Self-Assembling Tissues

Living Legos can be directed to form tissue-like structures.

Tissue engineers are ambitious. If they had their way, a dialysis patient could receive a new kidney made in the lab from his own cells, instead of waiting for a donor organ that his immune system might reject. Likewise, a diabetic could, with grafts of lab-made pancreatic tissue, be given the ability to make insulin again. But tissue engineering has stalled in part because bioengineers haven’t been able to replicate the structural complexity of human tissues. Now researchers have taken an important first step toward building complex tissues from the bottom up by creating what they call living Legos. These building blocks, biofriendly gels of various shapes studded with cells, can self-assemble into complex structures resembling those found in tissues.

Living Legos: Polymer building blocks studded with cells self-assemble into structures whose complexity mimics that of human tissues. The cross-shaped gel contains cells stained green; the rod-shaped gels, which are about 200 micrometers across, contain cells stained red.

“Living tissues have repeating functional units,” says Ali Khademhosseini, a bioengineer at Harvard Medical School. The liver, for example, is made up of repeated hexagonal lobes. Each has a central branching vessel that brings in blood for filtration; the vessel and its branches are surrounded by toxin-filtering cells surrounded by canals that transport filtered blood to other vessels leading out of the organ. Traditional approaches to tissue engineering, says Khademhosseini, “rely on the cells to self-assemble and re-create structures found in the body.” Bioengineers seed cells onto the outside of polymer scaffolds in the hopes that they will migrate inside and organize themselves. Cells do self-organize to some extent, but such top-down attempts have had limited success.

Khademhosseini is trying to re-create complex tissue structures by carefully controlling cell organization from the bottom up. He mixes cells into a solution of a biocompatible polymer called polyethylene glycol, then pours the mixture into molds shaped like blocks, stars, spheres, or any other shape. When exposed to a flash of light, the polymer blocks solidify. The living Legos can then be built up into more-complex structures and exposed to another flash of light that bonds them together. But assembly is painstaking: each block is only about a hundred micrometers across.

So Khademhosseini and a group of researchers at MIT and Harvard have come up with a simple two-step process to make the living Legos self-assemble. Their method, described in a paper published today in the Proceedings of the National Academy of Sciences, relies on the basic fact that water and oil don’t mix. When water is dropped into a pool of oil, it will form a sphere, the shape that minimizes its interaction with the oil, says Khademhosseini. The polymer building blocks are hydrophilic–they easily absorb water and resist interacting with oil. But they can’t change their shape, so when Khademhosseini places them in an agitating bath of mineral oil, the blocks clump together in order to minimize their contact with the oil. The polymer blocks, now assembled into branches, cubes, and other shapes, are bonded together with another flash of light. The organization of the resulting structures can be controlled by varying the shape and size of the building blocks and the agitation speed.

By repeating the process, Khademhosseini can build up larger and larger structures that resemble, for example, blood vessels running through tissue. And by combining building blocks of different shapes that fit together like a lock and key, Khademhosseini can build even more complex structures. Spherical blocks made by the MIT and Harvard researchers slip into the corners of star-shaped blocks.

“This will be an effective way to put the cells where we want them to be,” says Hai-Quan Mao, a materials scientist at Johns Hopkins University. “You can probably generate a tissue with a higher complexity” using the new method than is possible with a scaffold that has to be seeded with cells, he says.

“This initial demonstration is inspiring,” agrees Suichi Takayama, a biomedical engineer at the University of Michigan. Researchers have had success with self-assembling materials for nonbiological applications such as computer chips. “People have thought of self-assembling biological materials, but he’s actually done it,” says Takayama of Khademhosseini. However, both caution that the work is in its early stages, and scaling the process up to larger, ever more complex structures will be a challenge.

Mao says that the self-assembling cell blocks could also be used to study how adjacent cells influence each other during development. Creating structural complexity isn’t the only hurdle that tissue engineers face. They also need a better understanding of the chemical and environmental signals that will help them grow tissues from stem cells in the lab: just what influences a stem cell’s decision to become a liver cell or a blood-vessel cell? Signals from other cells play an important role, and Khademhosseini’s structures, through which cell-communication molecules such as growth factors readily diffuse, could be used to study how the tissue environment influences stem cells.

Khademhosseini is currently working on making more-complex self-assembling structures that resemble the repeating units of the liver, the pancreas, and the heart muscle.

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