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J Thorac Cardiovasc Surg 2007;134:20-22
© 2007 The American Association for Thoracic Surgery
Editorial |
Department of Cardiac Surgery, University of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.
Received for publication March 12, 2007; revisions received March 21, 2007; accepted for publication March 29, 2007. * Address for reprints: Hans-Hinrich Sievers, MD, University of Schleswig-Holstein, Campus Luebeck, Department of Cardiac Surgery, Ratzeburger Allee 160, Luebeck D-23538 Germany. (Email: herzchir{at}medinf.mu-luebeck.de).
Since the 1950s, conventional bioprosthetic and mechanical heart valve substitutes have significantly improved survival and quality of life for millions of patients. Nevertheless, these replacement devices are subject to serious, still unsurmounted, shortcomings, among others macroembolic and microembolic events, anticoagulation, premature degeneration and failure, functional imperfection, and lack of growth. Thus, there is an undoubted need for better prostheses. Tissue engineering has evolved during the last 20 years as an appealing alternative with great promise, bringing into play the application of principles and methods of engineering and life science.E1 Understandably, the ultimate goal is to construct a living aortic valve substitute equal to the patient’s own native valve. This makes sense, because the native valve is the optimal solution as a valve mechanism for that particular position that has developed in an evolutionary process over millions of years, an inconceivable period for human beings. For tissue engineering, a thorough understanding of developmental processes, as well as of relationships of structure to function, is indispensable. Some issues are touched on in the present study with regard to semilunar heart valves.
The heart and the valves are the first organs to form during a complex morphogenetic process harmonizing with evolving hemodynamic forces.1 In addition to transition of endothelial to mesenchymal cells and migration of these cells to form the endocardial cushions, numerous genes, molecules, signals, and proteins are involved.E2,E3 Of most interest, multipotent neural crest cells migrate to the outflow tract2 (Figure 1) and semilunar valves,E4,E5 contributing to development.E4 This process follows a finely tuned, albeit vulnerable,E6-E8 biologic concert not yet completely known, which is also true for the molecular mechanisms to maintain structural integrity, regeneration, aging, and remodeling in response to dynamic environmental factors.3 How do cells differentiate at the right time, to the right extent, into the right type, and in the right position? What is the control mechanism? Is the neural system the major player during development?
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The aortic valve is integrated in the aortic root, forming the structural and dynamic continuity between the left ventricle and ascending aorta. It is composed of the leaflets, the crown-shaped annulus, intervalvular trigones, sinuses of Valsalva, commissures, and the sinotubular junction. All components are in close relationship and cross-talk among each other, the environment, and the whole body during dynamic, cyclic function,4 warranting undisturbed unidirectional flow. None of these components stands alone. Novel visualization techniques have revealed the aortic valve leaflets to have a highly complex multilayer mesostructure, providing anisotropic mechanical behavior that differs distinctly from the currently known three-layer morphology.5 Endoscopic and microscopic evaluation of the pressure-loaded porcine root has shown strong collagen fibers with smaller connecting fibers embedded in hammock-shaped, thin membranes in between (Figure 2), which is a perfect blueprint for suspension bridges. Furthermore, the crimped design of fibers allows stress compensation. Nerve fibers, a complex pattern of extracellular matrix components, and different interstitial and endothelial cellular phenotypes have been identified. They control the transformation of structural, secretory, mitogenic, contractile, and remodeling shear stress stimuliE10–E15 (Figure 3).
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; however, fewer than 10 tissue-engineered products have made it to the clinical setting.E16 Altogether, tissue engineering a copy of a patient’s specific native valve hardly seems possible at present. But on the way to this ultimate goal, knowledge has already increased and will continue to increase, aiding the production of more biomimetic, improved valve substitutes for clinical use.
In this issue, Hayashida and colleagues7 present their respectable results on development of an in vivo tissue-engineered autologous heart valve (biovalve) and their preparation of a prototype. A special mold consisting of a silicone rod and a crown-shaped tubular polyurethane scaffold was implanted subcutaneously in rabbits, inducing the formation of a semilunar valve construct. The authors revived an old concept of tissue engineering for vascular graftsE17 unfortunately prone to several complications, such as early and late thrombosis as well as aneurysm formation.8 Although this technique may have several advantages in providing an autologous construct, conceptual questions remain open. There were no hemodynamic forces to program structural stimuli, so what were the type and arrangement of collagen fibers, the mesostructure, and the whole spectrum of extracellular matrix components? Immunoreactivity was not found for vimentin, contrary to normal aortic valves.E12 Furthermore, how do the cells of this construct change their phenotype after coming into contact with pressure and blood?E18 Finally, what is the durability of the biovalve in circulation? Will thrombotic and aneurysmal complications occur even though the construct looks quite and promising? The underlying mechanism of this kind of valve formation is probably more a foreign-body reaction trying to encapsulate the artificial material rather than a true developmental process. At any rate, the concept of in vivo autologous tissue engineering with the patient as an autologous "bioreactor" is undoubtedly appealing. Other approaches will follow, with more perfect molds or with a hybrid technique that uses 4D biodegradable or nonbiodegradable artificial, xenologous, or autologous scaffolds in an environment simulating hemodynamic forces.
Newly promising principles of regenerative medicine, including tissue engineering and stem cell biology, are entering the field.E19 The less differentiated the stem cells, the greater is their potential plasticity to develop into different cells. To prevent uncontrolled, teratogenic differentiation, however, they need strategies of control, the right stimuli for structure, function, and time; something like a plan. Furthermore, engineering technology develops rapidly and may contribute to tissue engineering or regenerative medicine by providing, for example, biomimetic, anisotropic, microscale, 3-dimensional, woven composite scaffolds,E20 ready to take over full load immediately, or even more sophisticated nanomembranes of organic-inorganic interpenetrating networks.E21 Recently, an artificial polyprotein with nanomechanical properties comparable to those of naturally evolved elastomeric proteins was produced by using single-molecule atomic force microscopy techniques.E22 In addition, interspecies comparison of evolution might add new and interesting knowledge. For example, the codfish has two semilunar valves in series in the conus arteriosus (Figure 4). Why? For depulsation? For stress reduction?
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and hopes should be raised but not overstated. As I write these lines, Michelangelo’s depiction of the creation of Adam by God, depicted with a drapery looking something like the human brain, enters my mind. Let’s use our creativity and consciousness and try to get what we can. The bar is set very high.
| See related article on page 152.
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References
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  N. W. Guldner, I. Jasmund, H. Zimmermann, M. Heinlein, B. Girndt, M. Grossherr, M. Klinger, and H. H. Sievers The first self-endothelialized titanium-coated glutaraldehyde-fixed heart valve prosthesis within systemic circulation J. Thorac. Cardiovasc. Surg., July 1, 2009; 138(1): 248 - 250. [Full Text] [PDF]
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