a-surgical-approach-for-optic-nerve-crush-in-a-rabbit-model

A Surgical Approach for Optic Nerve Crush in a Rabbit Model

Optic nerve crush (ONC) is an experimental technique used to model and study the mechanisms of optic neuropathies and potential therapeutic interventions. ...

Stanford University

Targeted drug delivery to the optic nerve head may be useful in the preclinical study and later clinical management of optic neuropathies, however, there are no FDA-approved drug delivery systems to achieve this. The purpose of this work was to develop an optic nerve head drug delivery technique.

Development of a novel SupraChoroidal-to-Optic-NervE (SCONE) drug delivery system.

-forming hydrogels are an attractive option for corneal regeneration, and the delivery of growth factors from such constructs have the potential to improve re-epithelialization and stromal remodeling. However, challenges persist in controlling the release of therapeutic molecules from hydrogels. Here, an -forming bio-orthogonally crosslinked hydrogel containing growth factors tethered  photocleavable linkages (PC-HACol hydrogel) was developed to accelerate corneal regeneration. Epidermal growth factor (EGF) was conjugated to the hydrogel backbone through photo-cleavable (PC) spacer arms and was released when exposed to mild intensity ultraviolet (UV) light (2-5 mW/cm, 365 nm). The PC-HACol hydrogel rapidly gelled within a few minutes when applied to corneal defects, with excellent transparency and biocompatibility. After subsequent exposure to UV irradiation, the hydrogel promoted the proliferation and migration of corneal epithelial cells . The rate of re-epithelialization was positively correlated to the frequency of irradiation, verified through  rabbit cornea organ culture studies. In an  rat corneal wound healing study, the PC-HACol hydrogel exposed to UV light significantly promoted re-epithelialization, the remodeling of stromal layers, and exhibited significant anti-scarring effects, with minimal α-SMA and robust ALDH3A1 expression. Normal differentiation of the regenerated epithelia after healing was evaluated by expression of the corneal epithelial biomarker, CK12. The remodeled cornea exhibited full recovery of corneal thickness and layer number without hyperplasia of the epithelium.

Photoactivated growth factor release from bio-orthogonally crosslinked hydrogels for the regeneration of corneal defects.

Corneal defects can lead to stromal scarring and vision loss, which is currently only treatable with a cadaveric corneal transplant. Although -forming hydrogels have been shown to foster regeneration of the cornea in the setting of stromal defects, the cross-linking, biomechanical, and compositional parameters that optimize healing have not yet been established. This, Corneal defects are also almost universally inflamed, and their rapid closure without fibrosis are critical to preserving vision. Here, an  forming, bioorthogonally cross-linked, nanocluster (NC)-reinforced collagen and hyaluronic acid hydrogel (NCColHA hydrogel) with enhanced structural integrity and both pro-regenerative and anti-inflammatory effects was developed and tested within a corneal defect model . The NCs serve as bioorthogonal nanocross-linkers, providing higher cross-linking density than polymer-based alternatives. The NCs also serve as delivery vehicles for prednisolone (PRD) and the hepatocyte growth factor (HGF). NCColHA hydrogels rapidly gel within a few minutes upon administration and exhibit robust rheological properties, excellent transparency, and negligible swelling/deswelling behavior. The hydrogel's biocompatibility and capacity to support cell growth were assessed using primary human corneal epithelial cells. Re-epithelialization on the NCColHA hydrogel was clearly observed in rabbit eyes, both  and , with expression of normal epithelial biomarkers, including CD44, CK12, CK14, α-SMA, Tuj-1, and ZO-1, and stratified, multilayered morphology. The applied hydrogel maintained its structural integrity for at least 14 days and remodeled into a transparent stroma by 56 days.

-Forming, Bioorthogonally Cross-linked, Nanocluster-Reinforced Hydrogel for the Regeneration of Corneal Defects.

Corneal transplantation is the primary treatment for corneal blindness, affecting millions globally. However, challenges like donor scarcity and surgical complications remain. Recently, in situ-forming corneal stroma substitutes have emerged, offering potential solutions to these limitations. These substitutes enable liquid-to-hydrogel formation in situ, eliminating sutures and reducing complications. Here we performed a direct, side-by-side comparison of a composite hyaluronan-collagen (HA-Col) hydrogel crosslinked by either photochemistry or bio-orthogonal chemistry to ascertain the impact of reaction specificity on corneal wound healing. Testing in rodent and rabbit models suggests that composite HA-Col gels crosslinked by bio-orthogonal chemistry results in more rapid and optically favorable wound healing compared to the same composition crosslinked by photochemistry as well as bio-orthogonally crosslinked collagen alone. These findings underscore biochemical parameters that may be important to the success of crosslinked, in situ-forming hydrogels as an alternative to corneal transplantation, with the potential for expanded access to treatment and improved outcomes.

Bio-orthogonal crosslinking and hyaluronan facilitate transparent healing after treatment of deep corneal injuries with in situ-forming hydrogels.

There is an unmet need for point-of-care therapies to prevent scarring and promote corneal clarity after injury, which is essential for maintaining vision. Verteporfin, an inhibitor of Yes-associated protein (YAP), has been shown to prevent fibrosis in several organs. Visudyne (VP) is an FDA-approved liposomal formulation of verteporfin used to treat abnormal blood vessels in the eye. Here, we showed that VP reduces myofibroblast formation in corneal stromal fibroblasts. To prolong the residence time of verteporfin on the ocular surface, the cohesive viscoelastic ProVisc® hyaluronic acid (HA) gel was hybridized to VP. This formulation is readily translatable because both VP and ProVisc® HA gel are FDA-approved agents. The ProVisc® HA gel increased the residence of subconjunctivally injected verteporfin 12-fold at 24 h after injection compared with pure VP. A single subconjunctival administration of VP hybridized within ProVisc® HA gel (VP/HA hydrogel) significantly reduced YAP activation, corneal fibrosis, neovascularization, and inflammation, leading to reduced opacity without compromising epithelial wound healing in mechanically injured rat corneas. This work demonstrated that VP hybridized with a viscoelastic HA gel can be readily repurposed to promote scar-less healing in the cornea.

Article	Year
Development of a novel SupraChoroidal-to-Optic-NervE (SCONE) drug delivery system. Drug delivery\| PubMed ID: 39010743	2024
Photoactivated growth factor release from bio-orthogonally crosslinked hydrogels for the regeneration of corneal defects. Bioactive materials\| PubMed ID: 39022184	2024
-Forming, Bioorthogonally Cross-linked, Nanocluster-Reinforced Hydrogel for the Regeneration of Corneal Defects. ACS nano\| PubMed ID: 39106436	2024
Bio-orthogonal crosslinking and hyaluronan facilitate transparent healing after treatment of deep corneal injuries with in situ-forming hydrogels. NPJ Regenerative medicine\| PubMed ID: 39905045	2025
Repurposing verteporfin and hyaluronic acid gel for ocular surface treatment to prevent corneal scarring. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 39986473	2025

Kyeongwoo Jang

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