Using 3D bioprinting technologies to Create an Organ-on-Chip Device for Osteosarcoma and Its Surrounding Bone Microenvironment: A Platform for Drug Discovery and Therapeutic Innovation
Osteosarcoma, a highly aggressive bone cancer primarily affecting children, adolescents, and young adults, poses a significant global health challenge with an annual incidence of 26,000 new cases. Despite incremental advancements in cancer treatment, the 5-year survival rate for resistant forms of osteosarcoma remains distressingly below 20%, emphasizing the urgent need for innovative therapeutic approaches. Conventional drug development models, such as two-dimensional (2D) cell cultures and animal testing, have limitations in replicating the complexity of the primary tumour environment. Animal models, while traditionally employed, are resource-intensive and often yield untranslatable results due to species-specific differences. Additionally, the rarity of osteosarcoma complicates clinical trial recruitment, necessitating collaborative efforts, as demonstrated by initiatives like the European and American Osteosarcoma Study Group (EURAMOS). Addressing these challenges, organ-on-a-chip technologies emerge as a promising alternative, providing controllable cell cultures within an organotypic microarchitectural environment. The recent approval of the FDA Modernization Act 2.0 in December 2022 recognizes the potential of organ-on-chip data for drug discovery, especially in rare paediatric diseases like osteosarcoma where conventional clinical trials are challenging. This proposal seeks to leverage 3D bioprinting technologies to create a sophisticated organ-on-chip device that accurately models osteosarcoma and its surrounding bone microenvironment. This will be realized by first testing the hypothesis that the development and characterization of a bioink designed to mimic the extracellular microenvironment of osteosarcoma will yield a biomimetic substrate that accurately reproduces the critical features of the tumour microenvironment (Aim 1). The ability to accurately model the complexities of the tumour microenvironment is crucial for developing effective and novel therapeutics for osteosarcoma. Currently, there is no model allowing the study of osteosarcoma origin, progression, and response to drugs. Therefore, a predictive model that models the interaction between tumour cells and non-tumour elements within the osteosarcoma microenvironment will be developed (Aim 2). To validate our model, we will establish if our engineered model can predict pre-clinical data, utilizing the miR-29b nanoparticle-mediated therapy, a previously established therapeutic approach by the applicant (Aim 3). By achieving these specific aims, the project aims to fill a crucial gap in existing organ-on-a-chip devices, which often focus on bone metastasis or lack comprehensive integration of the three-dimensional microvasculature and bone tissue microenvironments. The successful implementation of this project is anticipated to significantly contribute to overcoming challenges in developing novel therapeutics for osteosarcoma and potentially other rare diseases.