Engineering a multifunctional injectable scaffold for spinal cord repair

设计用于脊髓修复的多功能可注射支架

• 批准号: 7589538
• 负责人: Anthony M Lowman
• 金额: $ 16.41万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589538
• 关键词: Affect; Area; Axon; Biocompatible Materials; Biological Assay; Bladder; Brain-Derived Neurotrophic Factor; Cell Transplants; Cells; Clinical Trials; Complex; Cytoskeleton; Disabled Persons; Discipline; Dose; Engineering; Ensure; Environment; Ethylene Glycols; Gel; Growth; Growth Factor; Hydrogels; Implant; In Vitro; Individual; Injectable; Injection of therapeutic agent; Injury; Intestines; Invasive; Lead; Left; Life; Localized; Mechanics; Modeling; Molds; Natural regeneration; Nature; Neurobiology; Neuroglia; Neurons; Neurosciences; Neurotrophin 3; Numbers; Operative Surgical Procedures; Paralysed; Peptides; Pharmaceutical Preparations; Polymers; Production; Property; Rate; Recovery of Function; Rodent; Rodent Model; Sexual Dysfunction; Signal Pathway; Site; Solutions; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Stem cells; Syndrome; System; Technology; Temperature; Testing; Therapeutic; Therapeutic Effect; Tissue Engineering; Tissues; Transplantation; United States; Water; Work; axon growth; base; biomaterial compatibility; cell growth; design; disability; dosage; ethylene glycol; implantation; in vivo; in vivo Bioassay; injured; nerve stem cell; neurosurgery; neurotrophic factor; novel; painful neuropathy; precursor cell; relating to nervous system; research study; response; restoration; scaffold; spinal cord repair; therapeutic protein; young adult

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.

描述（由申请人提供）：美国每年约有 10,000 人受到脊髓损伤 (SCI) 的影响。 脊髓损伤最常见于年轻人，使他们终生严重残疾。 除了瘫痪外，SCI 患者还患有其他残疾，包括膀胱、肠道和性功能障碍以及神经性疼痛综合征。 过去十年中出现了几种潜在有用的治疗策略，包括使用支架和桥、递送神经营养因子、其他治疗肽以及使用干细胞促进神经元再生和功能恢复。 然而，目前的策略都没有显示出足够的效果来进入临床试验，也没有采取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，并产生更大的治疗效果。 因此，需要开发一种可以整合多种有前途的治疗策略的多功能构建体。 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，试图开发一种多学科的解决方案来解决脊髓损伤的复杂问题。 我们相信，所提出的系统比之前描述的中枢神经系统中的水凝胶、细胞和神经营养蛋白递送系统具有许多优点。 值得注意的是，水凝胶是可注射的，其特性可以很容易地调整以匹配宿主组织的顺应性，以定制的速率输送治疗因子，并将细胞输送到损伤部位。 在这种情况下，我们将神经干细胞 (NPC) 输送到脊髓损伤 (SCI) 部位。 这些细胞已被证明能够存活并分化为神经元和神经胶质细胞，水凝胶基质可以充当支架，其中包含生长因子，以进一步促进 NPC 的存活和分化。 我们假设将多种治疗蛋白与可注射的聚合物细胞支架一起局部、持续、同时递送至中枢神经系统，通过同步调节受损环境并激活不同的信号传导途径，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颖的平台技术，用于治疗 SCI 和其他组织工程应用。 所有设计参数都将使用脊髓损伤啮齿动物模型进行体外生物测定和体内实验进行测试和验证。 公共健康相关性：美国每年约有 10,000 人受到脊髓损伤 (SCI) 的影响。 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，并假设将多种治疗蛋白与可注射聚合物细胞支架一起局部、持续、同时递送到中枢神经系统中，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。