Researchers advance microtissue technology to support liver disease research, potential therapeutics
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Each year in the U.S., approximately 5,600 people die while waiting for a liver transplant. End-stage liver failure, caused by cirrhosis, non-fatty alcoholic liver disease, autoimmune liver disease, viral hepatitis, medication overdose, toxins, heart failure, and genetic diseases, currently has limited treatment options beyond an organ transplant from a donor.
Robert Uyetani Collegiate Professor, Richard and Loan Hill Department of Biomedical Engineering Associate Department Head, and Director of Graduate Studies Salman Khetani and his team have addressed this critical challenge through innovative research. They used promising microtissue technology using high-throughput droplet microfluidics to engineer 3D microtissues from induced pluripotent stem cell-derived hepatocyte-like cells (iHeps).
“A person only needs about 10% of their liver mass for basic survival functions without intense activity,” Khetani said. “Our work aims to create robust building blocks that can support future developments of larger liver constructs, potentially bridging the gap for patients awaiting organ transplants.”
Khetani collaborated with former PhD students Regeant Panday and Kerry M. Rogy, and former post-doctoral student Yong Duk Han, to use an existing Nobel Prize-winning technique that uses skin cells or blood cells and converts them to stem cells, also called induced pluripotent stem cells (IPSCs). From there, those stem cells can be differentiated outsidethe body into liver-like cells, called hepatocytes. More than 70% of the liver is made of hepatocytes.
Historically, previous efforts to achieve the mature functionality of these hepatocyte-like cells in vitro have been challenging, with other methods achieving only about 10% of native liver cell functionality. To overcome this limitation, Khetani and his team developed a dynamic microfluidic environment mimicking liver development, significantly enhancing the maturity and functionality of the engineered hepatocytes.
“If the cells in these droplets achieve greater maturity, they could be extremely valuable for drug discovery, tackling liver disease, such as alcoholic liver disease, hepatitis B infection, and other viral infections,” Khetani said. “Additionally, these droplets could serve as bio-inks for printing larger, more complex liver structures for potential implantation. The versatility of this engineered platform also makes it an excellent tool for studying basic liver biology.”
A key innovation of Khetani and his team’s approach is the adaptation of high-throughput microfluidic techniques, enabling the simultaneous generation of tens of thousands of collagen-based droplets, compared with traditional single-droplet methods.
“While the underlying platform was established in one of our earlier publications, our novel application using human iHeps and our sequential addition of embryonic fibroblasts and liver endothelial cells significantly enhances hepatocyte maturity,” Khetani said.
Khetani expressed optimism that continued advancements from this research may one day support the development of fully engineered liver tissues for therapeutic applications.
Their research was published in Acta Biomaterialia, a leading journal in biomaterials and biomedical engineering.