Dynamic modelling of liver-bone axis: A microphysiological approach to hepatic osteodystrophy.

Hepatic osteodystrophy (HOD) is a metabolic bone disorder associated with chronic liver disease (CLD), marked by disrupted bone remodelling, reduced mineralization, and altered osteoblast-osteoclast dynamics. Despite its clinical relevance, mechanistic understanding of the liver-bone axis remains limited due to the shortcomings of conventional in-vitro and in-vivo models in capturing inter-organ crosstalk. To address this, we developed dual-organ perfusion-based micro-physiological devices (MPDs) that integrates human-derived liver and bone tissues-like scaffolds enabling unidirectional perfusion, permitting dynamic exchange of metabolites, cytokines, and signalling factors between hepatocyte spheroids and osteogenic co-cultures under physiologically relevant and controlled dynamic flow. Hepatic fibrosis was induced using carbon tetrachloride (CCl4), effectively mimicking fibrotic liver pathology. The fibrotic liver environment increased inflammatory cytokines which significantly impacted bone homeostasis, promoting osteoclast activation and reducing osteoblast function and mineral deposition-hallmarks of HOD. Compared to static cultures, the MPDs more accurately replicated pathological liver-bone interactions. The MPDs were also analysed as a potential tool for drug screening and toxicity, where diclofenac was used as a model drug. A clear response of diclofenac and its metabolites on bone homeostasis could be observed in dual-organ MPDs conditions, closely mirroring physiological healthy outcomes. This platform offers a physiologically relevant, perfusable, mechanically tunable and translational approach for investigating HOD pathogenesis and assessing therapeutic interventions. By bridging the gap between static cultures and animal models, it enables real-time monitoring of inter-organ interactions and serves as a powerful tool for advancing research in CLD-related bone disorders.