Biomaterials for Liver Tissue Engineering

End-stage liver diseases such as acute and chronic liver failure, cirrhosis, and liver cancer are serious health threats with high morbidity and mortality. There is currently no way to compensate for the absence of liver function in the long term, although liver dialysis techniques can be used in the short term. Artificial livers are yet to be developed to promote long term replacement in the absence of the liver. As of now, liver transplantation is the only option for complete liver failure, but limited by a severe shortage of donor organs, high cost of treatment, and lifetime immunosuppression [124]. Inquiry into materials for liver transplantation research has been necessary. Researchers intend to reconstruct the liver by tissue engineering, specifically, reseeding hepatocytes or stem cells in scaffolds to reconstruct liver like tissue to compensate liver function [125]. One of the main limiting factors hindering liver tissue engineering application is the lack of an ideal scaffold, which not only has all the necessary microstructural and ECM such as collagen, mucopolysaccharide and growth factor for cell adhesion, functioning, proliferation, migration, differentiation, but also provides microvascular networks for oxygen and nutrient transport, as well as metabolite excretion [126, 127]. So far, the types of biomaterials used in liver tissue engineering mainly include synthetic/natural polymeric scaffolds, decellularized scaffolds, and hydrogels [128].

Three-dimensional synthetic polymer scaffolds could facilitate liver tissue regeneration. Several types of biocompatible and biodegradable polymers, including PLGA, PCL, poly (glycolic acid) (PGA), and poly (Llactic acid) (PLLA) have been used to fabricate 3D scaffolds [129]. These synthetic polymers have advantages in pro-accessibility, good mechanical properties and manipulating degradation rate. Importantly, they have been approved by the Food and Drug Administration for specific applications in the human body. However, synthetic polymer scaffolds manufactured with current technology lack cell recognition signals and hinder successful cell seeding because of their hydrophobic trait [130]. Therefore, to encourage cell ingrowths, the effective hybridization with bioactive molecules is needed [131]. Moreover, synthetic polymers have the problem of potential toxicity from acidic degradation products [132].

Three-dimensional scaffolds fabricated with naturally derived polymers are suitable for cell activity and interaction because natural polymers contain numerous integrin-binding sites and growth factors [130]. Natural polymers used for liver tissue engineering include hyaluronate, collagen, alginate, and chitosan. However, scaffolds fabricated purely from these molecules exhibit poor mechanical strength and are not easy to handle. Meanwhile, controlling the rate and mode of degradation is difficult when compared with synthetic polymer scaffolds [133].

Injectable hydrogels may be useful for efficient and minimally invasive cell transplantation, especially for defects that are irregular in shape because of their in situ polymerization. The advantages of hydrogels include their viscoelastic characteristics, biocompatibility, easiness of fabrication in different shapes, and quickly mass transfer between nutrients and cells. Various types of hydrogel systems have been prepared from synthetic or natural polymers and applied as scaffold platforms for hepatocyte culture and transplantation. Due to the variability, the manufacturing techniques of hydrogels need to be further studied and developed [134, 135].

Hepatocytes and hepatic linage cells require 3D scaffolds with perfect ECM structures in order to maintain their hepatic stability and liver-specific functions. Thus, decellularized organ scaffold became one of the most popular biomaterials in liver tissue engineering because of its advantages of favorable biocompatibility, native ECM and vascular system which provide incomparable convenience for tissue culture and in vivo implantation. Researchers from different groups demonstrated the feasibility of recellularization of hepatocytes or stem cells on decellularized liver scaffold and compensatory liver function of organoids in rodent, goat and swine, that creates a decellularization upsurge all over the world [136-140]. There has also been report to use three-dimensional decellularized splenic scaffold as potential liver scaffold, considering the more extensive organ source [141].

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