A biomimetic reverse thermal gel for optic nerve regeneration

描述(申请人提供)：据估计，美国有220万患有青光眼和青光眼相关视神经疾病的患者占美国所有失明病例的9%至12%，而且人们认识到，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。目前的治疗模式主要集中在降低眼压(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的唯一原因。最近的研究采取了一种更直接的方法，将导致视神经损伤的视网膜神经节细胞(RGC)死亡作为保护视力或逆转视力丧失的一种手段。虽然一些方法纯粹是药理学的，但更广泛的神经再生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，由于其反向热凝胶特性，它本身很好地适用于这一应用。这些特性使得它可以快速且可逆地 室温下的液体和体温下的固体，允许通过小口径的针头或套管直接在目标部位注射，然后在达到体温时形成粘合的固体聚合物网络。与其他基于支架的方法相比，该方法具有许多优点，包括微创部署、损伤部位的原位构象以及可调节的物理特性来模拟宿主环境。此外，这一点 该系统可以很容易地功能化与功能模拟生物分子，以促进RGC轴突再生。通过将这些生物分子直接与我们新型的可注射生物材料捆绑在一起，我们改进了它们在损伤部位影响的靶向性和时间尺度，以开发能够最大限度地发挥这些优势的系统，我们围绕两个特定目标构建了这一应用：1)设计和表征一种适当的功能化、仿生可注射生物材料，具有良好的反向热凝胶行为和适于模拟视神经再生宿主环境的物理化学特性；2)证明这种反向热凝胶(RTG)的功能化版本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，将生物分子很好地控制地结合到温度响应性聚合物材料中将导致一种新型的仿生可注射生物材料，这种材料在原位符合 并模拟宿主环境，以最大限度地促进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.