Dysregulated wound healing in the cornea can lead to corneal scars and corneal haze resulting in a loss of visual acuity. While many elements of corneal wound healing are well characterized, the biophysical attributes of the wound space and the impact of these on cellular activities critical to wound healing have not been adequately investigated. Along with soluble signaling molecules present in the extracellular milieu, biophysical cues are emerging as key factors in determining cell behaviors. We propose to quantitatively analyze the alterations in stromal topography and compliance throughout the wound healing process. Our hypothesis is that the biophysical cues in the wound space alter throughout wound healing and that these directly influence the transition of keratocytes to myofibroblasts in the corneal stromal layer. The myofibroblasts, in turn, would alter the compliance of the wound microenvironment through active contraction. Ultimately, the change in the biophysical cues in the wound bed would activate apoptotic pathways, promoting removal of the myofibroblasts and an optically clear cornea would return. Using the measured alterations in the biophysical environment as a guide, we will fabricate hydrogel substrates with similar biophysical properties (of compliance and topography) to determine the cellular consequences of these alterations on myofibroblast behavior in vitro. The information that we obtain about the cellular behaviors and gene and protein alterations could enable the therapeutic targeting of biophysical cues during wound healing. Attributes of the wound bed could be directly modulated, such as the contractile elements of the corneal stromal cells, to improve wound healing outcomes.
Wound healing in the cornea can lead to corneal scars and can lead to impairment or loss of vision. While many elements of corneal wound healing are well characterized, biophysical attributes of the wound space have not been adequately investigated. Along with soluble signaling molecules present in the extracellular milieu, biophysical cues are emerging as key regulators of cell behaviors. This proposal would determine the biophysical cues (specifically topography and compliance) present throughout corneal sromal wound healing. Our hypothesis is that the biophysical attributes of the wound space changes throughout the healing process and that the transition of phenotypes of the cells in the corneal stromal layer is modulated by alterations in the biophysical cues of the wound space. In addition, the myofibroblast, a central player in normal and dysregulated wound healing will modify the compliance of the wound microenvironment and thereby assist in wound repair, but also in ultimately triggering signals necessary to prevent corneal haziness. If proven true, our hypothesis would indicate that direct modulation of the biophysical properties and contractile elements of the corneal stromal cells could improve wound healing outcomes.
|Thomasy, Sara M; Raghunathan, Vijay Krishna; Miyagi, Hidetaka et al. (2018) Latrunculin B and substratum stiffness regulate corneal fibroblast to myofibroblast transformation. Exp Eye Res 170:101-107|
|Miyagi, Hidetaka; Jalilian, Iman; Murphy, Christopher J et al. (2018) Modulation of human corneal stromal cell differentiation by hepatocyte growth factor and substratum compliance. Exp Eye Res 176:235-242|
|Raghunathan, VijayKrishna; Eaton, J Seth; Christian, Brian J et al. (2017) Biomechanical, ultrastructural, and electrophysiological characterization of the non-human primate experimental glaucoma model. Sci Rep 7:14329|
|Raghunathan, Vijay Krishna; Thomasy, Sara M; Strøm, Peter et al. (2017) Tissue and cellular biomechanics during corneal wound injury and repair. Acta Biomater 58:291-301|
|Thomasy, Sara M; Cortes, Dennis E; Hoehn, Alyssa L et al. (2016) In Vivo Imaging of Corneal Endothelial Dystrophy in Boston Terriers: A Spontaneous, Canine Model for Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci 57:OCT495-503|
|Strom, Ann R; Cortés, Dennis E; Rasmussen, Carol A et al. (2016) In vivo evaluation of the cornea and conjunctiva of the normal laboratory beagle using time- and Fourier-domain optical coherence tomography and ultrasound pachymetry. Vet Ophthalmol 19:50-6|
|Strom, Ann R; Cortés, Dennis E; Thomasy, Sara M et al. (2016) In vivo ocular imaging of the cornea of the normal female laboratory beagle using confocal microscopy. Vet Ophthalmol 19:63-7|
|Horikawa, Taemi; Thomasy, Sara M; Stanley, Amelia A et al. (2016) Superficial Keratectomy and Conjunctival Advancement Hood Flap (SKCAHF) for the Management of Bullous Keratopathy: Validation in Dogs With Spontaneous Disease. Cornea 35:1295-304|
|Ali, Maryam; Raghunathan, VijayKrishna; Li, Jennifer Y et al. (2016) Biomechanical relationships between the corneal endothelium and Descemet's membrane. Exp Eye Res 152:57-70|
|Morgan, Joshua T; Kwon, Heung Sun; Wood, Joshua A et al. (2015) Thermally labile components of aqueous humor potently induce osteogenic potential in adipose-derived mesenchymal stem cells. Exp Eye Res 135:127-33|
Showing the most recent 10 out of 34 publications