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Current therapy involves multiple rounds of chemotherapy and surgical resection, which are associated with significant morbidity and suboptimal survival rates. A key challenge in developing new treatments is the difficulty in replicating the OS tumor microenvironment, particularly cell interactions with the extracellular matrix (ECM). This study uses an in\u00a0vitro model of OS to investigate the cell response to collagen (COL) type I, the primary component of the OS ECM. After 7\u2009days of culture within three\u2010dimensional COL hydrogels, OS cells displayed a more elongated cellular morphology and reduced sensitivity to the standard chemotherapy used for OS treatment compared to cells grown on two\u2010dimensional substrates. To test whether this model could be used to study treatment strategies used for high\u2010risk OS patients, we applied a metronomic regimen combining regorafenib, a multi\u2010tyrosine kinase inhibitor, with front\u2010line chemotherapy to overcome cell\u2010matrix induced chemoresistance. We identified overexpression of the ATP\u2010binding cassette transporter ABCG2, a drug efflux pump, as a potential mechanism of resistance in 3D culture. Regorafenib's inhibitory effect on ABCG2 suggests a mechanistic basis for its ability to restore chemosensitivity in 3D culture. Altogether, these findings highlight the importance of cell\u2013matrix interactions in in\u00a0vitro OS models, provide valuable insights into a matrix\u2010induced mechanism of OS chemoresistance, and suggest an approach to its treatment.<\/jats:p>","DOI":"10.1002\/jbm.a.37985","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T14:48:38Z","timestamp":1757688518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting Cell\u2010Matrix Induced Chemoresistance With Regorafenib in a <scp>3D<\/scp> Model of Osteosarcoma"],"prefix":"10.1002","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0136-2807","authenticated-orcid":false,"given":"Rameshwar R.","family":"Rao","sequence":"first","affiliation":[{"name":"Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Division of Pediatric Hematology, Oncology, Bone Marrow Transplant, and Cellular Therapies, Department of Pediatrics University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1814-7786","authenticated-orcid":false,"given":"Michelle S.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7259-0948","authenticated-orcid":false,"given":"Daiyao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Huerta\u2010L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giselle Aviles","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther A. 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