| Editor's Note |
| by Edward H. Kincaid, MD, Anthony Atala, MD , Neal D. Kon, MD |
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Tissue Engineered Heart Valves: A Potential Cure for Valvular Heart Disease
Since the advent of surgery for valvular heart disease, scientists and surgeons have sought the ideal valve prosthesis when replacement is required. Over the span of four decades, significant advancements in valve design and construction include increased use of pyrolytic carbon and other inert materials with increased durability, less obstructive designs, better processing of tissue valves for added longevity, and stentless constructs including homografts, autografts, and xenograft tissue bioprostheses. None of these advancements, however, can be regarded as truly revolutionary. All valve replacement options have advantages and disadvantages which are discussed with patients on a daily basis.
The ideal valve substitute in the future may arise from tissue engineering, a science that combines the principles of bioengineering, cell transplantation, hematology, and material science. This field is in its infancy, with many more dreams than reality, but with incredible potential to revolutionize treatment for heart disease. A small step in the application of tissue engineering for heart valves has been the creation of the Synergraft decellularized homograft and xenograft aortic prosthesis. Cryopreserved and completely decellularized, these valves have the theoretical advantage of allowing for repopulation of the matrix by host cells which provide the functions of a living structure: growing, healing (regeneration), resistance to infection (immune function), and creation of extracellular substances such as matrix and biologically active compounds. While histologic studies have demonstrated recipient cells within these types of grafts [1], the functionality of these cells is unclear. Certainly, clinical follow-up of decellularized aortic valves has not proven any clear benefits and some evidence of early degeneration [2,3]. To understand why the potential advantages of the Synergraft have not been realized, one must understand the basic concepts of tissue engineering. These include creation of a suitable scaffold, repopulation with appropriate cells, promotion of neovascularization, and mechanical conditioning.
Scaffold
The development of an appropriate matrix for heart valve creation presents enormous obstacles. The perfect scaffold would be completely biodegradable, immunologically inert, extremely malleable, low profile, and provide conditions necessary for cell repopulation. For valves, these elements must be added to a structure that physically is quite complex and under enormous forces. This last requirement makes the decellularized homograft an attractive option. It is unclear, however, how this scaffold will fare in terms of biodegradability and its ability to allow for complete replacement by autologous tissue, a probable necessity for growth and regeneration. On a positive note, these grafts do appear to be nonimmunogenic, invoking minimal panel reactive antibody response [2]. Other biologic scaffolds include fibrin gel and extracellular matrix. Man-made matrices include polymers of glactin and glycolic acid. These malleable compounds have predictable degradation and cell-seeding potential, and can also be implanted with growth factors and other biologically active substances.
Seeding of Appropriate Cells
Repopulation of the scaffolding by host cells can occur passively as discussed above and actively in which cells are forced onto the matrix. Active seeding presents many technical obstacles but may be required for acceptable results. This is suggested by the early results of the passively seeded Synergraft and by research involving the genitourinary system. For example, in animals, investigators replaced portions of urethra with tubular collagen matrices, some of which were actively seeded with cultured bladder cells. After one month, the bare collagen scaffolds all had strictures while the seeded grafts had normal urethral caliber and transitional cell histology [4]. Other important seeding issues relate to sources and types of cells used. Autologous endothelial cells and myofibroblasts are readily available from harvested arteries and veins and can be grown and seeded successfully onto appropriate scaffolds. Limitations of this technique include morphologic differences in vascular and valvular cells, disease states of the donor which may diffusely affect the cells of the donor cardiovascular system, and the need to sacrifice healthy tissue. As an alternative, bone marrow progenitor cells are an attractive alternative. Also known as mesenchymal stem cells, they can be harvested from bone marrow after drug-induced mobilization. Stem cells have the tremendous potential to differentiate into many cell lines and tissues, including cardiovascular structures. Allogenic stem cells, often derived from embryonic tissue, may also be used for tissue engineering as can cells created by therapeutic cloning. Each of these options has the theoretical advantage of near-limitless supply, but are both hampered by ethical issues.
Creation of the Tissue-Engineered Valve
To create human valve leaflets, researchers have seeded cultured stem cells on biodegradable tri-leaflet scaffolds and then subjected the model to pulsatile flow. Application of biological forces appears to stimulate the cells to differentiate into valvular myofibroblasts that produce extracellular matrix and have similar in vitro mechanical properties of native trileaflet valves [5]. A clinically acceptable time frame of 6-8 weeks will likely be required to produce tissue-engineered leaflets. Initially, one would envision these being mounted on permanent stents, similar to a stented xenograft prosthesis. This will limit use in the pediatric setting and in adults where total aortic root replacement is warranted. When constructing the tissue-engineered root, additional challenges will be encountered. These will include more complex scaffolding, necessity of other cell lines to create aortic and sinus tissue, and creation of living tissue with increased strength to allow attachment of the graft to the recipient outflow tract. Further, to create such an organ, neovascularization will be needed for cells not nourished by diffusion, as occurs with leaflet and endothelial cells. Methods of creating these microvessels involve addition of growth factors to the model or seeding with bone marrow-derived endothelial progenitor cells. Additional engineering hurdles will be encountered in mitral valve construction because of the complex subvalvular apparatus.
Implications for Surgeons
Valvular heart disease is primarily a surgical condition. It is therefore imperative that we stay involved with valve engineering efforts. Tissue engineering offers the rare chance for cure of a serious medical condition. This will certainly involve surgery offered in earlier stages of valve degeneration to prevent late structural myocardial damage and arrhythmias. In this setting, familiarity with complex implantation techniques will become more important as will minimizing operative morbidity and mortality in this asymptomatic patient population. Opportunities for advancement in congenital heart disease are endless as well and include obviation of multiple repeat operations and potential cure of some conditions. Those surgeons whose outlook on our specialty is one of pessimism should look into the crystal ball of technology.
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References: |
1. Elkins RC, Dawson PE, Goldstein S, Walsh SP, Black KS. Decellularized human valve allografts. Ann Thorac Surg 2002;71:S428-32.
2. Bechtel JF, Muller-Steinhardt M, Schmidtke C, Brunswik A, Stierle U, Sievers HH. Evaluation of the decellularized pulmonary valve homograft (SynerGraft). J Heart Valve Dis 2003;12:734-9.
3. Simon P, Kasimir MT, Seebacher G, et al. Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients. Eur J Cardiothorac Surg 2003;23:1002-6.
4. De Filippo RE, Yoo JJ, Atala, A. Urethral replacement using cell seeded tubularized collagen matrices. J Urology 2002;168:1789-93.
5. Hoerstrup SP, Kadner A, Melnitchouk S, et al. Tissue engineering of functional trileaflet heart valves from human marrow stromal cells. Circulation 2002;106:I143-50.
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