Engineering a multifunctional injectable scaffold for spinal cord repair

描述（由申请人提供）：在美国，脊髓损伤（SCI）每年影响大约10,000人。脊髓损伤最常见于年轻人，使他们终生严重残疾。除了瘫痪，脊髓损伤患者还会遭受其他残疾，包括膀胱、肠道和性功能障碍，以及神经性疼痛综合征。在过去的十年中出现了几种潜在的有用的治疗策略，包括使用支架和桥梁，传递神经营养因子，其他治疗肽和使用干细胞来促进神经元再生和功能恢复。然而，目前没有一种策略显示出足够的效果，可以进入临床试验，也没有做出重大努力来测试这些策略的组合，这些策略可能具有协同作用，并导致更大的治疗效果。因此，需要开发一种多功能结构，可以整合多种有前途的治疗策略。该项目汇集了生物材料工程、神经生物学、基础神经科学和神经外科等学科，试图为脊髓损伤的复杂问题开发一个多学科的解决方案。我们认为，与之前描述的水凝胶、细胞和神经营养物质传递系统相比，该系统具有许多优点。值得注意的是，水凝胶是可注射的，它的特性可以很容易地调整，以匹配宿主组织的顺应性，以定制的速率提供治疗因子，并将细胞递送到损伤部位。在这种情况下，我们将神经干细胞（NPC）输送到脊髓损伤（SCI）的部位。这些细胞已被证明能够存活并分化为神经元和胶质细胞，水凝胶基质可以作为支架，其中包括生长因子，以进一步促进npc的存活和分化。我们假设，多种治疗性蛋白与可注射的聚合物细胞支架一起局部、持续、同时递送到中枢神经系统，通过同步调节受损环境和激活不同的信号通路，产生协同效应。通过设计这种可注射水凝胶和基于细胞的支架来模拟宿主组织，我们可以创建一种新的平台技术，用于治疗脊髓损伤和其他组织工程应用。所有的设计参数将通过体外生物测定和动物脊髓损伤模型的体内实验进行测试和验证。公共卫生相关性：在美国，脊髓损伤（SCI）每年影响大约10,000人。脊髓损伤最常见于年轻人，使他们终生严重残疾。我们建议开发一种含有神经前体细胞和神经营养因子的新型可注射支架，并假设多种治疗性蛋白质与可注射的聚合物细胞支架一起局部、持续、同时递送到中枢神经系统，通过同步调节损伤环境和激活不同的信号通路来产生协同效应。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) affects approximately 10,000 individuals in the United States every year. SCI occurs most commonly in young adults, leaving them seriously disabled for the remainder of their lives. Apart from paralysis, patients of SCI suffer from additional disabilities including bladder, bowel and sexual dysfunction, and neuropathic pain syndromes. Several potentially useful therapeutic strategies have emerged over the last decade including the use of scaffolds and bridges, delivery of neurotrophic factors, other therapeutic peptides and use of stem cells to promote neuronal regeneration and functional recovery. However, none of the current strategies have shown enough effect to move to clinical trials and no major efforts have been undertaken to test a combination of these strategies, which can potentially be synergistic, and lead to greater therapeutic effect. Therefore, a need exists to develop a multifunctional construct which can integrate multiple, promising therapeutic strategies. This project brings together the disciplines of biomaterial engineering, neurobiology, basic neuroscience and neurosurgery in an attempt to develop a multi-disciplinary solution to the complex problem of spinal cord injury. We believe that the proposed system holds a number of benefits over previously described hydrogels, cellular and neurotrophin delivery systems in the CNS. Notably, the hydrogel is injectable and its properties can be readily tuned to match the compliance of host tissues, deliver therapeutic factors at tailored rates, and deliver cells to the injury site. In this case, we are delivering neural stem cells (NPC) to the site of spinal cord injury (SCI). These cells have been shown to survive and differentiate into neurons and glia and the hydrogel matrix can act as a scaffold that will include growth factors to further survival and differentiation of NPCs. We hypothesize that localized, sustained, simultaneous delivery of multiple therapeutic proteins into the CNS along with an injectable polymeric-cellular scaffold creates a synergistic effect by synchronously modulating the injured environment and activating different signaling pathways. By engineering this injectable hydrogel and cellular based scaffold to mimic the host tissues we can create a novel platform technology with applications in treatment of SCI and other tissue engineering applications. All the design parameters will be tested and validated using in-vitro bioassays and in-vivo experiments using rodent models of spinal cord injury.PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) affects approximately 10,000 individuals in the United States every year. SCI occurs most commonly in young adults, leaving them seriously disabled for the remainder of their lives. We propose to develop a novel, injectable scaffold containing neural precursor cells and neurotrophic factors and hypothesize that localized, sustained, simultaneous delivery of multiple therapeutic proteins into the CNS along with an injectable polymeric-cellular scaffold creates a synergistic effect by synchronously modulating the injured environment and activating different signaling pathways.