Engineering Tissues of the Central Nervous System: Interfacing Conductive Biomaterials with Neural Stem/Progenitor Cells

Abstract

Conductive biomaterials provide an important control for engineering neural tissues, where electrical stimulation can potentially direct neural stem/progenitor cell (NS/PC) maturation into functional neuronal networks. It is anticipated that stem cell-based therapies to repair damaged central nervous system (CNS) tissues and ex vivo, "tissue chip" models of the CNS and its pathologies will each benefit from the development of biocompatible, biodegradable, and conductive biomaterials. Here, technological advances in conductive biomaterials are reviewed over the past two decades that may facilitate the development of engineered tissues with integrated physiological and electrical functionalities. First, one briefly introduces NS/PCs of the CNS. Then, the significance of incorporating microenvironmental cues, to which NS/PCs are naturally programmed to respond, into biomaterial scaffolds is discussed with a focus on electrical cues. Next, practical design considerations for conductive biomaterials are discussed followed by a review of studies evaluating how conductive biomaterials can be engineered to control NS/PC behavior by mimicking specific functionalities in the CNS microenvironment. Finally, steps researchers can take to move NS/PC-interfacing, conductive materials closer to clinical translation are discussed.

Keywords: cell-material interfaces; central nervous system degeneration; conductive biomaterials; neural engineering; neural stem/progenitor cells; regenerative medicine.

Figure 1.. NS/PC niches in adult humans.

Well-characterized populations of NS/PCs reside in the cortical SVZ and SGZ of the dentate gyrus. The regions of the grey commissure most proximal to the central canal and the filum terminale (not shown) may also harbor populations of NS/PCs or NS/PC-like cells jnto adulthood. Each site is populated by mature neurons, glia, and stem-like cells at varying points of differentiation, such as the Type B, Type C, and Type A cells of the SVZ. Thus, interfaced NS/PCs may display varying amount of differentiation, proliferation, or other phenotypes based on the time at which it was isolated or the region from which it was isolated.

Figure 2.. Cell-cell contacts are integral in development of the central nervous system.

NS/PCs interact with each other through N-cadherin-based adherens junctions. NS/PCs also interact with surrounding cells through notch and its receptors and Eph/ephrin. Gap junctions, formed by connexin proteins, facilitate ion transport between NS/PCs, playing an integral role in the propagation of current due to endogenous or exogenously applied fields.

Figure 3.. Acellular components of the NS/PC microenvironment include soluble factors and biochemical and physical influences of the ECM.

Soluble factors secreted by local vasculature, ependymal cells that produce CSF, and neighboring glial cells determine NS/PC fate. Proteins and polysaccharides in the ECM interact with NS/PC cell surface receptors to affect proliferation, migration and fate. NS/PCs are also affected by local tissue mechanics (e.g., viscoelasticity) and diffusion of various soluble factors through the porous ECM. Extracellular vesicles packaged with biomolecules (e.g., miRNA) are also secreted by cells and contribute to NS/PC behavior.

Figure 4.. Potential mechanisms of EF effects on NS/PCs.

Signaling proteins mediating cell migration, including PI3K/AKT, RhoA/ROCK, and MAPK/ERK, are thought to polarize within the cell membrane in response to an EF to mediate galvanotaxis. In neural cells, ionotropic receptors, such as NMDA, and other ion channels have been implicated in galvanotaxis and other EF-induced behaviors.

Figure 5.. Conductive biomaterials for NS/PC interfacing

include electroactive materials (e.g., metals, silicon, carbon-based materials or electrically conductive polymers) and composite materials in which electroactive materials are integrated with highly biocompatible materials (e.g., natural or synthetic polymers). These composite materials can take on various forms, including 2D films, nanofibrous mats, hydrogels, and 3D microporous or tubular scaffolds.