J Thorac Cardiovasc Surg 2003;126:2113-2114
© 2003 The American Association for Thoracic Surgery
A few critical aspects—and Achilles heels—of tissue engineering approaches to restore injured myocardium
Theo Kofidis, MD,
Leora B. Balsam, MD,
Robert C. Robbins, MD
Cardiothoracic Surgery/Falk Research Center, Stanford University Medical School, Stanford, CA 94305, USA
To the Editor:
We enjoyed reading Osawa and colleagues' article about histologic changes of biomaterials used to repair ventricular heart defects in small animals1 as published in this Journal and also have followed this group's work elsewhere.2 Our own review on the current literature in this area has spawned many questions and suggestions for future study designs.
Most published studies do not present clinically applicable, reparative options. We believe that a critical analysis of these studies with respect to geometry, physiology, and inflammatory and immunologic responsiveness of myocardium will help identify flaws in current study designs and also help define standardized quality criteria to guide future attempts to manufacture implantable myocardium.
Few studies, for instance, have reliably and convincingly proved enhancement of cardiac function after induction of myocardial injury relative to control values. We frequently see distorting scaffolds "sitting" on the heart, or replacing previously beating muscle, and identify in most of the cases significant foreign-body reaction and reactive neovascularization3 interpreted as angiogenesis. Frequently the immunologic response to the implanted scaffold and the inoculated cells is neglected, even when species barriers are crossed. Furthermore, many study designs fail to adhere to well-described "hard problems" in the development of bioartificial myocardium:
- With respect to cardiac geometry, the ventricular muscle constitutes a complex helical structure.4 Symmetric and isotropic matrices would promote scarring and aneurysm formation. The issues of asymmetry and anisotropy of the heart have never been addressed.
- With respect to cardiac hemodynamics, the modified law of Laplace for the heart* defines circumferential wall stress values that would not be tolerated by most of the described matrices. Very likely these matrices would decompose, leading to severe hemorrhage, or would form aneurysms.
- With respect to microscopic structure, we are unaware of approaches that involve both including nerves (conductive microstructures) and preformed chaotic and plastic microchannnels simultaneously.
- With respect to issues of storage, conservation, and scale, an infant or child with congenital defects will most probably need a graft different from one destined to replace failing myocardium in a 75-year-old patient.
- With respect to the cells, Wagers and associates5 have demonstrated that bone marrow stem cells have little developmental plasticity. Most of the tissue engineering approaches with bone marrow stem cells use whole bone marrow, rather than specific subpopulations of it, and they frequently lack identification of the inoculated cells because of missing labeling and reliable colocalization studies. What are we implanting? What happens to each particular cell population, and to what extent do these cells transdifferentiate into cardiomyocytes? Studies with myoblasts do no better. Reliability and interpretability of the results would be significantly enhanced if cell labeling and tracking methods would be used routinely. Some worth mentioning are the green fluorescent protein or carboxyfluorescein diacetate succinimidyl ester methods, the membrane fluorescent intercalated dye pkh26-gl method, and colocalization or confocal studies to identify cell identity, location, differentiation status and host immune response (Figure 1).
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Figure 1. Triple staining of carboxyfluorescein diacetate succinimidyl ester–labeled cells in 3-dimensional scaffold consisting of collagen type 1. Nuclei stain blue. Red "halo" marks myocytes (MF 20 stain). Here, cluster of cells aligns along fibers (longitudinal structures at left encompassing the cells) of collagen network.
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The commentary of this group will certainly initiate fruitful discussion on basic requirements for future scientific approaches to restoring injured myocardium.
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Footnotes
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*CWS = Pb/h x (1 - b2/2a2 - h/2b + h/8a2), where: CWS is circumferential wall stress (in dyne/cm2 x 103), P is left ventricular pressure (in dyne/cm2), a and b are major and minor semiaxes, respectively (in cm) and h is left ventricular wall thickness (in cm). 
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References
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- Osawa T, Mickle D, Weisel R, Koyama, N, Wong H, Ozawa S, Li RK. Histologic changes of nonbiodegradable and biodegradable biomaterials used to repair right ventricular heart defects in rats. J Thorac Cardiovasc Surg. 2002;1241157-63
- Yau TM, Tomita S, Weisel RD, Jia ZQ, Tumiati LC, Li RK. Beneficial effect of autologous cell transplantation on infarcted heart function: comparison between bone marrow stromal cells and heart cells. Ann Thorac Surg. 2003;75:169–177[Abstract/Free Full Text]
- Eschenhagen T, Didie M, Heubach J, Ravens U, Zimmermann WH. Cardiac tissue engineering. Transplant Immunol. 2002;9:315–321[Medline]
- Buckberg GD. Basic science review: the helix and the heart. J Thorac Cardiovasc Surg. 2002;124:863–883[Free Full Text]
- Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;27:2256–2259
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