A biomimetic reverse thermal gel for optic nerve 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变，占美国所有失明病例的9 - 12%，以及承认接受适当治疗的患者中有10%继续经历视力丧失，因此显然需要替代治疗策略。目前的治疗模式集中在降低眼内压（IOP）的药理学方法上，尽管有大量证据表明IOP不是青光眼病理生理学中的唯一致病因素。最近的工作已经采取了一种更直接的方法，其中视网膜神经节细胞（RGC）死亡导致视神经损伤被作为一种手段来保护视力或逆转视力丧失。虽然有些方法是纯药理学的，但神经再生更广泛领域的经验告诉我们，基于支架的方法可能是最有前途的策略。我们最近开发了一种聚合物可注射生物材料，由于其反向热胶凝特性，该材料本身很好地用于该应用。这些特性允许它在两种状态之间快速且可逆地转变， 在室温下为液体，在体温下为固体，允许通过小规格针或套管直接在目标部位注射，然后在达到体温时形成粘性固体聚合物网络。这种方法与其他基于支架的方法相比具有许多优点，包括微创部署，原位构象损伤部位和可调的物理性质，以模拟宿主环境。另外这款 系统可以容易地用功能模拟生物分子功能化以增强RGC轴突再生。通过将这些生物分子直接功能性地束缚到我们的新型可注射生物材料上，我们改进了它们在损伤部位的靶向和影响的时间尺度。为了开发能够最大化这些优势的系统，我们围绕两个特定目标构建了该应用：1）设计和表征合适的官能化，仿生可注射生物材料，具有良好的逆热凝胶行为和适合于模拟宿主环境用于视神经再生的理化性质;和2）证明该反向热凝胶（RTG）的功能化形式在体外和体内视神经挤压模型中显著增强RGC轴突再生。我们假设，将生物分子良好控制地掺入温度响应性聚合物材料将导致一种新型的仿生可注射生物材料， 的损伤部位，并模仿宿主环境，以最大限度地RGC轴突再生。

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.