{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:47:51Z","timestamp":1790747271011,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T00:00:00Z","timestamp":1631404800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of this study was to generate novel models of bioartificial human oral mucosa with increased vascularization potential for future use as an advanced therapies medicinal product, by using different vascular and mesenchymal stem cell sources.<\/jats:p><\/jats:sec><jats:sec><jats:title>Background<\/jats:title><jats:p>Oral mucosa substitutes could contribute to the clinical treatment of complex diseases affecting the oral cavity. Although several models of artificial oral mucosa have been described, biointegration is a major issue that could be favored by the generation of novel substitutes with increased vascularization potential once grafted <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three types of mesenchymal stem cells (MSCs) were obtained from adipose tissue, bone marrow, and dental pulp, and their <jats:italic>in vitro<\/jats:italic> potential was evaluated by inducing differentiation to the endothelial lineage using conditioning media. Then, 3D models of human artificial oral mucosa were generated using biocompatible fibrin\u2010agarose biomaterials combined with human oral mucosa fibroblasts and each type of MSC before and after induction to the endothelial lineage, using human umbilical vein endothelial cells (HUVEC) as controls. The vascularization potential of each oral mucosa substitute was assessed <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> in nude mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic> induction of MSCs kept in culture was able to increase the expression of VEGF, CD31, and vWF endothelial markers, especially in bone marrow and dental pulp\u2010MSCs, and numerous proteins with a role in vasculogenesis become overexpressed. Then, <jats:italic>in vivo<\/jats:italic> grafting resulted in a significant increase in blood vessels formation at the interface area between the graft and the host tissues, with significantly positive expression of VEGF, CD31, vWF, and CD34 as compared to negative controls, especially when pre\u2010differentiated MSCs derived from bone marrow and dental pulp were used. In addition, a significantly higher number of cells committed to the endothelial lineage expressing the same endothelial markers were found within the bioartificial tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results suggest that the use of pre\u2010differentiated MSCs could contribute to a rapid generation of a vascular network that may favor <jats:italic>in vivo<\/jats:italic> biointegration of bioengineered human oral mucosa substitutes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.12927","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T17:23:14Z","timestamp":1631467394000},"page":"1116-1131","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Generation of a novel model of bioengineered human oral mucosa with increased vascularization potential"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0992-0113","authenticated-orcid":false,"given":"Cristina","family":"Blanco\u2010Elices","sequence":"first","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"},{"name":"Doctoral Programme in Biomedicine University of Granada Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Chato\u2010Astrain","sequence":"additional","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Oyonarte","sequence":"additional","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"},{"name":"Andalusian Network for Transfusional Medicine, Cells and Tissues and Blood and Tissue Bank of Granada Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Bermejo\u2010Casares","sequence":"additional","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Espa\u00f1a\u2010L\u00f3pez","sequence":"additional","affiliation":[{"name":"Craniofacial Malformations and Cleft Lip and Palate Management Unit, University Hospital Virgen de las Nieves Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Fern\u00e1ndez\u2010Valad\u00e9s","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"},{"name":"Division of Pediatric Surgery University Hospital Virgen de las Nieves Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria del Carmen","family":"S\u00e1nchez\u2010Quevedo","sequence":"additional","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Alaminos","sequence":"additional","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel Angel","family":"Mart\u00edn\u2010Piedra","sequence":"additional","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Garz\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Histology (Tissue Engineering Group) University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32279-7"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1088\/1748-6041\/11\/1\/015015"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.10.073"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13770-017-0108-4"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/polym12030538"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20180155"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/07388551.2016.1209157"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0BM01379J"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2008.0097"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9214831"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29111"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2005.03.016"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-019-0169-3"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-019-03161-0"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma13071692"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v037a14"},{"issue":"9","key":"e_1_2_7_18_1","first-page":"969","article-title":"Transfer of mesenchymal stem cells and cyclosporine a on alkali\u2010injured rabbit cornea using nanofiber scaffolds strongly reduces corneal neovascularization and scar formation","volume":"31","author":"Cejka C","year":"2016","journal-title":"Histol Histopathol"},{"issue":"10","key":"e_1_2_7_19_1","first-page":"1041","article-title":"Seven days post\u2010injury fate and effects of genetically labelled adipose\u2010derived mesenchymal cells on a rat traumatic brain injury experimental model","volume":"32","author":"Dori I","year":"2017","journal-title":"Histol Histopathol"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/term.2397"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tec.2011.0508"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22062"},{"issue":"11","key":"e_1_2_7_23_1","first-page":"1321","article-title":"Ex vivo and in vivo modulatory effects of umbilical cord Wharton\u2019s jelly stem cells on human oral mucosa stroma substitutes","volume":"30","author":"Alfonso\u2010Rodr\u00edguez CA","year":"2015","journal-title":"Histol Histopathol"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(02)03301-0"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2017.02.005"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tec.2018.0337"},{"key":"e_1_2_7_27_1","volume-title":"Translational Research in Coronary Artery Disease: Pathophysiology to Treatment Current Approaches to Treatment of Ventricular Arrhythmias in Patients with Coronary Artery Disease","author":"Jacobson JT","year":"2016"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1053\/joms.2001.20489"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.5301\/jabfm.5000312"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/tan.13808"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.transproceed.2005.08.001"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-019-02297-y"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1080\/14653240600855905"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202000974"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-015-3808-7"},{"key":"e_1_2_7_36_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2019\/6279721","article-title":"Bone tissue regeneration in the oral and maxillofacial region: a review on the application of stem cells and new strategies to improve vascularization","volume":"2019","author":"Wu V","year":"2019","journal-title":"Stem Cells Int"},{"issue":"4","key":"e_1_2_7_37_1","first-page":"3924","article-title":"Effects of vascular endothelial growth factor and insulin growth factor\u20101 on proliferation, migration, osteogenesis and vascularization of human carious dental pulp stem cells","volume":"20","author":"Lu W","year":"2019","journal-title":"Mol Med Rep"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tice.2019.08.003"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.10.010"},{"key":"e_1_2_7_40_1","volume-title":"Translational Research in Coronary Artery Disease: Pathophysiology to Treatment Vasculogenesis and Angiogenesis","author":"Kolte D","year":"2016"},{"issue":"5","key":"e_1_2_7_41_1","first-page":"941","article-title":"Interaction of PF4 (CXCL4) with the vasculature: a role in atherosclerosis and angiogenesis","volume":"104","author":"Aidoudi\u2010Ahmed S","year":"2010","journal-title":"Thromb Haemost"},{"issue":"1","key":"e_1_2_7_42_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000330682","article-title":"Epithelial and stromal developmental patterns in a novel substitute of the human skin generated with fibrin\u2010agarose biomaterials","volume":"196","author":"Carriel V","year":"2012","journal-title":"Cells Tissues Organs"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.2008.01159.x"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9092069"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(96)00379-6"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.4A6514.2005"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1272\/jnms.67.118"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084179"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1053\/ejso.2000.1052"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10529-011-0645-1"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/iej.12511"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.a.36836"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2016.03.002"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.03.004"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-017-0529-y"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2010.07.020"}],"container-title":["Journal of Periodontal Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jre.12927","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jre.12927","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jre.12927","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T12:45:54Z","timestamp":1693140354000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jre.12927"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,12]]},"references-count":55,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1111\/jre.12927"],"URL":"https:\/\/doi.org\/10.1111\/jre.12927","archive":["Portico"],"relation":{},"ISSN":["0022-3484","1600-0765"],"issn-type":[{"value":"0022-3484","type":"print"},{"value":"1600-0765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,12]]},"assertion":[{"value":"2021-07-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}