44 SCIENTIFIC AMERICAN NOVEMBER 2004CREDIT CREDIT COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.By hobbling the heart muscle’s normal synchronous contrac-tions, the scar, known as an infarct, also increases strain on the healthy parts of the muscle, leading to further cell death and deformation of the cardiac wall. This cycle of deterioration can cause an infarct to double in size within just months.Medical interventions are allowing more people to survive the crisis of a heart attack. But at least a third of these will experience the subsequent steady weakening of their injured hearts, termed heart failure, for which there is only one cure at present: transplantation—a complicated, expensive alter-native limited by a severe shortage of donors. Last year in the U.S., for example, more than 550,000 new cases of heart failure were diagnosed, but only about 2,000 transplants were performed. For the remainder of patients, quality of life steadily erodes, and less than 40 percent will survive fi ve years after the initial attack.If doctors could repair an infarct in the human heart, or even just halt its expansion, they would transform millions of lives. Thus, building a patch of living human heart tissue has become one of the most urgent goals in tissue engineering. It is also one of the most ambitious. Cardiac muscle fi bers must organize themselves in parallel, then form physical and neural connections in order to conduct the electrical signals that al-low the fi bers to synchronize contractions. Skin and cartilage are far less complex, and growing them in the lab is also sim-pler because those tissues do not require internal vasculature. For thicker structures such as heart muscle, fi nding a way to integrate the requisite blood supply into a three-dimensional piece of tissue remains a major obstacle. Still, the prospect of “building” any kind of living tissue outside the body was widely considered outlandish just 15 years ago. Since that time, cell biologists and materials engi-neers have brought novel insights and techniques from their respective disciplines to the challenge and made substantial progress. In our own collaboration, for example, engineer-ing principles played a crucial role in enabling us to develop a www.sciam.com SCIENTIFIC AMERICAN 45ANITA KUNZREBUILDING BROKEN HEARTSBiologists and engineers working together in the fl edgling fi eld of tissue engineering are within reach of one of their greatest goals: constructing a living human heart patchBy Smadar Cohen and Jonathan LeorA heart broken by love usually heals with time, but damage to cardiac muscle caused by a heart attack gets progressively worse. Unlike liver or skin, heart tissue cannot regenerate, so the scar left after a heart attack remains a noncontractile dead zone. COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.scaffold that encourages heart cells and blood vessels to grow, even in the dead zone of an infarct.Laying the Groundworka myocardial infarction, popularly known as a heart attack, usually happens because a major blood vessel supplying the heart’s left ventricle is suddenly blocked by an obstruction, such as a clot. Part of the cardiac muscle, or myo-cardium, is deprived of blood and therefore oxygen, which kills the heart’s contractile muscle cells (called cardiomyo-cytes) and leaves a swath of dead tissue. The size of this infarct will depend on the size of the area fed by the blood vessel that was blocked. Because myocytes rarely divide, surviving cells cannot re-populate the area by replicating themselves. Local stem cells, which act as progenitors of new cells in some other tissues, are proving elusive in the heart and seem unable to heal the wound on their own. Instead, noncontractile fi brous cells gradually replace an infarct’s dead myocytes. Healthy myo-cytes adjacent to the infarct may also die, causing the infarct to expand further. In this process, known as remodeling, the ventricle wall in the area of the infarct becomes thinner and eventually distends [see illustration on opposite page] or even ruptures. In the past few years, researchers have attempted to re-grow heart tissue in an infarct zone by transplanting stem cells f rom ot her tissues , such as bone marrow or skeletal mus-cle. The hope was that these cells would either adapt to their surroundings and begin producing new cardiomyocytes or at least help to spur any natural regenerative capacity the heart itself might possess. Unfortunately, trials of this approach have had limited success. Most of the stem cells do not survive the transplant. Those that do tend to congregate at the edges of the infarct but fail to make physical contact with adjacent healthy tissue or to conduct the electrical signals that allow heart cells to synchronize their contractions. These implanted cells cannot thrive in the infarct primari-ly because the damaged area lacks the vital natural infrastruc-ture t hat normally supports living cel ls. I n healthy tissue, this extracellular matrix is composed of structural proteins, such as collagen, and complex sugar molecules known as poly-saccharides, such as heparan sulfate. The extracellular matrix both generates growth-signaling chemicals and provides physical support for cells.Aware of the importance of extracellular matrix, tissue engineers have long sought an ideal substitute to serve as a platform for growing living tissues. Such a material could form a scaffold to support cells, allowing them to thrive, divide and organize themselves into a three-dimensional tissue as they do in nature. The structure would solve the problem of trans-planted cells migrating away from a scarred area. But after the cells have established themselves and begun secreting their own extracellular matrix, the scaffold should dissolve, leaving behind only healthy tissue. Perhaps most important, the scaf-fold should allow—better still, promote—rapid vasculariza-tion within the new tissue. Blood vessels delivering oxygen to every cell and carrying away their wastes are essential to the cells’ survival once they are transplanted into the living host. During the late 1980s, one of us (Cohen) had the pleasure of working with Robert Langer, a pioneer in the fi eld of tissue engineering [see “Tissue Engineering: The Challenges Ahead,” by Vacanti and Langer; Scientific American, April 1999], in his lab at the Massachusetts Institute of Technology. At the time, the very idea of building living tissue was
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