A biomimetic reverse thermal gel for optic nerve regeneration

用于视神经再生的仿生反向热凝胶

基本信息

批准号：
8770848
负责人：
Malik Y. Kahook
金额：
$ 21.72万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770848
关键词：
Accounting Acute Address Affect American Attention Behavior Biocompatible Materials Biomimetics Blindness Body Temperature Cannulas Cell Culture Techniques Cell Death Cell Proliferation Cell Survival Characteristics Communities Coupled Development Drug Formulations Educational process of instructing Ensure Environment Exhibits Functional disorder Gel Glaucoma Growth Health Implant In Situ In Vitro Inflammatory Response Injectable Injection of therapeutic agent Injury Lead Link Liquid substance Location Mechanics Medical Medicine Methodology Modeling Molecular Conformation Monitor Natural regeneration Needles Nerve Nerve Crush Nerve Regeneration Neurodegenerative Disorders Neuropathy Operative Surgical Procedures Optic Nerve Optic Nerve Injuries Outcome Patients Peptides Pharmaceutical Preparations Pharmacological Treatment Physiologic Intraocular Pressure Polymers Positioning Attribute Procedures Property RGD (sequence)Reaction Research Retinal Retinal Ganglion Cells Rodent Site Sol-Gel Phase Transitions Solid Solutions Staining method Stains System Temperature Therapeutic Time Tissues Vision Visual Acuity Visual Fields Work alternative treatment aqueous axon growth axon regeneration axonal degeneration base compliance behavior design experience improved in vivo meetings minimally invasive nerve injury neurofilament neuroprotection novel novel strategies optic nerve disorder optic nerve regeneration physical property public health relevance reconstruction research and development scaffold success treatment strategy valyllysine

项目摘要

DESCRIPTION (provided by applicant): With an estimated 2.2 million Americans with glaucoma and glaucoma-related 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. The current treatment paradigm is focused on pharmacological approaches to lowering intraocular pressure (IOP), despite myriad evidence indicating IOP is not the only causative factor in the pathophysiology of glaucoma. Recent work has taken a more direct approach in which the retinal ganglion cell (RGC) death causing damage to the optic nerve is targeted as a means to preserve vision or reverse vision loss. While some approaches are purely pharmacological, experience in the wider field of neural regeneration has taught us that a scaffold-based approach may be the most promising strategy. We have recently developed a polymeric injectable biomaterial that serves itself well to this application owing to its reverse thermal gelling properties. These properties allow it too rapidly and reversibly transition between a liquid at room temperature and a solid at body temperature, permitting injection through a small gauge needle or cannula directly at the target site and then formation of a cohesive solid polymer network upon reaching body temperature. This approach has many advantages over other scaffold-based approaches including minimally-invasive deployment, in situ conformation to the injury site and tunable physical properties to mimic the host environment. In addition, this system can be readily functionalized with function-mimicking biomolecules to enhance RGC axon regeneration. By functionally tethering these biomolecules directly to our novel injectable biomaterial, we improve both the targeting and the time-scale of their influence at the injury site Towards developing a system that can maximize these advantages, we have constructed this application around two specific aims: 1) design and characterize an appropriate functionalized, biomimetic injectable biomaterial with favorable reverse thermal gelling behavior and physiochemical properties suited to mimic the host environment for optic nerve regeneration; and 2) demonstrate that the functionalized version of this reverse thermal gel (RTG) substantially enhances RGC axon regeneration in vitro and in in vivo optic nerve crush models. We hypothesize that well-controlled incorporation of biomolecules into a temperature responsive polymeric material will lead to a novel and biomimetic injectable biomaterial that conforms in situ to the injury site and mimics the host environment to maximize RGC axon regeneration.

描述（由申请人提供）：估计有220万美国人患有青光眼和青光眼相关的视神经病，占美国所有失明病例的9％至12％，并且确认接受适当医疗的10％的患者继续经历视力丧失，因此需要另一种治疗策略。当前的治疗范式集中在降低眼内压（IOP）的药理学方法上，尽管无数证据表明IOP并不是青光眼病理生理学中唯一的病因。最近的工作采用了一种更直接的方法，其中视网膜神经节细胞（RGC）死亡导致视神经损害是一种保护视力或反向视力丧失的手段。尽管某些方法纯粹是药理，但在更广泛的神经再生领域的经验告诉我们，基于脚手架的方法可能是最有前途的策略。我们最近开发了一种可注入的聚合物生物材料，由于其反向热胶凝特性，该应用非常适合该应用。这些属性允许它在在室温下进行液体，并在体温下使用固体，可以直接在目标部位通过小规格针或套管注射，然后在达到体温后形成粘性的固体聚合物网络。这种方法比其他基于脚手架的方法具有许多优势，包括最小侵入性的部署，对伤害部位的原位构成和可调的物理特性，以模仿宿主环境。此外，这可以通过模仿功能的生物分子来容易地将系统功能化，以增强RGC轴突再生。 By functionally tethering these biomolecules directly to our novel injectable biomaterial, we improve both the targeting and the time-scale of their influence at the injury site Towards developing a system that can maximize these advantages, we have constructed this application around two specific aims: 1) design and characterize an appropriate functionalized, biomimetic injectable biomaterial with favorable reverse thermal gelling behavior and physiochemical properties suited to mimic the视神经再生的宿主环境； 2）证明该反向热凝胶（RTG）的功能化版本显着增强了体外和体内视神经挤压模型的RGC轴突再生。我们假设将生物分子置良好地掺入温度响应的聚合物材料将导致一种新颖而仿生的注射式生物材料，该材料与原位相吻合到损伤部位并模仿宿主环境，以最大化RGC轴突再生。