{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:11:18Z","timestamp":1778217078112,"version":"3.51.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"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. Ophthalmol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Corneal endothelial dysfunction, most commonly caused by Fuchs endothelial corneal dystrophy (FECD) or pseudophakic bullous keratopathy (PBK), leads to stromal edema and corneal decompensation when endothelial cell density (ECD) falls below 500\u2013700cells\/mm\u00b2. Standard treatment via corneal transplantation, including Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK), is limited by the need to standardize corneal endothelial cell culture, donor shortages, immune rejection, and technical complications.<\/jats:p>\n                    <jats:p>This review aims to summarize recent advances in injectable corneal endothelial cell (CEC) therapy, critically appraise translational challenges, and discuss future directions for establishing this regenerative approach as a global treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Narrative review of pre-clinical and clinical studies examining CEC injection therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Relevant literature was analyzed to evaluate innovations in Human corneal endothelial cells (HCEC) preparation, culture techniques, delivery methods, and strategies to enhance cell adhesion and survival. Studies reporting preclinical models and human clinical trials were included to assess safety, efficacy, and translational feasibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Corneal endothelial cells (CEC) injections have achieved significant advancement since their development. Simple cultured CEC injections showed poor efficacy due to limited cell adhesion and survival, but the introduction of ROCK inhibitors along with cultured CECs demonstrated improvement in corneal transparency up to 5 years. Advancements in cell delivery techniques like hydrogel, carrier-assisted injections, magnetically guided injections, as well as alternative cell sources have shown promising results in pre-clinical studies, but human studies are still ongoing. Despite advancements, persisting challenges include phenotypic stability, and longterm safety and efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Injectable CEC therapy is a promising minimally invasive alternative to corneal transplantation. While early clinical outcomes are encouraging, further work is required to optimize cell preparation, delivery, and long-term safety, and to establish the therapy as a scalable, globally applicable treatment for endothelial failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fopht.2026.1799892","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T04:48:18Z","timestamp":1778215698000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Injectable corneal endothelial cell therapy: recent progress, translational barriers, and future directions"],"prefix":"10.3389","volume":"6","author":[{"given":"Ghadeer","family":"Mohammed","sequence":"first","affiliation":[{"name":"University of Kufa College of Medicine","place":["Najaf, Iraq"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Abbas","family":"Tayyab","sequence":"additional","affiliation":[{"name":"King Edward Medical University","place":["Lahore, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaffer","family":"Hussain","sequence":"additional","affiliation":[{"name":"King Edward Medical University","place":["Lahore, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renad","family":"AlDhib","sequence":"additional","affiliation":[{"name":"MAHSA University","place":["Selangor, Malaysia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mifrah Rahat Khan","family":"Sherwani","sequence":"additional","affiliation":[{"name":"Duke University Hospital","place":["Durham, NC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johar","family":"Abbas","sequence":"additional","affiliation":[{"name":"Al-Shifa Trust Eye Hospital","place":["Rawalpindi, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahra","family":"Arsalan","sequence":"additional","affiliation":[{"name":"Al-Shifa Trust Eye Hospital","place":["Rawalpindi, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Mercado","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute","place":["Naples, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.4103\/tjo.TJO-D-23-00115","article-title":"Therapeutic future of Fuchs endothelial corneal dystrophy: An ongoing way to explore","volume":"14","author":"Liu","year":"2024","journal-title":"Taiwan J Ophthalmol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032982","article-title":"A framework for human corneal endothelial cell culture and preliminary wound model experiments with a new cell tracking approach","volume":"24","author":"Bandeira","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1039\/d4bm00941j","article-title":"Biomaterial-based strategies for primary human corneal endothelial cells for therapeutic applications: From cell expansion to transplantable carrier","volume":"13","author":"Enkhbat","year":"2025","journal-title":"Biomater Sci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241512433","article-title":"Corneal endothelial-like cells derived from induced pluripotent stem cells for cell