Dissertation Defense - Jessica Chen
Analysis of tissue sparing and circuit regeneration in spinal cord injuries treated with biomaterials and gene therapy
Dr. Lonnie Shea, Chair
Each year, the U.S. sees nearly 17,700 new cases of spinal cord injuries (SCIs). Despite intense rehabilitation, patients with SCIs most often suffer lifelong physical consequences and substantial increases in medical expenses per individual. While immobilization and surgery can be used for immediate stabilization of the injury, no clinical methods exist to address the subsequent inflammation and lack of tissue regeneration that further contribute to the motor and sensory deficits seen after an SCI. In a mouse SCI model, where a left C5 hemisection results in loss of function of the left arm, a poly(lactide-co-glycolide) (PLG) scaffold or “bridge” can be implanted in place of the resected tissues. The bridge can be loaded with lentiviruses, such as anti-inflammatory interleukin-10 (IL10), for local delivery of gene therapy that can aid in control of the post-SCI microenvironment. Using a combination of behavioral tests, histology, and optogenetics, we show that IL10 treatment improves muscle function through the sparing of motor circuitry tissues from inflammatory damage. We also found that IL10 enhances axonal regeneration, with 3D imaging showing regenerated axons traversing across the entirety of the injury site. Furthermore, electrophysiological studies demonstrate that these axons are able to carry action potentials. Taken together, these studies suggest early immunomodulation can have long-lasting benefits through tissue sparing, and that regenerated axons have the potential to contribute towards signal transduction across an injury. These findings provide novel insights into how the pathophysiology following an SCI can be altered using biomaterials and gene therapy.