by variations in thickness, morphology and density of NPs films. With an industrial partner NANOMADE Concept, which develops a patented touch technology relying on MNPs-based resistive strain gauges, we propose to develop strain sensors based on the use of nanohelices assemblies coated with conductive nanoparticles interconnected via ligands to be advantageously used to overcome such critical points: the helical morphology exhibits enhanced flexibility that will increase the measurable range of strain; the positioning of metallic NPs with ligands on the nanohelices can be done with a high degree of precision; alignment of highly ordered wires of metallic NPs will be straightforward since they are already positioned on the nanohelices. The aim of this project is to improve the electromechanical properties of strain sensors both in terms of sensitivity as well as reproducibility and stability.

Dysfunctions of the central nervous system are a major economic and social issue. Neural prostheses and brain-computer interfaces offer promising perspectives to restore motor functions and communication capabilities in patients suffering from severe paralysis. These approaches require the implantation of arrays of microelectrodes offering the possibility to record brain activity with stability on the long term. However, to date, the fabrication of brain implants housing a large number of microelectrodes and offering a stable connection with the neural tissue on the long term remains impaired by two major limitations. The first one stems from the electrode material itself when the size of the electrodes becomes small. Noble metals such as Platinum or Iridium have been used for decades to make macroscopic electrodes, which are now used in routine for neural recording and stimulation in several clinical applications such as cochlear implants, deep brain stimulation for Parkinson disease, and also the pre-surgical functional evaluation of epilepsy. However, thanks to the development of microfabrication technologies, the past decades have seen the development of new types of implants housing tens or even hundreds of microelectrodes on the micrometer scale. Yet, when the size of the electrodes diminishes, two problems arise: The intrinsic (thermal) noise level of the electrodes increase, and their safe charge injection limits decrease, which prevents delivering sufficient currents to activate neural networks without inducing lesions due to electrochemical reactions at the electrode/tissue interface. In this context, the first goal of the NeuroMeddle project will be to consider new types of materials based on the electrodeposition of pure or doped PEDOT/PSS to develop electrodes with improved performance and stable on the long term. A second main problem of existing brain implants (for instance like the Utah array) is the instability over days and even the loss of neural signals along time after a few weeks or months. This is especially the case for action potential signals, either of single or multiple units. This instability is mostly due to the combined effect of the movements of the brain and the inadequacy of the rigidity of implant materials versus the soft properties of the brain tissue. For this reason, an important line of research worldwide is the development of flexible implants matching the geometry and the mechanical properties of the brain, while still compatible with intracortical recordings. In this quest, an important open challenge remains to find strategies to insert flexible microelectrodes so that they meddle into the brain to create intimate and stable connections with individual neurons on the long term. Hence, the second goal of the NeuroMeddle project will be to develop implants offering such conformational stability, based on transient rigidification of flexible electrodes using biodegradable embedding materials (PEG, PLA, Chitosan, Silk fibroin) for the time of implantation. We will particularly focus on silk fibroin, which offers high rigidity and is not yet used in Europe for this type of application, while well mastered by one of the NeuroMeddle partner. The new electrode materials based on PEDOT/PSS, as well as biodegradable materials will first be tested in vivo in the rat. In a second step, we will consider another model closer to the human brain in order to face similar problems of stability of implants. We will use a paradigm for cortical recordings underlying vocalization in the awake mini pig, which allows to test the stability of long term recordings of unit and multiunit signals using the new conformational implants developed in the project.