{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:54:56Z","timestamp":1786978496696,"version":"build-2736575974"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":275,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"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":[],"published-print":{"date-parts":[[2021,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>While mesenchymal stromal cells are an appealing therapeutic option for a range of clinical applications, their potential to induce clotting when used systemically remains a safety concern, particularly in hypercoagulable conditions, such as in patients with severe COVID-19, trauma, or cancers. Here, we tested a novel preclinical approach aimed at improving the safety of mesenchymal stromal cell (MSC) systemic administration by use of a bioreactor. In this system, MSCs are seeded on the exterior of a hollow-fiber filter, sequestering them behind a hemocompatible semipermeable membrane with defined pore-size and permeability to allow for a molecularly defined cross talk between the therapeutic cells and the whole blood environment, including blood cells and signaling molecules. The potential for these bioreactor MSCs to induce clots in coagulable plasma was compared against directly injected \u201cfree\u201d MSCs, a model of systemic administration. Our results showed that restricting MSCs exposure to plasma via a bioreactor extends the time necessary for clot formation to occur when compared with \u201cfree\u201d MSCs. Measurement of cell surface data indicates the presence of known clot inducing factors, namely tissue factor and phosphatidylserine. Results also showed that recovering cells and flushing the bioreactor prior to use further prolonged clot formation time. Furthermore, application of this technology in two in vivo models did not require additional heparin in fully anticoagulated experimental animals to maintain target activated clotting time levels relative to heparin anticoagulated controls. Taken together the clinical use of bioreactor housed MSCs could offer a novel method to control systemic MSC exposure and prolong clot formation time.<\/jats:p>","DOI":"10.1002\/sctm.20-0454","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T18:30:42Z","timestamp":1612377042000},"page":"883-894","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Mesenchymal stromal cell delivery via an ex vivo bioreactor preclinical test system attenuates clot formation for intravascular application"],"prefix":"10.1093","volume":"10","author":[{"given":"Brian","family":"O'Rourke","sequence":"first","affiliation":[{"name":"Sentien Biotechnologies, Inc , Lexington, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Sentien Biotechnologies, Inc , Lexington, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arno W.","family":"Tilles","sequence":"additional","affiliation":[{"name":"Sentien Biotechnologies, Inc , Lexington, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Bynum","sequence":"additional","affiliation":[{"name":"Blood and Coagulation Research Program US Army Institute of Surgical Research , Fort Sam Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Cap","sequence":"additional","affiliation":[{"name":"Blood and Coagulation Research Program US Army Institute of Surgical Research , Fort Sam Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biju","family":"Parekkadan","sequence":"additional","affiliation":[{"name":"Sentien Biotechnologies, Inc , Lexington, Massachusetts, USA"},{"name":"Department of Surgery, Center for Surgery, Innovation, and Bioengineering Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children , Boston, Massachusetts, USA"},{"name":"Harvard Stem Cell Institute , Cambridge, Massachusetts, USA"},{"name":"Department of Biomedical Engineering Rutgers University , Piscataway, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita N.","family":"Barcia","sequence":"additional","affiliation":[{"name":"Sentien Biotechnologies, Inc , Lexington, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,1]]},"reference":[{"key":"2022061708590461300_sct312901-bib-0001","doi-asserted-by":"crossref","DOI":"10.1038\/mtm.2016.53","article-title":"Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia","volume":"3","author":"Beegle","year":"2016","journal-title":"Mol Ther Methods Clin Dev"},{"key":"2022061708590461300_sct312901-bib-0002","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3389\/fmed.2018.00179","article-title":"Stem\/stromal cells for treatment of kidney injuries with focus on preclinical models","volume":"5","author":"Torres Crigna","year":"2018","journal-title":"Front Med"},{"key":"2022061708590461300_sct312901-bib-0003","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.ebiom.2019.08.073","article-title":"Meta-analysis of preclinical studies of mesenchymal stromal cells to treat rheumatoid arthritis","volume":"47","author":"Liu","year":"2019","journal-title":"EBioMedicine"},{"key":"2022061708590461300_sct312901-bib-0004","doi-asserted-by":"crossref","DOI":"10.1089\/ten.teb.2019.0351","article-title":"Mesenchymal stem cells for chronic wound healing: current status of preclinical and clinical studies","author":"Huang","year":"2020","journal-title":"Tissue Eng B Rev"},{"key":"2022061708590461300_sct312901-bib-0005","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/nri2395","article-title":"Mesenchymal stem cells in health and disease","volume":"8","author":"Uccelli","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"2022061708590461300_sct312901-bib-0006","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1002\/sctm.19-0073","article-title":"Mesenchymal stromal cells anno 2019: Dawn of the therapeutic era? 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