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，限制了目前药物递送和细胞移植方法的有效性。我们假设生物材料支架可用于指导胚胎干细胞衍生祖运动神经元（pMNs）的分化，提供生长因子营养线索，并传递药物以克服成人脊髓的抑制性。通过使用生物材料支架，我们假设我们将能够提供必要的联合治疗，以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)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祖运动神经元（pMNs）在体外环境中存活并分化为运动神经元，其水平与传统分化方案相当或更好。(2)在亚急性（14天）脊髓损伤的体内环境中，与单独pMN移植（无支架）相比，基于纤维蛋白的生物材料支架的生长因子递送能够增强胚胎干细胞来源的运动神经元祖细胞（pMN）的存活和向运动神经元的分化。(3)为了验证生物材料支架（与生长因子递送）、细胞移植和药物递送相结合的假设，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联合治疗。

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 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. PUBLIC HEALTH RELEVANCE: Spinal cord injury is a major clinical problem. In the United States, about 12,000 people per year join the population of approximately 200,000 traumatic spinal cord injury patients. Spinal cord injuries typically occur in young patients (average age of 32, 55% of injuries occur at ages 16 to 30) and the impact of these injuries on the quality of life and productivity of these individuals is dramatic. In addition, the average cost of caring for a patient during the first year following spinal cord injury is $307,847(58). Therapeutic approaches to be developed and the mechanistic knowledge gained in this study may contribute to future clinical therapies for spinal cord injury patients. Approaches for the transplantation of motoneurons developed in this project may also be useful for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).