Controlled Release Scaffolds for Nerve Regeneration

描述(申请人提供)：脊髓损伤会导致损伤水平以下的瘫痪，目前还没有能够恢复功能的治疗方法。有限的再生是局部环境的结果，局部环境缺乏刺激因子，而抑制因子过多。我们的长期目标是开发多功能生物材料，连接损伤部位，控制微环境，促进和引导轴突生长进入和穿过，并重新进入宿主组织，与完整的电路形成功能连接。在之前的资助期间，我们已经开发了多个通道桥来机械地稳定损伤以限制二次损伤，并使用主要在皮质脊髓束(CST)表达GFP报告结构的转基因小鼠模型，我们证明了大量CST轴突通过桥生长，重新进入宿主组织，并在植入后10周沿脊髓延伸至3 mm。此外，我们拥有无与伦比的定位基因治疗载体的能力，通过表达神经营养因子显著增加再生轴突的数量。这一建议建立在这些结果的基础上，重点是增加神经前体细胞的数量(无论是通过招募还是移植)，并促进它们分化为成熟的少突胶质细胞，这些细胞可以髓鞘化轴突，并在功能上将大量再生轴突与损伤下方完整的回路重新连接。我们开发的桥梁针对的是14%的脊髓损伤，这些损伤是由穿透伤在脊髓上造成缺口造成的，可能需要一种不同于挫伤/压迫损伤的恢复功能的方法。我们建议在穿透性损伤后不久提供一座桥，以稳定脊髓并减弱宿主 回应。桥接物可能是一种现成的产品，很容易植入，最初设计的桥接物是针对内源性祖细胞群体的存活、迁移和分化。或者，我们研究在桥被植入一周或更长时间后，神经干细胞在吻端和尾端向桥的输送。虽然损伤后不久就可以进行桥接，但损伤后立即进行干细胞移植是禁忌的，因为这些细胞是同种异体的，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上的免疫反应而成为靶点(目标1)。我们建议使用桥来调节巨噬细胞对M2的表型，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针对祖细胞功能的营养因子。桥接平台可以支持再生过程的多个方面，已经在临床上使用的定义良好的组件可能有助于最终转化到临床。

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.