Biohybrid Neural Interfaces: Exploring the Role of Regional Astroglia in Neuronal Integration and Functionality

Abstract

Biohybrid Neural Interfaces (BNIs) offer an innovative approach to neural implantation by incorporating living neurons and traditional neural implants. This creates a dynamic cellular environment that allows for more natural interactions with host neural tissues. Given that BNIs incorporate living neurons, their functionality is potentially impacted either by co-transplanted astroglia immediately post-implantation or by those existing in the host neuronal tissue. Importantly, astroglia may exert diverse impacts on these neurons due to their regional heterogeneity, however, this aspect is less often addressed in current BNI research. In the first chapter, we conducted a thorough scoping review of the developments and challenges facing current BNIs. During the developmental phase of our research (Chapters 6-11), we built a foundation for subsequent advanced experiments. This phase included fabricating a trial electrode array using 3D-printing techniques, testing different carrier hydrogels for neuron incorporation, and establishing a preliminary cochlear implantation and astrocytic bridging model. These developmental works laid the groundwork for the advanced experiments that followed. Building on this foundation, our advanced experiments (Chapters 2-4) focused on investigating the electrophysiological impact of co-culturing induced human glutamatergic neurons (iNeurons) with astroglia from different brain regions. This work provided critical insights into the modulatory role of astroglia on BNI functionality, specifically how regional astroglia influenced neurite extension and branching in iNeurons, which are essential processes for establishing functional connections with host tissues. Our findings showed that co-culturing regional astroglia with iNeurons exsert distinct impacts on the electrophysiology than iNeurons cultured alone, and these impacts may become more significant with time. This regional impact was evident not only in electrophysiological attributes but also in structural aspects such as neurite growth and branching. Later experiments demonstrated the functional integration of iNeurons co-cultured with cortical or brainstem astroglia, forming functional connections with spiral ganglion neurons on microelectrode array (MEA) plates. This proof-of-concept underscores the critical role of astroglia in enhancing BNI design and their potential for clinical applications, notably in cochlear implants. In summary, our work highlights the significant yet often overlooked role of regional astroglia in the functional development of BNIs. Consideration of astroglial impacts, whether through co-transplantation or site-specific selection, is crucial for future BNI design. These insights contribute to the advancement of BNIs, paving the way for next-generation neural prosthetics and innovative treatments for neural impairments, particularly in applications such as cochlear implants.