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.

Public Health Relevance

Over past decades, the number of medical treatment options for patients with glaucoma, the most common optic neuropathy, 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 glaucoma, 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 optic nerve 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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Chin, Hemin R
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University of Colorado Denver
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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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
Yun, Donghwa; Lee, Young M; Laughter, Melissa R et al. (2015) Substantial Differentiation of Human Neural Stem Cells Into Motor Neurons on a Biomimetic Polyurea. Macromol Biosci 15:1206-11