Animal models have long been the cornerstone of drug development and toxicity testing, but they often fall short in accurately predicting human responses. This leads to drug failures during clinical trials, black box warnings (serious warnings on drugs that may cause harm or death) and even the withdrawal of marketed drugs. Moreover, due to the limitations of animal testing and efforts to reduce the use of animals in research, there is a need for human relevant in-vitro models to predict drug toxicity testing more accurately. 

And as researchers seek alternatives to animal testing, a team led by Biman B Mandal from the Indian Institute of Technology, Guwahati, has developed a new lab model called the ​‘human physiomimetic liver acinus model (HPLAM).’ This model is designed to better detect various types of drug-induced liver injury (DILI). Their study published in Biomaterials, reported how they used advanced 3D printing and microfluidic technology to create this model, combining engineering with biological phenomena to mimic the human liver more accurately. 

One of the reasons why animal models may incorrectly predict drug responses is the species-specific differences in drug-metabolising enzymes between animals and humans. 

“This leads to variations in how drugs are absorbed, distributed, metabolised, and transported in these different species,” says Surat Saravanan, a senior strategist at the Humane Society International, India, who is not associated with this study. As per regulatory requirements for new drug development, in vivo animal testing data is required before initiating clinical trials in humans. However, due to genetic and metabolic differences, there is often low consistency between animal and human liver toxicity data, which increases the risk for clinical trial patients. 

Researchers have created the HPLAM model using transdisciplinary approach combining stem cell biology, advanced micro-technology, and biomaterials. Mandal says, ​“These microfluidic models have the potential to effectively mimic the complex physiological functions of native human tissues and organs in a miniaturised scale”.

For the 3D printing of hepatic (liver) constructs, researchers used special liver mimetic biomaterial ink made from regenerated B. mori silk fibroin (silk protein) providing ink strength and flexibility; porcine liver decellularised extracellular matrix creating a realistic liver microenvironment and gelatin, improving the ink’s flow and printing quality. The ink is designed to closely mimic real human liver tissue. They also developed a bioreactor platform that simulates the smallest functional units of liver (micro physiomimetic liver acinus), mimicking blood flow and stress effects on liver cells.

To accurately test diverse phenotypes of liver toxicity, the model includes three types of tissue specific stem cells that help maintain long-term physiological functionality and create a realistic liver microenvironment. This model, with its fluid flow system, maintained the necessary levels of key markers and drug metabolising enzymes, proving it to be a good representation of a real human liver. The researchers tested the model with various drugs to confirm its accuracy in detecting different types of liver damage.

Overall, the 3D printed liver model closely mimics the structure and function of a real human liver model. Mandal adds, 

The platform can be an affordable tool for evaluating liver injuries caused by various drugs, helping researchers and pharmaceutical companies better determine safety and risks for human health.

Thus, the model holds significance for drug toxicity evaluation of human relevance. Further mechanistic and biomarker studies will pave way for assessing repeated drug dose as well as combined drug toxicities.