Biodegradable Polymer Implants for Spinal Cord Repair

描述(申请人提供)：脊髓轴突具有损伤后再生的能力。然而，在患者和实验动物模型中脊髓损伤(SCI)后的功能改善一直难以捉摸。我们聚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上进行的初步研究表明，该植入物具有促进轴突再生的潜力。植入物在脊髓内耐受性良好，并装载了存活的雪旺细胞。在植入后的三个月内，整个移植物长度都有轴突生长。我们假设，植入物可以作为支架，支持跨越缝隙的轴突生长，作为支持细胞的来源，并作为一种可控的局部输送促进再生的药物的载体。我们现在建议系统地操纵再生脊髓的结构、细胞和分子环境。在第一个目标中，我们将研究两种聚合物：聚乳酸-共乙醇酸(PLGA)和聚富马酸己内酯(PCLF)的降解特性和生物相容性。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(微型打印)产生的最佳建筑。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。将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输送载体的作用。软骨基质酶-ABC将被用作模型蛋白。它是一种酶，可以促进脊髓中的轴突再生。将比较微球或移植物中活性酶的输送情况，并评估酶在再生脐带中的输送效果。Micro-CT和MR显微镜成像将与组织学和功能评估相结合，以衡量在促进再生方面的成功。

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.