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Bioengineered livers for transplants: How close are we to success?

Liver bioengineering has been a hotbed of intense research in the past few decades. Ever since the concept of whole liver acellular scaffolds generated by perfusion decellularization was introduced, liver bioengineering has focused on making a success of bioengineered livers fit for liver transplants.

Liver development is a stepwise process that includes distinct biological events. Embryologically, the foregut endoderm transforms to hepatic lineage and forms the early hepatic progenitor stem cells, the hepatoblasts, with the potential to differentiate into liver cells, and bile duct epithelial cells. These cells go on to mature as adult cells at various stages along with differentiating into either hepatocytes or cholangiocytes.

The stem cell microenvironment plays an important role in regulating stem cell specification and differentiation into mature cell types. 

Cell behavior is highly influenced by various complicated biochemical signaling as well as its mechanical environment. This includes the stiffness of the surrounding tissue, fluid shear stress, and interstitial fluid pressure that also respond to liver injury. This extra cellular matrix is only a minor constituent of the liver, but it has an essential role by providing a structural framework to the liver cells.

It also plays a vital role in facilitating cell attachment and migration and controlling differentiation, repair and development. The connection between the cell and the extra cellular matrix also enables the cells to endure the constant changes in the mechanical forces without being detached.

Variations in the stiffness of the tissue in response to liver damage states such as liver cirrhosis and fibrosis may lead to alterations in the normal behavior of a particular cell and the extra cellular matrix.  With this basic knowledge as a background, a potential application emerged – one of the use of liver matrices for the bioengineering of human livers.

As early as 2005, researchers termed the matrices as bioscaffolds, which preserve their original tissue microarchitecture and an intact vascular network that can be readily used as a route for recellularization by perfusion of different cell populations with defined culture media.

This organ engineering approach has several advantages over the injection of cell suspensions into solid organs. The matrices provide sufficient volume for the transplantation of an adequate cell mass up to whole-organ equivalents, without oxygen and nutrient limitations, since continuous perfusion of oxygenated culture media is provided. Using the organ scaffold technology, several laboratories have recently bioengineered livers using human or animal cells.

These bioengineered livers exhibit some of the key functions of a native liver: secretion of urea and albumin, and drug metabolism. The basic endothelialized vascular network is also maintained, which is crucial factor for transplant surgery; however, after a few hours blood clotting can block the network and, therefore there became an urgent need to increase the efficiency of organ scaffold’s re-vascularization, to avoid blood clotting after in vivo anastomosis and make transplantation of bioengineered organs possible.

To make bioengineered livers, the two most important ingredients are hepatic cells and supportive materials. In the past decades, dozens of hydrogels have been developed to act as supportive materials. Currently none of the hydrogels are suitable for in vivo transplantation that can suitably mimic the liver extra cellular matrix.

A hydrogel composed of alginate and cellulose nanocrystal was found suitable for bio-printing of liver-mimetic honeycomb 3D structures. Recently, synthetic hydrogels are popular as they have a defined composition and structure. They are less complex than biological hydrogels and have stronger mechanical structure, of no animal origin, can be well controlled, commercially friendly, and relatively easier to be FDA-approved.

Polyethylene glycol (PEG) hydrogels are being widely used to provide a biocompatible matrix enabling primary human fetal liver cells to self-assemble into a 3D configuration and preserve advanced hepatic functions for at least five months.

Research in liver tissue engineering is ongoing aiming at future clinical applications in hepatology.