CREDIT 44 SCIENTIFIC A MERIC A N COPYRIGHT 2004 SCIENTIFIC AMERICAN INC NOVEMBER 2004 REBUILDING BROKEN HEARTS Biologists and engineers working together in the edgling eld of tissue engineering are within reach of one of their greatest goals constructing a living human heart patch By Smadar Cohen and Jonathan Leor A NITA KUNZ A 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 By hobbling the heart muscle s normal synchronous contractions 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 alternative 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 five 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 www sciam com 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 fibers must organize themselves in parallel then form physical and neural connections in order to conduct the electrical signals that allow the fibers to synchronize contractions Skin and cartilage are far less complex and growing them in the lab is also simpler because those tissues do not require internal vasculature For thicker structures such as heart muscle finding 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 engineers have brought novel insights and techniques from their respective disciplines to the challenge and made substantial progress In our own collaboration for example engineering principles played a crucial role in enabling us to develop a COPYRIGHT 2004 SCIENTIFIC AMERICAN INC SCIENTIFIC AMERIC AN 45 scaffold that encourages heart cells and blood vessels to grow even in the dead zone of an infarct Laying the Groundwork a m yo c a r d i a l i n fa r c t i o n 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 myocardium is deprived of blood and therefore oxygen which kills the heart s contractile muscle cells called cardiomyocytes 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 repopulate 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 fibrous cells healthy tissue or to conduct the electrical signals that allow heart cells to synchronize their contractions These implanted cells cannot thrive in the infarct primarily because the damaged area lacks the vital natural infrastructure that normally supports living cells In healthy tissue this extracellular matrix is composed of structural proteins such as collagen and complex sugar molecules known as polysaccharides 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 transplanted cells migrating away from a scarred area But after the cells have established themselves and begun secreting their Implanted cells cannot thrive in the INFARCT because the area lacks vital natural INFRASTRUCTURE gradually replace an infarct s dead myocytes Healthy myocytes 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 regrow heart tissue in an infarct zone by transplanting stem cells from other tissues such as bone marrow or skeletal muscle 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 Overview Mending Hearts Scarred cardiac muscle will lead to heart failure in millions of heart attack survivors unless the damaged area can be restored or replaced with new tissue Constructing living tissue brings together the biologist s understanding of cell behavior and the material chemist s mastery of engineering Tissue engineers already able to coax heart muscle regeneration in vivo are building on what they have learned to generate working heart muscle in the lab 46 SCIENTIFIC A MERIC A N own extracellular matrix the scaffold should dissolve leaving behind only healthy tissue Perhaps most important the scaffold should allow better still promote rapid vascularization within the new tissue Blood vessels delivering oxygen to every cell and carrying away their
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