Controlled Release Scaffolds for Nerve Regeneration

用于神经再生的控释支架

• 批准号: 8440808
• 负责人: Aileen J Anderson
• 金额: $ 48.01万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-22 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440808
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Axon; Biocompatible Materials; Cell Death; Cell Transplantation; Cell physiology; Cells; Cessation of life; Chondroitin Sulfate Proteoglycan; Chondroitinases; Cicatrix; Clinic; Combined Modality Therapy; Complex; Controlled Environment; Cyst; Demyelinations; Deposition; Ensure; Environment; Event; Fiber; Foundations; Funding; Gene Delivery; Gene Transduction Agent; Goals; Growth; Growth Factor; Hyaluronidase; Implant; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Left; Length; Movement; Natural regeneration; Nerve Regeneration; Neurons; Oligodendroglia; Paralysed; Phenotype; Production; Research; Schwann Cells; Secondary to; Signal Transduction; Site; Solutions; Speed; Spinal Cord; Subfamily lentivirinae; Support System; Supporting Cell; System; Therapeutic; Time; Tissues; Transducers; Translations; axon growth; axon regeneration; base; combinatorial; controlled release; design; functional outcomes; functional restoration; macrophage; myelination; nanoparticle; neuroinflammation; neurotrophic factor; particle; physical property; prevent; public health relevance; regenerative; relating to nervous system; scaffold; small hairpin RNA; tool; vector

DESCRIPTION (provided by applicant): Injury to the spinal cord results in paralysis below the level of the injury, and there are no current therapies that are able to restore function. Limited regeneration occurs as result of the local environment, which is deficient in stimulatory factors and has an excess of inhibitory factors. Our long-term goal is to develop multi-functional biomaterials that bridge the injury site to control the microenvironment to promote and direct axonal growth into and through, and to re-enter the host tissue to form functional connections with intact circuitry. In the initial funding period, we have developed multiple channel bridges that mechanically stabilize the injury site that limits secondary damage, and promotes axonal growth into and across the injury, with axonal re-entry into the host tissue. Additionally, we have an unparalleled ability to localize delivery of gene therapy vectors, with which expression of neurotrophic factors significantly enhanced the number of regenerating axons. Having established a system that supports axonal growth through the injury and into the host tissue, we now focus on forming functional connections of these regenerating axons with intact circuitry of the spinal cord. Thus, the objectives of this proposal are to i) myelinate the regenerating axons provide the appropriate conduction speed of neural impulses, ii) enhance axonal re-entry into the host tissue, and iii) extension of the re-entering axons to healthy tissue for connection with intact circuitry. The initial step towards these objectives is to regulate the inflammatory response, which normally initiates a cascade of events leading to secondary tissue damage, including neural and glial death, and production of chondroitin sulfate proteoglycans (CS), a major component of the glial scar. Inflammation will be targeted by the bridge architecture (Aim 1a), as cell infiltration differs between the channels and pores of the bridge. Additionally, our gene delivery transducers macrophages, and we will investigate strategies to promote a more regenerative phenotype (M2) rather than a more inflammatory phenotype (M1) (Aim 1b). Reducing inflammation is expected to increase survival of neurons and glial, which should enhance the number of regenerating fibers and enhance myelination. Subsequently, we propose to employ shRNA to target the inhibitory components of the glial scar (Aim 2), which is deposited at the interface between the bridge and host tissue. Preventing deposition of these inhibitory components is anticipated to enhance the number of axons re-entering host tissue. Finally, nanoparticle based gene delivery will be employed to create gradients caudal to the bridge and promote extension of axons that have re-entered the host tissue, which can enable connections with intact circuitry (Aim 3). These controllable systems can identify the design necessary for the formation of functional connections. Additionally, these systems have well-defined components that have been used in the clinic, which may facilitate the ultimate translation to the clinic.

描述（由申请人提供）：脊髓损伤导致损伤水平以下瘫痪，目前没有能够恢复功能的治疗方法。由于局部环境缺乏刺激因子而具有过量的抑制因子，因此发生有限的再生。我们的长期目标是开发多功能生物材料，桥接损伤部位，控制微环境，促进和引导轴突生长进入和穿过，并重新进入宿主组织，与完整的电路形成功能连接。在最初的资助期间，我们已经开发了多通道桥，其机械地稳定损伤部位，限制继发性损伤，并促进轴突生长进入和穿过损伤，轴突重新进入宿主组织。此外，我们有一个无与伦比的能力，本地化交付的基因治疗载体，与神经营养因子的表达显着增加再生轴突的数量。在建立了一个支持轴突通过损伤生长并进入宿主组织的系统后，我们现在专注于形成这些再生轴突与脊髓完整电路的功能连接。因此，该提议的目的是i）使再生轴突髓鞘化，提供神经冲动的适当传导速度，ii）增强轴突重新进入宿主组织，以及iii）将重新进入的轴突延伸到健康组织以与完整的回路连接。实现这些目标的第一步是调节炎症反应，炎症反应通常会引发一系列导致继发性组织损伤的事件，包括神经和神经胶质死亡，以及硫酸软骨素蛋白聚糖（CS）（神经胶质瘢痕的主要成分）的产生。由于细胞浸润在桥的通道和孔之间不同，因此桥结构将靶向炎症（目的1a）。此外，我们的基因传递转导巨噬细胞，我们将研究策略，以促进更多的再生表型（M2），而不是更多的炎症表型（M1）（目标1b）。减少炎症预期会增加神经元和神经胶质的存活，这应该会增加再生纤维的数量并增强髓鞘形成。随后，我们建议采用shRNA靶向胶质瘢痕的抑制成分（Aim 2），其沉积在桥和宿主组织之间的界面处。预期防止这些抑制性组分的沉积会增加重新进入宿主组织的轴突的数量。最后，基于纳米颗粒的基因递送将用于在桥尾侧产生梯度，并促进重新进入宿主组织的轴突的延伸，这可以实现与完整电路的连接（目标3）。这些可控系统可以识别功能连接形成所需的设计。此外，这些系统具有已在临床中使用的明确定义的组件，这可能有助于最终转化为临床。