Injury to the spinal cord results in paralysis below the level of the injury, which results from cell death and limited regeneration. Although spinal cord neurons have the innate capacity to regenerate, they are limited by 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 bridge the injury site to control the microenvironment. The bridge microstructure will direct axonal outgrowth and localized drug delivery will provide factors that stimulate regeneration yet limit the factors that inhibit axonal outgrowth. Bridges capable of localized DMA delivery will transfect cells locally, whereas protein delivery will degrade inhibitors to regeneration. This bridge releasing DMA encoding for neurotrophic factors will be employed to test the hypothesis that the transfection profile will initiate axonal elongation into the bridge, across the injury site, and facilitate re-entry into the host tissue. This hypothesis is based on the observations that i) DMA delivery can induce sustained, localized transgene expression in vivo, ii) neurotrophin delivery to the injury site can promote axonal elongation into a synthetic bridge, iii) cell transplantation or osmotic pump implantation does not provide a controllable concentration of neurotrophins for promoting regeneration, iv) axonal re-entry into the host is encouraged by reducing the growth promoting stimuli within the bridge to levels comparable to host tissue, and degrading inhibitors in the scar adjacent to the bridge. Based on these observations, the experimental focus is on designing bridges for efficient gene transfer and applying them in a spinal cord model of regeneration.
Specific Aim 1 : Investigate transgene expression (quantity, duration) and transfection (cell number, distribution, and identity) in the spinal cord by sustained release from the multiple channel bridge.
Specific Aim 2 : Investigate axonal elongation with the transfection profile using an in vitro model.
Specific Aim 3 : Investigate the dependence of axonal growth through the bridge in vivo on the transfection profile to maximize the number of axons crossing the bridge.
Specific Aim 4 : Investigate dual delivery of neurorophin-encoding plasmid and chondroitinase to enable axons crossing the bridge, the focus of Aim 3, to re-enter the host tissue.
|Margul, Daniel J; Park, Jonghyuck; Boehler, Ryan M et al. (2016) Reducing neuroinflammation by delivery of IL-10 encoding lentivirus from multiple-channel bridges. Bioeng Transl Med 1:136-148|
|Dumont, Courtney M; Margul, Daniel J; Shea, Lonnie D (2016) Tissue Engineering Approaches to Modulate the Inflammatory Milieu following Spinal Cord Injury. Cells Tissues Organs 202:52-66|
|Liu, Jeffrey M H; Zhang, Jesse; Zhang, Xiaomin et al. (2016) Transforming growth factor-beta 1 delivery from microporous scaffolds decreases inflammation post-implant and enhances function of transplanted islets. Biomaterials 80:11-19|
|McCreedy, Dylan A; Margul, Daniel J; Seidlits, Stephanie K et al. (2016) Semi-automated counting of axon regeneration in poly(lactide co-glycolide) spinal cord bridges. J Neurosci Methods 263:15-22|
|Skoumal, Michael; Seidlits, Stephanie; Shin, Seungjin et al. (2016) Localized lentivirus delivery via peptide interactions. Biotechnol Bioeng 113:2033-40|
|Thomas, Aline M; Palma, Jaime L; Shea, Lonnie D (2015) Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries. J Control Release 204:1-10|
|Pawar, Kiran; Cummings, Brian J; Thomas, Aline et al. (2015) Biomaterial bridges enable regeneration and re-entry of corticospinal tract axons into the caudal spinal cord after SCI: Association with recovery of forelimb function. Biomaterials 65:1-12|
|Dumont, Courtney M; Park, Jonghyuck; Shea, Lonnie D (2015) Controlled release strategies for modulating immune responses to promote tissue regeneration. J Control Release 219:155-166|
|Thomas, Aline M; Gomez, Andrew J; Palma, Jaime L et al. (2014) Heparin-chitosan nanoparticle functionalization of porous poly(ethylene glycol) hydrogels for localized lentivirus delivery of angiogenic factors. Biomaterials 35:8687-93|
|Thomas, Aline M; Seidlits, Stephanie K; Goodman, Ashley G et al. (2014) Sonic hedgehog and neurotrophin-3 increase oligodendrocyte numbers and myelination after spinal cord injury. Integr Biol (Camb) 6:694-705|
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