By adapting a programmable device used to manufacture integrated circuits, researchers have devised a semi-automated process to build polymer scaffolds for guiding the development of three-dimensional heart tissue. The method, which entails layer-by-layer fabrication, will enable more precise investigation of the three-dimensional cues that drive cells to organize and form tissue—and could serve as a platform for the development of implantable organ tissue.
Tissue engineers can already make three-dimensional constructs of relatively simple tissues. But highly ordered cellular architectures essential to the function of complicated organs like the heart are much harder to replicate.
Tissue is grown in the lab by “seeding” scaffolds—usually composed of a porous elastic or gelatinous material—with cells meant to develop into specific tissues. Cardiac tissue’s function stems from its “multiscale architecture,” in which individual cells align to form multicellular fibers, which in turn form sheets of tissue, says Martin Kolewe, a postdoctoral researcher at MIT’s Institute of Medical Engineering and Science. Recent work has focused on determining how to guide cells to make them align correctly and form these hierarchical components. But such research has mostly been confined to two dimensions. Kolewe and lead investigator Lisa Freed of Draper Laboratory set out to develop a way to more precisely control the design of pore “networks,” with the aim of adding a third dimension. A new paper in Advanced Materials describes the research.
Using fabrication techniques adapted from the microelectronics industry, the researchers made thin sheets of a polymer known as biorubber, patterned with microscale rectangular holes of uniform dimensions. They then adapted a programmable machine—used by the electronics industry to automatically stack thin material layers and build circuit boards and integrated circuit packages—to stack the porous biorubber sheets, one by one. A computer program helped precisely position the pores of each sheet relative to those of the sheet below.
The researchers systematically tested various pore patterns and demonstrated ones that could produce “interwoven muscle-like bundles” out of mouse muscle cells and rat neonatal heart cells. They also showed they could control the directional orientation of the bundles, and that tissue built from the heart cells could beat in response to electrical stimulation.
The new scaffolding technique allowed the researchers to form tissue that mimics an important structural quality of heart tissue called “anisotropy,” says Gordana Vunjak-Novakovic, a professor of biomedical engineering and medical sciences at Columbia University. This quality provides heart tissue with different mechanical properties depending on the direction in which it is stretched. “On the microscopic and cell level and tissue level, they really recapitulated some of the critically important structural and mechanical features of the native heart muscle,” says Vunjak-Novakovic, who was not involved in the research.
This work may represent an important step toward implantable heart tissue for humans, but several daunting engineering challenges remain. Engineered tissue must be made even thicker, which will require some sort of vascular network to keep it from dying. It also must be engineered to perform cardiac muscle’s highly specialized task. And researchers will need to demonstrate that tissues made from human cells can survive and carry out specialized functions.
Freed and Kolewe say their relatively simple system has opened “a whole new design space” thanks to the unprecedented level of control it offers over the arrangement of pore networks in the biorubber. Such control, they say, can now be used to more precisely investigate the three-dimensional factors that influence cell alignment and tissue formation, and to test new designs with the goal of developing more clinically relevant organ tissues. They also plan to test the viability of their tissue constructs by implanting them on the surface of rat hearts after a heart attack.
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