Harnessing extracellular niche for liver regeneration: Mechanobiological and immunological unmet needs in decellularised hydrogel-based strategies.

While the liver has astonishing regenerative capabilities, its potential wanes in pathological conditions such as fibrosis, cirrhosis and carcinoma, posing significant global health challenges. The regenerative process is critically dependent on the regulated cellular signals, extracellular matrix (ECM), and its mechanical dynamics. Accordingly, hydrogel-based tissue engineering strategies replicate the liver ECM microenvironmental architecture, including bioactivity, biocompatibility, porosity, and stiffness. Studies have demonstrated that hydrogels, whether derived from natural polymers, synthetic materials, or decellularised liver tissue, can be fine-tuned in their properties. However, many fail to recapitulate the dynamic mechanical, immunological, and vascular cues required for regeneration. Studies have reported that the ECM-derived hydrogel helps preserve the phenotype (KRT, AAT, HNF4α) and functions (CYP activity, albumin & urea production) of hepatocytes. Therefore, dECM-based hydrogels are particularly important for cellular transplantation and the delivery of bioactive agents for liver regeneration. However, deviations from the normal stiffness range of 4-6 kPa may trigger pathological responses, such as hepatic stellate cell (HSC) differentiation into myofibroblasts, leading to liver fibrosis. Ineffective decellularisation can cause scaffold rejection during transplantation. Additionally, because vascularisation is critical given the liver's rich blood supply, endothelial cells tend to spread randomly within hydrogel scaffolds. The random spreading of endothelial cells can lead to the deformation of lobular zonation, which profoundly impacts hepatocyte functions and has been documented to affect conditions like hepatocellular carcinoma and alcoholic/non-alcoholic fatty liver disease (AFLD/NAFLD). In discussing hydrogel-based strategies, the article highlights the importance of addressing immunogenic concerns and matrix remodelling during decellularisation. It also argues that current studies lack integration of vascular-based zonation, which is fundamental to accurately mimicking the liver's native structural and functional architecture. This approach will facilitate the development of relevant patient-specific models.