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，占美国所有失明案件的9％至12％，并且确认接受适当医疗治疗的患者中有10％的患者继续遭受视力丧失，因此显然需要另一种治疗策略。目前的治疗是主要的药理，但是治疗剂的生物利用度仍然是基本问题。最近的研究已经建立了一种更直接的方法，其中负责视觉功能丧失的视网膜神经节细胞（RGC）死亡被定为维护视力甚至反向视力丧失的手段。尽管通过玻璃体内注射直接给予神经营养因子（NTF）取得了一些成功，但对这些NTF的变性的敏感性限制了其临床成功。此外，由于这种玻璃体内给药最大程度地影响了保留层的RGC，因此在神经神经系统内再生的RGC轴突延伸也受到限制。我们最近开发了一种可注射的生物材料，它非常适合该应用，这是由于其反向热胶凝性能以及其用额外的细胞基质（ECM）模仿生物分子高度官能化的能力。热胶凝特性使其可以在室温下从室温下的液体快速和可逆地过渡到物理凝胶，从而在目标部位直接通过小规格针或套管注射，然后在到达物体温度时，聚合物可以在该目标位点形成一个粘性的固体聚合物网络。这种方法具有许多优势，包括（1）最低侵入性的部署，（2）对损伤部位的原位构象，（3）NTF在目标部位持续表达，（（4）NTF在系统中的NTF的延长生物活性，以及（5）可调的物理特性以模仿主机环境。此外，扎根生物分子的能力表明，模拟ECM成分将增强损伤视神经的RGC轴突再生和扩展。为了开发一种可以最大化这些优势的系统，我们围绕两个特定的目的构建了此应用：（1）设计和表征模仿ECM的可注射生物材料，具有有利的反向热胶凝行为和适合于模仿宿主环境的RGC Axon再生的物理特性；（2）使用视神经挤压模型在体内证明了大量的RGC轴突再生。特别是，与传统的玻璃体内注射不同，我们将检查玻璃体幽默和视神经中DAL的共同处理效果。