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.
Over past decades, the number of medical treatment options for patients with optic neuropathies, has steadily increased with new drugs being developed every few years. Despite this attention from the research and development community, the percentage of patients that receive proper medical treatment and still experience vision loss is significant. An alternative treatment strategy has been developed in which the mechanism underlying the actual vision loss is targeted. This temperature-responsive injectable biomaterial addresses neural injuries in a one-time treatment platform that removes patient compliance as a barrier to therapeutic success. In the case of glaucomatous optic neuropathy, it is envisioned that this treatment would be coupled with intraocular pressure lowering surgery. In other optic neuropathies, such as traumatic optic neuropathy, the current approach might be coupled with intraorbital procedures that address the traumatic insult. The material will be developed both as a scaffold for retinal ganglion cell axon regeneration and as a biomolecule delivery vehicle to enhance its functionality. It is expected that this system will significantly improve vision outcomes in patients with optic neuropathies as well as provide a platform to develop nerve regenerating materials for application to other fields of medicine.
| Laughter, Melissa R; Ammar, David A; Bardill, James R et al. (2016) A Self-Assembling Injectable Biomimetic Microenvironment Encourages Retinal Ganglion Cell Axon Extension in Vitro. ACS Appl Mater Interfaces 8:20540-8 |
