Controlled Release Scaffolds for Nerve Regeneration

描述（由申请人提供）：脊髓损伤导致损伤水平以下的瘫痪，目前没有能够恢复功能的治疗方法。局部环境缺乏刺激因子，抑制因子过多，导致再生受限。我们的长期目标是开发多功能生物材料，桥接损伤部位，控制微环境，促进和指导轴突生长进入和穿过宿主组织，并重新进入宿主组织，形成完整电路的功能连接。在之前的资助期内，我们已经开发了多个通道桥，可以机械地稳定损伤，限制继发性损伤，并且使用一个主要在皮质脊髓束（CST）中表达的GFP报告结构的转基因小鼠模型，我们证明了大量的CST轴突通过桥生长，重新进入宿主组织，并在植入后10周向脊髓延伸至3mm。此外，我们拥有无与伦比的基因治疗载体的局部递送能力，神经营养因子的表达显著提高了再生轴突的数量。这一建议建立在这些结果的基础上，并着重于增加神经祖细胞的数量（通过招募或移植），并促进它们分化为成熟的少突胶质细胞，这些细胞可以为轴突提供髓鞘，并在功能上重新连接大量再生轴突，使其在损伤下方具有完整的电路。我们开发的桥是针对14%的脊髓损伤，这些损伤是由穿透伤造成的脊髓间隙造成的，可能需要一种不同的方法来恢复功能，而不是挫伤/压迫损伤。我们建议在穿透性损伤后尽快提供一个桥，以稳定脊髓和削弱宿主

DESCRIPTION (provided by applicant): Injury to the spinal cord results in paralysis below the level of the injury, and there are no current therapies that are able to restore function. Limited regeneration occurs as result of the local environment, which is deficient in stimulatory factors and has an excess of inhibitory factors. Our long-term goal is to develop multi- functional biomaterials that bridge the injury site to control the microenvironment to promote and direct axonal growth into and through, and to re-enter the host tissue to form functional connections with intact circuitry. In the previous funding periods, we have developed multiple channel bridges that mechanically stabilize the injury that limits secondary damage, and using a transgenic mouse model with a GFP reporter construct expressed predominantly in the corticospinal tract (CST), we demonstrated that large numbers of CST axons grow through the bridge, re-enter the host tissue, and extend up to 3 mm down the cord by 10 weeks post- implantation. Additionally, we have an unparalleled ability to localize delivery of gene therapy vectors, with which expression of neurotrophic factors significantly enhanced the number of regenerating axons. This proposal builds on these results and focuses on enhancing the number of neural progenitors (either through recruitment or transplantation) and promoting their differentiation into mature oligodendrocytes that can myelinate axons and functionally reconnect a significant number of regenerating axons with the intact circuitry below the injury. Our development of bridges is targeted toward the 14% of spinal cord injuries that result from penetrating wounds that create a gap in the spinal cord, and may necessitate a different approach to restoring function than contusion/compression injuries. We propose that providing a bridge soon after a penetrating injury in order to stabilize the spinal cord and attenuate the host response. The bridges could be an off-the- shelf product that is readily available for implantation, and the bridge is initially designed to target survival, migration, and differentiatin of the endogenous progenitor cell population. Alternatively, we investigate delivery of neural stem cells rostral and caudal to the bridge a week or more after the bridge is implanted. While a bridge can be delivered soon after injury, stem cell transplants immediately after injury are contraindicated, as the cells are allogeneic and would require immunosuppression. The survival, recruitment, proliferation, and differentiation of endogenous or exogenous progenitor cells will be targeted through the immune response at the scaffold (Aim 1). We propose to use the bridges to modulate the macrophage phenotype towards M2 in order to promote secretion of pro-regenerative factors following injury. Alternatively, we propose to delivery trophic factors tht target the function of progenitor cells by complementary pathways. 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.