Osteosarcoma (OS) is the most frequent malignant bone tumour with a survival rate of less than 25% in metastatic disease. Treatment is a combination of surgical resection and systemic chemotherapy with doxorubicin (DOX). However, this can cause serious long-term adverse effects. To overcome this limitation, we have developed an advanced rat OS model that converges tissue engineering and regenerative medicine principles to improve treatment outcomes for OS patients.
A humanized bone microenvironment was created by implanting an orthotopic tissue engineered bone construct (ohTEBC) fabricated from melt electrowritten medical grade polycaprolactone coated with calcium phosphate (mPCL-CaP) together with fibrin glue (Baxter) and 45 µg rhBMP-2 (Medtronic) around the femur of an immunocompromised rat. A primary OS tumour was then created by injecting human SaOS-2-luc human OS cells into the humanized bone niche. Bone volume was measured with in vivo CT (Molecubes µPET-CT) and tumour formation and metastasis was monitored using bioluminescent imaging (BLI) (IVIS Spectrum, Perkin Elmer). The humanized bone niche and primary OS tumour was characterised by ex vivo histology and immunohistochemistry.
A humanized bone microenvironment formed within 6 weeks of implantation, with µCT confirming increased bone volume around the femur. Following SaOS-2-luc injection, BLI confirmed primary OS tumour growth and development of lung metastases over a 14-week period. µCT revealed pathological increase in bone volume within the OS tumour. In future studies, the humanized rat OS model will be used to investigate the efficacy of scaffold-mediated local DOX delivery following surgical resection of the primary OS tumour, in comparison to systemic DOX chemotherapy delivery. The model will also be used to study the regeneration of post-DOX-treated critical-sized segmental bone defects using scaffold-guided tissue engineering and regenerative medicine approaches.
Here, we have created an orthotopic OS tumour model that recapitulates the hallmarks of human disease within an immunocompromised rat. This model will allow to study complex surgical interventions and regenerative medicine techniques never before possible in previous model systems. The outcomes of this study will improve the chemotherapeutic and limb sparing surgery options for those affected by OS."