{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:10:53Z","timestamp":1789683053347,"version":"4.0.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"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. Physiol."],"abstract":"<jats:p><jats:bold>Methods:<\/jats:bold> Herein, we obtained and characterized deltaN p63- and adenosine triphosphate-binding cassette subfamily G member 2-expressing limbal stem cells (LSCs). Chitosan and carboxymethyl chitosan (CTH) were cross-linked to be an in situ thermosensitive hydrogel (ACH), which was printed through four-dimensional (4D) printing to obtain a porous carrier with uniform pore diameter (4D-CTH). Rabbits were injected with alloxan to induce diabetes mellitus (DM). Following this, the LSC-carrying hydrogel was spread on the surface of the cornea of the diabetic rabbits to cure corneal epithelium injury.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Compared with the control group (LSCs only), rapid wound healing was observed in rabbits treated with LSC-carrying 4D-CTH. Furthermore, the test group also showed better corneal nerve repair ability. The results indicated the potential of LSC-carrying 4D-CTH in curing corneal epithelium injury.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> 4D-CTH holds potential as a useful tool for studying regenerative processes occurring during the treatment of various diabetic corneal epithelium pathologies with the use of stem cell-based technologies.<\/jats:p>","DOI":"10.3389\/fphys.2024.1285850","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T04:37:56Z","timestamp":1717389476000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Limbal stem cells carried by a four-dimensional -printed chitosan-based scaffold for corneal epithelium injury in diabetic rabbits"],"prefix":"10.3389","volume":"15","author":[{"given":"Mengyuan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaibin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nailong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqing","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"108437","DOI":"10.1016\/j.exer.2021.108437","article-title":"Limbal stem cell diseases","volume":"205","author":"Bonnet","year":"2021","journal-title":"Exp. Eye Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e10328","DOI":"10.1002\/btm2.10328","article-title":"An injectable gelatin\/sericin hydrogel loaded with human umbilical cord mesenchymal stem cells for the treatment of uterine injury","volume":"8","author":"Chen","year":"2023","journal-title":"Bioeng. Transl. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.diabres.2018.02.023","article-title":"IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045","volume":"138","author":"Cho","year":"2018","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B4","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1038\/s41598-020-80133-3","article-title":"Chitosan hydrogel\/silk fibroin\/Mg(OH)(2) nanobiocomposite as a novel scaffold with antimicrobial activity and improved mechanical properties","volume":"11","author":"Eivazzadeh-Keihan","year":"2021","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"8778","DOI":"10.3390\/ijms23158778","article-title":"Borrowing the features of biopolymers for emerging wound healing dressings: a review","volume":"23","author":"Gardikiotis","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.urology.2018.01.002","article-title":"Stem cells for urinary incontinence: functional differentiation or cytokine effects?","volume":"117","author":"Gill","year":"2018","journal-title":"Urology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/j.apsb.2012.07.004","article-title":"Modified chitosan hydrogels as drug delivery and tissue engineering systems: present status and applications","volume":"2","author":"Giri","year":"2012","journal-title":"Acta Pharm. Sin. B"},{"key":"B8","doi-asserted-by":"publisher","first-page":"68","DOI":"10.3390\/gels9010068","article-title":"Binary hydrogels: induction methods and recent application progress as food matrices for bioactive compounds delivery-A bibliometric review","volume":"9","author":"Hilal","year":"2023","journal-title":"Gels"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e1800412","DOI":"10.1002\/adhm.201800412","article-title":"4D biofabrication: materials, methods, and applications","volume":"7","author":"Ionov","year":"2018","journal-title":"Adv. Healthc. Mater."},{"key":"B10","doi-asserted-by":"publisher","first-page":"119453","DOI":"10.1016\/j.lfs.2021.119453","article-title":"Timolol induces necroptosis, apoptosis and senescence concentration-dependently in rabbit Limbal stem cells in vitro","volume":"277","author":"Jiang","year":"2021","journal-title":"Life Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"100522","DOI":"10.1016\/j.mtbio.2022.100522","article-title":"Extracellular vesicle-loaded hydrogels for tissue repair and regeneration","volume":"18","author":"Ju","year":"2023","journal-title":"Bio"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.3390\/biomedicines9091134","article-title":"Derivation and characterization of EGFP-labeled rabbit limbal mesenchymal stem cells and their potential for research in regenerative ophthalmology","volume":"9","author":"Khorolskaya","year":"2021","journal-title":"Biomedicines"},{"key":"B13","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.jtos.2017.11.002","article-title":"The diagnosis of limbal stem cell deficiency","volume":"16","author":"Le","year":"2018","journal-title":"ocular Surf."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1038839","DOI":"10.3389\/fchem.2022.1038839","article-title":"Advances of hydrogel combined with stem cells in promoting chronic wound healing","volume":"10","author":"Li","year":"2022","journal-title":"Front. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"154402","DOI":"10.1016\/j.metabol.2020.154402","article-title":"Hyperglycemia-reduced NAD+ biosynthesis impairs corneal epithelial wound healing in diabetic mice","volume":"114","author":"Li","year":"2021","journal-title":"Metabolism Clin. Exp."},{"key":"B16","doi-asserted-by":"publisher","first-page":"5536","DOI":"10.1002\/anie.202012618","article-title":"4D-Printing of photoswitchable actuators","volume":"60","author":"Lu","year":"2021","journal-title":"Angewandte Chemie Int. ed. Engl."