{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T14:21:30Z","timestamp":1774534890360,"version":"3.50.1"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":463,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"California Institute for Regenerative Medicine, Preclinical Development Awards","award":["TR2-01787"],"award-info":[{"award-number":["TR2-01787"]}]},{"name":"California Institute for Regenerative Medicine, Preclinical Development Awards","award":["PC1-08118"],"award-info":[{"award-number":["PC1-08118"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)-based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia-preconditioned, allogeneic human MSCs combined with the beta-adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 \u03bcM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5\u2009\u00d7\u2009105\u2009cells\/cm2 on Integra Matrix Wound Scaffold (MSC\/T\/H\/S) applied to wounds and combined with daily topical timolol applications at 2.9\u2009mM resulted in optimal wound epithelialization 65.6% (24.9%\u2009\u00b1\u200913.0% with MSC\/T\/H\/S vs 41.2%\u2009\u00b1\u200920.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7-day treatment, accumulative steady-state timolol concentration is minimal. In the early inflammation stage of healing, the MSC\/T\/H\/S treatment increased CCL2 expression, lowered the pro-inflammatory cytokines IL-1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2\/M1 to 1.9 in the wound, demonstrating an anti-inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5-fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds.<\/jats:p>\n               <jats:sec>\n                  <jats:title\/>\n               <\/jats:sec>","DOI":"10.1002\/sctm.19-0380","type":"journal-article","created":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T13:20:51Z","timestamp":1595942451000},"page":"1353-1364","source":"Crossref","is-referenced-by-count":50,"title":["Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice"],"prefix":"10.1093","volume":"9","author":[{"given":"Hsin-ya","family":"Yang","sequence":"first","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Fierro","sequence":"additional","affiliation":[{"name":"2 Department of Cell Biology and Human Anatomy University of California, Davis, Sacramento, California, USA"},{"name":"3 Stem Cell Program, Department of Internal Medicine University of California, Davis, Davis, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"So","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Yoon","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan Vu","family":"Nguyen","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"},{"name":"4 Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Gallegos","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle D.","family":"Bagood","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Rojo-Castro","sequence":"additional","affiliation":[{"name":"5 Department of Biological Sciences California State University, Sacramento, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Alex","sequence":"additional","affiliation":[{"name":"5 Department of Biological Sciences California State University, Sacramento, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Stewart","sequence":"additional","affiliation":[{"name":"3 Stem Cell Program, Department of Internal Medicine University of California, Davis, Davis, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne","family":"Chigbrow","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohan R.","family":"Dasu","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas R.","family":"Peavy","sequence":"additional","affiliation":[{"name":"5 Department of Biological Sciences California State University, Sacramento, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athena M.","family":"Soulika","sequence":"additional","affiliation":[{"name":"1 Department of Dermatology University of California, Davis, Sacramento, California, USA"},{"name":"4 Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan A.","family":"Nolta","sequence":"additional","affiliation":[{"name":"3 Stem Cell Program, Department of Internal Medicine University of California, Davis, Davis, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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