(3z) Engineering 3D Microenvironments for Neural Tissue Engineering: Directing Survival, Differentiation, and Neurite Growth

Neural regeneration within the central nervous system (CNS) is a critical unmet challenge as brain and CNS disorders continue to be the leading cause of disability nationwide. Three-dimensional (3D) tissue engineering strategies present an innovative therapeutic approach for the delivery of cells, growth factors, and drugs to CNS tissue to restore lost function. Regeneration in the CNS is limited: inhibitory reactive oxygen species result in secondary insult after injury, and signal-transmitting neurons are not capable of proliferation to replace lost tissue. Engineering microenvironments conducive to neuronal cell growth in vitro and regeneration in vivo requires control over known design parameters affecting neural stem cell (NSC) viability, proliferation, and differentiation into functional neurons.

In my thesis research, I used a poly(ethylene glycol) (PEG) poly(lactic acid) (PLA) block copolymer to create 3D hydrogels with tunable stiffness and degradability. Through systematic tailoring of the hydrogel mechanics in both 2D and more physiologically relevant 3D environments, I found that the differentiation of NSCs down the desired neuronal pathway was enhanced within biomaterials of stiffness comparable to that of native tissue. I also discovered that modulating the hydrogel degradation kinetics enabled direct control over the release of lactic acid, a reactive oxygen species scavenger. As a result, these PEG-PLA copolymers directly affected NSC intracellular redox state and promoted cell survival. To demonstrate therapeutic potential, I showed for the first time that degradable PEG-based hydrogels induce a minimal inflammatory response in the brain and can be used to temporally and spatially control the delivery of neurotrophic factors to local brain tissue, a critical step toward directing growth of transplanted tissue within the brain.

As a postdoctoral scholar I have further developed my ability to rationally design new materials by transitioning to the use of protein-engineered biomaterials for dynamic modulation of neuronal fate and in vivo delivery of cells. These protein-engineered materials allow careful independent tuning of several functional properties including cell-binding site density, cell-mediated degradation, and mechanical stiffness. With this platform, I have investigated the control of cell-matrix interactions using 3D primary neuronal cultures. These studies have enabled tailoring of the material properties in 3D such that neurons survive and extend neurites over thousands of microns into the surrounding matrix.

I intend to leverage my expertise at the intersection of biomaterials design, stem cell biology, drug delivery transport, and reactive oxygen species kinetics to build a nationally-recognized lab with a multidisciplinary, 3D tissue engineering approach. While keeping an eye on feasibility for clinical treatment strategies, I will focus on applications for neurodegenerative diseases and injuries of the central nervous system. In this role I hope to educate a new generation of diverse young engineers and cultivate their interest in chemical and biomolecular engineering.