{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:53:22Z","timestamp":1781844802490,"version":"3.54.5"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Canine corneal ulcers are commonly encountered in clinical practice and may progress to stromal melting and perforation if not appropriately managed. Adjunctive therapy has traditionally focused on collagenolysis inhibition and is often guided by morphological severity rather than dominant biological drivers. While anticollagenase strategies remain essential, ulcer progression involves interconnected processes, including inflammatory amplification, impaired epithelial repair, and ocular surface instability. This conceptual analysis therefore seeks to develop a mechanism-based conceptual framework that prioritizes these biological processes and guides adjunctive therapeutic decision-making.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A targeted literature search was conducted using PubMed and Scopus for studies published between January 2000 and February 28, 2026. Relevant canine, animal model, and human studies were narratively synthesized to identify key pathophysiologic drivers and construct a mechanism-based hierarchical framework for adjunctive therapy. Interventions were categorized according to primary mechanistic targets and levels of supporting canine evidence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The proposed framework delineates four therapeutic domains (Structural Preservation, Inflammatory Modulation, Regenerative Augmentation, and Functional Optimization) together with a meta-level component termed Precision Stratification. Structural Preservation, centered on protease inhibition, represents the highest biological priority in cases of active stromal melting. Inflammatory Modulation targets upstream amplification processes, whereas Regenerative Augmentation and Functional Optimization address epithelial repair and ocular surface stability, respectively. Precision Stratification is conceptualized as a meta-level decision-support component that aligns domain prioritization with dominant biological drivers. Evidence strength varies across domains; structural preservation strategies are supported by the broadest canine clinical evidence, whereas inflammatory modulation, regenerative, and precision-oriented strategies rely predominantly on translational or investigational data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The principal contribution of this work is the development of a mechanism-based hierarchical framework for adjunctive management of canine corneal ulcers. The framework preserves the central role of protease inhibition while situating it within a broader biologically structured model of corneal ulcer progression. Canine-specific validation of domain-targeted interventions and development of objective stratification tools represent important priorities for future investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fvets.2026.1825605","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:29:56Z","timestamp":1781843396000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic domains in canine corneal ulcer progression: a conceptual framework for adjunctive management"],"prefix":"10.3389","volume":"13","author":[{"given":"Takuya","family":"Yogo","sequence":"first","affiliation":[{"name":"Department of Veterinary Surgery, Nippon Veterinary and Life Science University","place":["Musashino, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e70154","DOI":"10.1111\/vop.70154","article-title":"Anticollagenase therapy for canine corneal ulcers: a narrative review of mechanisms, efficacy, and clinical implementation","volume":"29","author":"Yogo","year":"2026","journal-title":"Vet Ophthalmol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.2460\/ajvr.69.10.1341","article-title":"Evaluation of matrix metalloproteinase concentrations in the precorneal tear film of dogs with Pseudomonas aeruginosa-associated keratitis during healing","volume":"69","author":"Wang","year":"2008","journal-title":"Am J Vet Res"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/j.1463-5224.2006.00457.x","article-title":"Topical effect of various agents on gelatinase activity in the tear film of normal dogs","volume":"9","author":"Couture","year":"2006","journal-title":"Vet Ophthalmol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"5832","DOI":"10.1038\/s41467-023-41391-7","article-title":"NLRP3 selectively drives IL-1\u03b2 secretion by Pseudomonas aeruginosa-infected neutrophils and regulates corneal disease severity","volume":"14","author":"Minns","year":"2023","journal-title":"Nat Commun"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.jtos.2024.09.007","article-title":"Recent advances in NLRP3 inflammasome in corneal diseases: preclinical insights and therapeutic implications","volume":"34","author":"Ge","year":"2024","journal-title":"Ocul Surf"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1097\/ACI.0000000000001004","article-title":"Impact of inflammasomes on the ocular surface","volume":"24","author":"Stinnett","year":"2024","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s41392-024-01933-x","article-title":"Neutrophil extracellular traps in homeostasis and disease","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e00189-25","DOI":"10.1128\/mbio.00189-25","article-title":"Mechanisms and immune crosstalk of neutrophil extracellular traps in response to infection","volume":"16","author":"Liu","year":"2025","journal-title":"MBio"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"641265","DOI":"10.3389\/fvets.2021.641265","article-title":"Corneal ulcer in dogs and cats: novel clinical application of regenerative therapy using subconjunctival injection of autologous platelet-rich plasma","volume":"8","author":"Farghali","year":"2021","journal-title":"Front Vet Sci"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.3390\/ijms26051926","article-title":"The hidden power of the secretome: therapeutic potential on wound healing and cell-free regenerative medicine\u2014a systematic review","volume":"26","author":"Prado-Yupanqui","year":"2025","journal-title":"Int J Mol Sci"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"103178","DOI":"10.1016\/j.tice.2025.103178","article-title":"Exosome as emerging therapeutic platform for wound healing: current status, advancement and future crosstalk","volume":"98","author":"Ashique","year":"2025","journal-title":"Tissue