{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:15:31Z","timestamp":1791980131672,"version":"4.4.0"},"reference-count":90,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T00:00:00Z","timestamp":1683936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"R01","award":["EY024349"],"award-info":[{"award-number":["EY024349"]}]},{"name":"R01","award":["EY001792"],"award-info":[{"award-number":["EY001792"]}]},{"name":"R01","award":["UH3 EY031809"],"award-info":[{"award-number":["UH3 EY031809"]}]},{"name":"NEI\/NIH","award":["EY024349"],"award-info":[{"award-number":["EY024349"]}]},{"name":"NEI\/NIH","award":["EY001792"],"award-info":[{"award-number":["EY001792"]}]},{"name":"NEI\/NIH","award":["UH3 EY031809"],"award-info":[{"award-number":["UH3 EY031809"]}]},{"name":"UIC Department of Ophthalmology and Physician-Scientist Award","award":["EY024349"],"award-info":[{"award-number":["EY024349"]}]},{"name":"UIC Department of Ophthalmology and Physician-Scientist Award","award":["EY001792"],"award-info":[{"award-number":["EY001792"]}]},{"name":"UIC Department of Ophthalmology and Physician-Scientist Award","award":["UH3 EY031809"],"award-info":[{"award-number":["UH3 EY031809"]}]},{"name":"Research to Prevent Blindness, and Eversight","award":["EY024349"],"award-info":[{"award-number":["EY024349"]}]},{"name":"Research to Prevent Blindness, and Eversight","award":["EY001792"],"award-info":[{"award-number":["EY001792"]}]},{"name":"Research to Prevent Blindness, and Eversight","award":["UH3 EY031809"],"award-info":[{"award-number":["UH3 EY031809"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Mesenchymal stromal\/stem cells (MSCs) and their secreted factors have been shown to have immunomodulatory and regenerative effects. In this study, we investigated human bone-marrow-derived MSC secretome (MSC-S) for the treatment of corneal epithelial wounds. Specifically, we evaluated the role of MSC extracellular vesicles (EV)\/exosomes in mediating the wound-healing effects of the MSC-S. In vitro studies using human corneal epithelial cells showed that MSC-CM increased cell proliferation in HCEC and HCLE cells, while EV-depleted MSC-CM showed lower cell proliferation in both cell lines compared to the MSC-CM group. In vitro and in vivo experiments revealed that 1X MSC-S consistently promoted wound healing more effectively than 0.5X MSC-S, and MSC-CM promoted wound healing in a dose-dependent manner, while exosome deprivation delayed wound healing. We further evaluated the incubation period of MSC-CM on corneal wound healing and showed that MSC-S collected for 72 h is more effective than MSC-S collected for 48 h. Finally, we evaluated the stability of MSC-S under different storage conditions and found that after one cycle of freeze\u2013thawing, MSC-S is stable at 4 \u00b0C for up to 4 weeks. Collectively, we identified the following: (i) MSC-EV\/Exo as the active ingredient in MSC-S that mediates the wound-healing effects in the corneal epithelium, providing a measure to optimize its dosing for a potential clinical product; (ii) Treatment with EV\/Exo-containing MSC-S resulted in an improved corneal barrier and decreased corneal haze\/edema relative to EV\/Exo-depleted MSC-S; (iii) The stability of MSC-CM for up to 4 weeks showed that the regular storage condition did not significantly impact its stability and therapeutic functions.<\/jats:p>","DOI":"10.3390\/pharmaceutics15051486","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T08:28:16Z","timestamp":1684139296000},"page":"1486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Wound-Healing Effects of Mesenchymal Stromal Cell Secretome in the Cornea and the Role of Exosomes"],"prefix":"10.3390","volume":"15","author":[{"given":"Seungwon","family":"An","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khandaker","family":"Anwar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammadjavad","family":"Ashraf","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"},{"name":"Department of Pathology, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyungjo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6551-2475","authenticated-orcid":false,"given":"Raghuram","family":"Koganti","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9275-3813","authenticated-orcid":false,"given":"Mahmood","family":"Ghassemi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali R.","family":"Djalilian","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41536-019-0083-6","article-title":"Mesenchymal stem cell perspective: Cell biology to clinical progress","volume":"4","author":"Pittenger","year":"2019","journal-title":"NPJ Regen. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1478-811X-9-12","article-title":"Different populations and sources of human mesenchymal stem cells (msc): A comparison of adult and neonatal tissue-derived msc","volume":"9","author":"Hass","year":"2011","journal-title":"Cell Commun. Signal"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"An, S., Shen, X., Anwar, K., Ashraf, M., Lee, H., Koganti, R., Ghassemi, M., and Djalilian, A.R. (2022). Therapeutic potential of mesenchymal stem cell-secreted factors on delay in corneal wound healing by nitrogen mustard. