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In work that could pave the way for creating viable artificial liver devices, a University of California, San Diego (UC San Diego) bioengineer is for the first time successfully demonstrating that liver cells can function at an elevated level (5-10 times higher than cells inside the body), outside of the body, for up to six weeks. In prior studies, cells only functioned at levels similar to that inside the body. By optimizing cell performance, fewer cells will be needed to perform the liver’s tasks, thus enabling future external devices to operate more efficiently.

Sangeeta Bhatia, assistant professor of bioengineering at the UC San Diego Jacobs School of Engineering will discuss her work at the BioMEMS & Biomedical Nanotechnology World 2000 conference at 4 p.m. September 25 at the Hyatt Regency in Columbus, Ohio. Her presentation is entitled “Customizing Cellular Microenvironments for Hepatic Tissue Engineering.”

As the most diverse human organ, the liver is responsible for much of metabolism, detoxification of foreign compounds, production of bile for digestion, and secretion of many serum proteins. Liver disease is responsible for over 30,000 deaths per year in the U.S., and transient decompensation of liver function is responsible for more than 300,000 annual U.S. hospital admissions. Current therapy for liver failure is currently largely supportive (fluids and intensive monitoring).

Bhatia says: “The scientific community is working on three main cell-based approaches to improving liver disease treatment: transplantation of liver cells by injection into the blood stream, development of liver tissue substitutes for implantation, and extracorporeal (outside-of –the-body) circuits which house live cells to ‘process’ the patient’s blood. However, a common limitation to all these approaches is the difficulty in maintaining liver-specific functionality of cells once they have been harvested.”

Bhatia has demonstrated the utility of microfabrication tools in reproducing key components of the cellular environment that are known to affect hepatocyte function: cell-cell interactions; cell-extracellular matrix interactions; and cell interaction with soluble factors. Some of the techniques she is employing include soft lithography (using polymers for to make small structures), photolithography (using semiconductor technology for patterning), and electrochemical etching techniques to elucidate the relative role of each of these in hepatic tissue engineering.

Bhatia is excited about the electrochemical etching tool which she is utilizing to lay the foundation for the development a new kind of micro-bioreactor — the external device that will house the cells (i.e. the artificial liver). Specifically, this technique is used to interface cells with silicon chips. “UC San Diego chemistry professor Michael Sailor and I are growing liver cells in individually etched silicon pores to pave the way for engineering an artificial liver. This work is important because it allows for a transition from two-dimensional to three-dimensional studies of structure and function, and reveals how to best house the cells,” explains Bhatia, the only researcher in the world using electrochemical etching in this manner. When it is time for the devices to actually be built, Bhatia foresees the task being completed by the biotech industry.

In 1998, Bhatia also successfully patented a micropatterning technique, which enables her to assemble different liver cells on glass chips in much the same way electrical engineers assemble integrated circuits on silicon chips. She has used this method to prove that hepatocyte function improves when cells are located beside fibroblasts, which form the membrane around the liver.

By using these cutting-edge cell culture experiments to gain greater understanding of the liver’s cells and molecules and their interactions with one another, Bhatia hopes to improve liver disease treatment. Her work could lead to the creation of an external artificial liver device able to effectively hold patients over until transplantation. Of the individuals dying from liver disease each year, most are on a waiting list for a new liver. A full-functioning device would also assist patients requiring another transplant due to a second liver failure, keeping them alive in between livers. Finally, according to Bhatia, “The third application of this technology, which is the real Holy Grail, is to utilize a functional extracorporeal artificial liver to keep patients alive long enough for their liver to recover, thus avoiding an expensive and risky transplant. The liver is one of the only organs in the body that can actually regenerate itself.”

Lastly, Bhatia will chair another session at the conference focusing on cell-based biosensors, another area of research for which she has gained recognition. At the Jacobs School she has worked with electrical and computer engineering professor Sadik Esener on a new way to rapidly assemble and disassemble different types of cells in an array. The technology involves attracting negatively charged cells with positively charged electrodes. This novel yet simple technique could see applications in drug discovery and electronic circuit assembly. By making cell chips, like DNA chips, researchers can carefully monitor cell response to toxins and drugs without injecting animals or humans.

Ranked among the nation’s top ten engineering schools according to the most recent National Academy of Sciences survey and number 15 in the nation by U.S. New & World Report, the Irwin and Joan Jacobs School of Engineering at the University of California, San Diego is an excellent institution in the midst of vibrant growth.

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