© 1999 American Heart Association, Inc.
Editorials |
Vascular Tissue Engineering
Designer Arteries
From the Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Mass, and Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Elazer R. Edelman, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Room 16-343, 77 Massachusetts Ave, Cambridge, MA 02139. E-mail eedelman{at}mit.edu
Key Words: tissue engineering • vascular graft
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Introduction |
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 Top Introduction Vascular GraftingVascular Tissue EngineeringWhat Have We Learned?Biological Tool or Potential...References |
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The fields of vascular biology and vascular medicine are so intertwined that advances in one predict, explain, or are required for progress in the other. Bypass grafting, which once served as a "bailout" procedure,1 2 is now performed more than 600 000 times annually in the United States. In major part, this increase can be attributed to a surge in understanding of the vascular response to injury. At the same time, the science of vascular biology has been primarily stimulated by the clinical imperative to combat complications that ensue from vascular interventions.3 Thus, when a novel vascular biological finding or cardiovascular medical/surgical technique is presented, we are required to ask the 2-fold question: what have we learned about the biology of the blood vessel, and how might this knowledge be used to enhance clinical perspective and treatment? The innovative method of engineering arterial conduits presented by Campbell et al4 in this issue of Circulation Research presents us with just such a challenge, and I will attempt to deal with the biological and clinical ramifications of this work.
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Vascular Grafting |
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TopIntroductionVascular GraftingVascular Tissue EngineeringWhat Have We Learned?Biological Tool or Potential...References |
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Although routinely applied and ubiquitously used, vascular grafting is not without significant constraints and complications.3 Arterial conduits are in limited supply and restricted dimensions. Venous conduits are more abundant but lack vasomotor tone and are prone to thrombotic and hyperplastic occlusion and, less frequently, infection. Veins and arteries must be harvested from sites that leave wounds that can break down or become infected. Synthetic materials do not fare well in small-bore vascular beds and are excessively thrombotic. Graft passivation has been attempted to minimize material-blood interaction by surface modification with coatings of proteins,5 polymer materials, or cells.6 7 Although somewhat successful in limiting thrombosis and hyperplasia, such linings do not provide vascular responsiveness or other biochemical secretory function seen with the normal blood vessel. Furthermore, passivated grafts are still subject to bacterial colonization and graft infection. As a result of these problems with native, synthetic, and modified grafts, there have been multiple attempts at creating tissue-engineered vessels composed of biological materials and autologous cells. Because of space limitation, I will discuss only four of the pivotal studies that address the field of vascular tissue engineering and the lessons learned as we attempt to obtain designer arteries.4 8 9 10 Many other innovative and creative approaches have been published and all have added to our understanding of vascular biology, vascular medicine, and vascular grafting.
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Vascular Tissue Engineering |
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TopIntroductionVascular GraftingVascular Tissue EngineeringWhat Have We Learned?Biological Tool or Potential...References |
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Tissue engineering has been classified as an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function.11 12 In 1986, Weinberg and Bell8 produced the first tissue-engineered vessel. Cultured bovine endothelial cells, smooth muscle cells, and fibroblasts were mixed to construct artificial blood vessels in vitro that served as effective permeability barriers. Surface cells produced von Willebrand factor and prostacyclin, and the strength of the vessel depended on its multiple layers of collagen integrated with a Dacron mesh. L’heureux et al 9 improved on the mechanical strength of these engineered grafts by culturing mesenchymal cells (smooth muscle cells and fibroblasts) in the presence of vitamin C, to create a three-dimensional extracellular matrix with characteristics similar to those observed in vivo. An acellular extracellular matrix was formed from the dehydrated