therapy","volume":"24","author":"Ng","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1056\/NEJmoa1712770","article-title":"Injection of cultured cells with a ROCK inhibitor for bullous keratopathy","volume":"378","author":"Kinoshita","year":"2018","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.5041\/rmmj.10531","article-title":"The role of mesenchymal stem cells for corneal endothelial regeneration: A systematic review","volume":"15","author":"Siska","year":"2024","journal-title":"Rambam Maimonides Med J"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.5500\/wjt.v15.i2.102507","article-title":"Current concepts and recent trends in endothelial keratoplasty","volume":"15","author":"Nishant","year":"2025","journal-title":"World J Transplant"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/ICU.0000000000001050","article-title":"Current state of endothelial cell therapy","volume":"35","author":"Koo","year":"2024","journal-title":"Curr Opin Ophthalmol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2022.109241","article-title":"Corneal endothelial transplantation from bench to bedside: A review of animal models and their translational value for therapeutic development","volume":"224","author":"Chew","year":"2022","journal-title":"Exp Eye Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1097\/ico.0000000000003844","article-title":"Escal\u00f3n: A prospective randomized trial of corneal endothelial cell therapy in subjects with corneal edema","volume":"44","author":"Holland","year":"2025","journal-title":"Cornea"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101847","article-title":"A first-inhuman clinical study of an allogenic iPSC-derived corneal endothelial cell substitute transplantation for bullous keratopathy","volume":"6","author":"Hirayama","year":"2025","journal-title":"Cell Rep Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/6644114","article-title":"New horizons in the treatment of corneal endothelial dysfunction","volume":"2021","author":"Rocha-de-Lossada","year":"2021","journal-title":"J Ophthalmol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/cxo.12060","article-title":"Corneal oedema and its medical treatment","volume":"96","author":"Costagliola","year":"2013","journal-title":"Clin Exp Optom"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1097\/01.ico.0000214224.90743.01","article-title":"Descemet-stripping automated endothelial keratoplasty","volume":"25","author":"Gorovoy","year":"2006","journal-title":"Cornea"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4103\/ijo.IJO_1313_22","article-title":"A review of techniques and outcomes of endothelial keratoplasty in congenital hereditary endothelial dystrophy","volume":"70","author":"Mandal","year":"2022","journal-title":"Indian J Ophthalmol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-018-0492-7","article-title":"Advances in culture, expansion and mechanistic studies of corneal endothelial cells: A systematic review","volume":"26","author":"Chen","year":"2019","journal-title":"J\u00a0BioMed Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2010.194571","article-title":"Enhancement of corneal endothelium wound healing by Rho-associated kinase (ROCK) inhibitor eye drops","volume":"95","author":"Okumura","year":"2011","journal-title":"Br J Ophthalmol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/aos.14722","article-title":"New developments in corneal endothelial cell replacement","volume":"99","author":"Spinozzi","year":"2020","journal-title":"Acta Ophthalmol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2025.05.020","article-title":"Long-term corneal rejuvenation after transplantation of cultured human corneal endothelial cells","volume":"132","author":"Kinoshita","year":"2025","journal-title":"Ophthalmol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2006-0516","article-title":"Differentiation of human embryonic stem cells into corneal epithelial-like cells by in vitro replication of the corneal epithelial stem cell niche","volume":"25","author":"Ahmad","year":"2007","journal-title":"Stem Cells"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26020695","article-title":"Biomedical application of MSCs in corneal regeneration and repair","volume":"26","author":"De Miguel","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2018\/6482095","article-title":"From DMEK to corneal endothelial cell therapy: Technical and biological aspects","volume":"2018","author":"Nuzzi","year":"2018","journal-title":"J Ophthalmol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2008.305","article-title":"Penetrating keratoplasty: Indications, outcomes, and complications","volume":"23","author":"Rahman","year":"2008","journal-title":"Eye Lond"},{"key":"B24","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.nano.2014.12.002","article-title":"Magnetic field-guided cell delivery with nanoparticle-loaded human corneal endothelial cells","volume":"11","author":"Moysidis","year":"2015","journal-title":"Nanomed: NBM"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.18-26001","article-title":"Magnetic human corneal endothelial cell transplant: Delivery, retention, and short-term efficacy","volume":"60","author":"Xia","year":"2019","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1089\/ten.TEC.2018.0077","article-title":"Mini-sheet injection for cultured corneal endothelial transplantation","volume":"24","author":"Jia","year":"2018","journal-title":"Tissue Eng Part C