John Mayer MD

Professor of Surgery Harvard Medical School

Senior Associate in Cardiac Surgery Boston Children's Hospital Boston, Massachusetts

Tissue engineering unites engineering and biology in an attempt to develop replacement tissues. Normal tissues draw much of their strength and flexibility from specialized proteins and polysaccharide-protein complexes that are produced by their cells. Although it has been possible to grow specific types of cells in the lab for some time, it is difficult to cause these cells to organize into the complex structures that are found in normal tissues or to produce normal structural proteins in an organized fashion.

To overcome this challenge, we are attempting to "grow" heart valves and large arteries by using biodegradable polymers as temporary scaffolds. These polymer scaffolds provide the structure and stability necessary for tissues to develop. Ideally, these scaffolds would degrade as the cells produce normal structural proteins and begin to replicate normal, organized tissue structures.

Diseases of the heart valves and large arteries account for about sixty thousand surgeries each year in the United States, including many replacement surgeries with synthetic substitutes. Ideally, any valve or artery substitute would function like the normal valve or artery, allowing blood to pass through it without narrowing or leakage, but it would also have the following characteristics: 1) durability, 2) growth potential, 3) compatibility with blood so that blood clots will not form on its surface, and 4) resistance to infection.

None of the currently available devices constructed from prosthetic or biological materials meets these criteria. Our concept, however, was to develop new valves or arteries from individual cells in the hope that these new tissues will have these desirable characteristics. The potential for growth is of particular importance to children with malformed or diseased valves or arteries.

Several projects have been undertaken in our laboratory to construct a heart valve leaflet and large arteries by using tissue engineering. We used cells from normal arteries that could be removed and separated into the various cell components. We found it was important to use the animal's own tissue as the source of the cells, thereby eliminating the possibility of immune rejection once the tissues were reimplanted. The cells were "expanded" in cultures by allowing them to divide, and then suspen sions of the cells were mixed with the polymer scaffolds. The cellpolymer constructs were then incubated in culture for several more days before they were implanted as a valve replacement or an artery replacement. Valve leaflets and segments of large arteries functioned well for up to four months without structural failure or formation of blood clots on their surfaces. Importantly, when these structures were implanted into growing animals, they demonstrated growth. The tissues appeared to have relatively normal structure, and they produced the normal matrix proteins.

Despite these encouraging results, many questions remain to be resolved.

y First, all of these experiments have been carried out in animals, and it remains to be determined if human cells could be used to develop tissues in the same way.

y Second, the polymer used as the scaffold in these initial experiments is stiff, biodegradable polymer that may or may not have acceptable strength and flexibility ("handling") characteristics while still providing a hospitable environ ment for the cells to develop into tissues. y Third, the ideal source of the cells for the developing "tissues" has not been determined. In patients, it would be preferable to use veins rather than arteries as the initial source of the cells because veins are more plentiful and their removal does not compromise blood supply to normal tissues. We have some evidence that heart valves developed by using cells from the skin do not function as well as those developed with cells from the wall of the artery, but vein wall cells seem to work reasonably well. y Fourth, because all of our experiments have been carried out in immature growing animals, it is not clear whether the cells that are used to form these "tissues" must be from immature animals. There is some reason to believe that fetal cells would be preferable. Because it is now possible to diagnose many forms of congenital heart disease while the embryo is still in utero, one might imagine using fetal cells to develop replacement valves or ar teries while gestation is continuing. At birth, these replacement valves or arteries could be ready to be implanted. y Fifth, it is not clear whether the "tissues" should be implanted while they are still dependent on the polymer scaffold for their physical integrity or if they should be allowed to develop further in culture before implantation into the body. One of our current ideas is that if the developing tissues are subjected to physical forces and/or chemical signals while in the laboratory, it may be possible to guide their development further before implantation into the body. Our understanding of how these developing tissues will respond to any number of physical and chemical signals remains very limited.

Tissue engineering is one new approach to solving the problem of creating replacement tissues for use as heart valves or arteries. Although initial animal studies have been encouraging, numerous questions must be resolved before we embark on clinical trials in humans.

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