Chip-based system models drug-induced muscle and kidney damage in real time
Researchers at KAIST have developed a modular organ-on-a-chip platform that recreates the cascade of drug-induced rhabdomyolysis and acute kidney injury in laboratory conditions. The biomicrofluidic system allows muscle and kidney tissues to be connected or separated as needed, enabling precise observation of inter-organ interactions following exposure to medications such as statins and fibrates.
First platform to model muscle-kidney interactions
Rhabdomyolysis, characterised by skeletal muscle breakdown, can lead to life-threatening complications including acute kidney injury (AKI). Drug-induced cases represent the most common subset, yet studying the connection between damaged muscle tissue and kidney function has proven challenging. Traditional experimental methods using isolated cells or animal models have limitations in replicating the complex interactions between human organs.
The research team, led by Professor Jessie S. Jeon from KAIST’s Department of Mechanical Engineering, in collaboration with Professor Gi-Dong Sim and Professor Sejoong Kim from Seoul National University Hospital, has addressed this gap. Their muscle-kidney proximal tubule-on-a-chip (MKoaC) represents the first system to precisely reproduce the stepwise progression from drug-induced muscle damage to kidney injury in a controlled laboratory environment.
“This study establishes a foundation for analysing the interactions and toxic responses occurring between muscle and kidney in a manner closely resembling the human body,” said Professor Jeon. “We expect this platform to enable the early prediction of drug side effects, identification of the causes of acute kidney injury, and further expansion towards personalised drug safety assessment.”
Modular design enables flexible tissue analysis
The platform’s key innovation lies in its modular architecture. Three-dimensionally engineered skeletal muscle tissue, derived from murine C2C12 myoblasts, is housed in a detachable plug-shaped compartment. This connects to an open-top socket compartment containing human proximal tubular epithelial cells (HK-2), which represent the primary site of myoglobin-induced nephrotoxicity during rhabdomyolysis.
The muscle-to-kidney tissue ratio in the chip was set at 24:1, reflecting the estimated proportion between skeletal muscle and proximal tubule masses under rhabdomyolysis-related injury conditions. A 200-micrometre gap between compartments enables paracrine signalling whilst preventing direct cell-to-cell contact.
Crucially, each tissue type can be cultured independently under optimal conditions before assembly. Following experimental exposure to drugs or other stimuli, the compartments can be separated again for tissue-specific molecular and functional analyses, including RNA extraction, contractility measurements and viability assays.
Atorvastatin and fenofibrate induce measurable tissue damage
To validate the platform, researchers treated the integrated system with atorvastatin and fenofibrate for three days, mirroring the acute onset timeframe observed clinically. Both medications are known to cause rhabdomyolysis, particularly when used in combination for managing mixed dyslipidaemia.
Following exposure to 20 μM atorvastatin, muscle tissue exhibited severe functional impairment. Contractile force decreased from 82.66 μN in control conditions to 13.49 μN in treated tissue. Myoglobin levels increased markedly to 4,003.9 pg/mL compared with 1,054.5 pg/mL in controls, whilst CK-MM enzyme activity rose from 31.8 mU/mL to 93.3 mU/mL. Immunofluorescence imaging revealed disrupted myotubes and structural defects exceeding 100 micrometres in diameter.
The kidney compartment showed corresponding pathological changes. Live cell area decreased from 63.5% to 19.2%, whilst dead cell ratios increased from 5.2% to 19.1%. Gene expression analysis revealed significant upregulation of injury markers NGAL (11.49-fold increase) and alterations in KIM-1 expression, alongside changes in functional transporters SGLT2 and CUBN.
As the authors note in their paper: “The MKoaC serves as a robust platform for studying drug toxicity and tissue interactions, advancing preclinical drug screening and therapeutic strategies for rhabdomyolysis and AKI.”
Dr Jaesang Kim (left) and Professor Seongyun Jeon, Department of Mechanical Engineering, KAIST
Implications for personalised medicine
The platform’s separable design offers particular advantages for studying tissue crosstalk. When muscle and kidney compartments were cultured together, muscle tissue demonstrated enhanced differentiation and a threefold increase in contractile force compared with isolated culture. This suggests bidirectional signalling between tissues that goes beyond simple toxic insult.
Future applications may include patient-specific drug safety testing using induced pluripotent stem cell-derived tissues, potentially identifying individuals at heightened risk of drug-induced complications before therapy commences.
Reference
Kim, J., Lee, Z. F., Sim, G.-D., et. al. (2025). Implementation of drug-induced rhabdomyolysis and acute kidney injury in microphysiological system. Advanced Functional Materials, e13519. https://doi.org/10.1002/adfm.202513519
