Multi-Scale In Vitro 3D Tissue Model of Vascularized Bone-Cartilage Interactions

Abstract Current in vitro models of vascularized bone tissues do not mimic the in vivo microenvironment comprising of diverse cell types in communication with each other through stromal barriers. In addition, they are hampered by lack of real-time visualization and quantitation of vasculature- bone as well as bone-cartilage interactions. In contrast, animal models while providing useful information are time consuming, expensive and in recent years, have increasingly raised ethical concerns. Furthermore, animal studies provide limited understanding of mechanistic behavior compared to well-controlled in vitro studies. Thus, there is an unmet need for an in vitro platform for improved monitoring and analysis of vascularized bone-cartilage interactions. In Phase I we successfully developed and demonstrated a multi-scale in vitro model comprising of a micro scale microfluidic device and a meso scale bioreactor to mimic the in vivo conditions. We successfully differentiated in the platform patient derived human mesenchymal stem cells (hMSCs) towards osteogenic and chondrogenic lineages highlighting interactions with vascular endothelial cells. Following detailed functional characterizations, we demonstrated the capability of the platform to evaluate functionality for an anti-inflammatory therapeutic. In Phase II we will test additional pro-inflammatory components that mimic the native osteochondral microenvironment. We will also use our multi-scale system for (a) mechanistic understanding and (b) therapeutic screening of candidate treatments following inflammatory insults. Finally, we will develop the infrastructure to increase the throughput capability by multiplexing the platform for automation. A multi-disciplinary industry-academic partnership with expertise in microfluidics cell-based assays and musculoskeletal biology and tissue regeneration has been assembled for successful completion of this project. By providing an accurate, quantitative and predictive model of physiological interactions, the developed multi-scale platform promises to establish a new paradigm for in vitro assessment of the physiological response to therapeutics.