Putting liver on a chip

PRINCETON, N.J.—With a $5 million commitment from Battelle Ventures LP and its Tennessee affiliate, Innovation Valley Partners, Hepregen Corp. has been spun out from the Massachusetts Institute of Technology (MIT).

 

The company's first goal will be advancing and commercializing a microliver platform into the drug development pipeline for the pharmaceutical and biotechnology sectors, says Battelle Ventures General Partner Mort Collins. Hepregen received the first $3 million from the funds last summer, with the additional $2 million available at management's request.

Leading Hepregen as president and CEO will be Bernadette "Bonnie" Fendrock, a 15-year biotech veteran who co-founded the Medford, Mass.-based company in July 2007 along with Drs. Sangeeta Bhatia and Salman Khetani, the two MIT scientists behind the technology. Hepregen has an exclusive license agreement with MIT for 10 patents and patent applications related to the microliver platform technology.

 

An established health and life science sector investor, Battelle Ventures focuses on breakthrough technologies that "fill a key market need and mitigate marketplace pain." The fund recognized in Hepregen's toxicity testing platform the potential to minimize drug failures and allow iterative improvements to drug candidates in development, which could save pharmaceutical companies millions in R&D costs and in the downstream catastrophic costs of drug recall, potential liability and patient harm.

 

"Hepregen's platform offers a previously unavailable tool for predicting the chronic toxicity—long-term, low-dose exposures as in the marketplace—of candidate drugs prior to human clinical trials," says Collins, who is chairman of the Hepregen board of directors.

 

"Liver toxicity is the leading cause of preclinical failures of drugs, post-market drug withdrawals, black-box warnings and acute liver failures," he notes. "With the typical cost of developing a drug and taking it to market being more than a billion dollars, improved predictivity can dramatically increase drug-development success rates and greatly improve economics for pharmaceutical and biotech companies."

 

"Hepregen is producing a unique, bioengineered microliver platform that is highly functional, stable, and more representative of an in vivo liver," Fendrock states. "Innovations extend to the functionality of the platform imparted by our tissue engineering techniques and microfabrication technologies. Together, they enable development of integrated tissue models in a 'liver on a chip.' The cells are arranged in 500 micron-sized colonies (2D monolayer) approximately 1,200 micrometers apart from each other and behave as though they are in the human body—they act like the liver which has 2D plates stacked up to form a functional unit."

 

Hepregen's microlivers occupy industry-standard multi-well (i.e. 96-well format) plates, which enable medium- to high-throughput screening applications without the need for specialized equipment or specially trained personnel, Fendrock notes. Each well in a 24 well-plate contains approximately 100 islands and each well in the 96 well-plate contains approximately 16 islands. Each hepatocyte island contains up to 300 liver cells. Multi-well plates containing Hepregen's microlivers can fit in existing robotic fluid handling systems and are also compatible with plate readers and standard microscopy.

 

"The liver tissue is precise, organized, optimized and miniaturized," Fendrock states. Hepregen has determined that micro-patterned co-cultures (cell-cell interactions) have a critical role in tissue organization leading to long-term stability of the liver cells.

 

According to the Hepregen CEO, the bioengineering and microfabrication steps have yielded multiple advantages over other platforms. Hepregen microlivers retain liver-specific gene expression, phenotypic functions (e.g. synthesis of important proteins, nitrogen metabolism, detoxification of endogenous and exogenous compounds and bile flow), metabolic enzyme activities and enzyme induction (i.e. cytochrome P450) at levels very similar to those observed in vivo. They are stable for four to six weeks compared to at most a few days for providers of conventional 2D cultures. In addition, Hepregen's rat microliver platform is stable for 10-12 weeks in vitro.

 

Fendrock says she expects the Hepregen development to provide expanded utility for drug discovery and development because the microliver platform technology is "scalable and reproducible, miniaturized, and may be a better model of the human liver." The platform may also be modified to represent a diseased human liver, such as with diabetes or infectious disease, and may provide a unique system for drug discovery, she notes.