Surgical removal of the vitreous and its replacement with substitutes has become the most common posterior segment eye surgery. Present substitutes, while functional, are temporary and are either absorbed (gases) or require secondary surgery for removal (silicone oils). Surgical complications include development of nuclear cataract, glaucoma, corneal decompensation, and retinal re-detachments. Our long-term objective is to deepen our understanding of the macromolecular organization of the vitreous components and then to use this information to develop more physiological vitreous substitutes that can exert an osmotic pressure to tamponade the retina. Our central hypothesis is that we can accomplish this by using water-soluble thiolated synthetic analogues of the collagen and hyaluronic acid, the two primary components of the vitreous. In our specific aims we will substitute collagen with deacylated gellan while hyaluronic acid will be substituted by a methacrylamide/sodium methacryate copolymer. Statistically designed polymers and their hydrogels will be characterized using nuclear magnetic resonance, Fourier transform infrared, raman, circular dichroism, and light- scattering spectroscopies, and rheology. Computational and macromolecular modeling techniques will be employed to study the relationship between the structure and mechanical properties of the natural vitreous. It is our expectation that the techniques will enable us to develop a 3-D molecular profile of the vitreous in vivo by using light scattering techniques. Vitreous substitutes will be further tested by using light scattering, tisse culture and one-month in vivo rabbit studies followed by examination of the implant and histological evaluation of the retina. Our goal is to generate optimal biomimetic formulations of vitreous substitutes to be potentially translated into clinical interventions. This contribution wll be significant because these physiological gel substitutes could lessen patient burden by eliminating the need for removal of the substitute by secondary surgery, eliminating refractive error, possibly lowering the incidence of glaucoma and cataract postvitrectomy, and reducing redetachment of the retina. They could also be used to study the molecular mechanism of vitreous liquefaction and for intravitreal drug delivery therapies. The proposed research is innovative because it focuses on understanding and mimicking the natural vitreous and utilizing recent advances in soft condensed matter physics. Our two-component system representing rigid collagen and flexible hyaluronic acid will be endowed with sticky thiol groups. After injection of material as an aqueous solution, the rigid component will instantaneously form a physical gel imbedding the flexible copolymer. Upon subsequent exposure to oxygen, the thiol groups in the two components will form disulfide cross-links, resulting in a permanent hydrogel capable of providing osmotic pressure to tamponade the retina.
The proposed research is relevant to public health because a biomimetic vitreous gel substitute would yield a much-needed alternative to non-physiological vitreous substitutes such as perfluorocarbons and silicone oils, thus dramatically decreasing patient burden. The vitreous gel plays a central role in the growth and overall health of the eye. To avoid the long-term deleterious effects of current materials, it is critical that vitreous substitutes mimic the natural vitreous. This project is in line with the underlying mission of the NIH since we seek to understand how the vitreous has been engineered in nature and will apply that understanding to the prevention or decrease of vision loss.
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