Project Portugal 2030

Summary

The technological progress in the field of BMIs boosted the development of intracortical MEAs capable of high-density recording/stimulation and specificity. However, their clinical translation remains elusive, mainly due to the development of a glial scar sheath, which reduces the quality and the stability of signal transfer, compromising their functional performance [1,2]. This project addresses the need of efficient approaches to reduce astrogliosis and neuronal loss at the electrode brain-tissue interface. To fulfill this need, we propose to develop a biomimetic surface replicating relevant aspects of brain ECM, for neuronal rescuing and to reduce gliosis. Specifically, a hydrogel coating mechanically compliant with brain tissue presenting rhLN 521 and affinity-bound BDNF, to promote neuronal survival and neurite extension of adjacent neurons towards the electrode surface, and to minimize the inflammatory response. This coating will differ from previous electrode coatings in the following aspects: - Use of rhLN521 as bioactive adhesive protein instead of LN 111, which is the LN isoform used in previous coatings. LN 111 is reported to reduce gliosis [1,3], but is rarely expressed in the adult brain [4]. Since LN 521 is the main LN isoform present in adult brain ECM [4], we expect rhLN 521 to outperform LN 111 bioactivity. - Exploring LN 521 ability to sequester BDNF via high affinity binding [5], in contrast to BDNF physical adsorption or entrapment. This is expected to increase BDNF bioavailability at the electrode surface by overcoming BDNF rapid diffusion, and to contribute to its efficient presentation. - Immobilizing rhLN521 through its agrin-binding domain [18,19], in contrast to the LN immobilization methods previously used for LN immobilization onto electrodes (adsorption, non-specific covalent binding through LN multiple free amines), which can compromise the exposure of LN cell adhesion and growth factor-binding epitopes upon immobilization. We will use parylene-C substrates as surrogates of existing intracortical MEAs, as parylene-C is commonly used for insulation of implantable intracortical electrodes (i.e. the FDA-approved Utah MEA used in clinical research), and since it has proven promising for use as device substrate for the fabrication of flexible MEAs. As such, we have engineered this biomimetic hydrogel coating to enable its application in flexible MEAs currently under development, and to further increase their biocompatibility for long-term neural interfacing. Specific objectives include: 1) Preparation and characterization of a hydrogel coating presenting site-specific-immobilized rhLN 521; 2) Evaluation of the rhLN 521-presenting coating in terms of ability to sequester BDNF and its sustained delivery; 3) Characterization the multifunctional hydrogel (presenting rhLN 521 and affinity-bound BDNF), in terms of bioactivity towards cortical neurons and glial cells; 4) To determine the effect of the multifunctional coating on MEAs electrical properties; 5) To assess the capability of the multifunctional hydrogel coating to reduce neuronal and gliosis at the electrode-brain tissue interface, in a rat model of brain tissue response. By exploring different approaches and their combination, the successful development of this hydrogel is expected to advance the current state of the art of the field of chronically-implanted electrodes, and make of long-term electrode-neural interfacing a more attainable challenge.