Lisa E. Freed clearly remembers her first successful experiment in engineering heart tissue: the cells she'd "seeded" on a three-dimensional scaffold outside a living body began beating as one.
"It was my most awesome laboratory moment ever. No one had ever done this before," said Dr. Freed, a principal research scientist in the Harvard-MIT Division of Health Sciences and Technology (HST).
That was five years ago. Since then Dr. Freed, Gordana Vunjak-Novakovic (her collaborator then and now), and colleagues from MIT, Harvard Medical School, Boston University and Brigham and Women's Hospital have been painstakingly studying the engineered cardiac tissue.
Among other things, they've characterized the tissues' structural and electrical properties (heart function depends on the ability to conduct electrical impulses), and they've defined key parameters for growing the tissues. Two papers published this month and last report their results.
The work is key to engineering 3-D cardiac tissue that could eventually be used to repair damaged heart tissue inside the body, test new drugs, and study general cardiac tissue development and function. Although it could theoretically lead to the creation of an entire heart, the researchers stress that substantial problems must be solved before that could happen.
The MIT approach involves seeding cardiac cells onto a 3-D polymer scaffold that slowly biodegrades as the cells develop into a full tissue. The researchers have used the same technique to grow other tissues; in 1996 Drs. Freed and Vunjak-Novakovic and NASA colleagues grew cartilage aboard the space station Mir in the first tissue-engineering experiment in space (MIT Tech Talk, October 23, 1996 and December 10, 1997).
The cardiac cells are cultivated on scaffolds 5mm in diameter by 2mm thick. The cell/scaffold constructs are placed in a rotating bioreactor that supplies the cells with nutrients and gases and removes wastes. "The bioreactor is a kind of microenvironment that gives cells the signals they would ordinarily see in the body," said Dr. Vunjak-Novakovic.
"This overall system allows us to study specific effects of the cells, scaffold and regulatory signals on tissue development and function," Dr. Freed said.
In the August issue of the American Journal of Physiology, the researchers characterize the structure and electrical properties of the cardiac constructs. Using a custom-designed electrode array, they applied electrical signals to the tissues and got them beating. They then studied parameters associated with impulse propagation through the tissue. For example, they found that constructs conducted electrical impulses half as fast as tissues grown the old-fashioned way (in an animal's body).
A second paper, which appeared in the September 1999 issue of Biotechnology and Bioengineering, describes how parameters like cell density, cell source (neonatal rat or chick embryo) and different cultivation conditions affect tissue growth. "We've identified a set of conditions that so far appear to be best for cardiac tissue engineering," Dr. Vunjak-Novakovic said.
Work continues. "There are substantial problems that must be addressed before we could use these tissues for, say, repair of heart defects inside the body," Dr. Freed said. For example, the current constructs resemble heart muscle, but the heart also contains blood vessels. "We've developed one component, but that's only the first step," she noted.
In addition, constructs must be bigger, stronger, and made of human rather than animal cells that have been modified so they will not be rejected by a recipient. Dr. Freed noted that at least one other group, in Germany, is also working on cardiac tissue engineering.
The first successful experiment five years ago "showed that cardiac tissue engineering was possible," Dr. Vunjak-Novakovic said. The current papers are the first to quantitatively characterize tissue properties. "They're really the beginning," she concluded.
Authors of the American Journal of Physiology paper are Nenad Bursac, a Boston University graduate student and HST visiting scholar; Maria Papadaki, an HST postdoctoral associate; Richard J. Cohen, the Whitaker Professor of Biomedical Engineering at HST; Frederick J. Schoen, associate director of HST, professor at Harvard Medical School and affiliate of Brigham and Women's Hospital; Professor Solomon R. Eisenberg, associate dean of engineering at BU; Rebecca L. Carrier, a graduate student in MIT's Department of Chemical Engineering; Dr. Vunjak-Novakovic and Dr. Freed.
Authors of the Biotechnology and Bioengineering paper are Ms. Carrier; Dr. Papadaki; chemical engineering research affiliate Maria Rupnick of Harvard Medical School and Brigham and Women's; Dr. Schoen; Mr. Bursac; Robert S. Langer, the Germeshausen Professor of Chemical and Biomedical Engineering; Dr. Freed and Dr. Vunjak-Novakovic.
The work was supported by NASA.
A version of this article appeared in MIT Tech Talk on September 29, 1999.
