Engineering Tunable Biomimetic Adhesive Hydrogel to Deliver and Enhance MSC Function for Corneal Regeneration

About This Grant

Project Summary Corneal diseases pose a significant public health challenge in the United States, often leading to vision impairment and decreased quality of life. Mesenchymal stem cell (MSC) delivery to the cornea after a severe injury has shown promise by accelerating repair and significantly suppressing inflammation. However, a major bottleneck in developing MSC therapy for corneal repair is the lack of effective delivery methods. Moreover, optimizing the dosage and timing of MSC therapy is crucial for achieving therapeutic outcomes while minimizing side effects. MSCs must also survive and integrate into corneal tissue to exert their therapeutic effects. To date, MSCs have been delivered via surface injection, fibrin gel, or as a sheet on an amniotic membrane. However, these methods are limited by poor MSC survival and/or rapid matrix degradation. To address these issues, we propose the development of adhesive hydrogels that can effectively encapsulate and release MSCs in a sustained manner while having similar biomechanics as the corneal tissue. Our platform composed of a single hybrid polymeric structure with tunable variables to generate two distinct mechanical properties and degradation rates: 1) a soft/controlled degradable adhesive hydrogel to function as a bandage containing MSCs that release secreted factors for promoting corneal epithelial regeneration and 2) a strong/highly adhesive hydrogel that can adhere to corneal stromal defects and simultaneously serves as a stromal replacement while providing a platform for the delivery of MSCs to promote repair of stromal injuries/ulcerations. Our proposed biomaterial is a photocurable adhesive composite hydrogel based on chemically modified gelatin and hyaluronic acid (HA), encapsulated with MSCs. First, gelatin will be dual-functionalized with methacrylic anhydride (MA) and phenylboronic acid (PBA) to control mechanical properties and promote tissue adhesion. The incorporation of methacrylate HA derivatives in the hydrogel will also control the viscosity of the prepolymer and improve its mechanical properties. The physical properties of the resulting hydrogels, such as stiffness, swelling ratio, and degradation rate, which affect MSCs differentiation, will be tuned by varying polymer ratios, degree of polymer functionalization, final polymer concentration, and crosslinking time. We will first optimize the mechanical properties of the proposed hydrogels, and their degradation rates will be tuned to achieve a rate supporting MSCs growth and proliferation (Aim 1). We will then assess the in vitro epithelial proliferation and MSCs differentiation using in vitro models developed in our labs (Aim 2). Finally, we will test the in vivo efficacy of MSC-laden hydrogels using two animal models: a corneal epithelial wound healing model and a corneal stromal injury model (Aim 3). Based on our preliminary data, we anticipate that successfully achieving the Specific Aims of this project will result in a novel treatment that enhances MSC survival and retention by providing a 3D environment resembling the corneal extracellular matrix. The treatment is expected to improve visual outcomes, seal and repair stromal injuries, facilitate re-epithelialization, and reducing the healthcare system burden.