{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T22:09:04Z","timestamp":1767650944744,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The success rate of grafting using acellular dermal matrix (ADM) for chronic tympanic membrane was reported in previous studies to be lower than fascia or perichondrium. Combining mesenchymal stem cells (MSCs) and growth factor-loaded ADM for the regeneration of chronic TMP has not been reported so far. In this study, we hypothesized that combining growth factor-loaded ADM\/MSCs could promote the recruitment of MSCs and assist in TMP regeneration. We evaluated the regeneration and compared the performance of four scaffolds in both in vitro and in vivo studies. MTT, qPCR, and immunoblotting were performed with MSCs. In vivo study was conducted in 4 groups (control; ADM only, ADM\/MSC, ADM\/MSC\/bFGF, ADM\/MSC\/EGF) of rats and inferences were made by otoendoscopy and histological changes. Attachment of MSCs on ADM was observed by confocal microscopy. Proliferation rate increased with time in all treated cells. Regeneration-related gene expression in the treated groups was higher. Also, graft success rate was significantly higher in ADM\/MSC\/EGF group than other groups. Significant relationships were disclosed in neodrum thickness between each group. The results suggest, in future, combining EGF with ADM\/MSCs could possibly be used as an outpatient treatment, without the need for surgery for eardrum regeneration.<\/jats:p>","DOI":"10.3390\/jcm10071541","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T10:34:12Z","timestamp":1617705252000},"page":"1541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effect of Growth Factor-Loaded Acellular Dermal Matrix\/MSCs on Regeneration of Chronic Tympanic Membrane Perforations in Rats"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2149-5095","authenticated-orcid":false,"given":"Gwang-Won","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Biology, College of Natural Science, Chosun University, Gwangju 61452, Korea"},{"name":"BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju 61452, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2451-0374","authenticated-orcid":false,"given":"Changjong","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anji","family":"Song","sequence":"additional","affiliation":[{"name":"BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju 61452, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-8549","authenticated-orcid":false,"given":"Karthikeyan A.","family":"Vijayakumar","sequence":"additional","affiliation":[{"name":"BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju 61452, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0998-3069","authenticated-orcid":false,"given":"Mary Jasmin","family":"Ang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4084-2301","authenticated-orcid":false,"given":"Chul Ho","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Medical School, Chonnam National University, Hakdong 8, Dongku, Gwangju 61452, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.anl.2019.06.005","article-title":"Surgical outcomes of myringoplasty using platelet-rich plasma and evaluation of the outcome-associated factors","volume":"47","author":"Shiomi","year":"2020","journal-title":"Auris Nasus Larynx"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1080\/00016489.2020.1731595","article-title":"Comparison of bilateral same-day and sequential endoscopic cartilage myringoplasty for bilateral chronic tympanic membrane perforation","volume":"140","author":"Lou","year":"2020","journal-title":"Acta Oto Laryngol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"405","DOI":"10.5152\/iao.2019.6978","article-title":"Prevention of Craniofacial Pain Secondary to Harvesting of Temporalis Fascia\u2014A Novel Technique","volume":"15","author":"Bhat","year":"2019","journal-title":"J. Int. Adv. Otol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Aleemardani, M., Bagher, Z., Farhadi, M., Chahsetareh, H., Najafi, R., Eftekhari, B., and Seifalian, A.M. (2020). Can tissue engineering bring hope in the development of human tympanic membrane?. Tissue Eng.","DOI":"10.1089\/ten.teb.2020.0176"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1177\/0194599820938345","article-title":"Acellular Collagen Scaffold With Basic Fibroblast Growth Factor for Repair of Traumatic Tympanic Membrane Perforation in a Rat Model","volume":"164","author":"Yao","year":"2020","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1097\/MOO.0000000000000650","article-title":"A design-thinking approach to therapeutic translation: Tympanic regeneration","volume":"28","year":"2020","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"104219","DOI":"10.1016\/j.jmbbm.2020.104219","article-title":"Fabrication of tissue-engineered tympanic membrane patches using 3D-Printing technology","volume":"114","author":"Ilhan","year":"2021","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"50132","DOI":"10.1002\/app.50132","article-title":"3D printing-assisted combinatorial approach for designing mechanically-tunable and vascular supportive nanofibrous membranes to repair perforated eardrum","volume":"138","author":"Liu","year":"2021","journal-title":"J. Appl. Polym. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"032004","DOI":"10.1088\/1748-605X\/abcf5d","article-title":"Necessities, opportunities, and challenges for tympanic membrane perforation scaffolding-based bioengineering","volume":"16","author":"Hussain","year":"2021","journal-title":"Biomed. Mater."