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脊髓损伤成功治疗的发展至关重要。在缺乏生物材料支架的情况下，损伤脊髓中缺乏促进再生的基质，限制了生长因子递送和细胞移植方法的有效性。我们假设需要长时间（数周）从纤维蛋白基生物材料支架单独或与胚胎干细胞衍生的神经谱系细胞（ESNLCs）联合释放生长因子来实现脊髓损伤后的显著再生。这一假设将通过解决以下具体目标进行系统测试，所有这些目标都是实现脊髓再生目标所必需的。本研究的目的是：(1)在大鼠脊髓损伤模型中，与不受控制的生长因子释放相比，基于纤维蛋白的生物材料支架能够充分控制生长因子（神经营养因子-3）的释放，从而增强短期和长期再生。(2)验证基于纤维蛋白的生物材料支架的生长因子递送将使胚胎干细胞衍生的神经谱系细胞（ESNLCs）在体外环境中存活并分化为神经元，这一假设与传统分化方案相当或更好。(3)验证基于纤维蛋白的生物材料支架的生长因子递送能够提高胚胎干细胞衍生的神经谱系细胞（ESNLCs）在脊髓损伤情况下的存活率和向神经元的分化，与单独的ESNLCs（无支架）相比。

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.