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911510"},{"key":"ref_4","first-page":"208","article-title":"Isolation, differentiation, and characterization of mesenchymal stem cells from human bone marrow","volume":"10","author":"Baghaei","year":"2017","journal-title":"Gastroenterol. Hepatol. Bed Bench"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Vasanthan, J., Gurusamy, N., Rajasingh, S., Sigamani, V., Kirankumar, S., Thomas, E.L., and Rajasingh, J. (2020). Role of human mesenchymal stem cells in regenerative therapy. Cells, 10.","DOI":"10.3390\/cells10010054"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Guillamat-Prats, R. (2021). The role of msc in wound healing, scarring and regeneration. Cells, 10.","DOI":"10.3390\/cells10071729"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e2062","DOI":"10.1038\/cddis.2015.327","article-title":"Mesenchymal stem cells and immunomodulation: Current status and future prospects","volume":"7","author":"Gao","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1016\/j.intimp.2010.06.019","article-title":"The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy","volume":"10","author":"Hoogduijn","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nbt.2816","article-title":"Mesenchymal stem cells: Immune evasive, not immune privileged","volume":"32","author":"Ankrum","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1182\/blood-2007-02-069716","article-title":"Immunomodulatory properties of mesenchymal stromal cells","volume":"110","author":"Nauta","year":"2007","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"626755","DOI":"10.3389\/fimmu.2021.626755","article-title":"Mscs and inflammatory cells crosstalk in regenerative medicine: Concerted actions for optimized resolution driven by energy metabolism","volume":"12","author":"Varin","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.2147\/IJN.S355366","article-title":"Targeted therapy for inflammatory diseases with mesenchymal stem cells and their derived exosomes: From basic to clinics","volume":"17","author":"Wang","year":"2022","journal-title":"Int. J. Nanomed."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.2174\/157488810791268564","article-title":"Adipose tissue derived stem cells secretome: Soluble factors and their roles in regenerative medicine","volume":"5","author":"Salgado","year":"2010","journal-title":"Curr. Stem. Cell Res. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/6529","article-title":"Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta","volume":"5","author":"Horwitz","year":"1999","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"132642","DOI":"10.1155\/2013\/132642","article-title":"Bone-marrow-derived mesenchymal stem cells for organ repair","volume":"2013","author":"Li","year":"2013","journal-title":"Stem Cells Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12020-012-9839-0","article-title":"Extracellular vesicles as an emerging mechanism of cell-to-cell communication","volume":"44","author":"Tetta","year":"2013","journal-title":"Endocrine"},{"key":"ref_17","first-page":"1327","article-title":"Micrornas transported by exosomes in body fluids as mediators of intercellular communication in cancer","volume":"7","year":"2014","journal-title":"Onco Targets Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24534","DOI":"10.1074\/jbc.M115.679217","article-title":"Inhibition of oncogenic epidermal growth factor receptor kinase triggers release of exosome-like extracellular vesicles and impacts their phosphoprotein and DNA content","volume":"290","author":"Montermini","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ncb1596","article-title":"Exosome-mediated transfer of mrnas and micrornas is a novel mechanism of genetic exchange between cells","volume":"9","author":"Valadi","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.jmb.2015.09.019","article-title":"Exocarta: A web-based compendium of exosomal cargo","volume":"428","author":"Keerthikumar","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13287-016-0363-7","article-title":"Mechanisms of mesenchymal stem\/stromal cell function","volume":"7","author":"Spees","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1177\/0963689719837897","article-title":"The pros and cons of mesenchymal stem cell-based therapies","volume":"28","author":"Kot","year":"2019","journal-title":"Cell Transpl."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3722","DOI":"10.1182\/blood-2002-07-2104","article-title":"Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific t cells to their cognate peptide","volume":"101","author":"Krampera","year":"2003","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"574","DOI":"10.2174\/156652412800619950","article-title":"Immunosuppressive properties of mesenchymal stem cells: Advances and applications","volume":"12","author":"Pascual","year":"2012","journal-title":"Curr. