Development Of A Biomimetic Liver Tumor-on-a Chip Model Based On Decellularized Liver Matrix For Toxicity Testing

Globally,liver cancer has become the second leading cause of cancer-related mortality,with nearly 850,000 new cases each year.Despite the serious clinical crisis,few new anticancer drugs are available,since traditional drug screening models(two-dimensional(2D)cell culture and animal models)often fail in clinical practice The inadequacies of traditional 2D cell culture models are due to their inability to simulate complex pathophysiological conditions and predict the in vivo toxicity of therapeutic compounds.As well,gold standard animal models for drug testing are expensive,time-consuming,and more importantly,the physiological differences between humans and model animals render toxicity and efficacy often times untranslatable.Therefore,the creation of reliable,cost-effective in vitro models which promote the development of anti-cancer drugs and compensate for the drawbacks of conventional models is essential for improving the clinical management of liver cancer.Although tumor-on-a-chip technologies offer a viable approach to screening for drug toxicity,they are still limited in their ability to mimic the extracellular matrix(ECM)to better recapitulate physiologically relevant environments.To better mimic ECM,we developed a biomimetic three-dimensional(3D)liver tumor-on-a-chip that incorporates the essential components from decellularized liver matrix(DLM)and gelatin methacryloyl hydrogel(GelMA)in a dynamic 3D microfluidic cell culture system.Compared to GelMA only,this biomimetic liver tumor-on-a-chip better maintains cell viability and enhances hepatocyte function under dynamic flow conditions.The improved performance of the DLM-GelMA-based tumor-on-a-chip can be attributed to the provision of biochemical factors(e.g.,growth factors),preservation of scaffold proteins,and reconstruction of cellular biophysical responses(e.g.,hardness and shear stress),better mimicking the 3D liver ECM.In addition,this DLM-GelMA-based tumor chip showed a response to acetaminophen and sorafenib in a linear dose-dependent drug toxicity.In summary,our research indicates that DLM-GelMA-based biomimetic liver tumor chips better mimic ECM in vivo and offer great promise for a wide range of pathophysiological and pharmacological studies.