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瘫痪，目前没有能够恢复功能的治疗方法。由于局部环境缺乏刺激因子而具有过量的抑制因子，因此发生有限的再生。我们的长期目标是开发多功能生物材料，桥接损伤部位以控制微环境，从而促进和引导轴突生长进入和穿过宿主组织，并重新进入宿主组织以与完整的电路形成功能连接。在之前的资助期间，我们已经开发了多通道桥，其机械地稳定限制继发性损伤的损伤，并且使用具有主要在皮质脊髓束（CST）中表达的GFP报告基因构建体的转基因小鼠模型，我们证明了大量CST轴突通过桥生长，重新进入宿主组织，并且在植入后10周沿着脊髓向下延伸高达3 mm。此外，我们有一个无与伦比的能力，本地化交付的基因治疗载体，与神经营养因子的表达显着增加再生轴突的数量。该提案建立在这些结果的基础上，并专注于增加神经祖细胞的数量（通过招募或移植），并促进其分化为成熟的少突胶质细胞，这些少突胶质细胞可以使轴突髓鞘化，并在功能上将大量再生轴突与损伤下方的完整电路重新连接。我们的桥接开发针对的是14%的脊髓损伤，这些损伤是由穿透性伤口造成的，在脊髓中形成了一个缺口，并且可能需要一种与挫伤/压迫性损伤不同的方法来恢复功能。我们建议在穿透性损伤后不久提供一个桥，以稳定脊髓并减弱宿主 反应该桥可以是现成的产品，易于植入，并且该桥最初被设计为靶向内源性祖细胞群的存活、迁移和分化。或者，我们研究交付的神经干细胞吻和尾桥一周或更长时间后，桥植入。虽然桥可以在损伤后不久交付，但损伤后立即进行干细胞移植是禁忌的，因为细胞是同种异体的，需要免疫抑制。内源性或外源性祖细胞的存活、募集、增殖和分化将通过支架处的免疫应答而被靶向（目的1）。我们建议使用桥来调节巨噬细胞表型朝向M2，以促进损伤后促再生因子的分泌。或者，我们建议通过互补途径递送靶向祖细胞功能的营养因子。桥平台可以支持再生过程的多个方面，并且已经在临床中使用的定义明确的组件可以促进最终转化为临床。

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.