Fabricating ‘microlivers’ for Improving Drug Safety

Sangeeta N. Bhatia
Harvard-MIT Health Sciences and Technology

Liver toxicity is one of the main reasons pharmaceutical companies pull drugs off the market. These drugs slip through approval processes due in part to the shortcomings of liver toxicity tests. Existing tests rely on liver cells from rats, which do not always respond to toxins the way human cells do. Or they rely on dying human cells that survive for only a few days in the lab.

Liver cells in the micropatterned co-culture form tube-like structures (shown here in green) that resemble bile capillaries found in a human liver. (photo: Sangeeta Bhatia lab, MIT).

Liver cells in the micropatterned co-culture form tube-like structures (shown here in green) that resemble bile capillaries found in a human liver. (photo: Sangeeta Bhatia lab, MIT).

Sangeeta Bhatia’s group has devised a novel way to create tiny colonies of living human liver cells that model aspects of the full-sized organ. The approach uses microtechnology—traditionally developed for fabrication of integrated circuits or micro-electromechanical systems (MEMS)—to arrange human liver cells into tiny colonies that act much like a real liver and survive for up to six weeks. To build these model livers, her group adapted micropatterning technology from Bhatia’s early work as an MIT graduate student building micropatterned co-cultures of rat liver cells and supporting cells.

Microfabricated posts of silicone rubber are used to pattern biological protein arrays into plastic devices that are the workhorse of the biological world—the multiwell plate. The patterned proteins enable the attachment of the liver cells in 500 micron colonies where they are surrounded by supportive ‘neighboring’ cells. Such precisely arranged structures result in a “high-fidelity tissue model” because it so closely mimics the behavior of a human liver. For example, each model “organ” secretes the blood protein albumin, synthesizes urea, and produces the enzymes necessary to break down drugs and toxins.

MIT researchers use micropatterned stencils to build miniature model livers. Each stencil contains an array of wells. Each well contains a hexagonal matrix of 37 holes 500 micrometers in diameter. Using the stencil, they form islands by placing approximately 300 liver cells into each hole and surrounding each with a sea of supporting cells including collagen and other proteins. (image: Sangeeta Bhatia lab, MIT).

MIT researchers use micropatterned stencils to build miniature model livers. Each stencil contains an array of wells. Each well contains a hexagonal matrix of 37 holes 500 micrometers in diameter. Using the stencil, they form islands by placing approximately 300 liver cells into each hole and surrounding each with a sea of supporting cells including collagen and other proteins. (image: Sangeeta Bhatia lab, MIT).

To predict how close their model tissue is to real liver tissue, which has over 500 different functions, Bhatia and her group also evaluated its gene expression profiles, measures of the levels of gene activation in the tissues. They found that these profiles are very similar to those of fresh liver cells. For drug testing purposes, this affinity to the human liver allows each colony to provide a window into the human liver’s response to a drug without having to expose human patients to the drug in a clinical trial. Further, because the engineered tissue lives for so long, it has the potential to make new types of toxicity tests possible. For instance, it opens the door to testing the effects of long-term drug use akin to taking one pill a day over multiple weeks. It also will allow more extensive testing of drug-drug interactions.

The model uses a fraction of the costly human liver cells used in other test platforms and can be assembled using frozen cells.Moreover, the expanded toxicity testing capabilities have the potential to allow drug developers to identify toxicity earlier in the development process, thereby avoiding the expense of investing in formulas that are bound to fail. An MIT spinoff company called Hepregen has licensed the technology and is working to introduce it into the pharmaceutical marketplace. Bhatia hopes that the new model will make drugs safer, cheaper and as a result, better labeled. In her laboratory, with encouragement from the Gates Foundation, ongoing work is on exploring applications to global human diseases— hepatitis C and malaria, for which medical progress has been stunted due to a lack of model systems.

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