{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:39:04Z","timestamp":1792805944553,"version":"4.5.0"},"reference-count":82,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:00:00Z","timestamp":1780790400000},"content-version":"vor","delay-in-days":37,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Wound Repair Regeneration"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Diabetic wounds pose a major clinical challenge due to persistent inflammation, impaired angiogenesis and defective tissue remodelling. These defects stem partly from dysregulated macrophage polarisation, with sustained M1 dominance and impaired M2 transition hindering resolution and repair. This study evaluates extracellular vesicles (EVs) from IL\u20104\u2010polarised M2 macrophages of db\/+ heterozygous mice for promoting healing in db\/db type 2 diabetic wounds. M2 macrophages showed reduced IL\u20106, elevated IL\u201010, downregulated pro\u2010inflammatory genes (iNOS, TNF\u2010\u03b1, IL\u20106) and upregulated anti\u2010inflammatory markers (IL\u201010, ARG\u20101, TGF\u2010\u03b2). EVs, isolated by precipitation, displayed characteristic cup\u2010shaped morphology (mean diameter 100.5\u2009\u00b1\u200931.47\u2009nm) by SEM\/TEM and CD63, CD9 and CD81 expression. Following in\u00a0vitro migration and viability assessments, EVs were coated onto 3D\u2010printed carboxymethyl cellulose (CMC) scaffolds to enhance wound healing efficacy. In full\u2010thickness dorsal wound model (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924 mice; groups: NC, CMC, CMCE, PC), 1\u2009day post\u2010treatment, CMCE treatment markedly increased NO in serum and wound fluid and elevated IL\u201010 concentrations in wound exudate. By Day 20, CMCE treated wounds exhibited complete closure, with extensive re\u2010epithelialisation, collagen deposition, neovascularisation (&gt;\u200910 vessels\/HPF), reduced inflammation depth and well\u2010organised crust formation. These results indicate that M2\u2010macrophage\u2010derived EVs from heterozygous donors, delivered via bioactive scaffolds, rapidly modulate early inflammatory signalling and drive regenerative healing in homozygous diabetic mice' wounds, supporting a scalable cell\u2010free therapeutic approach.\n                  <\/jats:p>","DOI":"10.1111\/wrr.70177","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T06:24:26Z","timestamp":1780899866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Peritoneal\n                    <scp>M2<\/scp>\n                    Macrophage\u2010Derived Extracellular Vesicles From db\/+ Heterozygous Mice Enhance Diabetic Wound Healing in db\/db Homozygous Mice Model"],"prefix":"10.1111","volume":"34","author":[{"given":"Fahad","family":"Al\u2010Fahdi","sequence":"first","affiliation":[{"name":"Laboratory for Stem Cell and Regenerative Medicine Natural and Medical Sciences Research Center, University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Jamshidi\u2010adegani","sequence":"additional","affiliation":[{"name":"Laboratory for Stem Cell and Regenerative Medicine Natural and Medical Sciences Research Center, University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8854-8107","authenticated-orcid":false,"given":"Saeid","family":"Vakilian","sequence":"additional","affiliation":[{"name":"Laboratory for Stem Cell and Regenerative Medicine Natural and Medical Sciences Research Center, University of Nizwa  Nizwa Oman"},{"name":"Doctoral Programme in Biomedicine, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda","family":"Doustmohammadi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Chemistry College of Arts and Sciences, University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8238-8074","authenticated-orcid":false,"given":"Issa S.","family":"Al\u2010Amri","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Chemistry College of Arts and Sciences, University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sausan","family":"Alyaqoobi","sequence":"additional","affiliation":[{"name":"Central Analytical Services Unit University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khamis","family":"Al\u2010Riyami","sequence":"additional","affiliation":[{"name":"Central Analytical Services Unit University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-5942","authenticated-orcid":false,"given":"Ahmed","family":"Al\u2010Harrasi","sequence":"additional","affiliation":[{"name":"Laboratory for Stem Cell and Regenerative Medicine Natural and Medical Sciences Research Center, University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4010-116X","authenticated-orcid":false,"given":"Sulaiman","family":"Al\u2010Hashmi","sequence":"additional","affiliation":[{"name":"Laboratory for Stem Cell and Regenerative Medicine Natural and Medical Sciences Research Center, University of Nizwa  Nizwa Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hsr2.2004"},{"key":"e_1_2_11_3_1","article-title":"Burden of Chronic Nonhealing Wounds: An Overview of the Worldwide Humanistic and Economic Burden to the Healthcare System","volume":"25","author":"Sharma A.","year":"2024","journal-title":"International Journal of Lower Extremity Wounds"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S371939"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.115120"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2015.0635"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07583-3"},{"key":"e_1_2_11_8_1","first-page":"153","volume-title":"Updates in Diabetic Wound Healing, Inflammation, and Scarring, Seminars in Plastic Surgery","author":"Dasari N.","year":"2021"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph13040060"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.02.015"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009337"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.658"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/burnst\/tkac051"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2025.07.039"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202416159"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S518655"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202404966"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2012.10.004"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/20587384211016724"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901610"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/09603271241303320"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpta.2026.101131"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-022-01656-7"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.102423"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2022.06.063"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/wrr.12470"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2023.112089"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-025-00768-w"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carbpol.2021.118924"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2024.106189"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X20943823"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carbpol.2021.117921"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-475X.2006.00188.x"},{"issue":"5","key":"e_1_2_11_34_1","first-page":"1225","article-title":"Quantitative