Experimental modeling of cornea wound healing in diabetes: clinical applications and beyond

Abstract

Diabetes mellitus is the most common cause of blindness in working age populations worldwide. While much of the focus for public health has been on secondary prevention in sight-threatening diabetic retinopathy, the cornea, including its epithelium and nerves, represents a major site of damage by chronic hyperglycemia. On injury, the diabetic cornea exhibits a delayed wound-healing response, as well as an altered ocular surface immune response. This suggests a potential association between the dysfunctional wound healing response and altered inflammation on the ocular surface. However, the presence of potential confounders makes this association difficult to investigate in human epidemiological studies. Thus, we turn to animal diabetic models for a better understanding.In this review, 20 original studies, published between 2008 and 2018, describe in vivo and in vitro models of diabetic cornea disease. We compared different models of diabetic cornea wound healing and discussed the relative strengths and drawbacks of each model. A number of molecular and cellular components involved in the corneal wound healing response that are altered in the presence of diabetes have been identified in the reviewed studies. Particularly, altered corneal epithelial protein concentrations of lumician and occludin were detected in diabetic eyes compared with controls. Additionally, the importance of IL-1β in modulating the inflammatory response after corneal injury in patients with diabetes and controls was further elucidated. Meanwhile, abnormal P2×7 receptor localization and decreased corneal sub-basal nerve density in diabetic eyes were shown to contribute to altered corneal nerve signaling after injury and thus affecting the wound healing response. Finally, the discovery of the therapeutic effects of topically administered aloe vera, Serpine 1, Resolvin D1 (RvD1), pigment epithelium-derived factor (PEDF) and Pro-His-Ser-Arg-Asn in diabetic animal models of cornea epithelial and nerve injury provide encouraging evidence for the future availability of effective treatment for diabetic keratopathy.

MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress

“…The main clinical manifestations of patients with DK are the delayed corneal epithelial wound healing and decreased corneal sensitivity (37). It is well documented that diabetes causes damage to corneal epithelial wound healing and nerve regeneration (1)(2)(3)(4)(5)(6)(7)(8)(9). However, the related mechanisms are not completely understood and lack of effective clinical treatment methods at present.…”

“…Patients with diabetes often present with decreased corneal wound healing, reduced corneal innervation, and a loss of corneal sensitivity (1)(2)(3)(4)(5)(6)(7)(8)(9). These complications of diabetes in the cornea are known as diabetic keratopathy (DK), which can lead to severe visual impairment (10).…”

Challenges and strategies for the delivery of biologics to the cornea

“…Quick and complete healing of the cornea is of utmost importance, however, in certain patients such as those suffering from neurotrophic keratopathy, the healing process is altered after damage resulting in persisting epithelial defects [2]. Also, the cornea of diabetic patients can exhibit a delayed wound-healing response leading to ocular surface irregularities or scarring, thus hindering clear vision [3].…”

Resolvin D1 attenuates the inflammatory process in mouse model of LPS‐induced keratitis

“…Among the specialized pro‐resolving mediators (SPMs), Resolvin D1 (RvD1) has emerged as a promising therapeutic tool. Derived from the w‐3‐polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA), 9 RvD1 was able to affect a pattern of mediators proper to inflammation and tissue repair, such as cytokines, IL‐10, keratinocyte‐derived chemokine (KC), 10,11 lymphocytes and M1/M2 macrophages 5 in conjunctivitis, 12‐14 uveitis, 3 choroid and retina, 7,8,15‐18 by resolving several inflammation‐based ocular diseases 3‐6,15,19 …”

“…specialized pro-resolving mediators (SPMs), Resolvin D1 (RvD1) has emerged as a promising therapeutic tool. Derived from the w-3-polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA), 9 RvD1 was able to affect a pattern of mediators proper to inflammation and tissue repair, such as cytokines, IL-10, keratinocyte-derived chemokine (KC), 10,11 lymphocytes and M1/ M2 macrophages 5 in conjunctivitis, [12][13][14] uveitis, 3 choroid and retina, 7,8,[15][16][17][18] by resolving several inflammation-based ocular diseases. [3][4][5][6]15,19 Interestingly, RvD1 has shown anti-inflammatory actions also in corneal epithelial cells, by inducing a dose-response reduction of pro-inflammatory cytokines and exerting positive actions on corneal epithelial wound healing.…”