Multi-channeled Bridges for Promoting Chronic Spinal Cord Repair

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Spinal Cord Injury (SCI) causes paralysis below the level of damage, which results from neuron and oligodendrocyte cell death, axonal loss, demyelination, and critically, the limited capacity of spinal cord neurons to regenerate. In contrast to patients with contusion injuries, individuals with penetrating SCI do not recover some function due to plasticity and are reliant on reconnection of spinal pathways, such as through biomaterial bridge that support true axonal regeneration. Although spinal cord neurons have the innate capacity to regenerate, they are limited by the environment, which contains an insufficient supply of factors to promote regeneration, and an abundant supply of factors that inhibit regeneration. Our long-term goal is to develop a combination therapy based on biomaterials that can 1) bridge, 2) modulate the injury microenvironment, 3) drive axon growth through an inhibitory milieu enabling the promotion and direction of axonal growth into, through, and re-entering spared host tissue to form functional connections with intact circuitry below the injury. We have shown that the bridge architecture leads to integration with the host tissue, reduces secondary injury, and prevents cyst formation. The channels of the bridge support robust axonal ingrowth into and through the bridge for corticospinal tract (CST) axons and extend >2 mm down the cord by 10 weeks post-implantation. Bridge implantation enhances functional recovery by itself, and modification of the bridge to express anti-inflammatory factors further enhances function recovery by decreasing the secondary damage and initiating a regenerative program that consists of genes associated with neural development and repair. This proposal builds on these results and focuses on regeneration at chronic time points by providing anti-inflammatory factors acutely after a penetrating injury combined with a biomaterial bridge at a chronic time points. We hypothesize that acute delivery of factors to reduce inflammation will minimize inhibitory molecules and spare regeneration competent axons adjacent to the injury, and that combination of this approach with delayed bridge implantation and pharmaceutical microtubule stabilization will drive directed axon regrowth through the channels to re-enter the caudal parenchyma and synapse onto intact circuitry in chronic SCI. Toward this goal, gene delivery will be used to modulate inflammation and reduce inhibitory molecule expression during the acute stage of injury (Aim 1). Regeneration at chronic times is investigated using bridges in combination with the microtubule stabilizer epothilone B (EpoB), which drives axon growth through the injury to connect with intact circuitry (Aims 2). The combination of acute and chronic therapies is investigated in Aim 3. The bridge platform can support multiple aspects of the regenerative process, and the well-defined components, which have been used in the clinic, may facilitate the ultimate translation to the clinic. These studies provide critical information on how early injury interventions can impact regeneration at later times.