products of adult human skin fibroblasts and wrapped around a polytetrafluoroethylene mandril. A sheet of umbilical venous smooth muscle cells was wrapped around the first sheet to form the vascular media. The device was placed in a bioreactor, and 1 week later, a sheet of fibroblasts was added to construct the outer media and adventitia. After 56 days of additional maturation, an integrated tubular structure could be removed from the pipette intact. This structure was implanted as a canine femoral arterial interposition graft and remained patent in 3 of 6 animals at 1 week. Bench-top seeding with umbilical venous endothelial cells was also performed. Niklason et al10 grew blood vessels in polymeric tubes under flow conditions. Bovine aortic smooth muscle cells were placed on tube-shaped polyglycolic acid scaffoldings and placed in a silicone tube circuit that pumped media at 165 beats per minute with 5% radial distention. After 8 weeks, the grafts were removed and the surfaces coated with bovine aortic endothelial cells. Pulsed grafts were thicker, had greater suture retention, more physiological smooth muscle cell density and collagen density, and were patent longer as porcine saphenous arterial xenografts than nonpulsed engineered grafts. Campbell et al4 now report an innovative means of engineering vascular grafts. Silastic tubing of variable dimensions was inserted in the peritoneal cavity of rats or rabbits. In that position, the inflammatory reaction that ensued covered the tubes with successive layers of myofibroblasts, collagen matrix, and a monolayer of mesothelial cells. These structures could be removed from the Silastic tubes and everted to create a synthetic artery whose architecture mirrored that of the normal vessel, with the mesothelial cells serving as the endothelium, the myofibroblasts as smooth muscle cell analogues in a bed of collagen and elastin, and a collagenous adventitia. These structures were interpositionally grafted end-to-end into rabbit carotid arteries or rat abdominal aortas in the very same animals in which they had grown and remained patent for at least 4 months. In that time, the engineered vessels underwent transformation to develop structures that resemble elastic lamellar and high volume of myofilaments to gain contractile responsiveness to pharmacologic agonists.
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What Have We Learned? |
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TopIntroductionVascular GraftingVascular Tissue EngineeringWhat Have We Learned?Biological Tool or Potential...References |
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Each of the four pivotal studies4 8 9 10 in vascular tissue engineering has been an important advance in the progression to a tissue-engineered blood vessel that can serve as a living graft, responsive to the biological environment as a self-renewing tissue with an inherent healing potential. Weinberg and Bell8 taught us that a tissue-engineered graft could be constructed and could be composed of human cells. L’heureux et al9 demonstrated that the mechanical strength of such a material derived in major part from the extracellular matrix and production of matrix and integrity of cellular sheets could be enhanced by alterations in culture conditions. Niklason et al10 noted that grafts are optimally formed when incubated within environmental conditions that they will confront in vivo or would have experienced if formed naturally. Campbell et al4 now demonstrate that it is possible to remove the immune reaction and acute rejection that may follow cell-based grafting by culturing tissues in the anticipated host and address a fundamental issue of whether cell source or site of cell placement dictates function after cell implantation. It appears that the vascular matrix can be remodeled by the body according to the needs of the environment. It may very well be that the ultimate configuration of autologous cell-based vascular graft need not be determined at outset by the cells that comprise the device, but rather by a dynamic that is established by environmental needs, wherein the body molds tissue-engineered constructs to meet local flow, metabolic, and inflammatory requirements. In other words, cell source for tissue reconstruction may be secondary to cell pliability to environmental influence. Endothelial and smooth muscle cells from many, perhaps any, vascular bed can be used to create new grafts and will then achieve secondary function once in place in the artery. The dynamic environmental remodeling that is observed after implantation may address the potential limitation of grafts that are composed of nonvascular peritoneal cells and whose initial structure is neither venous nor arterial. It appears that once in place as a graft, myofilament density and collagen and elastin content conform to the needs of the environment.
