A Functional Reverse Thermal Gel for Retinal Ganglion Cell Axon Regeneration

 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 - 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。目前的治疗主要是药理学，但治疗剂的生物利用度仍然是根本问题。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）死亡被作为保护视力甚至逆转视力丧失的手段。虽然通过玻璃体内注射直接施用神经营养因子（NTFs）已经取得了一些成功，但是这些NTFs对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影响视网膜层中的RGC，因此在本体神经内再生的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，由于其反向热胶凝特性和其与细胞外基质（ECM）模拟生物分子高度功能化的能力，该材料非常适合这种应用。热胶凝性质允许其从室温下的液体快速且可逆地转变为体温下的物理凝胶，使得能够通过小规格针或套管直接在目标部位注射，其中聚合物然后可以在达到体温时形成内聚固体聚合物网络。这种方法具有许多优点，包括（1）微创部署，（2）原位构象的损伤部位，（3）持续表达的NTFs在靶位点，（4）延长的生物活性的NTFs截留在系统中，和（5）可调的物理性质，以模拟宿主环境。此外，束缚模拟ECM组分的生物分子的能力将增强受损视神经中的RGC轴突再生和延伸。 为了开发可以最大化这些优点的系统，我们围绕两个特定目标构建了该应用：（1）设计和表征具有有利的反向热凝胶化行为和适合于模拟RGC轴突再生的宿主环境的物理化学性质的ECM模拟可注射生物材料;以及（2）使用视神经挤压模型在体内证明实质性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中注射dal的联合治疗效果。

 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.