From scaffold to function: A systematic review on dLECM-based hydrogels for liver tissue engineering - Fabrication,
Ziba Majidi1, Mohammad Mahdi Sarvi2,3, Mohammad Aref Rajabi2
1Department of Medical Laboratory Science, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
Background:
Liver tissue engineering is a rapidly advancing field aiming to address the critical shortage of donor organs and improve in vitro models for drug screening and disease modeling. Decellularized liver extracellular matrix (dLECM)-based hydrogels have emerged as a leading biomaterial platform due to their ability to preserve the native biochemical composition, microstructure, and biomechanical cues of the liver microenvironment. This systematic review aims to comprehensively evaluate the methodologies, physicochemical properties, biological performance, and translational applications of dLECM-derived hydrogels in liver tissue engineering, with a focus on fabrication protocols, functional outcomes, and challenges toward clinical implementation.
Methods:
A systematic search was conducted in accordance with PRISMA 2020 guidelines across PubMed, Scopus, Google scholar and Web of Science. A total of 74 studies were included after screening 536 records identified from databases. Data were extracted on tissue source, decellularization techniques, dECM solubilization, hydrogel formulation, crosslinking methods, physicochemical characterization, and in vitro/in vivo functional outcomes.
Results:
The majority of studies utilized porcine or rodent livers, with immersion/agitation and vascular perfusion as the primary decellularization methods. Sodium dodecyl sulfate (SDS), Triton X-100, and ammonium hydroxide were the most common detergents, often combined with enzymatic treatments (e.g., DNase, trypsin) to enhance nuclear removal. dLECM was predominantly solubilized using pepsin in acidic conditions (acetic acid or HCl) and reconstituted into hydrogels via thermal gelation at 37 °C. The resulting hydrogels demonstrated excellent biocompatibility, supporting high viability and enhanced functional activity-including albumin secretion, urea synthesis, and expression of hepatic markers (e.g., CYP450, CK18, AFP)-in primary hepatocytes, HepG2 cells, and stem cell-derived hepatocyte-like cells. Advanced applications such as 3D bioprinting, organoid culture, and in vivo transplantation in liver injury models (e.g., CCl4-induced fibrosis, acute liver failure) further highlight the therapeutic potential of these biomaterials. However, significant heterogeneity was observed in decellularization efficacy, residual DNA content (ranging from 1.04 % to 21.74 ng/mg), and mechanical characterization, with many studies lacking standardized reporting of storage modulus (G') or gelation kinetics.
Conclusion:
dLECM-based hydrogels represent a highly promising and biomimetic platform for liver tissue engineering, capable of supporting complex cellular functions and regenerative outcomes. Despite significant progress, standardization of fabrication protocols, comprehensive physicochemical characterization, and long-term in vivo safety assessments are essential to advance these materials toward clinical translation.
