Advancement in Scaffold-Based 3D Cell Culture Models for Osteosarcoma Drug Screening

Osteosarcoma (OS), an extremely aggressive bone cancer that primarily occurs in children and teenagers, continues to pose critical clinical challenges due to its high propensity for metastasis, resistance to conventional therapies, and lack of specific biomarkers for early detection. Despite advances in surgical techniques and chemotherapeutic regimens, patient outcomes remain suboptimal, predominantly because conventional two-dimensional (2D) cell culture systems do not accurately mimic the intricate tumor microenvironment (TME), which often results in limited success when translating preclinical results to clinical success. In response to the shortcomings, the field has shifted toward three-dimensional (3D) culture systems, which more accurately mimic the spatial, mechanical, and biochemical characteristics of native OS TME. This review systematically examines the evolution and current state of 3D OS models, with a particular focus on scaffold-based systems. These models, utilizing biomimetic scaffolds provide enhanced platforms for studying tumor-stroma interactions, drug responses, and chemoresistance. It also briefs the use of scaffold-free spheroid models, which, despite their utility in replicating certain aspects of tumor heterogeneity and cell-cell interactions, are limited in their ability to fully emulate the <i>in vivo</i> microenvironment. The review further discusses technical and translational hurdles, such as optimizing scaffold properties and integrating patient-derived cells, which must be addressed to realize the full potential of 3D models in personalized medicine and drug discovery. The significant advancement of scaffold-based 3D OS models offers a more physiologically relevant platforms to bridge the gap between experimental research and clinical application in chemotherapy.