Multimodal induction of stem cells synergistically mediates enhanced cartilage-bone cross-talk in a 3D bioprinted human osteochondral microphysiological system.

Abstract

A humanized microphysiological system (MPS) emulating the morphophysiology of the osteochondral complex can revolutionize research and drug development for joint diseases. Despite significant efforts, in vitro osteochondral models fail to recapitulate the microarchitecture and physiological spatiotemporal signals essential for controlling cell fate in 3D microenvironments and development of a phenotypically stable multiphasic osteochondral model. In this study, we formulated two bioinspired cell-specific and multifunctional bioinstructive bioinks to recreate the intricate morphogen gradients in the osteochondral unit, considering cellular, architectural and mechanical properties. We further employed mechanobiological stimulus, 3D bioprinting and microfluidic technology to bioengineer a phenotypically stable human osteochondral microphysiological system that recapitulates the native-like tissue organization and physiological spatiotemporal signals critical for modelling cartilage-bone crosstalk. Intriguingly, the resultant osteochondral microphysiological model cultured under physiomimetic conditions synergistically promoted maturation of the multiphasic osteochondral construct through native-like inter-tissue crosstalk with enhanced phenotypic commitment, tissue specific extracellular matrix deposition and maintenance of key secretome levels and physiological hallmarks for several weeks. Our concept for extrinsically guiding the fate commitment of MSCs will enable accurate modelling of phenotypically mature in-vivo like osteochondral tissue units for mechanistic studies of morphogenesis, physiology and pathophysiology of the osteochondral complex and to test potential therapeutics.