Corneal Scar Repair through SPAACKL: Sutureless, Pro-regenerative Anterior Additive Collagen gel KeratopLasty

通过 SPAACKL 修复角膜疤痕：无缝线、促再生前部添加剂胶原蛋白凝胶 KeratopLasty

• 批准号: 10570965
• 负责人: David Myung
• 金额: $ 50.69万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570965
• 关键词: Actins; Address; Affect; Alkynes; Anterior; Autologous; Azides; Behavior; Biological Assay; Biomedical Engineering; Blindness; Burr hole procedure; Cadaver; Cell Survival; Cells; Central Scar; Chemistry; Cicatrix; Clinical; Coculture Techniques; Collagen; Copper; Cornea; Corneal Diseases; Corneal Injury; Custom; Data; Defect; Dimensions; Disease; Encapsulated; Engineering; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; Esters; Evaluation; Excision; Exhibits; Eye; FDA approved; Fluorescamine; Fluorescein; Fostering; Gel; Growth; Growth Factor; HGF gene; Harvest; Hydrogels; Immunohistochemistry; In Situ; In Vitro; Inflammation; Keratoplasty; Light; Liquid substance; Mechanics; Mediating; Modality; Modeling; Morphology; Natural regeneration; Operative Surgical Procedures; Optics; Organ Culture Techniques; Oryctolagus cuniculus; Paracrine Communication; Patients; Phenotype; Photochemistry; PicoGreen; Procedures; Proliferating; Property; Proteins; Regenerative capacity; Research; Rheology; Riboflavin; Shapes; Side; Site; Source; Spectrophotometry; Stains; Stromal Cells; Succinimides; Surface; Surgical sutures; Suspensions; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Thick; Time; Tissue Donors; Tissue Grafts; Tissues; Transplantation; Transplantation Surgery; Viscosity; Vision; Visual Pathways; Visual impairment; Western Blotting; Work; analog; beneficiary; biological systems; catalyst; clinical translation; corneal epithelial wound healing; corneal epithelium; corneal scar; corneal surgery; cross reactivity; crosslink; curative treatments; cycloaddition; design; graft failure; healing; improved; in vivo; mesenchymal stromal cell; novel therapeutics; oxidative damage; paracrine; phenotypic biomarker; preservation; prevent; regenerative; regenerative growth; repaired; severe injury; sight restoration; wound; wound healing

PROJECT SUMMARY/ABSTRACT As the dome-shaped, transparent outermost part of the eye, the cornea provides the majority of the focusing power for the visual pathway. When it is damaged due to severe injury or disease, scarring often ensues, resulting in reduced vision and, in many cases, blindness. In spite of the various types of corneal transplants that are available, there remains a major clinical need for new modalities to restore transparency to scarred corneas without donor tissue, which is in short supply worldwide. Corneal mesenchymal stromal cells (c- MSCs) have known therapeutic effects on corneal scarring and wound healing, but the optimal way to deliver their benefits to the eye have yet to be determined. We are developing Sutureless, Pro-regenerative, Anterior Additive Collagen gel KeratopLasty (SPAACKL), a procedure that removes and replaces blinding corneal scars with a transparent, stroma-like gel matrix containing c-MSCs. After removal of corneal scar tissue, the material is applied to the defect as a viscous liquid suspension of c-MSCs, forming a crosslinked, transparent cellularized stromal substitute within minutes that not only recreates the smooth surface necessary for clear vision but also promotes rapid re-epithelialization. This technology leverages a crosslinking technology known as copper-free click chemistry that is bio-orthogonal: it does not react with proteins, cells, or biologic systems of any kind. As such, it can be safely applied to a corneal wound and around c-MSCs without producing toxic side products, and without the need for light energy, catalysts or accelerators. Our central hypothesis is that bio-orthogonal crosslinking can improve the regenerative benefits of c-MSCs by preserving the bioactivity of its encapsulated cargo compared to less specific crosslinking chemistries that are used currently in corneal surgery. In preliminary work, we have demonstrated that bio-orthogonally crosslinked gels support the growth of encapsulated stromal cells and have demonstrated the regenerative capacity of these cell-matrix composites to support rapid, multi-layered epithelialization both ex vivo and in vivo. Motivated by this data, our first aim is to test the hypothesis that matrix stiffness, composition, and crosslinking chemistry influence c-MSCs’ viability and secretion of pro- regenerative factors. Our second aim is to test the hypothesis that encapsulated c-MSCs exert their pro- regenerative influence on the corneal epithelium primarily through paracrine signaling. Our third aim is to evaluate the ability of bio-orthogonally crosslinked hydrogels to deliver therapeutic cargo that enhances epithelial and stromal regeneration through an in vivo keratectomy model. This research will build the foundational data for eventual clinical translation of a new way to treat corneal blindness without the need for sutures, light energy, or cadaveric donor tissue, and has the potential to one day help patients avoid the need for a traditional corneal transplant.

项目总结/文摘