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1182\/blood-2004-04-1559","article-title":"Human mesenchymal stem cells modulate allogeneic immune cell responses","volume":"105","author":"Aggarwal","year":"2005","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1182\/blood-2005-07-2657","article-title":"Human mesenchymal stem cells modulate b-cell functions","volume":"107","author":"Corcione","year":"2006","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.5966\/sctm.2015-0298","article-title":"Human umbilical cord-derived mesenchymal stromal cells improve left ventricular function, perfusion, and remodeling in a porcine model of chronic myocardial ischemia","volume":"5","author":"Liu","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4197","DOI":"10.1182\/blood-2008-09-176198","article-title":"Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells","volume":"113","author":"Otsu","year":"2009","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.21037\/sci-2022-025","article-title":"Adverse events, side effects and complications in mesenchymal stromal cell-based therapies","volume":"9","author":"Baranovskii","year":"2022","journal-title":"Stem Cell Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"220","DOI":"10.4161\/cam.20875","article-title":"Mesenchymal stem cells in tumor development: Emerging roles and concepts","volume":"6","author":"Cuiffo","year":"2012","journal-title":"Cell Adh. Migr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12448","DOI":"10.1038\/s41598-020-69020-z","article-title":"Topical cell-free conditioned media harvested from adipose tissue-derived stem cells promote recovery from corneal epithelial defects caused by chemical burns","volume":"10","author":"Park","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1002\/sctm.18-0042","article-title":"Anti-inflammatory and anti-fibrotic effects of human amniotic membrane mesenchymal stem cells and their potential in corneal repair","volume":"7","author":"Navas","year":"2018","journal-title":"Stem Cells Transl. Med."},{"key":"ref_33","first-page":"4953","article-title":"Anti-fibrotic effect of adipose-derived mesenchymal stem cell conditioned medium in muscle fibrosis","volume":"25","author":"Oki","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s13287-021-02270-4","article-title":"Adipose-derived mesenchymal stem cells attenuate dialysis-induced peritoneal fibrosis by modulating macrophage polarization via interleukin-6","volume":"12","author":"Yang","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sagaradze, G., Grigorieva, O., Nimiritsky, P., Basalova, N., Kalinina, N., Akopyan, Z., and Efimenko, A. (2019). Conditioned medium fromhuman mesenchymal stromal cells: Towards the clinical translation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071656"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"654210","DOI":"10.3389\/fcell.2021.654210","article-title":"Mesenchymal stromal cell-conditioned medium for skin diseases: A systematic review","volume":"9","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1186\/s13287-019-1491-7","article-title":"The superiority of conditioned medium derived from rapidly expanded mesenchymal stem cells for neural repair","volume":"10","author":"Chen","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4754","DOI":"10.1038\/s41598-022-08398-4","article-title":"Anti-inflammatory effects of mesenchymal stem cell-conditioned media inhibited macrophages activation in vitro","volume":"12","author":"Jin","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5555","DOI":"10.1002\/jcp.29486","article-title":"Mesenchymal stem cell-conditioned media: A novel alternative of stem cell therapy for quality wound healing","volume":"235","author":"Joseph","year":"2020","journal-title":"J. Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/s13287-015-0214-y","article-title":"Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair","volume":"6","author":"Katsuda","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1089\/scd.2012.0395","article-title":"Exosomes derived from humanumbilical cord mesenchymal stem cells alleviate liver fibrosis","volume":"22","author":"Li","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/scrt465","article-title":"Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models","volume":"5","author":"Tan","year":"2014","journal-title":"Stem Cell Res. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e346","DOI":"10.1038\/emm.2017.63","article-title":"Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases","volume":"49","author":"Lou","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.kint.2016.12.023","article-title":"Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation","volume":"92","author":"Eirin","year":"2017","journal-title":"Kidney Int."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bruno, S., Grange, C., Collino, F., Deregibus, M.C., Cantaluppi, V., Biancone, L., Tetta, C., and Camussi, G. (2012). Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033115"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/978-981-10-4397-0_12","article-title":"Therapeutic effects of mesenchymal stem cell-derived exosomes in cardiovascular disease","volume":"998","author":"Suzuki","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"209","DOI":"10.5966\/sctm.2015-0386","article-title":"Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal microRNA-21","volume":"6","author":"Wang","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5736059","DOI":"10.1155\/2016\/5736059","article-title":"Potential therapies by stem cell-derived exosomes in cns diseases: Focusing on the neurogenic niche","volume":"2016","author":"Luarte","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1161\/STROKEAHA.116.015204","article-title":"Microrna cluster