Fibrin-based scaffolds for spinal cord injury

描述(由申请人提供)：本提案的统一假设是，生物材料支架的使用对于开发成功的脊髓损伤治疗方法至关重要。在缺乏能够帮助修复损伤部位的生物材料支架的情况下，损伤脊髓中缺乏促进再生的底物，限制了生长因子转移和细胞移植方法的有效性。我们推测，在脊髓损伤后，需要单独或与胚胎干细胞衍生的神经干细胞(ESNLCs)联合使用，在较长的一段时间(几周)内从基于纤维蛋白的生物材料支架上控制生长因子的释放，以实现显著的再生。这一假设将通过解决以下具体目标进行系统检验，所有这些目标都是实现脊髓再生的目标所必需的。这项建议的目的是：(1)在大鼠脊髓损伤模型中，验证基于纤维蛋白的生物材料支架能够充分控制地释放生长因子(神经营养因子-3)以增强短期和长期再生的假说。(2)验证一种假设，即从纤维蛋白为基础的生物材料支架中输送生长因子将使胚胎干细胞来源的神经谱系细胞(ESNLCs)在与传统分化方法观察到的条件相当或更好的体外环境中存活并分化为神经元。(3)在脊髓损伤模型中，验证以纤维蛋白为基础的生物材料支架输送生长因子可促进胚胎干细胞来源的神经干细胞(ESNLCs)存活和向神经元分化的假说。

DESCRIPTION (provided by applicant): The unifying hypothesis of this proposal is that the use of biomaterial scaffolds is critical to the development of successful therapies for spinal cord injury. In the absence of a biomaterial scaffold that can help to bridge the injury site, the lack of regeneration promoting substrates in the injured spinal cord limits the efficacy of growth factor delivery and cell transplantation approaches. We hypothesize that controlled release of growth factors over a prolonged period of time (weeks) from a fibrin-based biomaterial scaffold alone or in combination with embryonic stem cell-derived neural lineage cells (ESNLCs) is needed to achieve significant regeneration following spinal cord injury. This hypothesis will be tested systematically by addressing the following specific aims, all of which are necessary to achieve the goal of spinal cord regeneration. The aims of this proposal are: (1) To test the hypothesis that a fibrin-based biomaterial scaffold enables sufficient controlled release of growth factor (neurotrophin-3) to enable enhanced short and long-term regeneration compared to uncontrolled growth factor release in a rat spinal cord injury model. (2) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable survival and differentiation of embryonic stem cell-derived neural lineage cells (ESNLCs) into neurons in an in vitro setting comparable to or better than that observed with traditional differentiation protocols. (3) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable enhance survival and differentiation of embryonic stem cell-derived neural lineage cells (ESNLCs) into neurons compared with ESNLCs alone (no scaffold) in vivo in the setting of spinal cord injury.