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.amjoto.2018.12.008","article-title":"Bacterial cellulose graft versus fat graft in closure of tympanic membrane perforation","volume":"40","author":"Mandour","year":"2019","journal-title":"Am. J. Otolaryngol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1177\/0145561319900388","article-title":"A comparison of the autologous platelet-rich plasma gel fat graft myringoplasty and the fat graft myringoplasty for the closure of different sizes of tympanic membrane perforations","volume":"99","author":"Gultekin","year":"2020","journal-title":"Ear Nose Throat J."},{"key":"ref_12","first-page":"554","article-title":"Surgical outcomes of tympanoplasty using a sterile acellular dermal allograft: A prospective randomised controlled study","volume":"38","author":"Lee","year":"2018","journal-title":"Acta Otorhinolaryngol. Ital. Organo Uff. Della Soc. Ital. Di Otorinolaringol. E Chir. Cervico Facciale"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1177\/000313481908500953","article-title":"Human Acellular Dermal Matrix Is a Viable Alternative to Autologous Skin Graft in Patients with Cutaneous Malignancy","volume":"85","author":"Lewis","year":"2019","journal-title":"Am. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1097\/00005537-200104000-00025","article-title":"Tympanic membrane repair with a dermal allograft","volume":"111","author":"Laidlaw","year":"2001","journal-title":"Laryngoscope"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1067\/mhn.2000.105920","article-title":"Tympanic membrane perforation repair using AlloDerm","volume":"123","author":"Bojrab","year":"2000","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1001\/jamaoto.2016.0580","article-title":"Effect of Basic Fibroblast Growth Factor in Tympanic Membrane Perforation","volume":"142","author":"Lou","year":"2016","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1097\/MAO.0b013e31822e96bc","article-title":"The impact of platelet-derived growth factor on closure of chronic tympanic membrane perforations: A randomized, double-blind, placebo-controlled study","volume":"32","author":"Gassmann","year":"2011","journal-title":"Otol. Neurotol. Off. Publ. Am. Otol. Soc. Am. Neurotol. Soc. Eur. Acad. Otol. Neurotol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1017\/S002221511800083X","article-title":"Regeneration of the tympanic membrane using fibroblast growth factor-2","volume":"132","author":"Lou","year":"2018","journal-title":"J. Laryngol. Otol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1089\/ten.tea.2016.0395","article-title":"Functional Outcomes of Heparin-Binding Epidermal Growth Factor-Like Growth Factor for Regeneration of Chronic Tympanic Membrane Perforations in Mice","volume":"23","author":"Gottlieb","year":"2017","journal-title":"Tissue Eng. Part A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1097\/MAO.0000000000000795","article-title":"Heparin Binding Epidermal Growth Factor-Like Growth Factor Heals Chronic Tympanic Membrane Perforations With Advantage Over Fibroblast Growth Factor 2 and Epidermal Growth Factor in an Animal Model","volume":"36","author":"Weierich","year":"2015","journal-title":"Otol. Neurotol. Off. Publ. Am. Otol. Soc. Am. Neurotol. Soc. Eur. Acad. Otol. Neurotol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1177\/019459989210700509","article-title":"Repair of chronic tympanic membrane perforations using epidermal growth factor","volume":"107","author":"Amoils","year":"1992","journal-title":"Otolaryngol. Head Neck Surg. Off. J. Am. Acad. Otolaryngol. Head Neck Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1097\/MAO.0000000000002628","article-title":"The effectiveness of bFGF in the treatment of tympanic membrane perforations: A systematic review and meta-analysis","volume":"41","author":"Huang","year":"2020","journal-title":"Otol. Neurotol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1801160","DOI":"10.1002\/adhm.201801160","article-title":"Epidermal growth factor\u2013releasing radially aligned electrospun nanofibrous patches for the regeneration of chronic tympanic membrane perforations","volume":"8","author":"Seonwoo","year":"2019","journal-title":"Adv. Healthc. Mater."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1080\/00016489.2016.1261411","article-title":"Histologic changes of mesenchymal stem cell repair of tympanic membrane perforation","volume":"137","author":"Goncalves","year":"2017","journal-title":"Acta Oto Laryngol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1002\/jcp.26048","article-title":"A perspective on stem cell therapy for ear disorders","volume":"233","author":"Mittal","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1080\/00016480701762508","article-title":"Stem cells and enhanced healing of chronic tympanic membrane perforation","volume":"128","author":"Rahman","year":"2008","journal-title":"Acta Oto Laryngol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1089\/scd.2016.0204","article-title":"Paracrine activity from adipose-derived stem cells on in vitro wound healing in human tympanic membrane keratinocytes","volume":"26","author":"Ong","year":"2017","journal-title":"Stem Cells Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1016\/j.biomaterials.2010.12.032","article-title":"Homing of endogenous stem\/progenitor cells for in situ tissue regeneration: Promises, strategies, and translational perspectives","volume":"32","author":"Chen","year":"2011","journal-title":"Biomaterials"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1001\/jamaoto.2014.2613","article-title":"Preoperative factors affecting tympanic membrane regeneration therapy