Liver Bioengineering: Promise, Pitfalls, and Hurdles to Overcome

Abstract

Purpose of Review-In this review, we discuss the recent advancements in liver bioengineering and cell therapy and future advancements to improve the field towards clinical applications. Recent Findings-3D printing, hydrogel-based tissue fabrication, and the use of native decellularized liver extracellular matrix as a scaffold are used to develop whole or partial liver substitutes. The current focus is on developing a functional liver graft through achieving a nonleaky endothelium and a fully constructed bile duct. Use of cell therapy as a treatment is less invasive and less costly compared to transplantation, however, lack of readily available cell sources with low or no immunogenicity and contradicting outcomes of clinical trials are yet to be overcome. Summary-Liver bioengineering is advancing rapidly through the development of in vitro and in vivo tissue and organ models. Although there are major challenges to overcome, through optimization of the current methods and successful integration of induced pluripotent stem cells, the development of readily available, patient-specific liver substitutes can be achieved.

Development of liver microtissues with functional biliary ductular network

“…To address the donor organ shortage, temporary procedures are developed to bridge the patients until transplantation, such as extracorporeal bioartificial livers, which still cannot compensate for the significant decline in the patients' quality of life (Kumar, Tripathi, & Jain, 2011). Another approach is hepatocyte transplantation, which is restricted by the low liver-engraftment rate and low survival rate of the transplanted hepatocytes (Ibars et al, 2016 with healthy liver cells such as primary or stem-cell-derived hepatocytes and nonparenchymal cells, especially with endothelial cells (Acun et al, 2019;Wang et al, 2017). The repopulation of the IHBDs, which is a critical component of the nonparenchymal population, has not been addressed in the engineered liver grafts until recently (Chen et al, 2019).…”

“…Recent advances in whole liver engineering hold the promise to create transplantable liver grafts by employing the native organ's extracellular matrix (ECM) as the template. In the whole liver engineering approach, the decellularized organ matrix is repopulated with healthy liver cells such as primary or stem‐cell‐derived hepatocytes and nonparenchymal cells, especially with endothelial cells (Acun et al, 2019; Wang et al, 2017). The repopulation of the IHBDs, which is a critical component of the nonparenchymal population, has not been addressed in the engineered liver grafts until recently (Chen et al, 2019).…”

“…The only available treatment of end‐stage liver disease requires orthotopic liver transplantation which is limited by the severe shortage of high‐quality donor organs. To address the gap in available donor organs, there have been advances in creating engineered liver grafts as donor liver substitutes using the whole organ engineering approach (Acun, Oganesyan, & Uygun, 2019; Uygun et al, 2010). Development of fully functional liver substitutes has proven to be complicated, as liver is one of the most complex organs, owing to its challenging functional and structural organization composed of different networks such as vasculature and biliary (Mazza, Al‐Akkad, Rombouts, & Pinzani, 2018; Shafiee & Atala, 2017).…”

Mechanisms Underlying Cell Therapy in Liver Fibrosis: An Overview

“…In the last two decades, multiple cell therapy techniques developed to treat liver fibrosis/cirrhosis gathered knowledge about in vitro cell manipulation improvement and the mechanisms by which transplanted cells could reverse liver fibrosis and promote liver regeneration. This knowledge is now supporting the development of new approaches targeting the generation of in vitro systems that could lead to the development of liver organoids or even whole bioengineered livers for transplantation, aided by emerging sophisticated technologies like 3D (bio)printing, microfluidics, and bioreactors, as recently reviewed elsewhere [176].…”

Current progress in hepatic tissue regeneration by tissue engineering

“…It was shown that administrated cells developed aggregates that block the microvasculature system and led to uneven distribution of cells throughout the parenchyma when cells were introduced through the portal vein. In contrast, by cell transplantation through bile duct, these cells were uniformly distributed throughout decellularized hepatic parenchyma [134]. Some authorities declared the potency of decellularized non-hepatic bioscaffolds such as placental tissue for the restoration of hepatic function [135].…”