Heart disease, the number one cause of death in the developed world, often manifests first as a heart attack - the sudden blockage of a coronary artery. Without blood supply, the portion of the heart fed by the artery begins to die within a few minutes. Although the area affected may be small at first, the remainder of the heart works harder to compensate for the loss of pumping power. Over time, the entire organ may enlarge, start failing, and eventually need to be replaced. But the need for heart transplants far outstrips available donors.
To address this problem, researchers are developing a “cardiac patch” - a functioning piece of laboratory-grown heart tissue that would replace the patient’s damaged tissue before the entire organ becomes diseased.
Brewing a Patch
Although clinical use is still years away, researchers have already achieved several milestones. "We have grown heart tissue, in vitro, which resembles in many ways native tissue - it has similar molecular composition, similar structure, similar contractile properties," says Gordana Vunjak-Novakovic, professor of Biomedical Engineering at Columbia University, and associate director of the Tissue Engineering Resource Center funded by the National Institute of Biomedical Imaging and Bioengineering, at Tufts University and the Massachusetts Institute of Technology. The cardiac patch is currently undergoing its extension from animal to human cells and first tests in animal models.
Cardiac patches are grown in a bioreactor, a laboratory device that recreates many of the conditions heart cells experience during development. Actual tissue cultivation takes place in a small chamber that contains a complex brew of individual cells, nutrients, and growth factors. The chamber is connected to external devices that control factors such as temperature and oxygen content of the circulating culture medium.
Creating the proper environment poses unique challenges because of the nature of heart tissue: unlike other tissues, which may contain large quantities of a supportive matrix, heart tissue consists almost entirely of heart cells. Because the heart beats continually, heart cells require intense oxygenation and are fed by a much denser network of capillaries than those found in other tissues. To pump effectively, the heart’s cells must respond synchronously to electrical stimulation from the heart’s pacer cells. A bioreactor for engineering a functional cardiac patch thus needs to be a truly "biomimetic" device, designed to supply oxygen and pace the cells by mechanisms found in native tissue.
Building the Tissue
An important element in creating these conditions in man-made tissue is a scaffold - a three-dimensional template to which individual heart cells adhere and then later fuse together to form actual tissue. The scaffold contains a dense network of channels that help carry culture medium that contains oxygen to the cells in the bioreactor.
Made from materials such as collagen and silk proteins or from a highly elastic glycerol-sebasic-acid polymer known as "Biorubber," scaffolds are designed to gradually degrade as the individual cells fuse together. "Once the heart tissue starts to assemble, we try to line the scaffold channels with endothelial cells - blood vessel cells - to obtain something that looks like normal vascularized heart muscle," says Vunjak-Novakovic. A clinical pacemaker trains the heart cells to respond to electrical stimulation while in the bioreactor.
Under these conditions, a thumbnail-sized piece of tissue can be cultivated relatively quickly. "We put the cells on a scaffold, in oxygenated medium, stimulate them electrically, and eight days later, they’re beautifully organized," says Vunjak-Novakovic.
Challenges to Overcome
This promising research faces several challenges. While it is possible to produce tissue that is centimeters in length, the patches are still relatively thin, about 1-2 mm; a thicker piece of tissue, 5 mm or more may be needed for clinical use. In addition, the researchers must generate a vascular network within the cultivated tissue and integrate it with the host tissue’s own vascular network. The transplanted patch has to respond to the host heart’s electrical stimulation by synchronous contractions.
Discovering a good source of human cells to grow heart patches is perhaps one of the biggest challenges the researchers face. In current animal trials, neonatal rat heart cells are used. One potential source of cells to cultivate a cardiac patch is a patient’s own stem cells - bone marrow and fat aspirates are considered potential sources of such stem cells. These cells would avoid two problems associated with transplantation of tissue from a foreign donor: rejection by the patient’s immune system and the possibility of infectious disease. So far, researchers have been unsuccessful in growing heart cells from these sources of stem cells but Vunjak-Novakovic is hopeful: "Once a better source is identified, we can easily switch to the better cell."
Much of the support for this research comes from National Institute of Biomedical Imaging and Bioengineering through the Tissue Engineering Resource Center and the National Heart, Lung, and Blood Institute.
Vunjak-Novakovic G, Freshney I. Culture of cells for tissue engineering, J. Wiley, 2006.
Radisic M, Park H, Shing H, Consi T, Schoen FJ, Langer R, Freed LE, Vunjak-Novakovic G. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proceedings of the National Academy of Sciences 101: 18129-18134, 2004.