using an atelocollagen and basic fibroblast growth factor","volume":"141","author":"Hakuba","year":"2015","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1097\/MAO.0b013e3181c34f01","article-title":"Basic fibroblast growth factor combined with atelocollagen for closing chronic tympanic membrane perforations in 87 patients","volume":"31","author":"Hakuba","year":"2010","journal-title":"Otol. Neurotol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ijporl.2016.12.028","article-title":"Rat model of chronic tympanic membrane perforation: A longitudinal histological evaluation of underlying mechanisms","volume":"93","author":"Wang","year":"2017","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.ijporl.2015.05.020","article-title":"Searching for a rat model of chronic tympanic membrane perforation: Healing delayed by mitomycin C\/dexamethasone but not paper implantation or iterative myringotomy","volume":"79","author":"Wang","year":"2015","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1288\/00005537-199308000-00007","article-title":"Localization of glucocorticoid receptors and glucocorticoid receptor mRNAs in the rat cochlea","volume":"103","author":"Curtis","year":"1993","journal-title":"Laryngoscope"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1098\/rsif.2006.0179","article-title":"Tissue engineering of replacement skin: The crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration","volume":"4","author":"Metcalfe","year":"2007","journal-title":"J. R. Soc. Interface"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1177\/014556130708611s11","article-title":"Wound healing in spontaneous perforation or myringotomy and middle ear reconstruction","volume":"86","author":"Giles","year":"2007","journal-title":"Ear Nose Throat J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3109\/00016489109134988","article-title":"Microvasculature of the tympanic membrane","volume":"111","author":"Masutani","year":"1991","journal-title":"Acta Oto Laryngol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chen, L., Tredget, E.E., Wu, P.Y., and Wu, Y. (2008). Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001886"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1177\/0194599816636845","article-title":"Effects of cell-based therapy for treating tympanic membrane perforations in mice","volume":"154","author":"Goncalves","year":"2016","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1159\/000381877","article-title":"Stem cells in wound healing: The future of regenerative medicine? A mini-review","volume":"62","author":"Duscher","year":"2016","journal-title":"Gerontology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0194-59989570071-4","article-title":"Effect of epidermal growth factor on tympanic membranes with chronic perforations: A clinical trial","volume":"113","author":"Ramsay","year":"1995","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1111\/coa.12627","article-title":"Topical application of epidermal growth factor with no scaffold material on the healing of human traumatic tympanic membrane perforations","volume":"41","author":"Lou","year":"2016","journal-title":"Clin. Otolaryngol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.amjoto.2018.11.011","article-title":"Comparative study of epidermal growth factor and observation only on human subacute tympanic membrane perforation","volume":"40","author":"Lou","year":"2019","journal-title":"Am. J. Otolaryngol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1097\/MAO.0b013e31822e0e53","article-title":"Regenerative treatment for tympanic membrane perforation","volume":"32","author":"Kanemaru","year":"2011","journal-title":"Otol. Neurotol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10735-010-9287-1","article-title":"The role of epidermal growth factor in the healing tympanic membrane following perforation in rats","volume":"41","author":"Redmond","year":"2010","journal-title":"J. Mol. Histol."},{"key":"ref_45","unstructured":"Dolhi, N., and Weimer, A.D. (2020, May 06). Tympanic Membrane Perforations, Statpearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK557887\/."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110196","DOI":"10.1016\/j.ijporl.2020.110196","article-title":"Expression of collagen type III in healing tympanic membrane","volume":"136","author":"Makuszewska","year":"2020","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e23348","DOI":"10.1002\/dvg.23348","article-title":"Developmental aspects of the tympanic membrane: Shedding light on function and disease","volume":"58","author":"Mozaffari","year":"2020","journal-title":"Genesis"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.msec.2016.11.094","article-title":"Mesenchymal stem cell-laden hybrid scaffold for regenerating subacute tympanic membrane perforation","volume":"72","author":"Jang","year":"2017","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ijbiomac.2013.08.049","article-title":"Regeneration of chronic tympanic membrane perforation using 3D collagen with topical umbilical cord serum","volume":"62","author":"Jang","year":"2013","journal-title":"Int. J. Biol. Macromol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/7\/1541\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:11:26Z","timestamp":1760364686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/7\/1541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,6]]},"references-count":49,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["jcm10071541"],"URL":"https:\/\/doi.org\/10.3390\/jcm10071541","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2021,4,6]]}}}