Biography
In order to translate regenerative surgery from concept to therapeutic reality, our lab focuses on a complex and vital solid organ, the liver, for several reasons. First, there is great clinical need to develop alternative therapies for end stage liver disease, which is currently treated by liver transplantation and severely limited by the shortage of donor organs. Second, the liver has enormous innate capacity to regenerate in response to injury and metabolic demand, a feature that can be exploited to facilitate development of regenerative surgical approaches. Finally, building a solid organ such as the liver ex vivo remains the most challenging goal in tissue engineering and a problem of sufficient difficulty that is worthy of intense focus.
Our lab has 3 major areas of investigation aimed at advancing the field of liver tissue engineering:
1) Understanding the role of the physical environment and mechano-signal transduction in regulating hepatocyte function in healthy and diseased liver.
2) Elucidating the importance of dimensionality in promoting the generation of highly-functional human stem cell-derived liver organoids.
3) Developing surgical strategies for efficient orthotopic engraftment of hepatocytes and hepatic organoids into the liver.
Education
1990-1992, California State University, Los Angeles, Early Entrance Program
1992-1994, University of California, Los Angeles, Bachelor of Science, Biology
1994-2003, Harvard Medical School and Harvard Graduate School of Arts and Sciences, M.D., Ph.D. Combined Degree
2003-2004 University of California, San Francisco, Surgery, Intern
2004-2009 University of California, San Francisco, Surgery, Resident
2009-2010 University of California, San Francisco, Surgery, Chief Resident
Board Certifications
American Board of Surgery
Collaboration Interests
I am interested in:
- physician scientist
Clinical Expertise
Hernia Repair
Complex Abdominal Surgery
Recurrent Hernia
Laparoscopic Inguinal Hernia Repair
Gastrointestinal Cancer
Intra-abdominal Sepsis
Pancreas Surgery
Soft Tissue Infections
Enterocutaneous Fistula
Program Affiliations
In the News
Grants and Funding
- The Role of Matrix Rigidity and Hepatocyte Mechanotransduction in Fibrotic Liver Disease | NIH | 2017-07-15 - 2022-06-30 | Role: Principal Investigator
- Defining the mechanism of function and engraftment potential of human hepatocyte organoids | American College of Surgeons | 2017-07-01 - 2022-06-30
- Liver tissue engineering in space | NSF/CASIS | 2018-09-01 - 2021-08-31 | Role: Principal Investigator
- Pioneering regenerative surgery - Mechanisms of cell death and regeneration in liver treated with non-thermal irreversible electroporation (NTIRE) | NIH | 2018-01-01 - 2020-12-31 | Role: Principal Investigator
- Using organoids to determine gravity effects on organogenesis and vasculogenesis | NASA | 2018-09-01 - 2020-08-31 | Role: Principal Investigator
- Innovating a method of in situ decellularization followed by organoid engraftment | Open Philanthropy Project | 2017-07-01 - 2020-06-30 | Role: PI
Research Narrative
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.
Research Interests
Liver Tissue Engineering
Publications
- Hepatocyte Rho-associated kinase signaling is required for mice to survive experimental porphyria-associated liver injury.| | PubMed
- Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors.| | PubMed
- Irreversible Electroporation of the Liver Increases the Transplant Engraftment of Hepatocytes.| | PubMed
- Isochoric Supercooling Organ Preservation System.| | PubMed
- An exploratory study on isochoric supercooling preservation of the pig liver.| | PubMed
- Self-Assembled Matrigel-Free iPSC-Derived Liver Organoids Demonstrate Wide-Ranging Highly Differentiated Liver Functions.| | PubMed
- Pancreatic islets implanted in an irreversible electroporation generated extracellular matrix in the liver.| | PubMed
- Self-assembled Matrigel-free iPSC-derived liver organoids demonstrate wide-ranging highly-differentiated liver functions| | UCSF Research Profile
- Neutrophils are important for the development of pro-reparative macrophages after irreversible electroporation of the liver in mice.| | PubMed
- Focal adhesion kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation.| | PubMed