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J Thorac Cardiovasc Surg 2003;126:2114-2115
© 2003 The American Association for Thoracic Surgery
Letter to the editor |
Division of Cardiac Surgery, Department of Surgery, Toronto General Research Institute, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
The letter of Kofidis and colleagues from Stanford University highlights several key issues that face regenerative medicine as it applies to the heart. Their insightful perspective will help spawn the critical discussion that is required to fulfill the promise of restoring cardiac structure and function after cardiac injury. Although we agree that engineered biomaterial cell-seeded patches and cellular transplantation are developing, less than a decade ago heart regeneration was considered science fiction. We hope that this discussion will generate more directed research in this emerging discipline.
With respect to cardiac geometry, living ventricular muscle constitutes a complex helical structure. It will be ideal to repair myocardial scar tissue or ventricular defects with asymmetric and anisotropic muscle tissue. However, scar tissue at site of reconstruction of ventricular aneurysm and synthetic material used for repair of congenital defects is not helical and lacks contractility and growth potential. An autologous cell-seeded conduit grows with the child1 when used during correction of congenital defects and may reduce the need for reoperation. Similarly, in large ventricular aneurysms in which resection needs to be complemented with a patch, autologous cell-seeded biomaterials2 may be preferable to the static materials currently used, such as pericardium, polytetrafluoroethylene, and Dacron polyester fabric.
Tissue engineering with cell-seeded biodegradable materials is a novel technology that allows the growth of muscle cells in three dimensions to regenerate injured muscle. The biodegradable material does not repair injured heart segments; rather, the biomaterial gradually degrades, and it is the cells in the biomaterial that secrete extracellular matrix proteins, stimulate angiogenesis, and form tissue resembling myocardial tissue.3,4 The resulting tissue is fed by neovasculature and consists of muscle as well as a complex matrix that interdigitates with the host myocardium. Although the graft is initially isotropic, it mediates an increase in elasticity and strength of the scar tissue, prevents scar expansion, and halts ventricular dilation.2 In addition, the engineered graft will remodel in response to ventricular pressure and stretch. Cellular hyperplasia and hypertrophy will enhance the strength of the graft as the biomaterial degrades. Importantly, the new muscle tissue has growth potential and would reduce the necessity for reoperation.1,3,5
With respect to cardiac hemodynamics, early biomaterials were unable to withstand wall stress of the left ventricle. However, modification of the biomaterials has increased their strength. We have evaluated2,4 a composite biomaterial consisting of a spongy central core made of 50% 
-caprolactone and 50% L-lactic acid that encourages tissue ingrowth. The outer layers are reinforced with knitted poly-L-lactide fabric, which provides sufficient strength to prevent disruption when placed in the left ventricle. The exciting feature of this new biomaterial is that the spongy portion, which supports the initial cell inoculum, is absorbed within 2 months and the fibrous portion, which provides the strength, persists for 1 to 2 years. We have shown that smooth muscle cells seed and survive within this material in vitro and form muscle tissue in vivo.3 The modified biomaterial continued to withstand right ventricular pressures at 6 months after implantation.5 We also used the cell-engineered graft (poly-L-lactide fabric with smooth muscle cells) to repair transmural defects of left ventricular free wall in adult rat hearts after myocardial infarction. The graft withstood left ventricular pressures and prevented ventricular dilation in this model.2 A similar material was used as an autologous cell-seeded patch in the repair of a congenital defect.1
These promising results will need to be evaluated in larger animal models that require thicker and more extensive grafts. The thicker grafts may be limited by the extent of tissue ingrowth in vitro and of neovascularization in vivo. The use of decellularized tissue provides the promise of a preformed vascular supply. However, the existing structure of the material will be quickly dissolved by the remodeling process, and cell survival will depend on the graft's ability to attract neovascularization. Whereas the field of therapeutic angiogenesis remains nascent, both mechanical support and vascular supply to the engineered graft could be enhanced by surgical strategies such as the placement of a pedicled muscular graft around the biomaterial.
With respect to microscopic structure, the microscopic appearance before implementation is rapidly altered by the remodeling process after engraftment. Preformed channels for nerves, arterioles, and lymphatics are rapidly replaced by host and transplanted cells, remodeling the region in response to chemical, electrical, physical, and hemodynamic stimuli.
With respect to electrical properties, those of the newly formed muscle tissue require further characterization. Skeletal myoblast implantation resulted in an increased risk of ventricular arrythmia after bypass grafting and autologous cell transplantation in patients with ischemic cardiomyopathy.6 Although this presents a hurdle to be overcome, it also provides the potential to convert electrically inert scar to tissue that is capable of passively conducting action potentials. Indeed, preliminary experiments in our laboratory have demonstrated that a QRS complex can be detected in a cell-transplanted scar where it had been electrically silent before implantation (unpublished observations). The electrical resynchronization may improve systolic performance, as reported from many centers, in the absence of myogenesis. Similar to the process by which multisite pacing has been shown to improve systolic function,7 cell transplantation may improve hemodynamics by allowing the entire myocardium to beat in unison again.
With respect to issues of storage, conservation, and scale, we agree that a child with a congenital defect will need a different graft than a 75-year-old patient with a ventricular aneurysm. There is no question that a variety of grafts need to be developed to tailor the surgical strategy to the patient. The autologous cell-seeded tissue engineered patch uses the component cells for repair. Aside from the choice of biomaterial, therefore, the tissue-engineered graft can be seeded with various combinations of cell types.
With respect to the cells, issues vary by cell type. Because congenital cardiac defects can be diagnosed in the fetal stage, umbilical cord blood cells could be used to engineer tissue.8,9 Experience with this cell type, however, is limited.
Bone marrow contains stem cells that can differentiate into myogenic cells with proper induction.10,11 In fact, bone marrow mesenchymal stem cells have extensive plasticity and have the potential to recreate all of the cell types in the heart. Because the tissue is easily obtained, these cells are excellent candidates for autologous tissue engineering.
Skeletal myoblasts have been used for cell transplantation to repair damaged hearts.6 The animal data and clinical trials have been relatively encouraging. The implanted cells formed muscle tissue in the myocardial scar tissue and improved heart function. These cells can certainly be used for autologous tissue engineering.
Smooth muscle cells represent another candidate cell type for tissue engineering. The smooth muscle cells can be harvested from a number of sources in the patient to construct an autologous cell patch. The cells are easily cultured, should induce angiogenesis in the graft, and can respond to in vivo mechanical stretch by hyperplasia and hypertrophy to prevent patch dilatation and thinning.2,5
With respect to cell fate, the fate of the transplanted cells and the mechanism by which they enhance myocardial function remain largely unknown. We agree with Kofidis and colleagues that appropriate tracking methods, such as those presented in their letter, will aid in answering these questions.
An equally important issue is the role that the host's immune response plays in the field of cell transplantation and biomaterial engineering. This has been an oft neglected issue. Recent evidence from our laboratory indicates that even transplantation of syngeneic cells grown in vitro for 2 weeks elicits a response that includes T- and B-cell infiltration (unpublished observations). The appropriate modulation of the immune response may improve the already promising results of cell transplantation.
In closing, we are grateful to Kofidis and colleagues for bringing these important issues to critical discussion. The area of regenerative medicine is promising and in our mind forms the basis for our future therapies. Although we have a long way to go, we must not forget that we have come an even longer way, in spite of the Achilles heels.
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