},{"key":"B17","doi-asserted-by":"publisher","first-page":"606","DOI":"10.3390\/gels8100606","article-title":"Recent advances in macroporous hydrogels for cell behavior and tissue engineering","volume":"8","author":"Ma","year":"2022","journal-title":"Gels"},{"key":"B18","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.addma.2018.10.038","article-title":"Additive manufacturing \u2014 a review of 4D printing and future applications","volume":"24","author":"Mitchell","year":"2018","journal-title":"Addit. Manuf."},{"key":"B19","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1083\/jcb.145.4.769","article-title":"Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface","volume":"145","author":"Pellegrini","year":"1999","journal-title":"J. Cell. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e1901255","DOI":"10.1002\/adhm.201901255","article-title":"Biofabrication strategies and engineered in vitro systems for vascular mechanobiology","volume":"9","author":"Pradhan","year":"2020","journal-title":"Adv. Healthc. Mater."},{"key":"B21","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/j.survophthal.2020.02.005","article-title":"Diabetic keratopathy: insights and challenges","volume":"65","author":"Priyadarsini","year":"2020","journal-title":"Surv. Ophthalmol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s13036-022-00309-5","article-title":"Nucleic acid direct delivery to fibroblasts: a review of nucleofection and applications","volume":"16","author":"Ren","year":"2022","journal-title":"J. Biol. Eng."},{"key":"B23","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.progpolymsci.2006.06.001","article-title":"Chitin and chitosan: properties and applications","volume":"31","author":"Rinaudo","year":"2006","journal-title":"Prog. Polym. Sci."},{"key":"B24","first-page":"180","article-title":"Diabetic keratopathy","volume":"79","author":"Schultz","year":"1981","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"B25","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1097\/ICL.0000000000000700","article-title":"Tear levels of IGFBP-3: a potential biomarker for diabetic nerve changes in the cornea","volume":"46","author":"Stuard","year":"2020","journal-title":"Eye contact lens"},{"key":"B26","doi-asserted-by":"publisher","first-page":"6852661","DOI":"10.1155\/2022\/6852661","article-title":"MSC-derived extracellular vesicles activate mitophagy to alleviate renal ischemia\/reperfusion injury via the miR-223-3p\/NLRP3 Axis","volume":"2022","author":"Sun","year":"2022","journal-title":"Stem cells Int."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2058","DOI":"10.1016\/j.ajpath.2012.08.029","article-title":"Reduced innervation and delayed re-innervation after epithelial wounding in type 2 diabetic Goto-Kakizaki rats","volume":"181","author":"Wang","year":"2012","journal-title":"Am. J. pathology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"115206","DOI":"10.1016\/j.biopha.2023.115206","article-title":"Corneal regeneration strategies: from stem cell therapy to tissue engineered stem cell scaffolds","volume":"165","author":"Wang","year":"","journal-title":"Biomed. Pharmacother."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1126787","DOI":"10.3389\/fendo.2023.1126787","article-title":"Epigenetic control of mesenchymal stem cells orchestrates bone regeneration","volume":"14","author":"Wang","year":"","journal-title":"Front. Endocrinol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.3390\/polym12102204","article-title":"Stereocomplexation of poly(lactic acid) and chemical crosslinking of ethylene glycol dimethacrylate (EGDMA) double-crosslinked temperature\/pH dual responsive hydrogels","volume":"12","author":"Wang","year":"2020","journal-title":"Polym. (Basel)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"204173142110285","DOI":"10.1177\/20417314211028574","article-title":"3D bioprinting for skin tissue engineering: current status and perspectives","volume":"12","author":"Weng","year":"2021","journal-title":"J. Tissue Eng."},{"key":"B32","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.diabres.2011.10.029","article-title":"IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030","volume":"94","author":"Whiting","year":"2011","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B33","doi-asserted-by":"publisher","first-page":"108002","DOI":"10.1016\/j.exer.2020.108002","article-title":"Corneal epithelial basement membrane: structure, function and regeneration","volume":"194","author":"Wilson","year":"2020","journal-title":"Exp. eye Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1002\/jbm.a.36589","article-title":"An in situ hydrogel based on carboxymethyl chitosan and sodium alginate dialdehyde for corneal wound healing after alkali burn","volume":"107","author":"Xu","year":"2019","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"B35","volume-title":"Preparation method of 4D chitosan-based thermosensitive hydrogel","author":"Xu","year":"2021"},{"key":"B36","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.stem.2020.09.014","article-title":"Pluripotent stem cell-based cell therapy-promise and challenges","volume":"27","author":"Yamanaka","year":"2020","journal-title":"Cell. stem Cell."},{"key":"B37","doi-asserted-by":"publisher","first-page":"101039","DOI":"10.1016\/j.preteyeres.2021.101039","article-title":"The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas","volume":"89","author":"Yu","year":"2022","journal-title":"Prog. Retin. eye Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.2337\/diabetes.55.04.06.db05-1581","article-title":"Insulin treatment ameliorates impaired corneal reepithelialization in diabetic rats","volume":"55","author":"Zagon","year":"2006","journal-title":"Diabetes"},{"key":"B39","doi-asserted-by":"publisher","first-page":"rbad039","DOI":"10.1093\/rb\/rbad039","article-title":"Thermo-induced physically crosslinked polypeptide-based block copolymer hydrogels for biomedical applications","volume":"10","author":"Zhao","year":"2023","journal-title":"Regen. Biomater."},{"key":"B40","doi-asserted-by":"publisher","first-page":"044101","DOI":"10.1088\/1758-5090\/ac1992","article-title":"Bioprinting of dual ECM scaffolds encapsulating limbal stem\/progenitor cells in active and quiescent statuses","volume":"13","author":"Zhong","year":"2021","journal-title":"Biofabrication"}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1285850\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T10:16:52Z","timestamp":1721384212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1285850\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,3]]},"references-count":40,"alternative-id":["10.3389\/fphys.2024.1285850"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2024.1285850","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,3]]},"article-number":"1285850"}}