Liver transplantation is currently the only treatment for patients with end-stage liver disease (ESLD), which is the 12th leading cause of death by disease in the U.S.  The shortage of donor organs remains a major treatment limitation.  Alternatives such as hepatocyte transplantation have shown promise in treating metabolic liver disorders, but low engraftment efficiency and poor long-term efficacy are barriers to broader clinical application.

Another strategy that holds great promise is ex vivo tissue engineering of a functional liver unit that can be implanted and then induced to further expand by host factors after incorporation.  Progress towards building three-dimensional (3D) tissue structure with biocompatible scaffolds has been hindered because these materials prevent normal cell-cell and cell-to-extracellular matrix (ECM) interactions.

The slow scaffold degradation rates also prevent remodeling and vascularization of the implant by the local host milieu. Moreover, it is increasingly clear that the surrounding environment is critically important for the durable function of hepatocytes. In particular, evidence shows that three factors independently improve and prolong primary hepatocyte differentiated functions ex vivo: 1) contact with ECM, 2) interaction with stromal cells (fibroblasts and endothelium), and 3) 3D cell-cell contact.

Dr. Chang's previous work showed that hepatocytes cultured in solid-body rotational bioreactors, which provide minimal shear stress with maximal 3D spatial freedom, produced self-aggregated spheroids with optimal metabolic and synthetic gene expression and function as compared to those cultured in two-dimensional (2D) monolayers.

Research in the The Chang Laboratory for Liver Tissue Engineering builds upon those observations and aims to generate "micro-liver-tissues" with endogenous ECM scaffolds and built-in microvascular networks through co-culture of hepatocytes with stromal cells within solid-body rotational bioreactors. Findings from this research are expected advance the field of tissue engineering by increasing our understanding of hepatocyte cellular response to matrix composition and heterotypic 3D cell contact. It will form the basis for the long-term goal of creating ex vivo engineered liver tissue for therapeutic implantation in patients with ESLD.