Nanotechnology-Based Approaches for Guiding Neural Regeneration

The mammalian brain is a phenomenal piece of "organic machinery" that has fascinated scientists and clinicians for centuries. The intricate network of tens of billions of neurons dispersed in a mixture of chemical and biochemical constituents gives rise to thoughts, feelings, memories, and life as we know it. In turn, subtle imbalances or damage to this system can cause severe complications in physical, motor, psychological, and cognitive function. Moreover, the inevitable loss of nerve tissue caused by degenerative diseases and traumatic injuries is particularly devastating because of the limited regenerative capabilities of the central nervous system (i.e., the brain and spinal cord). Among current approaches, stem-cell-based regenerative medicine has shown the greatest promise toward repairing and regenerating destroyed neural tissue. However, establishing controlled and reliable methodologies to guide stem cell differentiation into specialized neural cells of interest (e.g., neurons and oligodendrocytes) has been a prevailing challenge in the field. In this Account, we summarize the nanotechnology-based approaches our group has recently developed to guide stem-cell-based neural regeneration. We focus on three overarching strategies that were adopted to selectively control this process. First, soluble microenvironmental factors play a critical role in directing the fate of stem cells. Multiple factors have been developed in the form of small-molecule drugs, biochemical analogues, and DNA/RNA-based vectors to direct neural differentiation. However, the delivery of these factors with high transfection efficiency and minimal cytotoxicity has been challenging, especially to sensitive cell lines such as stem cells. In our first approach, we designed nanoparticle-based systems for the efficient delivery of such soluble factors to control neural differentiation. Our nanoparticles, comprising either organic or inorganic elements, were biocompatible and offered multifunctional capabilities such as imaging and delivery. Moving from the soluble microenvironment in which cells are immersed to the underlying surface, cells can sense and consequently respond to the physical microenvironment in which they reside. For instance, changes in cell adhesion, shape, and spreading are key cellular responses to surface properties of the underlying substrate. In our second approach, we modulated the surface chemistry of two-dimensional substrates to control neural stem cell morphology and the resulting differentiation process. Patterned surfaces consisting of immobilized extracellular matrix (ECM) proteins and/or nanomaterials were generated and utilized to guide neuronal differentiation and polarization. In our third approach, building on the above-mentioned approaches, we further tuned the cell-ECM interactions by introducing nanotopographical features in the form of nanoparticle films or nanofiber scaffolds. Besides providing a three-dimensional surface topography, our unique nanoscaffolds were observed to enhance gene delivery, facilitate axonal alignment, and selectively control differentiation into neural cell lines of interest. Overall, nanotechnology-based approaches offer the precise physicochemical control required to generate tools suitable for applications in neuroscience.