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Pharmaceuticals
Volume 18
Issue 12
10.3390/ph18121822
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Review

Challenge of Corneal Ulcer Healing: A Novel Conceptual Framework, the “Triad” of Corneal Ulcer Healing/Corneal Neovascularization/Intraocular Pressure, and Avascular Tendon Healing, for Evaluation of Corneal Ulcer Therapy, Therapy of Neovascularization, Glaucoma Therapy, and Pentadecapeptide BPC 157 Efficacy

by
Sanja Masnec
1,2,
Antonio Kokot
3,*,
Tamara Kralj
1,
Mirna Zlatar
1,
Kristina Loncaric
1,
Marko Sablic
3,
Miro Kalauz
2,
Iva Beslic
2,
Katarina Oroz
1,
Bozana Mrvelj
1,
Lidija Beketic Oreskovic
1,
Ivana Oreskovic
1,
Sanja Strbe
1,
Borna Staresinic
1,
Goran Slivsek
1,
Alenka Boban Blagaic
1,
Sven Seiwerth
4,
Anita Skrtic
4 and
Predrag Sikiric
4,*
1
Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
2
Department of Ophthalmology, University Hospital Center Zagreb, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
3
Department of Anatomy and Neuroscience, School of Medicine Osijek, University of Osijek, 31000 Osijek, Croatia
4
Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2025, 18(12), 1822; https://doi.org/10.3390/ph18121822 (registering DOI)
Submission received: 13 November 2025 / Revised: 24 November 2025 / Accepted: 26 November 2025 / Published: 28 November 2025
(This article belongs to the Special Issue Pleiotropic Agents and Their Therapeutic Potential in Gastroenterology, Angiology, and Musculoskeletal Disorders)
Versions Notes

Abstract

To better address the challenge of corneal ulcer healing, with already available standard agents, and those recently introduced, such as stable gastric pentadecapeptide BPC 157, we introduced a novel conceptual framework—the “triad” of corneal ulcer healing↔corneal neovascularization↔intraocular pressure—and extended it to avascular tissues such as tendon. Within this framework, cytoprotection serves as the unifying principle, underscoring that therapeutic effects are not isolated but interconnected. Preclinical studies with BPC 157 therapy, as a cytoprotection agent, illustrate this integration. BPC 157 rapidly normalizes elevated intraocular pressure in glaucomatous rats, preserves retinal integrity, restores pupil function, maintains corneal transparency during ulcer or abrasion healing, and counteracts both corneal neovascularization and dry eye. In parallel, its consistent efficacy in tendon injury models highlights a cytoprotective specificity across avascular tissues. The cornea’s “angiogenic privilege,” preserved during healing and tendon recovery together, provides strong proof of concept. Furthermore, mapping standard therapeutic agents used for corneal ulcers, neovascularization, or glaucoma onto this triad, and linking them with tendon healing, reveals both shared pathways and inconsistencies across existing drug classes. Analyzed were the ascorbate, fibronectin, hyaluronic acid, metalloproteinase inhibitors, EGF, FGF, NGF, insulin, and IGF-1 (corneal ulcer healing), the antiangiogenic agents (endostatin, PAI-1, PEDF, angiostatin, TSP-1, TSP-2, IFN-α), corticosteroids, NSAIDs, cyclosporine A, anti-VEGF drops (treatment of corneal neovascularization), and alpha 2-agonists, beta-blockers, carboanhydrase inhibitors, muscarinic agonists, Rho-kinase inhibitors, and prostaglandin analogs (glaucoma). Taken together, these findings advance cytoprotection as a unifying therapeutic paradigm, with BPC 157 emerging as its first exemplar, and encourage further translational research toward clinical application.
Keywords: corneal ulcer healing; corneal neovascularization; intraocular pressure; tendon healing; evaluation; corneal ulcer therapy; therapy of neovascularization; glaucoma therapy; pentadecapeptide BPC 157 corneal ulcer healing; corneal neovascularization; intraocular pressure; tendon healing; evaluation; corneal ulcer therapy; therapy of neovascularization; glaucoma therapy; pentadecapeptide BPC 157

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MDPI and ACS Style

Masnec, S.; Kokot, A.; Kralj, T.; Zlatar, M.; Loncaric, K.; Sablic, M.; Kalauz, M.; Beslic, I.; Oroz, K.; Mrvelj, B.; et al. Challenge of Corneal Ulcer Healing: A Novel Conceptual Framework, the “Triad” of Corneal Ulcer Healing/Corneal Neovascularization/Intraocular Pressure, and Avascular Tendon Healing, for Evaluation of Corneal Ulcer Therapy, Therapy of Neovascularization, Glaucoma Therapy, and Pentadecapeptide BPC 157 Efficacy. Pharmaceuticals 2025, 18, 1822. https://doi.org/10.3390/ph18121822

AMA Style

Masnec S, Kokot A, Kralj T, Zlatar M, Loncaric K, Sablic M, Kalauz M, Beslic I, Oroz K, Mrvelj B, et al. Challenge of Corneal Ulcer Healing: A Novel Conceptual Framework, the “Triad” of Corneal Ulcer Healing/Corneal Neovascularization/Intraocular Pressure, and Avascular Tendon Healing, for Evaluation of Corneal Ulcer Therapy, Therapy of Neovascularization, Glaucoma Therapy, and Pentadecapeptide BPC 157 Efficacy. Pharmaceuticals. 2025; 18(12):1822. https://doi.org/10.3390/ph18121822

Chicago/Turabian Style

Masnec, Sanja, Antonio Kokot, Tamara Kralj, Mirna Zlatar, Kristina Loncaric, Marko Sablic, Miro Kalauz, Iva Beslic, Katarina Oroz, Bozana Mrvelj, and et al. 2025. "Challenge of Corneal Ulcer Healing: A Novel Conceptual Framework, the “Triad” of Corneal Ulcer Healing/Corneal Neovascularization/Intraocular Pressure, and Avascular Tendon Healing, for Evaluation of Corneal Ulcer Therapy, Therapy of Neovascularization, Glaucoma Therapy, and Pentadecapeptide BPC 157 Efficacy" Pharmaceuticals 18, no. 12: 1822. https://doi.org/10.3390/ph18121822

APA Style

Masnec, S., Kokot, A., Kralj, T., Zlatar, M., Loncaric, K., Sablic, M., Kalauz, M., Beslic, I., Oroz, K., Mrvelj, B., Beketic Oreskovic, L., Oreskovic, I., Strbe, S., Staresinic, B., Slivsek, G., Boban Blagaic, A., Seiwerth, S., Skrtic, A., & Sikiric, P. (2025). Challenge of Corneal Ulcer Healing: A Novel Conceptual Framework, the “Triad” of Corneal Ulcer Healing/Corneal Neovascularization/Intraocular Pressure, and Avascular Tendon Healing, for Evaluation of Corneal Ulcer Therapy, Therapy of Neovascularization, Glaucoma Therapy, and Pentadecapeptide BPC 157 Efficacy. Pharmaceuticals, 18(12), 1822. https://doi.org/10.3390/ph18121822

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