mir-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats","volume":"48","author":"Xin","year":"2017","journal-title":"Stroke"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/jps.24251","article-title":"Quantitative analysis of tissue distribution of the b16bl6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice","volume":"104","author":"Morishita","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Aheget, H., Mazini, L., Martin, F., Belqat, B., Marchal, J.A., and Benabdellah, K. (2020). Exosomes: Their role in pathogenesis, diagnosis and treatment of diseases. Cancers, 13.","DOI":"10.3390\/cancers13010084"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Mansoor, H., Ong, H.S., Riau, A.K., Stanzel, T.P., Mehta, J.S., and Yam, G.H. (2019). Current trends and future perspective of mesenchymal stem cells and exosomes in corneal diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20122853"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"684712","DOI":"10.3389\/fphar.2021.684712","article-title":"Mini review: Current trends and understanding of exosome therapeutic potential in corneal diseases","volume":"12","author":"Tiwari","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4323","DOI":"10.1038\/s41598-017-04559-y","article-title":"Effects of mesenchymal stem cell-derived exosomes on experimental autoimmune uveitis","volume":"7","author":"Bai","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/5584_2018_219","article-title":"Therapeutic potential of mesenchymal stem cell-derived exosomes in the treatment of eye diseases","volume":"1089","author":"Harrell","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1167\/iovs.18-25617","article-title":"Exosomes derived from mesenchymal stem cells modulate mir-126 to ameliorate hyperglycemia-induced retinal inflammation via targeting HMGB1","volume":"60","author":"Zhang","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1007\/s00417-018-4097-3","article-title":"Effects of mesenchymal stem cells and their exosomes on the healing of large and refractory macular holes","volume":"256","author":"Zhang","year":"2018","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Hertsenberg, A.J., Shojaati, G., Funderburgh, M.L., Mann, M.M., Du, Y., and Funderburgh, J.L. (2017). Corneal stromal stem cells reduce corneal scarring by mediating neutrophil infiltration after wounding. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171712"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1002\/stem.1481","article-title":"Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis vii mice","volume":"31","author":"Caterson","year":"2013","journal-title":"Stem Cells"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1167\/tvst.10.10.3","article-title":"Preclinical evaluation of the safety and efficacy of cryopreserved bone marrow mesenchymal stromal cells for corneal repair","volume":"10","author":"Putra","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1007\/s11095-010-0073-2","article-title":"Critical evaluation of nanoparticle tracking analysis (nta) by nanosight for the measurement of nanoparticles and protein aggregates","volume":"27","author":"Filipe","year":"2010","journal-title":"Pharm. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1080\/02713683.2020.1762227","article-title":"Therapeutic effects of lyophilized conditioned-medium derived from corneal mesenchymal stromal cells on corneal epithelial wound healing","volume":"45","author":"Jabbehdari","year":"2020","journal-title":"Curr. Eye Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/sctm.18-0178","article-title":"Corneal wound healing effects of mesenchymal stem cell secretome delivered within a viscoelastic gel carrier","volume":"8","author":"Na","year":"2019","journal-title":"Stem Cells Transl. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.5966\/sctm.2015-0285","article-title":"Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model","volume":"5","author":"Furuta","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.14202\/vetworld.2021.2109-2117","article-title":"Wound healing potential of human umbilical cord mesenchymal stem cell conditioned medium: An in vitro and in vivo study in diabetes-induced rats","volume":"14","author":"Hendrawan","year":"2021","journal-title":"Vet. World"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/978-981-33-6064-8_18","article-title":"Mesenchymal stem cell-derived extracellular vesicles for skin wound healing","volume":"1310","author":"Kim","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5194","DOI":"10.1167\/iovs.18-24803","article-title":"Effect of human corneal mesenchymal stromal cell-derived exosomes on corneal epithelial wound healing","volume":"59","author":"Samaeekia","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jtos.2021.04.004","article-title":"In-situ porcine corneal matrix hydrogel as ocular surface bandage","volume":"21","author":"Yazdanpanah","year":"2021","journal-title":"Ocul. Surf."