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

Area of Science:

• Biomedical Engineering
• Translational Medicine
• Organ-on-a-Chip Technology

Background:

• Hepatic osteodystrophy (HOD) is a bone disorder linked to chronic liver disease (CLD), characterized by impaired bone remodeling and mineralization.
• Current in vitro and in vivo models inadequately capture the complex liver-bone axis interactions crucial for understanding HOD.
• Limited mechanistic insights into HOD hinder the development of effective therapeutic strategies for CLD patients.

Purpose of the Study:

• To develop and validate a dual-organ micro-physiological device (MPD) for modeling the human liver-bone axis in HOD.
• To investigate the impact of fibrotic liver disease on bone homeostasis using the developed MPD.
• To evaluate the MPD as a platform for drug screening and toxicity assessment in the context of HOD.

Main Methods:

• Integration of human-derived liver and bone tissue scaffolds within a unidirectional perfusion MPD.
• Induction of hepatic fibrosis using carbon tetrachloride (CCl4) to mimic CLD pathology.
• Co-culture of hepatocyte spheroids and osteogenic cells within the MPD to enable dynamic inter-organ crosstalk.

Main Results:

• The fibrotic liver environment in the MPD significantly increased inflammatory cytokines, promoting osteoclast activation and reducing osteoblast function and mineralization, hallmarks of HOD.
• The MPD demonstrated superior accuracy in replicating pathological liver-bone interactions compared to static culture models.
• Diclofenac treatment in the MPD revealed drug-specific effects on bone homeostasis, mirroring physiological outcomes and validating its use for drug screening.

Conclusions:

• The developed dual-organ MPD provides a physiologically relevant platform for studying HOD pathogenesis and inter-organ crosstalk.
• This innovative model overcomes limitations of conventional systems, enabling dynamic monitoring of liver-bone interactions.
• The MPD serves as a valuable tool for advancing research in CLD-related bone disorders and for assessing therapeutic interventions.