In the mid-1980s, Hynda Kleinman at the National Institutes of Health (NIH) had been
tudying an extract of mouse tumors that produces a basement membrane. Kleinman’s lab group was analyzing basement membrane chemistry, unrelated to cell biology. Some of her colleagues had suggested seeing what effect the extract would have on cells.

In 1983, in anticipation of a site visit by Harvard cell biologist Elizabeth Hay, Kleinman (who was traveling) told a postdoc to place some endothelial cells—the building blocks of blood vessels—on a sample of the matrix extract. “I had no clue as to what would happen,” recalls Kleinman.

“He threw some endothelial cells on it, and they went crazy. Within hours they had formed capillary-like vessels with hollow lumens,” says Kleinman. “The reviewers and Dr. Hay loved it! They took some home with them. Then we published on this and on many other cell types, and a lot of people wanted to use it in their research. ”
The extract was eventually sold commercially under the name Matrigel, the first and still widely used basement membrane substrate for 3-D cultures. A common application is to study metastasis: cancer cells placed on a thick slab of the gel will migrate to the interior, modeling a process that can’t be replicated in two dimensions.

A 3-D Bridge

The rise of 3-D cultures does not spell the demise of standard cultures, by any means. Even in cancer research, says Brugge, 2-D methods are still useful for studying cell cycle progression pathways, apoptosis, protein interactions in signaling pathways, and some aspects of drug sensitivity.

Scientists say that 3-D culture is establishing itself as a bridge between traditional cell culture and animal models. Cells grown in the new systems can replicate the features of some diseases better than costly animal models do. Functions of genes and proteins can be studied first in these cultures before going on to more laborious experiments in animals. And, of course, conditions can be controlled much more easily in a 3-D culture experiment than in a living animal.

The list of applications of 3-D studies goes on and on: new assays for blood vessel formation, drug discovery, and cancer invasiveness; studies of the effectiveness of drug delivery methods; tissue engineering experiments of all kinds.

Surveying the leaps that 3-D methods have made in a little more than 20 years, NIH’s Kleinman says, “I’m just blown away by the very creative ways people are using it.”

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