Next-generation hydrogels and strategies to recreate 3D tumour microenvironments for osteosarcoma: from bioprinting...

Osteosarcoma (OS) is one of the most prevalent primary malignant bone tumours, with a poor prognosis in metastatic cases due to its aggressive nature, high metastatic potential and frequent resistance to conventional therapies. A most crucial approach for investigating drug resistance, metastasis and tumour progression is the recapitulation of the complex tumour microenvironment (TME), which is limited in traditional 2D cell cultures. Sophisticated 3D in vitro models developed via recent advances in materials sciences and cancer biology including cell spheroids, organoids and scaffold-based and hydrogel-based systems more precisely mimic the tumour microenvironment, thus offering deeper insights into tumour biology and therapeutic responses. Hydrogels inherently provide biomimetic cues that promote cell adhesion, proliferation & differentiation, particularly their porous and hydrated characteristics closely replicate the native extracellular matrix. Most importantly, hydrogels can be used for OS therapy both as a depot for therapeutic agents and scaffolds for bone tissue regeneration. This approach could be particularly promising for adjuvant therapy of tumours, as it provides options for both treatment and tissue regeneration. This review explores the emerging innovations in hydrogel-based OS in vitro models, their fabrication methods and applications in drug screening and adjuvant therapies. Furthermore, the challenges in clinical translation and advancing OS models for clinical applications are discussed. Finally, the challenges and future perspectives are outlined by emphasizing the need for multidisciplinary collaboration to advance OS research and therapy.