A Functional Reverse Thermal Gel for Retinal Ganglion Cell Axon Regeneration

University Of Colorado Denver, Aurora CO

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Abstract

? 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.