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Medical News & Perspectives
November 22/29, 2000

Tissue Engineering Approaches Utility

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JAMA. 2000;284(20):2582-2583. doi:10.1001/jama.284.20.2582-JMN1122-2-1

Chicago—Tissue engineering, only a theoretical possibility less than a decade ago, is moving closer to becoming a real discipline.

Researchers who presented their findings at the American College of Surgeons Clinical Congress here last month said they are making advances in engineering tissue for replacing heart valves and blood vessels and for treating ovarian cancer.

Rapid development

"This is perhaps the most rapidly developing, and potentially the most important, topic related to organ replacement and organ repair," said Dana K. Andersen, MD, professor and vice chair of the Department of Surgery at Yale University School of Medicine. "We're trying to focus attention on the science of directed growth and development of tissues and organs—which can be implanted into the patient—using the strategy of in vitro development."

Andersen charted the beginning of tissue engineering as an academic discipline from an article published in 1993 by Robert Langer, ScD, and Joseph P. Vacanti, MD (Science. 1993;260:920-926).

Andersen said the key issues facing tissue engineering today are control of tissue development (sometimes referred to as organogenesis); development of biomaterials that are biocompatible and that allow development of specific organs and structures; engineering fetal tissue for use in older patients to create younger, more vibrant organs for replacement or repair; maintenance of tissue mass (the control of proliferation and apoptosis); and finding methods of molecular modification and gene therapy.

Helping young hearts

John E. Mayer, Jr, MD, professor of surgery at Harvard Medical School and senior associate in cardiac surgery at Children's Hospital in Boston, is working on creating pulmonary valve leaflets and complete valves in vitro, beginning with cells derived from arterial walls and growing them on a biodegradable scaffold. He became interested in tissue engineering as a way to improve the health of children with heart problems.

"Many of the defects that children are born with that affect their heart and the major blood vessels involve the absence of a valve or very deformed valves that cannot function," Mayer said. "And many of the surgical procedures that we do to correct some of these defects involve the use of replacement devices." He added that the problem with replacement devices is that they don't grow with the child, forcing young patients to undergo several operations as they become older to replace small devices with larger ones.

So far, the work is encouraging. Tissue engineered valves implanted in lambs have functioned well for up to 5 months. When these valves are removed from the animals, their gross appearance and presentation under the microscope are similar in many ways to that of normal valves.

Mayer is currently attempting to use other cell types as the source for valve creation. These include circulating endothelial progenitor cells, which can be obtained from the bloodstream, and cells from fetal animals. Both types of cells have been successfully grown on biodegradable polymer scaffolding and will be implanted in animals within the next few months.

Mayer hopes his research will lead to clinical trials in patients within 5 years.

Laura Niklason, MD, PhD, an assistant professor of anesthesia and biomedical engineering at Duke University School of Medicine, is hoping to use tissue engineering to treat atherosclerosis—specifically, to grow blood vessels for use in coronary artery bypass grafting (CABG).

"Patients who have undergone one or more bypass operations rapidly run out of vein or artery that can be harvested from themselves," Niklason said. "So if they go on to need a subsequent bypass operation, they're kind of out of luck."

Niklason's team hopes to isolate cells from a patient, grow them in the laboratory, and create a new artery that can be used for CABG. Such engineered cells would not be rejected because they are used in the same patient from whom they were taken.

Using porcine and bovine cells, Niklason has grown arteries that are roughly as strong as native arteries and have some of the function, physiological properties, and appearance of native arteries.

"We've shown that it's possible to take cells from an animal, use them to reconstitute an artery, and then reimplant them back into the same animal," Niklason said. "We followed those for up to 4 weeks and found they function up to that time."

Difficulties to overcome

There are some difficulties, however. Niklason said that when the procedure is used in pigs, the arteries are not as strong as native arteries; she and others are working to improve them. She speculated that the problem may be the regulation of protein production in the arterial epithelium.

Another problem will be growing cells from human patients older than 50 years—the people most likely to need new arteries. These cells grow much more slowly and poorly in the laboratory than cells taken from immature animals. Recent work from other laboratories, she said, indicates that stem cells may be present in human skin and skeletal muscle. Niklason said she hopes to harness those and steer them into becoming vibrant vascular cells.

Another issue is that it takes about 2 months to "engineer" arteries—a prohibitively long time for some patients needing CABG. Finally, Niklason speculated that it will be 10 to 15 years before her research will allow for clinical trials in patients.

Inhibiting tumorigenesis

Another research project that may someday benefit patients was presented by Patricia K. Donahoe, MD, and Antonia E. Stephen, MD, from the Pediatric Surgical Laboratories and the Laboratory for Tissue Engineering and Organ Fabrication at Harvard Medical School and Massachusetts General Hospital in Boston.

Donahoe, Stephen, and colleagues are engineering tissue that is intended to inhibit tumor growth associated with ovarian cancer.

In their presentation, "Engineered Tissue Using Transfected Cells Inhibits Tumor Growth," the researchers show that müllerian inhibiting substance (MIS) causes regression of ovarian tumor cell lines in vitro.

"We did several experiments using a mouse model and showed statistically significant inhibition of tumors compared with the control animals we had," Stephen said.

They seeded Chinese hamster ovary cells, transfected with the human MIS gene (CHO-B9), onto a highly porous mesh of polyglycolic acid fibers. The mesh was implanted in the right ovarian pedicle of mice with severe combined immunodeficiency.

The investigators found the CHO-B9 cells seeded on the mesh secreted large quantities of immunoactive MIS in vitro and in vivo. The substance was detected in serum within 3 days of implantation and supraphysiologic levels were seen at 7 to 10 days. The serum MIS level remained in the supraphysiologic range for several weeks after mesh implantation, and removal of the mesh resulted in a decrease of MIS serum levels to normal. When the activity of the MIS was tested against the IGROV-1 human ovarian cancer cell line, tumor growth was significantly inhibited compared with control animals (the mean [SD] graft-size ratio of tumors in mice implanted with CHO-B9 cells was 1.62 [0.2] vs 3.25 [0.5] in untreated animals).

Donahoe and Stephen concluded that this technology may be useful for the production of potential chemotherapeutic agents. "The inhibition of ovarian cancer by MIS indicates that this delivery system could be used for MIS and other inhibitory proteins not otherwise amenable to conventional biochemical production methods," they said.

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