[R01] Engineering Tunable Biomimetic Adhesive Hydrogel to Deliver and Enhance MSC Function for Corneal Regeneration
Ente: National Eye Institute
Scadenza: 2030-04-30
Importo max: 527.987 EUR
Paese: US
Descrizione
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 n
Istituzione: UNIVERSITY OF CALIFORNIA LOS ANGELES
PI: Nasim Annabi, ALI R DJALILIAN, Reza Dana
Progetto: 1R01EY038446-01
Settori: National Eye Institute
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