Methods"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/term.2131","article-title":"Translational issues for human corneal endothelial tissue engineering","volume":"11","author":"Soh","year":"2016","journal-title":"J Tissue Eng Regener Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2010.0568","article-title":"A novel gelatin hydrogel carrier sheet for corneal endothelial transplantation","volume":"17","author":"Watanabe","year":"2011","journal-title":"Tissue Eng Part A"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2024.11.021","article-title":"Repair effects of thermosensitive hydrogels combined with iPSC-derived corneal endothelial cells on rabbit corneal endothelial dysfunction","volume":"191","author":"Chi","year":"2025","journal-title":"Acta Biomater"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1177\/2041731421990536","article-title":"Biomaterials for corneal endothelial cell culture and tissue engineering","volume":"12","author":"Parekh","year":"2021","journal-title":"J Tissue Eng"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1097\/ICO.0000000000001765","article-title":"Descemet\u2019s membrane biomimetic microtopography differentiates human mesenchymal stem cells into corneal endothelial-like cells","volume":"38","author":"Gutermuth","year":"2019","journal-title":"Cornea"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/rb\/rbac052","article-title":"Design of functional biomaterials as substrates for corneal endothelium tissue engineering","volume":"9","author":"Bosch","year":"2022","journal-title":"Regener Biomater"},{"key":"B33","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1089\/ten.teb.2020.0319","article-title":"Translational and regulatory challenges of corneal endothelial cell therapy: A global perspective","volume":"28","author":"Ting","year":"2021","journal-title":"Tissue Eng Part B Rev"},{"key":"B34","doi-asserted-by":"publisher","first-page":"100904","DOI":"10.1016\/j.preteyeres.2020.100904","article-title":"Corneal endothelial dysfunction: Evolving understanding and treatment options","volume":"82","author":"Price","year":"2020","journal-title":"Prog Retin Eye Res"},{"key":"B35","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.exer.2016.09.004","article-title":"Biomechanical relationships between the corneal endothelium and Descemet\u2019s membrane","volume":"152","author":"Ali","year":"2016","journal-title":"Exp Eye Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2019.01.040","article-title":"Magnetic targeting of corneal endothelial cells to enhance cell-based therapy","volume":"89","author":"Zhang","year":"2019","journal-title":"Acta Biomater"},{"key":"B37","doi-asserted-by":"publisher","first-page":"18072","DOI":"10.1038\/s41598-022-22522-4","article-title":"Quiescent innate and adaptive immune responses maintain the long-term integrity of corneal endothelium reconstituted through allogeneic cell injection therapy","volume":"12","author":"Toda","year":"2022","journal-title":"Sci Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering12111162","article-title":"Bioengineering strategies for corneal endothelial cell injection therapy: Advances, challenges, and clinical translation","volume":"12","author":"Choi","year":"2025","journal-title":"Bioeng Bsl"},{"key":"B39","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1097\/ICU.0000000000001071","article-title":"Emerging alternatives to keratoplasty for corneal endothelial cell dysfunction","volume":"35","author":"Kaufman","year":"2024","journal-title":"Curr Opin Ophthalmol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1097\/ICO.0000000000002687","article-title":"New therapies for corneal endothelial diseases: 2020 and beyond","volume":"40","author":"Soh","year":"2021","journal-title":"Cornea"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2020.09.002","article-title":"Five-year follow-up of first 11 patients undergoing injection of cultured corneal endothelial cells for corneal endothelial failure","volume":"128","author":"Numa","year":"2020","journal-title":"Am J Ophthalmol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/cells9061428","article-title":"A novel approach of harvesting viable single cells from donor corneal endothelium for cell-injection therapy","volume":"9","author":"Ong","year":"2020","journal-title":"Cells"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-019-0108-y","article-title":"Review: Corneal endothelial cell derivation methods from ES\/iPS cells","volume":"39","author":"Hatou","year":"2019","journal-title":"Inflammation Regener"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2013.0510","article-title":"Isolation and transplantation of corneal endothelial cell-like cells derived from in-vitro-differentiated human embryonic stem cells","volume":"23","author":"Zhang","year":"2014","journal-title":"Stem Cells Dev"}],"container-title":["Frontiers in Ophthalmology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2026.1799892\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T04:48:25Z","timestamp":1778215705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fopht.2026.1799892\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":44,"alternative-id":["10.3389\/fopht.2026.1799892"],"URL":"https:\/\/doi.org\/10.3389\/fopht.2026.1799892","relation":{},"ISSN":["2674-0826"],"issn-type":[{"value":"2674-0826","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]},"article-number":"1799892"}}