Liver spheroids on chips as emerging platforms for drug screening

Liver plays a critical role in drug metabolism and nowadays multi-cellular culture systems aiming at imitating liver-specific morphology and functionality are advancing robustly.Numerous immortalized or stem cell-induced hepatic cell lines have been investigated to enhance the hepatic phenotype in establishing co-culture systems.Owing to the robust progresses of microtechnology and bioengineering,two-dimensional(2D)co-cultures such as sandwich culture and micropatterned co-culture systems have emerged.Controllably arranging the hepatocytes and fibroblasts allows bio-mimic homotypic and heterotypic interactions,and the miniaturized co-culture platform realizes high-throughput and sensitive drug screening.Yet,to address the rapid dedifferentiation and the decreased maintenance of hepatic functions existing in 2D cellular systems,various three-dimensional(3D)and dynamic hepatocyte co-culturing formats have been established to obtain more physiologically relevant liver microsystems and prolonged hepatic functionalities,such as spheroid barcodes,liver organoids,bioengineered hepatic spheroids,and microfluidic perfused liver-on-a-chip.In this review,we first introduce the typical structural color spheroid barcodes which facilitate multiple screening and testing.Then we sketch various advances in liver-imitating cellular co-culture protocols through representative examples.Meanwhile,we summarize current difficulties and propose the prospects of bioengineered liver-on-barcode systems for reliable and high-throughput drug screening.

Developing tissue engineering strategies for liver regeneration

The regenerative function of liver can be destroyed by viral infection,drug poisoning and tumorigenesis,resulting in irreversible damage.Numerous approaches in promoting liver repair intend to replace liver transplantation,which is faced with a shortage of donors.Owing to the significant advantages in cell programming and bioscaf-fold engineering,liver tissue engineering is considered to be the most promising alternative for mimicking liver microstructure,maintaining hepatic function or implanting whole liver.Cell sources gradually develop from pri-mary hepatocytes,tumor cells,stem cell-induced cells to multiple cell coculture formats,spheroids and organoids,which have realized the improvement of cell function,overcome the problem of large-scale cell expansion and avoid the risk of immune rejection.Scaffolds,biocompatible materials are applied as cell carriers,and decel-lularized scaffolds and three-dimensional bioprinting liver pipeline structures are also used to accelerate cell colonization and proliferation.We enumerate sufficient research concerning liver tissue engineering in this re-view,including single and multiple cell sources,implantable and extracorporeal scaffold materials,and so on,providing critical conclusions and future implications of tissue engineering in liver regenerative applications.