Sustained release of decorin to the surface of the eye enables scarless corneal regeneration

Abstract

Disorganization of the transparent collagenous matrix in the cornea, as a consequence of a variety of infections and inflammatory conditions, leads to corneal opacity and sight-loss. Such corneal opacities are a leading cause of blindness, according to the WHO. Public health programs target prevention of corneal scarring, but the only curative treatment of established scarring is through transplantation. Although attempts to minimize corneal scarring through aggressive control of infection and inflammation are made, there has been little progress in the development of anti-scarring therapies. This is owing to eye drop formulations using low viscosity or weak gelling materials having short retention times on the ocular surface. In this study, we report an innovative eye drop formulation that has the ability to provide sustained delivery of decorin, an anti-scarring agent. The novelty of this eye drop lies in the method of structuring during manufacture, which creates a material that can transition between solid and liquid states, allowing retention in a dynamic environment being slowly removed through blinking. In a murine model of Pseudomonas keratitis, applying the eye drop resulted in reductions of corneal opacity within 16 days. More remarkably, the addition of hrDecorin resulted in restoration of corneal epithelial integrity with minimal stromal opacity endorsed by reduced α-smooth muscle actin (αSMA), fibronectin, and laminin levels. We believe that this drug delivery system is an ideal non-invasive anti-fibrotic treatment for patients with microbial keratitis, potentially without recourse to surgery, saving the sight of many in the developing world, where corneal transplantation may not be available.

Lowered Decorin With Aberrant Extracellular Matrix Remodeling in Aqueous Humor and Tenon's Tissue From Primary Glaucoma Patients

“…56 Decorin formulation has shown promising outcomes in the murine model showing reduced corneal opacity with antiscarring properties in patients with microbial keratitis. 57 The finding that decorin is lowered in Tenon's fibroblast and AH before surgery opens avenues for investigating decorin as a biomarker or as a therapeutic target to enhance its levels in patients undergoing trabeculectomy.…”

A Novel CD147 Inhibitor, SP-8356, Attenuates Pathological Fibrosis in Alkali-Burned Rat Cornea

“…Similarly, Hindman et al and Kim et al [38,39] reported that PA decreased the number of myofibroblast in damaged cornea, but this reducing effect disappeared when PA treatment is discontinued. In addition, Hill et al [40] reported that corticosteroid is ineffective to eliminate myofibroblast population in damaged cornea. Thus, PA seems to improve corneal haze regardless of depletion of myofibroblast population (Figure 1 and Supplementary Figure S1).…”

Proteoglycans in Biomedicine: Resurgence of an Underexploited Class of ECM Molecules

“…Postoperative results showed that rabbits treated with decorin had significantly less ECM deposition 14 days after surgery, as well as suppressed conjunctivital scarification. Hill et al (2018) designed gellan based fluid gels for sustained delivery of human recombinant decorin through eye drops for corneal regeneration and found improved ocular function. Due to its ability to delay collagen fibrillogenesis, decorin is an attractive therapeutic candidate for anti-scarring treatments.…”

“…Dermatan sulfate Macular degeneration, diabetic retinopathy, diabetic macular edema (Devore et al, 2010) Corneal wound healing (Grisanti et al, 2005;Hill et al, 2018) Anti-scarring (Stuart et al, 2011;Ahmed et al, 2014;Wang et al, 2016) Oncosupression (Yang et al, 2015;Wang et al, 2016;Liu et al, 2017;Oh et al, 2017a) Abdominal aortic aneurysm (Shen et al, 2017) Vascular neointimal hyperplasia (Paderi et al, 2011;Scott and Panitch, 2014;Scott et al, 2017) Lumican Keratan sulfate Corneal wound healing (Chakravarti, 2002;Gesteira et al, 2017) Bacterial lung infections (Shao et al, 2012;Shao et al, 2013a) Scarring (Yeh et al, 2005;Liu et al, 2013;Yamanaka et al, 2013;Zhao et al, 2016) Melanoma (Zeltz et al, 2009;Pietraszek et al, 2013)…”