Biodegradable Polymer Implants for Spinal Cord Repair

描述（由申请人提供）：脊髓轴突在损伤后具有再生能力。然而，脊髓损伤（SCI）患者和实验动物模型的功能改善一直是难以捉摸的。我们汇集了一个新的研究小组，结合了基于聚合物的组织工程、细胞和分子神经生物学、脊柱外科、神经外科和脊髓损伤方面的专业知识。我们开发了一系列用于治疗脊髓损伤的新型可生物降解聚合物植入物。在大鼠脊髓横断模型中进行的初步研究表明，该植入物具有促进轴突再生的潜力。植入物在脊髓中耐受性良好，并且装载了存活的雪旺细胞。移植后3个月，整个移植物长度都有轴突生长。我们假设植入物可以作为支撑轴突跨越间隙生长的支架，作为支持细胞的来源，以及作为促进再生的受控局部递送剂的载体。我们现在建议系统地操纵再生脐带的结构、细胞和分子环境。在第一个目标中，我们将研究两种聚合物的降解特性和生物相容性；聚乳酸-羟基乙酸（PLGA）和聚富马酸己内酯（PCLF）。我们将使用计算机辅助设计来生成支架的三维结构，然后确定真空成型或自由形式制造（微打印）是否产生最佳结构。在第二个目标中，我们将通过测试具有不同直径通道的PLGA和PCLF支架来检查支架几何形状对再生的影响。测量通过支架再生的轴突的数量和方向。在第三个目标中，我们将比较两种细胞类型（原代雪旺细胞和雪旺细胞系SpL201）支持再生和作为促进再生的生物分子来源的能力。在第四个目标中，我们将研究可生物降解聚合物作为治疗剂递送载体的作用。软骨素酶- abc将被用作模型蛋白。它是一种促进脊髓轴突再生的酶。将比较在微球包封后或在移植物中给酶的效果，并评估在再生脐带中给酶的效果。显微ct和MR显微成像将结合组织学和功能评估来衡量促进再生的成功。

DESCRIPTION (provided by applicant): Spinal cord axons have the capacity to regenerate following injury. However, functional improvement following spinal cord injury (SCI) in patients and in experimental animal models has been elusive. We have brought together a new research group combining expertise in polymer-based tissue engineering, cellular and molecular neurobiology, spine surgery, neurosurgery, and spinal cord injury. We have developed a series of novel biodegradable polymer implants for use in the treatment of SCI. Pilot studies of the implant in the rat transected spinal cord model demonstrated the potential for promoting axon regeneration. Implants were well-tolerated in the spinal cord and were loaded with Schwann cells that survive. During three months after implantation, there was axon growth throughout the length of the graft. We hypothesize that the implant can serve as a scaffold to support axon growth across a gap, as a source of supporting cells, and as a vehicle for controlled local delivery of agents that promote regeneration. We now propose to systematically manipulate the structural, cellular and molecular environment of the regenerating cord. In the first aim, we will study the degradation characteristics and biocompatibility of two polymers; poly (lactic-coglycolic)acid (PLGA) and poly(caprolactone fumarate) (PCLF). We will use computer-aided design to generate the three-dimensional structure of the scaffold and then determine whether vacuum molding or free-form fabrication (micro-printing) produces the best architecture. In the second aim we will examine the effect of scaffold geometry on regeneration by testing PLGA and PCLF scaffolds with varying diameter channels. The number and direction of axons regenerating through the scaffolds will be measured. In the third aim we will compare the ability of two cell types (primary Schwann cells and a Schwann cell line;SpL201) to support regeneration and to act as a source of biomolecules that promote regeneration. In the fourth aim we will examine the role of the biodegradable polymer as a delivery vehicle for therapeutic agents. Chondritinase-ABC will be used as a model protein. It is an enzyme that enhances axonal regeneration in the cord. Delivery of active enzyme after encapsulation in microspheres or in the graft will be compared and the effect of enzyme delivery in the regenerating cord will be assessed. Imaging with Micro-CT and MR microscopy will be combined with histological and functional assessments to measure success in promoting regeneration.