Bioactive peptide amphiphile scaffolds to enhance spinal cord regeneration

Spinal cord injury (SCI) is a debilitating condition affecting an estimated 1,275,000 Americans at a cost of over 40 billion dollars each year. SCI causes immediate damage of nervous tissue accompanied by loss of local blood vessels, release of inflammatory mediators and the cellular immune response at the site of injury. These processes lead to further axonal injury, cell death, and demyelination, which impede endogenous tissue repair and limit prospective repair approaches. While much effort has been dedicated to the development of treatments and cures for this condition, to date, there is no single biological intervention that can address all of the physiological events that damage the spinal cord. Previously, the Stupp Laboratory demonstrated that peptide amphiphile (PA) molecules self-assemble into nanofibers that can be used as bioactive scaffolds, which were beneficial upon injection in an experimental mouse model of SCI. Here, I propose to integrate orthogonal bioactive moieties that address different aspects of the injury response in order to increase the potency of the bioactive biomaterials that have already been shown to bridge the lesion site effectively. This will be accomplished by designing and testing new vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) mimetic PA molecules that self-assemble into nanostructures as an angiogenic and neurogenic biomaterial platform for treating SCI. The growth factor mimetic sequences incorporated in a PA will be co-assembled with a known PA that presents the neuroactive pentapeptide epitope from laminin, isoleucine-lysine-valine-alanine-valine (IKVAV-PA), to promote vascularization, nerve regeneration, functional recovery, and to limit the damage. This project will evaluate the synergies between the different PA sequences and define the most effective combinations, and determine the best stoichiometry in vitro. The combinatorial therapy will then be tested in vivo in the mouse SCI model.