FIBRIN BASED SCAFFOLDS FOR SPINAL CORD INJURY

摘要 这一建议的统一假设是，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，限制了目前药物输送和细胞移植方法的有效性。我们推测，这种生物材料支架可以用于指导胚胎干细胞来源的前体运动神经元(PMN)的分化，提供生长因子营养信号，并提供药物来克服成年脊髓的抑制性质。 通过使用生物材料支架，我们假设我们将能够提出必要的联合治疗，以实现脊髓损伤后的显着再生。 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)测试假设，从纤维蛋白为基础的生物材料支架输送生长因子将使胚胎干细胞衍生的祖细胞运动神经元(PMN)在体外存活并分化为运动神经元，其水平与传统分化方案观察到的水平相当或更好。(2)在体内验证这样一种假设：与仅移植中性粒细胞(无支架)相比，从纤维蛋白为基础的生物材料支架运送生长因子将增强胚胎干细胞来源的运动神经元前体细胞(PMN)的存活和向运动神经元的分化。 亚急性(14天)脊髓损伤的背景。(3)验证这样一种假设，即生物材料支架(与生长因子输送)、细胞移植和药物输送相结合以克服成人脊髓的抑制信号，将提供一种能够在亚急性(14天)脊髓损伤后实现再生的组合疗法。

ABSTRACT 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 bridge the injury site, the lack of regeneration promoting substrates in the injured spinal cord limits the efficacy of current drug delivery and cell transplantation approaches. We hypothesize that the biomaterial scaffolds can be used to direct the differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs), present growth factor trophic cues and deliver drugs to overcome the inhibitory nature of the adult spinal cord. Through the use of a biomaterial scaffold we hypothesize that we will be able to present combination therapies necessary 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 growth factor delivery from a fibrin-based biomaterial scaffold will enable the survival and differentiation of embryonic stem cell-derived progenitor motor neurons (pMNs) into motoneurons in an in vitro setting at levels comparable to or better than that observed with traditional differentiation protocols. (2) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable enhanced survival and differentiation of embryonic stem cell-derived motoneuron progenitors (pMNs) into motoneurons compared with pMN transplantation alone (no scaffold) in the in vivo setting of sub-acute (14 day) spinal cord injury. (3) To test the hypothesis that the combination of a biomaterial scaffold (with growth factor delivery), cell transplantation, and delivery of drugs to overcome the inhibitory cues of the adult spinal cord, will provide a combination therapy that is able to achieve regeneration following sub-acute (14 day) spinal cord injury.