REGULATING MSC FATE UNDER COMPLEX MECHANICAL LOAD

Given that its primary role is to distribute load with minimal friction, it is evident that the mechanical load experienced by cartilage on a daily basis is a significant factor in its homeostasis and regeneration. While these effects are typically considered during in vivo studies, in vitro studies often remain under static conditions. This decouples known key mechanical signals from the data obtained, potentially leading to incorrect interpretation of the potential of new therapies to have therapeutic benefits. Consequently, there is an increasing need for more complex in vitro culture models with the ultimate goal of accurately recreating the articulating joint. For many years, we have utilized a multiaxial load bioreactor capable of applying precisely regulated compression and shear loading protocols, that mimic the tribology of the articulating joint. Through the use of this bioreactor, we have demonstrated the mechanical induction of human bone marrow stromal cell (BMSC) chondrogenesis in the absence of exogenous growth factors, effectively coupling cell fate to mechanical stimulation. Building on previous bioreactor studies that showed the mechanical activation of endogenous TGFβ and subsequent chondrogenesis of human bone marrow-derived MSCs, we have further increased the complexity of in vitro models. For instance, incorporating high molecular weight hyaluronic acid, a component of synovial fluid, into the culture medium results in reduced hypertrophy and enhanced glycosaminoglycan deposition. Utilizing the mechanical activation of latent TGFβ allows for rapid screening of new materials for cartilage repair, and increasing the complexity of the ex vivo model aims to improve translation into large animal models and, ultimately, humans.