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
2006-2008 University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, Liver Tissue Engineering, American College of Surgeons Research Scholarship, Research Fellow
2010-2011 University of California, San Francisco, Minimally Invasive Surgery and Bariatric Surgery, Clinical Fellow
Board Certifications
American Board of Surgery
Collaboration Interests
I am interested in:
- PhysicianScientist
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 | Role:
- 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
- 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
- Jejunal prolapse and incarceration following feeding tube exchange.| | PubMed
- Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling.| | PubMed
- Intra-Vital Imaging Demonstrates Robust Recruitment of Neutrophils after Irreversible Electroporation Tissue Ablation.| | UCSF Research Profile
- Normal and fibrotic liver parenchyma respond differently to irreversible electroporation.| | PubMed
- Liver Fibrosis: Current Approaches and Future Directions for Diagnosis and Treatment.| | UCSF Research Profile
- Molecular and histological study on the effects of non-thermal irreversible electroporation on the liver.| | PubMed
- Using non-thermal irreversible electroporation to create an in vivo niche for exogenous cell engraftment.| | PubMed
- Reply.| | PubMed
- Direct orthotopic implantation of hepatic organoids.| | PubMed
- Force-dependent breaching of the basement membrane.| | PubMed
- Hepatic Focal Adhesion Kinase Signaling Modulates Development of Liver Fibrosis.| | UCSF Research Profile
- Gastrointestinal Zygomycosis Masquerading as Acute Appendicitis.| | PubMed
- Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.| | PubMed
- Spaceflight alters expression of microRNA during T-cell activation.| | PubMed
- Spaceflight impairs antigen-specific tolerance induction in vivo and increases inflammatory cytokines.| | PubMed
- Molecular mechanisms underlying the enhanced functions of three-dimensional hepatocyte aggregates.| | PubMed
- The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity.| | PubMed
- Monolayer and spheroid culture of human liver hepatocellular carcinoma cell line cells demonstrate distinct global gene expression patterns and functional phenotypes.| | PubMed
- Caudate split for open and laparoscopic liver resections.| | PubMed
- Implementation of a multidisciplinary treatment team for hepatocellular cancer at a Veterans Affairs Medical Center improves survival.| | PubMed
- Injury in the elderly and end-of-life decisions.| | PubMed
- Recovery from EAE is associated with decreased survival of encephalitogenic T cells in the CNS of B7-1/B7-2-deficient mice.| | PubMed
- Genetic background determines the requirement for B7 costimulation in induction of autoimmunity.| | PubMed
- Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity.| | PubMed
- Role of the B7-CD28/CTLA-4 pathway in autoimmune disease.| | PubMed