Engineering liver

Abstract

Interest in “engineering liver” arises from multiple communities: therapeutic replacement; mechanistic models of human processes; and drug safety and efficacy studies. An explosion of micro- and nano-fabrication, biomaterials, microfluidic, and other technologies potentially afford unprecedented opportunity to create microphysiological models of human liver, but engineering design principles for how to deploy these tools effectively towards specific applications, including how to define the essential constraints of any given application (including available sources of cells, acceptable cost, and user-friendliness) are still emerging. Arguably less appreciated is the parallel growth in computational systems biology approaches towards these same problems – particularly, in parsing complex disease processes from clinical material, building models of response networks, and in how to interpret the growing compendium of data on drug efficacy and toxicology in patient populations. Here, we provide insight into how the complementary paths of “engineering liver” – experimental and computational – are beginning to interplay towards greater illumination of human disease states and technologies for drug development.

Interactions of Hepatitis B Virus Infection with Nonalcoholic Fatty Liver Disease: Possible Mechanisms and Clinical Impact

“…However, primary adult hepatocytes are notorious for their survival and phenotype maintenance in routine cell culture systems; meanwhile, hepatoma cell lines are generally lack of convincible abilities to recapitulate the physiologic process inside the in vivo hepatocytes; therefore, they are restrainedly used for the validation of molecular biochemical reactions or very preliminary exploration of hypothesis [88,90]. With advances in the basic understanding of physiologic or pathophysiologic tissue morphogenesis, it is getting more clear that extracellular microenvironment, including both the chemical and physical elemental cues in a multicellular organism, is among the determinant factors for developing and maintaining the functional behavior and structural feature of the individual cells and then the tissue construct [91,92].…”

“…During the past 15 years, in the field of viral hepatitis, especially the HCV and HBV, experimental models including innovative animal models [82][83][84][85] and advanced Dig Dis Sci hepatic tissue engineering cellular models [86][87][88] have been substantially contributing for the rapid progress in understanding details of the infection process and developing effective therapeutics for antivirus. Because HBV restrictedly infects human liver, several animal models such as chimpanzees, tupaias, Peking ducks or woodchucks infected by HBV-related hepadnaviruses, and engineered mice model have been established for different purposes in the study of HBV [89].…”

A Pathway to Personalizing Therapy for Metastases Using Liver-on-a-Chip Platforms

“…Other considerations that should be included are common medium to accommodate heterogeneous cell types in the system and precise mechatronics to continuously supply nutrients at physiologic concentration and remove cellular wastes. Comprehensive requirements to ‘engineer’ the liver are extensively discussed elsewhere [56]. There are several platforms that have been constructed according to the aspects mentioned above such as LiverChip microphysiologic system (MPS), PEARL perfusion liver system and sequentially layered, self-assembly liver (SQL-SAL) platform.…”

“…Moreover, hepatocytes under these conditions tend to lose the functionality of differentiated cells in terms of CYP activities and albumin (ALB) secretion [68]. Under physiological flow in perfused 3D ex vivo hepatic MPS, this functionality can be maintained for 30 days [56,57,69–73]. Another main advantage of this source is that millions of cells can be isolated from each gram of liver tissues [74,75].…”

The Microphysiology Systems Database for Analyzing and Modeling Compound Interactions with Human and Animal Organ Models

“…Microfluidic human organ models, MicroPhysiology Systems (MPS), 1–6 have the potential to dramatically improve the prediction of drug safety and efficacy in humans, early in the discovery and development process. In addition, combining MPS into multi-organ systems, 2 including the ultimate goal of a human on-a-chip, 2, 7 will further enable the prediction of safety liabilities that result from organ interactions, such as liver metabolism that produces metabolites that are toxic to other organs.…”