text: The liver is a major organ of metabolism, and it is related to glycogen storage, decomposition of red blood cells, certain protein and hormone synthesis, and detoxification. Within these functions, its detoxification response is essential for new drug development and clinical trials. In addition, because of its multi-functions, the liver is prone to many diseases, and liver diseases have become a global challenge.
  Liver-on-a-chip devices utilize microfluidic techniques to simulate the hepatic system by imitating complex hepatic lobules that involve liver functions. Liver-on-a-chip devices provide a good model to help researchers work on dysfunction and pathogenesis of the liver with relatively low cost. Researchers use primary rat hepatocytes and other nonparenchymal cells. This coculture method is extensively studied and is proved to be beneficial for extension of hepatocytes survival time and support the performance of liver-specific functions. Many liver-on-a-chip systems are made of poly(dimethylsiloxane) (PDMS) with multiple channels and chambers based on specific design and objective. PDMS is used and has become popular because it has relatively low price for raw materials, and it is also easily molded for microfluidic devices. But PDMS can absorb important signaling molecules including proteins and hormones. Other more inert materials such as polysulfone or polycarbonate are used in liver-chips.
  A study by Emulate researchers assessed advantages of using liver-chips predicting drug-induced liver injury which could reduce the high costs and time needed in drug development workflows/pipelines, sometimes described as the pharmaceutical industry's "productivity crisis". Zaher Nahle subsequently outlined 12 "reasons why micro-physiological systems (MPS) like organ-chips are better at modeling human diseases".
  One design from Kane et al. cocultures primary rat hepatocytes and 3T3-J2 fibroblasts in an 8*8 element array of microfluidic wells. Each well is separated into two chambers. The primary chamber contains rat hepatocytes and 3T3-J2 fibroblasts and is made of glass for cells adhesion. Each of primary chamber is connected to a microfluidic network that supply metabolic substrate and remove metabolic byproducts. A 100 µm thick membrane of PDMS separates the primary and secondary chamber, allowing the secondary chamber to be connected to another microfluidic network that perfuses 37 °C room air with 10% carbon dioxide, and producing air exchange for rat hepatocytes. The production of urea and steady-state protein proves the viability of this device for use in high-throughput toxicity studies.
  Another design from Kang et al. cocultures primary rat hepatocytes and endothelial cells. A single-channel is made first. Hepatocytes and endothelial cells are then planted on the device and are separated by a thin Matrigel layer in between. The metabolic substrate and metabolic byproducts share this channel to be supplied or removed. Later, a dual-channel is made, and endothelial cells and hepatocytes cells have their own channels to supply the substrate or remove the byproduct. The production of urea and positive result on hepatitis B virus (HBV) replication  test shows its potential to study hepatotropic viruses.
  There are a few other applications on liver-on-a-chip. Lu et al. developed a liver tumor-on-a-chip model. The decellularized liver matrix (DLM)-gelatin methacryloyl (GelMA)-based biomimetic liver tumor-on-a-chip proved to be a suitable design for further anti-tumor studies. Zhou et al. analyzed alcohol injures on the hepatocytes and the signaling and recovery.
  The liver-on-a-chip has shown its great potential for liver-related research. Future goals for liver-on-a-chip devices focus on recapitulating a more realistic hepatic environment, including reagents in fluids, cell types, extending survival time, etc.