Assessment of the Age of Fibrotic Lesions Using Polarized Light Microscopy and Digital Image Analysis","volume":"138","author":"Pickering J. G.","year":"1991","journal-title":"American Journal of Pathology"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.wndm.2019.100155"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3DT02662K"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3A0520-338R"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132984"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0309207"},{"key":"e_1_2_11_40_1","first-page":"9","article-title":"Semi\u2010Mechanism\u2010Based Pharmacodynamic Model for the Anti\u2010Inflammatory Effect of Baicalein in LPS\u2010Stimulated RAW264.7 Macrophages","author":"Xiang L.","year":"2018","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2015.03.002"},{"key":"e_1_2_11_42_1","first-page":"B133","article-title":"Alpha\u2010Tocopheryl\u2010L\u2010Ascorbate\u20102\u2010O\u2010Phosphate Diester, a Hydroxy Radical Scavenger, Prevents the Induction of Tumor Necrosis Inducible Nitric Oxide Synthase but Not Interleukin\u20106 Induced by Lipopolysaccharide","volume":"30","author":"Yokoi I.","year":"2005","journal-title":"Research Communications in Biological Psychology Psychiatry and Neurosciences"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1177\/0394632015593228"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2909332"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-318264"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2022.12.002"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12647"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00225"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.3727\/000000008783906919"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031185"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.12.041"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-13948-7"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/s42825-024-00156-8"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201900513"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/mabi.202500500"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-023-08782-x"},{"key":"e_1_2_11_57_1","first-page":"161","article-title":"Exosome\u2010Mediated Macrophage Polarization: Pioneering Pathways in Diabetic Wound Healing","author":"Zheng Y.","year":"2025","journal-title":"International Immunopharmacology"},{"issue":"1","key":"e_1_2_11_58_1","first-page":"98","article-title":"Reprogramming Regulates Macrophage Polarization and Functional Transformation to Promote Diabetic Wound Healing","volume":"41","author":"Sun D.","year":"2025","journal-title":"Chinese Journal of Plastic Surgery"},{"key":"e_1_2_11_59_1","first-page":"8","article-title":"Macrophage Dysregulation and Impaired Skin Wound Healing in Diabetes","author":"Barman P. K.","year":"2020","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-023-02105-9"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomaterials.3c01833"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202509410"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.2174\/9789815079814122010010"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.143730"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.33549\/physiolres.931702"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2006.11.010"},{"key":"e_1_2_11_67_1","first-page":"10","article-title":"Nitric Oxide\u2010Releasing Gel Accelerates Healing in a Diabetic Murine Splinted Excisional Wound Model","author":"Sivaraj D.","year":"2023","journal-title":"Frontiers in Medicine"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-025-03135-1"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901024RR"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5701232"},{"key":"e_1_2_11_71_1","volume-title":"StatPearls [Internet]","author":"Alhajj M.","year":"2022"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13070624"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4804(77)90137-8"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2013.0473"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17122085"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2023.05.018"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20030673"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2021.0016"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-024-10762-y"},{"key":"e_1_2_11_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202307058"},{"key":"e_1_2_11_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.102298"},{"key":"e_1_2_11_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.101595"},{"key":"e_1_2_11_83_1","unstructured":"K.Eskandar Exosome\u2010Based Therapies for Scar\u2010Free Skin Regeneration: Clinical Applications and Emerging Trends."}],"container-title":["Wound Repair and Regeneration"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/wrr.70177","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/wrr.70177","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/wrr.70177","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T09:29:45Z","timestamp":1786181385000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/wrr.70177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":82,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1111\/wrr.70177"],"URL":"https:\/\/doi.org\/10.1111\/wrr.70177","archive":["Portico"],"relation":{},"ISSN":["1067-1927","1524-475X"],"issn-type":[{"value":"1067-1927","type":"print"},{"value":"1524-475X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"2025-11-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70177"}}