Programming a pro-regenerative microenvironment via a photocurable albumin-matrix hydrogel for hepatic tissue reconstitution

Liver tissue engineering (LTE) is constrained by poor hepatocyte survival and functional deterioration after transplantation. A central challenge is to support hepatocyte growth and expansion in vitro while preserving polarity and specialized hepatic functions. Graft immunogenicity and surgical intervention trigger inflammation and immune rejection, further compromising transplanted cell survival and performance. Limited vascularization also restricts graft survival, function, and expansion in vivo. Here, we developed a photocurable biomimetic composite hydrogel by combining bovine serum albumin methacrylate (BSA-MA) with decellularized liver extracellular matrix (dECM) derived from α1,3-galactosyltransferase knockout (GTKO) Bama miniature pigs, and used it to encapsulate primary hepatocyte spheroids to construct functional engineered hepatic tissue (EHT). The BSA-MA-dECM hydrogel exhibited favorable physicochemical properties, cytocompatibility, and histocompatibility, while sustaining and enhancing hepatocyte viability, function, and polarity. It also reduced inflammatory responses, promoted macrophage polarization toward the M2 phenotype, and stimulated angiogenesis through VEGF and FGF upregulation as well as PI3K-AKT pathway activation. Thus, the hydrogel established a pro-regenerative microenvironment that supported hepatocyte expansion and graft vascularization. Following implantation into the omentum of rats with CCl₄-induced liver injury, the EHT underwent rapid vascularization and showed robust expansion in vivo. It alleviated liver injury, collagen deposition, and fibrosis, while transcriptomic analysis revealed enhanced metabolic repair and cytoprotective programs along with the suppression of inflammatory and fibrotic pathways. Overall, these findings identify BSA-MA-dECM as a versatile photocurable hydrogel for hepatocyte delivery and provide a broadly applicable strategy that integrates immune modulation with vascular induction for scalable EHT construction and liver regenerative therapy.