The advancements in developing in vitro models for drug discovery such as organoids and organ-on-chips using multi-cellular arrangements and pluripotent stem cells have helped circumvent some of the financial and ethical challenges in drug discovery, such as drug attrition-related losses and animal models.
In a recent review published in Materials Today Bio, researchers examined the development and application of liver-on-chips and the factors preventing its widespread use in drug discovery.
They also focused on collaborative research with pharmaceutical industries that can emphasize the translational potential of liver-on-chips for predicting hepatic toxicity and hepatic clearance of drugs.
Study: Liver-on-chips for drug discovery and development. Image Credit: RaffMaster/Shutterstock.com
Background
The liver plays a vital role in detoxification and drug metabolism, making the development of reliable and efficient in vitro liver models imperative for drug discovery.
The difference in enzyme profiles between animal models and humans and the high rate of hepatoxicity-associated drug failures compound the need for suitable in vitro liver models.
The liver-on-chip technology improves over traditional hepatocyte cultures courtesy of the improved cell viability and metabolic activity over longer periods, as well as the ability of the model to mimic the vasculature, extracellular matrix, dynamic physiological flow, and the multicellular arrangement of cells found in vivo conditions.
Liver-on-chip technology also has the advantage of connecting with other organ-on-chip systems such as kidney- or gut-on-chips, to explore the pharmacokinetic profile of orally administered drugs comprehensively.
Although liver-on-chip platforms provide a promising alternative to animal models in drug discovery, there are challenges associated with reliable prediction of hepatotoxicity and drug clearance and the system's scalability for industrial applications that need to be addressed to ensure successful industrial applications.
Physiological mimicry of liver-on-chips
Liver-on-chips replicate the in vivo physiological conditions through various methods. One of them involves fluidic flow and its role in the maturation of liver tissue.
Dynamic microfluidic cultures extend cell survival by improving convection-mediated nutrient transport, enhancing the delivery of drugs to cultured cells, and improving inter-organ communication in systems consisting of multiple organ-on-chips.
Furthermore, the increase in shear stress applied to liver-on-chips replicates the conditions in the liver following a partial-hepatectomy, where increased blood flow elevates the levels of paracrine signaling molecules such as hepatocyte growth factor, which results in the proliferation of hepatocytes.
Dynamic microfluidic flow also results in a similar increase in hepatic proliferation as compared to static hepatocyte cultures. It shows an increase in functional markers such as the production of urea, albumin, and cytochrome P450 enzymes.
Co-culturing of hepatocytes with non-parenchymal cells such as liver sinusoidal endothelial cells, Kupffer cells, and stellate cells has been found to improve the proliferation and maturation of hepatocytes because of the hepatocyte growth factor produced by these cells.
Additionally, integrating vascular networks with organ parenchyma in organ-on-chips using dynamic flow to induce vessel formation also enhances the viability and proliferative ability of the cells in the culture.
In vitro to in vivo extrapolation and DILI predictions
One of the aspects of hepatic clearance discussed in the review was the application of liver-on-chips in in vitro to in vivo extrapolation, where the experimental observations or results are quantitatively and qualitatively transposed to predict hepatic clearance in vivo accurately.
Traditional cultures such as primary human hepatocyte cultures or liver microsomes often show close to three-fold underprediction of the in vivo hepatic clearance and are unsuitable for compounds that are metabolically stable because of the loss of metabolic activity over a short period.
Liver-on-chips mimic the in vivo conditions more accurately using physiological flow and maintain a higher level of metabolic activity, providing a more suitable system for extrapolating experimental findings to in vivo systems.
The researchers also addressed the issue of hepatic toxicity predictions and the various mechanisms of drug-induced liver injury (DILI). DILI remains one of the major causes of drug attrition since animal models often fail to detect drug compounds that could be toxic to humans.
Assays that apply to human biological systems are essential for accurate DILI predictions, and liver-on-chips are a promising option for predicting hepatotoxicity due to cholestasis, mitochondrial dysfunction, and immune responses.
Emerging applications and challenges
Rapid advances in organ-on-chip technology are resulting in the integration of liver-on-chips with the complex physiology of the human liver to develop organoids-on-chips, which can further enhance drug clearance and hepatotoxicity predictions.
Some major challenges in liver-on-chips technology include inadequate validation standards and guidelines. Furthermore, the current throughput of liver-on-chips technology, compared to traditional methods, continues to be lower.
Simplifying operational procedures, and lowering production costs are essential for the widespread industrial adaptation of liver-on-chips technology.
Conclusions
To summarize, the review presented a comprehensive understanding of the current achievements in live-on-chips technology and its applications in accurately extrapolating in vitro findings into in vivo conditions and predicting DILI due to mitochondrial dysfunction and immune responses.
The reviewers also provided a detailed discussion of the challenges in liver-on-chips technology that need to be addressed for large-scale industrial applications.
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