A Functional Reverse Thermal Gel for Retinal Ganglion Cell Axon Regeneration

用于视网膜神经节细胞轴突再生的功能性反向热凝胶

基本信息

批准号：
9087269
负责人：
Dae Won Park
金额：
$ 18.91万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087269
关键词：
Accounting Acute Address Affect Aftercare American Area Attention Axon Behavior Biocompatible Materials Biological Availability Blindness Body Temperature Cannulas Cell Death Cell Survival Cell Transplantation Cell Transplants Clinical Combined Modality Therapy Communities Coupled Cytoskeleton Environment Exhibits Gel Glaucoma Growth Health Immunohistochemistry In Situ Injectable Injection of therapeutic agent Injury Lead Link Liquid substance Medical Medicine Methods Modeling Molecular Conformation Natural regeneration Needles Nerve Nerve Crush Nerve Regeneration Neurodegenerative Disorders Neuropathy Operative Surgical Procedures Optic Nerve Optic Nerve Injuries Outcome Patients Peptides Peripheral Nerves Pharmacological Treatment Physiologic Intraocular Pressure Polymers Predisposition Procedures Property Proteins Reporting Research Retinal Ganglion Cells Risk Rodent Site Sol-Gel Phase Transitions Solid Spinal Cord Survival Rate System Temperature Testing Therapeutic Therapeutic Agents Time Transplantation Traumatic injury Treatment Step Vision Visual Visual Acuity Visual Fields Vitreous humor Work alternative treatment aqueous axon regeneration axonal degeneration base compliance behavior design experience improved in vivo injured intravitreal injection minimally invasive nerve injury neuroprotection neurotrophic factor novel strategies novel therapeutics optic nerve disorder physical property research and development response scaffold success treatment effect treatment strategy

项目摘要

DESCRIPTION: With an estimated 2.2 million Americans with optic neuropathies accounting for 9 to 12% of all cases of blindness in the U.S., and the acknowledgement that 10% of patients that receive proper medical treatment continue to experience vision loss, there is a clear need for an alternative treatment strategy. Current treatments are primarily pharmacological, but bioavailability of therapeutic agents remains fundamental problems. Recent research has established on a more direct approach, in which the retinal ganglion cell (RGC) death responsible for loss of visual function is targeted as a means to preserve vision or even reverse vision loss. While direct administration of neurotrophic factors (NTFs) via intravitreal injection has had some success, a susceptibility to denaturation of these NTFs limits its clinical success. In addition, since this intravitreal administration most affects RGCs in retial layer, regenerated RGC axon extension within the ontic nerve has also been limited. We have recently developed a polymeric injectable biomaterial that is uniquely well-suited to this application, owing to its reverse thermal gelling properties and its ability to be highly functionalized with extra cellular matrix (ECM)-mimicking biomolecules. The thermal gelling property allows it to rapidly and reversibly transition from a liquid at room temperature to a physical gel at body temperature, enabling injection through a small gauge needle or cannula directly at the target site where the polymer can then form a cohesive solid polymer network upon reaching body temperature. This approach has many advantages including (1) minimally-invasive deployment, (2) in situ conformation to the injury site, (3) sustained expression of NTFs at target site, (4) prolonged bioactivity of NTFs entrapped in the system, and (5) tunable physical properties to mimic the host environment. Furthermore, the ability to tether biomolecules that mimics ECM component will enhance RGC axon regeneration and extension in injured optic nerve. Towards developing a system that can maximize these advantages, we have constructed this application around two specific aims: (1) design and characterize an ECM-mimicking injectable biomaterial with favorable reverse thermal gelling behavior and physicochemical properties suited to mimic the host environment for RGC axon regeneration; and (2) demonstrate substantial RGC axon regeneration in vivo using optic nerve crush model. In particular, unlike traditional intravitreal injections, we will examine co-treatment effect by dal injections in vitreous humor and in optic nerve.

描述：估计有 220 万美国人患有视神经病变，占美国所有失明病例的 9% 至 12%，并且承认接受适当治疗的患者中有 10% 继续出现视力丧失，因此显然需要目前的治疗主要是药物治疗，但治疗药物的生物利用度仍然是一个根本问题，最近的研究建立了一种更直接的方法，其中视网膜神经节细胞。导致视觉功能丧失的 RGC 死亡被作为保留视力甚至逆转视力丧失的一种手段，虽然通过玻璃体内注射直接施用神经营养因子 (NTF) 已取得一些成功，但这些 NTF 对变性的敏感性限制了其应用。此外，由于这种玻璃体内给药对视网膜层的 RGC 影响最大，因此本体神经内的再生 RGC 轴突延伸也受到限制，我们最近开发了一种聚合物可注射生物材料。由于其反向热凝胶特性以及通过模拟细胞外基质 (ECM) 的生物分子进行高度功能化的能力，该材料非常适合该应用。热凝胶特性使其能够在将室温下的凝胶转化为体温下的物理凝胶，从而能够通过小规格针头或插管直接注射到目标部位，然后在达到体温时聚合物可以形成粘性固体聚合物网络。这种方法具有许多优点，包括（1）。微创部署，(2) 损伤部位的原位构象，(3) NTF 在目标部位的持续表达，(4) 系统内 NTF 的长期生物活性，以及 (5) 可调节的物理特性以模仿宿主此外，束缚模拟 ECM 成分的生物分子的能力将增强受损视神经的 RGC 轴突再生和延伸，为了开发能够最大限度地发挥这些优势的系统，我们围绕两个具体目标构建了该应用程序： (1) 设计和表征具有良好的反向热凝胶行为和物理化学性质的 ECM 模拟可注射生物材料，适合模拟 RGC 轴突再生的宿主环境；(2) 使用视神经挤压模型在体内展示大量的 RGC 轴突再生。特别是，与传统的玻璃体内注射不同，我们将检查玻璃体液和视神经注射dal的协同治疗效果。