Liver tissue engineering: From implantable tissue to whole organ engineering

Abstract

The term "liver tissue engineering" summarizes one of the ultimate goals of modern biotechnology: the possibility of reproducing in total or in part the functions of the liver in order to treat acute or chronic liver disorders and, ultimately, create a fully functional organ to be transplanted or used as an extracorporeal device. All the technical approaches in the area of liver tissue engineering are based on allocating adult hepatocytes or stem cell-derived hepatocyte-like cells within a three-dimensional structure able to ensure their survival and to maintain their functional phenotype. The hosting structure can be a construct in which hepatocytes are embedded in alginate and/or gelatin or are seeded in a pre-arranged scaffold made with different types of biomaterials. According to a more advanced methodology termed three-dimensional bioprinting, hepatocytes are mixed with a bio-ink and the mixture is printed in different forms, such as tissue-like layers or spheroids. In the last decade, efforts to engineer a cell microenvironment recapitulating the dynamic native extracellular matrix have become increasingly successful, leading to the hope of satisfying the clinical demand for tissue (or organ) repair and replacement within a reasonable timeframe. Indeed, the preclinical work performed in recent years has shown promising results, and the advancement in the biotechnology of bioreactors, ex vivo perfusion machines, and cell expansion systems associated with a better understanding of liver development and the extracellular matrix microenvironment will facilitate and expedite the translation to technical applications. (Hepatology Communications 2018;2:131-141).

Figure 1

Applications of liver tissue engineering. The direct infusion of hepatocytes in humans is an established methodology proposed to treat inborn errors of metabolism but is characterized by short‐term clinical benefits. Alternative strategies have been developed, including implantation of 3D constructs and tissue/whole‐organ engineering. At present, the clinical applicability of these strategies is inversely proportional to the long‐term cellular engraftment, which is indeed the ultimate goal. In addition, implantation of 3D constructs of liver cells can achieve a replacement of the hepatic mass below 5% and is therefore indicated only for inborn errors of metabolism and to a much lesser extent for acute liver failure. Based on current technological development, engineering of large portions of liver tissue (e.g., the left liver lobe) or even of the whole organ is able to provide less than 30% of the liver mass and could be used to treat acute and even chronic liver failure as an extracorporeal device.

Figure 2

Technical standards for liver tissue engineering. In vitro cell engraftment, biocompatibility, and maintenance of cell function are the key requisites for the clinical use of implantable liver constructs. After in vivo implantation, engineered constructs need long‐term maintenance of their metabolic function associated with biodegradability and absence of fibrotic reaction. The whole‐organ engineering approach presents more challenges compared to implantable constructs. Indeed, this approach requires a high cell number for recellularization, extensive or complete re‐endothelization, and maintenance of cell viability and function. In addition, before the engineered tissue can be proposed for clinical use, preclinical studies need to demonstrate the absence of thrombogenic reaction and the absence of an immunogenic response in addition to the long‐term maintenance of metabolic function.