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1186\/s12967-020-02622-3","article-title":"Mesenchymal stem cell derived-exosomes: A modern approach in translational medicine","volume":"18","author":"Nikfarjam","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/S0140-6736(96)11188-0","article-title":"Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium","volume":"349","author":"Pellegrini","year":"1997","journal-title":"Lancet"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/ICO.0000000000001820","article-title":"Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency","volume":"38","author":"Deng","year":"2019","journal-title":"Cornea"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/stcltm\/szab028","article-title":"Current and emerging therapies for limbal stem cell deficiency","volume":"11","author":"Elhusseiny","year":"2022","journal-title":"Stem Cells Transl. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1056\/NEJMoa0905955","article-title":"Limbal stem-cell therapy and long-term corneal regeneration","volume":"363","author":"Rama","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/2229-3485.83228","article-title":"Regulations and guidelines governing stem cell based products: Clinical considerations","volume":"2","author":"George","year":"2011","journal-title":"Perspect. Clin. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13045-021-01037-x","article-title":"Challenges and advances in clinical applications of mesenchymal stromal cells","volume":"14","author":"Zhou","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/mt.2015.44","article-title":"Mesenchymal stem cell-derived extracellular vesicles: Toward cell-free therapeutic applications","volume":"23","author":"Rani","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.stem.2014.01.013","article-title":"Msc-based product characterization for clinical trials: An fda perspective","volume":"14","author":"Mendicino","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"632717","DOI":"10.3389\/fcell.2021.632717","article-title":"Therapeutic use of mesenchymal stromal cells: The need for inclusive characterization guidelines to accommodate all tissue sources and species","volume":"9","author":"Wright","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1080\/14653240500319234","article-title":"Clarification of the nomenclature for msc: The international society for cellular therapy position statement","volume":"7","author":"Horwitz","year":"2005","journal-title":"Cytotherapy"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1002\/sctm.19-0044","article-title":"Challenges in clinical development of mesenchymal stromal\/stem cells: Concise review","volume":"8","author":"Mastrolia","year":"2019","journal-title":"Stem Cells Transl. Med."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Guadix, J.A., Lopez-Beas, J., Clares, B., Soriano-Ruiz, J.L., Zugaza, J.L., and Galvez-Martin, P. (2019). Principal criteria for evaluating the quality, safety and efficacy of hmsc-based products in clinical practice: Current approaches and challenges. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11110552"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.isci.2019.05.029","article-title":"Serum deprivation of mesenchymal stem cells improves exosome activity and alters lipid and protein composition","volume":"16","author":"Haraszti","year":"2019","journal-title":"iScience"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7","DOI":"10.21037\/sci-2020-037","article-title":"Exosomal therapy-a new frontier in regenerative medicine","volume":"8","author":"Muthu","year":"2021","journal-title":"Stem Cell Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s12964-022-00959-4","article-title":"A review on exosomes application in clinical trials: Perspective, questions, and challenges","volume":"20","author":"Rezaie","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"36162","DOI":"10.1038\/srep36162","article-title":"Trehalose prevents aggregation of exosomes and cryodamage","volume":"6","author":"Bosch","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2018.10.032","article-title":"Preservation of exosomes at room temperature using lyophilization","volume":"553","author":"Charoenviriyakul","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_87","first-page":"843","article-title":"Significance of hormones in reproduction","volume":"29","author":"Sugawa","year":"1971","journal-title":"Nihon Rinsho. Jpn. J. Clin. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s13238-018-0529-4","article-title":"Effect of ph, temperature and freezing-thawing on quantity changes and cellular uptake of exosomes","volume":"10","author":"Cheng","year":"2019","journal-title":"Protein Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s11626-018-0261-7","article-title":"The effect of storage temperature on the biological activity of extracellular vesicles for the complement system","volume":"54","author":"Park","year":"2018","journal-title":"Vitr. Cell Dev. Biol. Anim."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e2100538","DOI":"10.1002\/adhm.202100538","article-title":"Enhancing the stabilization potential of lyophilization for extracellular vesicles","volume":"11","author":"Trenkenschuh","year":"2022","journal-title":"Adv. Healthc Mater."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1486\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:34:18Z","timestamp":1760124858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,13]]},"references-count":90,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["pharmaceutics15051486"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15051486","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,13]]}}}