20 Décembre – Thesis defense - Amélie Degache

10 h30 Amphi Jean-Paul Dom - Laboratory IMS / building A1 (Talence campus)

Electrical impedance spectroscopy applied to the chronic monitoring of the fibrosis induced by cardiac active implants.

Cardiac arrhythmias represent about 50% of the cardiovascular diseases which are the first cause of mortality in the world. Implantable medical devices play a major role for treating these cardiac arrhythmias. In France, about 250.000 patients are equipped with an implanted device for arrhythmia treatment and need a regular monitoring. These devices use the latest technology of micro-nano-electronics and integrate a subcutaneous pulse generator connected to electrodes placed into the heart via intravenous leads. One of the main weaknesses of every implantable device lies in the electrode-tissue interface due to a sustained inflammatory response called fibrosis. This phenomenon jeopardizes the device biocompatibility, because it encapsulates the stimulation lead with an “insulating” tissue, creating adherences along the lead and often leading to an increase of the stimulation threshold over time and a larger electrical consumption. This response is well-known and minimized during the implantation surgery thanks the use of steroid-elution electrodes, however fibrosis still remains an impediment even for the most recent devices, enhancing the interest of studying long-term biocompatibility of cardiac implanted devices.
The understanding of fibrosis mechanisms is essential for this work. It consists in some cardiac cells activation and differentiation under a mechanical stress, inducing fibrosis initiation and modifying locally the active cardiac tissue. To characterize this modification, we use electrical impedance measurements, consisting in sending a sinusoidal electrical current I and then measuring the resulting voltage U in the tissue; the impedance Z is the U/I ratio. Depending on the frequency of the measurement signal, we can explore the tissue from the microscopic to the macroscopic scales.  As a patient is already equipped with cardiac leads connected to a stimulation device which can also record the cardiac electrical activity, the main idea of this work is to investigate the use of an electrical measurement that could characterize the fibrotic lead encapsulation, with the final objective to embed this characterization method in the implanted circuit. This brings us to the main question of our project: does the fibrosis developing around the cardiac leads have an electrical signature?
My thesis work is organized along three axes. Two experimental axes are conducted at cellular and tissue levels, on in vitro or ex vivo models. In addition, an axis studying the feasibility of embedded impedance measurement for in vivo mimicking conditions is also discussed. The ex vivo part presents the characterization of tissue of different natures, healthy or collagenous, it was developed with the IHU LIRYC laboratory, on porcine or ovine cardiac tissue (ventricles mainly), with stimulation electrodes used on patients The impedance spectra are analyzed using a known electrical model from which characteristic parameters of the two tissue types are extracted. After statistical analysis, these parameters are found to be significantly different allowing us to distinguish both tissue types. The in vitro part presents the electrical characterization, using impedance measurements, in parallel to the biological characterization, using immunocytochemistry, of a cellular fibrosis model. It consists in culturing human cardiac cells, activated or not by a growth factor. After a statistical analysis, the impedance values show a significantly different signature for cultures with growth factor, with respect to sham cultures, while the biological characterization confirmed the presence of more activated and differentiated cells over time. The last axis gives preliminary results of embedded impedance measurements in custom circuits.

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