Blood biomarkers dosage using red blood cells immuno-agglutination

The reference method for blood biomarkers dosage is ?enzyme-linked immunosorbent assay? (ELISA) technique. It is performed using blood serum or plasma, and implies a pre-analytical separation step of blood cells, usually achieved via centrifugation. For development of rapid biological test, such as Point-Of-Care (POC), the centrifugation step is not easily integrated, so biomarkers dosage implies the use lateral flow immuno-assays. The objective of this doctoral research work is to set up an alternative dosage method directly on whole blood. We propose to develop blood biomarkers dosage by following continuously an immuno-agglutination reaction of red blood cells using a bi-functional reagent. Owing this approach, red blood cells become the indicator of the dosage reaction, using a bispecific antibody which recognizes on one hand the targeted biomarker (protein, virus, micro-organism, cell) and on the other hand the red blood cells. Agglutination monitoring and detection will be achieved using imaging. This method is easily integrable in a portable device and presents sufficient resolution to visualize cells without any labeling and in real time during agglutination.

Biomaterials for the controlled delivery of hydrophilic and/or lipophilic therapeutics; their inclusion in smart bandages.

Several biomaterials, mainly polymers of natural origin, are studied or already used in medical devices. Different systems are designed for the encapsulation and delivery of therapeutic molecules; however chemical drugs and biomolecules (proteins, SiRNAs?) are not always well included in the material, and their kinetics of release is poorly controlled. We have developed, patented, and tested in vitro and in vivo biocompatible lipid nanoparticles able to vectorize lipophilic and/or hydrophilic therapeutics. The objective of the thesis is to include these nanoparticles, with performing vectorization properties, in biomaterial matrices based on polysaccharides, used for their structuration properties. The association of drug nanocargos with the structuring polymer matrix will be made by chemical bonds that can be cleaved specifically by external stimuli such as an electric field or light irradiation. Thus, the systems developed will allow a controlled release of drugs and biomolecules over time and space. In the thesis, the synthesis of these innovative bio-inspired nano-polymer materials, their characterization and their structuration, will be discussed. The new materials will be used to design smart bandages with controlled drugs and biomolecules kinetics of release, as an application demonstrator.

Dielectric filled MEMS resonators for ultrasensitive mass detection in liquid

Microfluidic system for the encapsulation control of biological living cells

At CEA-LETI, the division of systems for Health and Biology develops microfluidic chips for living cell encapsulation. Main applications of these systems are cell therapy or drug delivery. The first targeted application is Diabetes treatment. Indeed, one way of curing Diabetes is to graft either whole pancreas or cluster of pancreatic cells, called islet of Langerhans. This type of graft is always associated with immunosuppressor treatments. These treatments are not only highly expensive but also deleterious for patient's life expectancy. One way to avoid these treatments is to encapsulate the cell to be grafted into a biocompatible capsule. The role of the capsule is to hide the grafted cells from the immune system and also to preserve their integrity. Pancreas is then successfully replaced and glycemia is regulated. At CEA-LETI, we focus on the development of new technologies in order to improve the efficiency and performance of cell encapsulation. This work is done jointly with clinicians, who are international experts. These new microfluidic devices are based on microtechnologies development. These systems can generate capsules with high size precision and allow the automation of the whole process of encapsulation to produce highly reproducible capsules. Although few teams work on that topic, one point of the system is still not optimum. This is the precise control of number of cells in one capsule. This key point is essential to provide to the clinicians a highly reproducible batch of capsules. The aim of this PhD Thesis is to develop an innovative microfluidic device that will answer to that need. The first year of the PhD thesis will be focalised on the study of a CEA patented device. You will have in charge the evaluation of this first system. You will perform microfluidic experiments, analyse the results and propose new microfluidic design to optimise the performance of such a device. Your approach will join experiments and numerical model of the whole system. After these iterations, you will propose an optimise design and couple it with the currently developed automated system. During this project, you will acquire multiple competencies such as microtechnologies, microfluidic, cell culture, surface chemical modification and various characterization technologies (optical, electronic, mechanical and biological).

Suspended microchannel in hollow MEMS sensors, for real-time counting/weighting of cells and nanoparticles

Prostethic Synapses based on Resistive Memory Technologies

In neurobiology there is a strong need of advanced neuro-prostethic systems able to communicate with the brain cortex, serving both to map and locally stimulate the neuronal activity. These will enable researchers to take samples in real time, giving them a precise picture of the neuronal activities during certain processes such as Parkinson's disease. Resistive Random Access Memory devices by default become a very elementary or simplistic electrical model of the biological synapse for the following reasons: (a) Two ? Terminal, Nanoscale ; (b) Conductance/Resistance Modulation (i.e. can be programmed with electrical pulses analogous to neuron action potential) ; (c) changes (dynamic) and stores (non-volatile) simultaneously. The main idea of this Master stage will be thus to develop a specialized neural probe with intelligent RRAM array, with the following functionalities: 3D spatial mapping of neuron activity through different layers of cortex/brain tissue, offsite storage of synaptic weights/patterns in response to a stimuli, possibility of by-passing a real synapse with an artificial RRAM synapse. The object of the stage will be to make a proof of concept of the prostetic synapses by integration of RRAM neuron/synapses in NeuroPXI, the new real-time data acquisition system for neurosciences studies from the Health Department from CEA-LETI. This brain-interface platform already well-established will allow to test the RRAM demonstrator in-vitro and in-vivo (in collaboration with CLINATEC lab).

Methods of characterization of electrodes or packaging technics to be used in Active Implantable Medical Devices

The Active Implantable Medical Devices benefit from the miniaturization thanks to recent development in the field of micro and nanotechnologies, more and more functions are embedded in minimally invasive volumes. In particular electrodes used for neural recording or stimulation can be miniaturized in order to increase their number or their density or to reduce the volume of the device. Down scaling of devices requires a new assessment of stimulation paradigm and the technology at stake have to remain biocompatible. The PhD will take place at CEA/LETI/CLINATEC on the Minatec campus (Grenoble, France). Clinatec is a new biomedical research center at the CEA in partnership with the Grenoble Hospital, the French medical research agency (INSERM) and the University of Grenoble. Our mission is to demonstrate the proof of concept of preclinical and clinical medical devices based on micro and nanotechnologies. For 6 years, the LETI has been involved in the development of implantable packaging and electrodes (silicon or polymer based) for in-vitro or in-vivo devices. The characteristic dimension of electrodes goes from tens to hundreds of microns. The in-vivo behavior of these systems must be deeply investigated to specify their characteristic and their ?harmfulness?. The local tolerance of the electrodes and the packaging must be assessed by direct methods such as histology or indirect methods such as impedance spectroscopy or markers of inflammatory reaction. The research consists in developing a set of physical and biological methods using existing and innovative devices so as to fully characterize devices and to be able to better specify future component for recording and stimulation. The candidate has a Master of Science with knowledge in electrochemistry, clean room processes, electronic systems and eventually a background in biology.