In Situ Bioconjugation as a Therapeutic Delivery Modality to Enhance Ocular Wound Healing

摘要

ABSTRACT This is a K08 award application submitted by David Myung, MD, PhD, who is being hired as an Assistant Professor of Ophthalmology at the Byers Eye Institute at Stanford. Dr. Myung is establishing himself as an investigator in translational bioengineering research focused on corneal wound healing. The K08 award will provide Dr. Myung with the support necessary to further develop specific expertise in corneal wound healing and regenerative medicine, and to acquire the skills necessary to become an independent investigator. To help him achieve these goals, Dr. Myung has assembled an interdisciplinary mentorship team comprised of the following leading investigators in their fields: Dr. Ali Djalilian is an expert in corneal wound healing, and in particular ocular surface disease and stem cell transplantation; Dr. Sarah Heilshorn is an expert in biomaterials; Dr. Jeffrey Goldberg is an expert in nerve regeneration. In addition, he will consult with Dr. Edward Manche from Stanford, a clinical cornea specialist with expertise in corneal crosslinking chemistry, Dr. Christopher Murphy from UC Davis, an expert in testing growth factors in animal models of corneal wound healing, as well as Dr. Jeffrey Tok, who directs the soft and hybrid materials testing facility at Stanford's School of Engineering. In the treatment of traumatic injuries, ulcers, and burns of the eye, inadequate tissue healing remains a major challenge. The cornea is particularly vulnerable to the blinding consequences of delayed healing such as scarring, melts, and perforations. There is, therefore, a major clinical need for new ways to enhance wound healing in the eye. This research investigates the benefits of using highly cell-friendly bioconjugation chemistries to deliver therapeutic factors directly to wounded corneal tissue in three ways: (1) through an injectable gel that covers wounds and releases growth factors, (2) by chemically binding growth factors directly to the wound bed, and (3) by encapsulating human mesenchymal stem cells (hMSCs) within a gel at the ocular surface. The first aim is to characterize and control corneal re- epithelialization through growth-factor eluting collagen gels formed on wounds in situ. The second aim is to evaluate and optimize the epithelial and nerve regeneration effects of growth factors coupled directly to a nerve-ablated cornea. The third aim is to elucidate and maximize the bioactivity of hMSCs encapsulated within collagen gels on a chemically-injured ocular surface. This research may lead to new corneal wound healing therapies that overcome the limitations of topically delivered growth factors and stem cells, and will form the basis of an R01 application before the end of the K award.