Central nervous system (CNS) tissue lacks the ability to heal properly after spinal cord injury (SCI) due to complex pathophysiology. The combination of chronic inflammation, glial scarring, and blood-spinal-cord-barrier (BSCB) permeability create an inhibitory environment for regeneration. Any successful therapeutic for SCI must address these issues by resolving chronic inflammation, promoting angiogenesis and BSCB integrity, regenerating neural tissue, and integrating with host tissue. Hydrogels have been employed to accomplish those goals. However, there are a few design criteria that need to be considered including injectability, biocompatibility, biodegradability, interactivity, porosity, and swelling. Hyaluronic acid (HA) is an ideal base for hydrogels because it is non-immunogenic and has multiple chemical groups that can be easily functionalized using aqueous, biocompatible chemistries to create crosslinking sites.

The data presented in this dissertation highlights the importance of HA molecular weight (MW) and pore size in the design of HA-based biomaterials. HA is a simple molecule with an extremely complex bioactivity dependent on its MW. First, we characterized the effects of HA MW alone on human cerebral microvascular endothelial cells (HCMVECs), U937-derived macrophages, and human neural stem cells (hNSCs). Additionally, we also characterized the ability of HA to cluster its main receptor CD44 in a MW-dependent manner. Second, we characterized how chemical modification and subsequent crosslinking of HA into annealed, macroporous microparticle scaffolds (AMMS) affects this MW-dependent bioactivity and clustering of CD44. Last, we began characterization on how pore size in AMMS influences angiogenesis and inflammation. Altogether, the data presented in this dissertation highlights two critically important parameters in the design of HA-based biomaterials for spinal cord repair.