Cell"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1111\/vop.13256","article-title":"Investigation of ocular surface parameters in dogs with different cephalic conformations using veterinary ocular surface analyzer (OSA-VET)","volume":"28","author":"Li","year":"2025","journal-title":"Vet Ophthalmol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1007\/s11259-024-10610-x","article-title":"Application of OSA-VET\u00ae and qualiquantitative tear tests in brachycephalic dogs with and without keratoconjunctivitis sicca","volume":"49","author":"Voitena","year":"2025","journal-title":"Vet Med Sci"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1111\/vop.70108","article-title":"Beyond the ocular surface: nasal sensory input as a driver of reflex lacrimation in dogs","author":"Cochran","year":"2025","journal-title":"Vet Ophthalmol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.jtos.2025.07.012","article-title":"Deep learning-based classification of fungal and Acanthamoeba keratitis using confocal microscopy","volume":"38","author":"Erukulla","year":"2025","journal-title":"Ocul Surf"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/ICO.0000000000004018","article-title":"Deep learning model for extensive diagnosis of corneal deposits","volume":"13","author":"Taki","year":"2025","journal-title":"Cornea"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"4258","DOI":"10.3390\/s25144258","article-title":"Multimodal-based non-contact high intraocular pressure detection method","volume":"25","author":"Lan","year":"2025","journal-title":"Sensors (Basel)"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1167\/tvst.14.6.1","article-title":"Artificial intelligence aided analysis of anterior segment optical coherence tomography imaging to monitor the device-cornea joint after synthetic cornea implantation","volume":"14","author":"Akpek","year":"2025","journal-title":"Transl Vis Sci Technol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3390\/ijms252011121","article-title":"Molecular and cellular mechanisms of the therapeutic effect of mesenchymal stem cells and extracellular vesicles in corneal regeneration","volume":"25","author":"Kobal","year":"2024","journal-title":"Int J Mol Sci"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.jtos.2022.10.003","article-title":"Trends in using mesenchymal stromal\/stem cells (MSCs) in treating corneal diseases","volume":"26","author":"Venkatakrishnan","year":"2022","journal-title":"Ocul Surf"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"101325","DOI":"10.1016\/j.preteyeres.2024.101325","article-title":"Healing the cornea: exploring the therapeutic solutions offered by MSCs and MSC-derived EVs","volume":"105","author":"Jammes","year":"2025","journal-title":"Prog Retin Eye Res"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/s1350-9462(01)00008-8","article-title":"The corneal wound healing response: cytokine-mediated interaction of the epithelium, stroma, and inflammatory cells","volume":"20","author":"Wilson","year":"2001","journal-title":"Prog Retin Eye Res"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.preteyeres.2015.07.002","article-title":"Progress in corneal wound healing","volume":"49","author":"Ljubimov","year":"2015","journal-title":"Prog Retin Eye Res"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"158","DOI":"10.5326\/0410158","article-title":"Spontaneous chronic corneal epithelial defects in dogs: a review","volume":"41","author":"Bentley","year":"2005","journal-title":"J Am Anim Hosp Assoc"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"2616082","DOI":"10.1080\/07853890.2026.2616082","article-title":"Corneal macrophages and limbal stem cells: emerging roles in ocular surface regeneration","volume":"58","author":"Mao","year":"2026","journal-title":"Ann Med"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1016\/j.jtos.2025.07.010","article-title":"Topical pharmacologic treatments for dry eye disease: a systematic review","volume":"38","author":"Tong","year":"2025","journal-title":"Ocul Surf"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1080\/17512433.2025.2543380","article-title":"Current and emerging pharmacological treatment of dry eye disease","volume":"18","author":"Cukurova","year":"2025","journal-title":"Expert Rev Clin Pharmacol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/eye.1997.126","article-title":"A comparative approach to topical cyclosporine therapy","volume":"11","author":"Williams","year":"1997","journal-title":"Eye"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.cvsm.2007.12.002","article-title":"Immune-mediated keratoconjunctivitis sicca in the dog","volume":"38","author":"Williams","year":"2008","journal-title":"Vet Clin North Am Small Anim Pract"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.tvjl.2007.08.034","article-title":"Clinical evaluation of pimecrolimus eye drops for treatment of canine keratoconjunctivitis sicca: a comparison with cyclosporine a","volume":"179","author":"Ofri","year":"2009","journal-title":"Vet J"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1111\/vop.12412","article-title":"Effect of bandage contact lens wear and postoperative medical therapies on corneal healing rate after diamond burr debridement in dogs","volume":"20","author":"Dees","year":"2017","journal-title":"Vet Ophthalmol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1111\/vop.12202","article-title":"Effect of corneal contact lens wear on healing time and comfort post LGK for treatment of SCCEDs in boxers","volume":"18","author":"Wooff","year":"2015","journal-title":"Vet Ophthalmol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1111\/vop.13274","article-title":"Effect of owner presence on healing of spontaneous chronic corneal epithelial defects after anterior stromal puncture","volume":"28","author":"Rivera-Viscal","year":"2025","journal-title":"Vet Ophthalmol"}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2026.1825605\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:29:57Z","timestamp":1781843397000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2026.1825605\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":33,"alternative-id":["10.3389\/fvets.2026.1825605"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2026.1825605","relation":{},"ISSN":["2297-1769"],"issn-type":[{"value":"2297-1769","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]},"article-number":"1825605"}}