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Biological Tool or Potential Bypass Material? |
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TopIntroductionVascular GraftingVascular Tissue EngineeringWhat Have We Learned?Biological Tool or Potential...References |
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Having dealt with the question of what tissue engineering has taught us about the vascular biology of grafts and grafted vessels, we must now ask how might this information change our practice of vascular medicine. In the past, cardiac surgeons were confronted with the choice of using the internal mammary artery for one bypass graft and saphenous venous grafts in other positions. Venous harvest was tedious and required complete exposure of the vein along its length with skin incisions that stretched from groin to ankle. Today, an all-arterial bypass is possible if desired. Both internal mammary and radial arteries are available and, on occasion, the gastroepiploic artery as well. Excisional venous harvests are now a thing of the past, and minimally invasive techniques allow for long lengths of veins to be obtained with two small incisions. Tissue-engineered blood vessels might well supply a stock of grafts when replacement conduits are not available, but questions remain. For example, virtually all of the tissue-engineered vessels require weeks to months of incubation before vessels are suitable for implantation. The length of this incubation may be appropriate for planned surgery, but bypass is increasingly performed without such lengthy delay. This issue takes on added importance if these unpreserved cellular-tissue grafts have a limited shelf-life. Allografts and xenografts can be provided for constant updating of stock, but repeated formation of autografts is likely untenable. Similarly, the function of these grafts is also not yet fully defined. It is not clear whether tissue-engineered vessels will perform like, better, or worse than native arteries or veins. Patency of grafted internal mammary arteries far exceeds that of saphenous veins13 and for, as-yet, only partially explicable reasons that include not only differences in structure but also secretory function.14 15 It is the biochemical features of a blood vessel that may well identify it as an active organ, and although much emphasis has been placed on the mechanical aspects of grafting, eg, burst strength and suturability, differentiation of grafts may arise from differences in what they secrete. We have in fact shown that one can achieve control of the thrombotic, inflammatory, and hyperplastic aspects of vascular homeostasis without recapitulation tissue architecture. When three-dimensional matrices embedded with vascular endothelial cells were wrapped around injured arteries, there was no greater control of the vascular response to injury.16 17 Such findings emphasize the intricate nature of the vascular system as far more than a bed of pipes and tubes, the importance of the biochemical function of the blood vessel and the complex interplay between structure and function.
It seems that alterations in incubation time, changes in culture conditions or content, and maybe even site of incubation can change the structure of the tissue-engineered vessel. If the essential elements needed to establish biochemical control can be identified, and the difference in arterial and venous conduit performance can be defined or attributed to particular structures, then grafts can be optimally designed with specific cells and tissue architecture. In the interim, for tissue-engineered grafts to be embraced for clinical use and to replace native vessels, when native vessels are available, they will need to "out-perform" venous conduits and provide rates of thrombosis, hyperplasia, infection, and seroma formation that are lower than those that limit the average life span of venous conduits to less than 7 years. These issues will be resolved in the years to come. For now, tissue-engineered vessels represent a powerful tool to examine complex issues in vascular biology and cardiovascular surgery. Innovations such as the autologous peritoneal incubation proposed by Campbell et al4 might develop vessels that can be used in experiments to divorce issues of immune response from the remaining spectrum of the vascular response to injury. Studies might now be performed to examine the impact of specific drugs or molecular interventions when no anticipated immune rejection might be in play or similarly to gauge the impact of the rejection and inflammation that arise from host mismatch.
If the technical aspects of peritoneal incubation can be linked with advances in molecular biology, tissue engineering, gene therapy, and protein biochemistry, we might ultimately develop designer arteries that possess the mechanical and functional qualities we seek in autologous tissue-engineered vascular replacements.
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Acknowledgments |
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This work was supported in part by grants from the National Institutes of Health (GM/HL 49039 and HL 60407) and an Established Investigator Award from the American Heart Association. I wish to thank Dr Campbell Rogers for his critical review of this manuscript.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionVascular GraftingVascular Tissue EngineeringWhat Have We Learned?Biological Tool or Potential...References |
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1. Favaloro RG. Saphenous vein autograft replacement of severe segmental coronary artery occlusion: operative technique. Ann Thorac Surg. 1968;5:334–339.[Medline] [Order article via Infotrieve]
2. Kolessov VI. Mammary artery-coronary artery anastomosis as method of treatment for angina pectoris. J Thorac Cardiovasc Surg. 1967;54:535–544.[Medline] [Order article via Infotrieve]
3.
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4.
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14. Ferro M, Conti M, Novero D, Micca FB, Palestro G. The thin intima of the internal mammary artery as the possible reason for freedom from atherosclerosis and success in coronary bypass. Am Heart J. 1991;122:1192–1195.[Medline] [Order article via Infotrieve]
15. Chaikhouni A, Crawford FA, Kochel PJ, Olanoff LS, Halushka PV. Human internal mammary artery produces more prostacyclin than saphenous vein. J Thorac Cardiovasc Surg. 1986;92:88–91.[Abstract]
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