S.M. Engineering Sciences (Bioengineering),
A.B. Engineering Sciences (Biomedical Engineering) and Chemistry, Harvard University
Nervous system trauma, including spinal cord injury and peripheral nerve damage, often results in severely debilitating conditions for patients, with limited clinically available treatment options. There has been much interest in developing regenerative therapies for such injuries, however, several challenges remain to their implementation. Within the central nervous system, nerve regeneration is limited by the body’s natural inflammatory response that rapidly replaces injured spinal cord tissue with scar tissue. Furthermore, this inflammatory process results in significant oxidative damage to the surviving neurons, which further hampers regeneration. One strategy to remediate the damage caused by this inflammatory response is to implant a material at the injury site that is conducive to the growth of neurons and protects them from further damage, while limiting the formation of scar tissue. Recent work with engineered elastin-like proteins (ELPs) has shown that the extent of neurite growth through the material can be modulated by controlling the elastic modulus of, and cell adhesion ligand density within, the material. Such “cell-instructive” materials can be made “cell-responsive” by incorporating functionalities that react based on the presence of certain cellular products. For instance, it has been reported that the serine protease, urokinase plasminogen activator (uPA), is secreted from axonal growth cones. My project investigates the incorporation of uPA-cleavable sequences into ELP hydrogels to either modulate the degradation of the material itself or to selectively release compounds to aid in cell survival. uPA degradable ELP may allow for localized degradation of the hydrogel matrix at the tips of growing neurites, and patterning of this selectively degradable ELP would allow for spatial control over neurite growth. Certain small peptides have been reported to protect neurons against oxidative damage, such as that which occurs following a spinal cord injury. Conjugating these neuroprotective peptides to ELP via a uPA cleavable linker may allow for triggered release of these compounds due to neuronal growth, protecting the neurons within the material from further damage while aiding in regeneration.