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Nevertheless, several studies of agents targeting abnormal cancerous pathways have yielded disappointing results when translated into clinic because of the lack of accurate OS preclinical modeling. So, any effort to design preclinical drug testing may consider all inter\u2010, intra\u2010, and extra\u2010tumoral heterogeneities throughout models mimicking extracellular and immune microenvironment. Therefore, the bioengineering of patient\u2010derived models reproducing the OS heterogeneity, the interaction with tumor\u2010associated macrophages (TAMs), and the modulation of oxygen concentrations additionally to recreation of bone scaffold is proposed here. Eight 2D preclinical models mimicking several OS clinical situations and their TAMs in hypoxic conditions are developed first and, subsequently, the paired 3D models faithfully preserving histological and biological characteristics are generated. It is possible to shape reproducibly M2\u2010like macrophages cultured with all OS patient\u2010derived cell lines in both dimensions. The final 3D models pooling all heterogeneity features are providing accurate proliferation and migration data to understand the mechanisms involved in OS and immune cells\/biomatrix interactions and sustained such that engineered 3D preclinical systems will improve personalized medicine.<\/jats:p>","DOI":"10.1002\/adhm.202200195","type":"journal-article","created":{"date-parts":[[2022,9,4]],"date-time":"2022-09-04T15:02:05Z","timestamp":1662303725000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Engineering Novel 3D Models to Recreate High\u2010Grade Osteosarcoma and its Immune and Extracellular Matrix Microenvironment"],"prefix":"10.1002","volume":"11","author":[{"given":"Marina","family":"Pierrevelcin","sequence":"first","affiliation":[{"name":"UMR CNRS 7021 Laboratory of Biomaging and Pathologies Facult\u00e9 de Pharmacie  74 route du Rhin Illkirch 67405 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