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Corneal injuries are a major cause of blindness worldwide. To restore corneal integrity and clarity, there is a need for regenerative biointegrating materials for in situ repair and replacement of corneal tissue. Here, light‐curable cornea matrix (LC‐COMatrix), a tunable material derived from decellularized porcine cornea extracellular matrix containing un‐denatured collagen and sulfated glycosaminoglycans is introduced. It is a functionalized hydrogel with proper swelling behavior, biodegradation, and viscosity that can be cross‐linked in situ with visible light, providing significantly enhanced biomechanical strength, stability, and adhesiveness. The cross‐linked LC‐COMatrix strongly adheres to human corneas ex vivo and effectively closes full‐thickness corneal perforations with tissue loss. Likewise, in vivo, LC‐COMatrix seals large corneal perforations, replaces partial‐corneal stromal defects and biointegrates into the tissue in rabbit models. LC‐COMatrix is a natural ready‐to‐apply biointegrating adhesive that is representative of native corneal matrix with potential applications in corneal and ocular surgeries. [ABSTRACT FROM AUTHOR]

Silk fibroin films are excellent candidate biomaterials for corneal tissue engineering due to their optical transparency, biocompatibility, and mechanical strength. Their tunable chemical and mechanical properties open the possibility of engineering cellular microenvironments that can both mimic native corneal tissue and provide stimuli to actively promote wound regeneration. While silk film mechanical properties, such as surface topography, have demonstrated the ability to control corneal epithelial cell wound regenerating behavior, few studies have explored the stiffness tunability of these films and its cellular effects. Cells are known to actively sense the stiffness of their surroundings and processes such as cell adhesion, migration, proliferation, and expression of stem markers can be strongly influenced by matrix stiffness. This study develops technical solutions that allow for both the fabrication of films with stiffnesses similar to corneal tissue and also for their characterization in an aqueous, native‐like environment at a scale relevant to cellular forces. Physiological evidence demonstrates that corneal epithelial cells are mechanosensitive to films of different stiffnesses and show that cell spreading, cytoskeletal tension, and molecular mechanotransducer localization are associated with film stiffness. These results indicate that silk film stiffness can be used to regulate cell behavior for the purposes of ocular surface repair. [ABSTRACT FROM AUTHOR]

Abstract: In recent years, lymphangiogenesis, the process of lymphatic vessel formation from existing lymph vessels, has been demonstrated to have a significant role in diverse pathologies, including cancer metastasis, organ graft rejection, and lymphedema. Our understanding of the mechanisms of lymphangiogenesis has advanced on the heels of studies demonstrating vascular endothelial growth factor C as a central pro‐lymphangiogenic regulator and others identifying multiple lymphatic endothelial biomarkers. Despite these breakthroughs and a growing appreciation of the signaling events that govern the lymphangiogenic process, there are no FDA‐approved drugs that target lymphangiogenesis. In this review, we reflect on the lessons available from the development of antiangiogenic therapies (26 FDA‐approved drugs to date), review current lymphangiogenesis research including nanotechnology in therapeutic drug delivery and imaging, and discuss molecules in the lymphangiogenic pathway that are promising therapeutic targets. [ABSTRACT FROM AUTHOR]

The ability to visually observe angiogenesis and lymphangiogenesis simultaneously and repeatedly in living animals would greatly enhance our understanding of the inter-dependence of these processes. To generate a mouse model that allows such visualization via in vivo fluorescence imaging, we crossed Prox1- GFP mice with Flk1::myr-mCherry mice to generate Prox1- GFP/Flk1::myr-mCherry mice, in which lymphatic vessels emit green fluorescence and blood vessels emit red fluorescence. Corneal neovascularization was induced in these mice using three injury models: implantation of a vascular endothelial growth factor ( VEGF) pellet, implantation of a basic fibroblast growth factor (bFGF) pellet, and alkali burn injury. Vessel growth was observed in vivo by stereomicroscopy on days 0, 3, 7 and 10 after pellet implantation or alkali injury as well as in flat-mounted corneas via confocal microscopy after the final in vivo imaging time point. We observed blood and lymphatic vessel growth in all three models, with the most significant growth occurring from days 0-7. Upon VEGF stimulation, the growth kinetics of blood and lymphatic vessels were similar. Blood vessels exhibited similar growth patterns in VEGF- and bFGF-stimulated corneas. Alkali burn injury induced robust angiogenesis and lymphangiogenesis. The intrinsic fluorescence of blood and lymphatic endothelial cells in Prox1- GFP/Flk1::myr-mCherry mice permitted simultaneous in vivo imaging of angiogenesis and lymphangiogenesis. This allowed us to differentiate the processes as well as observe their inter-dependence, and will be valuable in development of therapies targeting angiogenesis and/or lymphangiogenesis. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury is a major neurological disorder that can cause severe motor and sensory dysfunction. Neurogenic effects of vascular endothelial growth factor (VEGF) have been found in the central nervous system, and we examined whether VEGF could promote anatomical and functional recovery of peripheral nerves after injury using an avascular corneal nerve injury model. We found that VEGF enhanced neurite elongation in isolated trigeminal ganglion neurons in a dose-dependent manner. This effect was suppressed by neutralizing antibodies for VEGF receptor (VEGFR) 1 and 2 or neuropilin receptor 1 or by VEGFR2 inhibitors (SU 1498 and Ki 8751). In vivo, mice receiving sustained VEGF via implanted pellets showed increased corneal nerve regeneration after superficial injury compared with those receiving vehicle. VEGF injected subconjunctivally at the time of injury accelerated reinnervation, the recovery of mechanosensation, and epithelial wound healing. Endogenous VEGF expression was up-regulated in the corneal epithelium and stroma after wounding. Thus, VEGF can mediate peripheral neuron growth but requires the activation of multiple VEGF receptor types. In addition, VEGF can accelerate the return of sensory and trophic functions of damaged peripheral nerves. Wounding induces the expression of VEFG, which may modulate physiological nerve repair. [ABSTRACT FROM AUTHOR]