A major focus of our lab is the repair of spinal cord injury (SCI), for which there are no treatments available that can achieve regeneration. Development of clinically effective strategies to restore function after SCI will require consideration of multiple aspects of this inhibitory environment. Ultimately, we aim to develop a combinatorial therapy that addresses multiple barriers to spinal cord repair by incorporating substrate-immobilized biochemical cues, genetically encoded regulatory factors, and cell replacement.
Injectable Biomaterials to Engineer the Neural Microenvironment
Hydrogel biomaterials are a clinically promising strategy for spinal cord repair because they can be designed to be injected and formed directly in the lesion, approximate mechanical and biochemical properties of the healthy spinal cord and finally as a medium to deliver regenerative factors. Our lab focuses on a combination of poly(ethylene) glycol (PEG) and hyaluronic acid (HA) precursors using aqueous chemistries that allow for in situ crosslinking of hydrogels and gentle encapsulation of biological agents and cells. HA is a linear-chain polysaccharide that has been shown to significantly augment wound healing, nerve regeneration, cell migration and is a principle extracellular matrix component in the central nervous system. HA-PEG hydrogels will be employed as a platform from which to modularly add various environmental components (e.g., extracellular matrix-derived adhesion sites, biodegradable crosslinks and mechanical properties). Using this modular platform, we have the unique opportunity to evaluate the individual and combinatorial effects of various aspects of the in vivo microenvironment on spinal cord regeneration in a mouse model.
Biomaterial-Mediated Gene Therapy
Delivery of lentiviral vectors from biomaterials is a powerful tool to influence the in vivo microenvironment. Lentiviral vectors enable sustained, localized protein expression and facile delivery of virtually any factor and combinations of factors simply by encapsulation of viral particles within hydrogels. This project aims to engineer HA-PEG-based hydrogel microenvironments that support delivery of lentiviral vectors encoding for neurotrophic factors and to evaluate their effects on regeneration in a mouse model of SCI. We are investigating delivery of lentiviral vectors encoding for factors that address multiple barriers to spinal cord repair, including axon survival and regeneration, glial scar formation, excessive and chronic inflammation and myelination.
Biomaterial Carriers for Neural Stem/Progenitor Cell Transplantation
SCI causes extensive death of oligodendrocytes, whose neurotrophic support and myelin wrapping of axons are vital to functional connectivity in the spinal cord. As mature oligodendrocytes cannot self-renew, insufficient quantity of oligodendrocytes is a significant barrier to recovery. Therapeutic delivery of neural stem/progenitor cells (NPCs) to replace lost oligodendrocytes has shown promise to treat SCI and other neurodegenerative conditions; however, low survival rates and inefficient differentiation after transplantation have been major limitations. In addition, despite reports of positive effects of stem cell transplants on SCI repair, differentiation and integration into host tissue are not observed on a scale adequate to achieve functional repair. To address these issue, we aim to design hydrogel constructs as vehicles for efficient, localized delivery of NPCs that will provide a microenvironment designed to shield transplanted cells from the host inflammatory response, actively promote NPC differentiation into oligodendrocytes and enhance functional myelination of host axons.