Nitric Oxide–Eluting Polyurethanes — Vascular Grafts of the Future?
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《新英格兰医药杂志》
Aristotle said, "In all things of nature there is something of the marvelous." Nitric oxide is one such marvel. Few could have predicted that one atom of nitrogen and one of oxygen would together be a fundamental regulator of the human body. Among the endogenous defenses against vascular injury, inflammation, thrombosis, and atherosclerosis, nitric oxide assumes the dominant role. Its release from the endothelium counters the activation and adhesion of leukocytes, limits platelet aggregation and thrombus formation, and maintains the vascular smooth muscle in a nonproliferative state, thereby maintaining the integrity of blood vessels and guarding against adverse vascular remodeling. These characteristics suggest that nitric oxide may improve the biologic properties of cardiovascular biomaterials,1 and a recent report by Jun and colleagues2 provides support for this hypothesis.
Autologous vessels, such as the internal thoracic artery and saphenous vein, are routinely used in coronary and peripheral arterial bypass surgery. Unfortunately, some patients do not have enough vessels for transplantation or they have preexisting disease in these vessels. Furthermore, the relative paucity of nitric oxide production by saphenous veins as compared with arterial conduits may contribute to early graft failure. Synthetic materials such as polyethylene terephthalate (Dacron) and expanded polytetrafluoroethylene (Teflon) are used for large-diameter (more than 6 mm) vascular substitutes, but these are prone to thrombosis, intimal hyperplasia, and thus, failure in small-diameter applications, especially coronary-artery bypass grafting. Perhaps a graft that releases nitric oxide would address these problems.
Jun et al.2 incorporated a nitric oxide donor (called diazeniumdiolate) into a polyurethane and then assessed its interactions with platelets, vascular smooth-muscle cells, and endothelial cells — all of which are critical to graft occlusion (Figure 1). The anionic portions of diazeniumdiolates, which contain the [N(O)NO]– functional group, spontaneously decompose in solution to release nitric oxide.
Figure 1. The Effect of a Nitric Oxide–Eluting Polyurethane Graft.
The synthesis of a nitric oxide–eluting polyurethane by Jun et al.2 presents the intriguing possibility of manufacturing a synthetic, small-diameter vascular graft for use in bypass procedures that would avert rapid occlusion and graft failure. Studies suggest that a small-caliber synthetic polyurethane graft without a thrombosis-resistant surface is quickly occluded when used to bypass a coronary vessel. In vitro experiments carried out by Jun et al.2 suggest that a graft composed of nitric oxide–eluting polyurethane may limit graft occlusion by promoting early endothelialization of the synthetic surface and inhibit the adhesion, aggregation, and activation of platelets.
The authors found that the mechanical properties of the synthesized polymer were similar to those of commercial polyurethane vascular grafts and that nitric oxide was released in two phases: a rapid burst during the first 48 hours, followed by a slower, sustained release over a two-month period. During both phases, endothelial cells exposed to the nitric oxide–eluting polyurethane films showed enhanced rates of proliferation and increased rates of migration and coverage of the synthetic surface, as compared with cells exposed to control polyurethane films. The development of a nascent endothelial lining within vascular conduits forms a physiologically relevant interface between blood and the vessel wall that is similar to that of native vessels and is considered to be a pivotal event required to protect against early thrombosis and graft occlusion. In addition, vascular smooth-muscle cells showed a reduced rate of proliferation when exposed to nitric oxide–eluting polyurethane films during both phases of the release of nitric oxide, indicating that the use of a nitric oxide–eluting polyethylene graft may limit the formation of occlusive scar tissue and neointimal hyperplasia. Finally, the level of platelet adhesion was significantly lower on nitric oxide–eluting polyurethane films than on control polyurethane films during both phases of nitric oxide release. This finding, too, predicts that the use of nitric oxide–eluting polyurethane grafts will inhibit the formation of occlusive thrombus.
The synthesis of a bioactive, nitric oxide–eluting polyurethane serves as a first step toward the generation of a synthetic, small-diameter vascular graft for use in bypass procedures involving small-caliber arteries. The concept is tantalizing, but several questions remain. Will the in vitro effects of nitric oxide–eluting polyurethane be maintained when the films are formed into cylindrical vascular grafts? And what about the effect of the physical forces of the circulation, especially shear stress, on the in vivo antithrombotic and antiocclusive properties of the polymer? Similarly, we need to determine the response of bone marrow–derived endothelial progenitor cells to nitric oxide–eluting polyurethane. These stem cells participate extensively in the reendothelialization of damaged vascular surfaces and actively contribute to the processes of neointimal formation, restenosis, and atherogenesis.3 The sustained release of nitric oxide may favorably influence this cell population, because endothelial nitric oxide synthase is critical for the activity of endothelial progenitor cells.
Will nitric oxide–eluting polyurethane grafts offer enduring vascular benefit? Early reendothelialization and inhibition of platelet aggregation should enhance long-term patency by establishing an endothelial environment resembling that of native vessels, but this possibility will require careful study. In humans, the endothelial cells that overlie atherosclerotic plaques in diseased blood vessels do not produce much biologically active endothelial-derived nitric oxide, in part because they express little endothelial nitric oxide synthase.4 The therapeutic potential of nitric oxide–eluting polyurethane grafts may therefore lie in the hope that they more closely mirror a healthy vascular endothelial phenotype.5
Source Information
From the Divisions of Cardiac Surgery (S.V.) and Nephrology (P.A.M.), St. Michael's Hospital and the University of Toronto, Toronto.
References
Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001;88:756-762.
Jun HW, Taite LJ, West JL. Nitric oxide-producing polyurethanes. Biomacromolecules 2005;6:838-844.
Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;8:403-409.
Wilcox JN, Subramanian RR, Sundell CL, et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 1997;17:2479-2488.
Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease. Circulation 2003;108:2054-2059.(Subodh Verma, M.D., Ph.D.)
Autologous vessels, such as the internal thoracic artery and saphenous vein, are routinely used in coronary and peripheral arterial bypass surgery. Unfortunately, some patients do not have enough vessels for transplantation or they have preexisting disease in these vessels. Furthermore, the relative paucity of nitric oxide production by saphenous veins as compared with arterial conduits may contribute to early graft failure. Synthetic materials such as polyethylene terephthalate (Dacron) and expanded polytetrafluoroethylene (Teflon) are used for large-diameter (more than 6 mm) vascular substitutes, but these are prone to thrombosis, intimal hyperplasia, and thus, failure in small-diameter applications, especially coronary-artery bypass grafting. Perhaps a graft that releases nitric oxide would address these problems.
Jun et al.2 incorporated a nitric oxide donor (called diazeniumdiolate) into a polyurethane and then assessed its interactions with platelets, vascular smooth-muscle cells, and endothelial cells — all of which are critical to graft occlusion (Figure 1). The anionic portions of diazeniumdiolates, which contain the [N(O)NO]– functional group, spontaneously decompose in solution to release nitric oxide.
Figure 1. The Effect of a Nitric Oxide–Eluting Polyurethane Graft.
The synthesis of a nitric oxide–eluting polyurethane by Jun et al.2 presents the intriguing possibility of manufacturing a synthetic, small-diameter vascular graft for use in bypass procedures that would avert rapid occlusion and graft failure. Studies suggest that a small-caliber synthetic polyurethane graft without a thrombosis-resistant surface is quickly occluded when used to bypass a coronary vessel. In vitro experiments carried out by Jun et al.2 suggest that a graft composed of nitric oxide–eluting polyurethane may limit graft occlusion by promoting early endothelialization of the synthetic surface and inhibit the adhesion, aggregation, and activation of platelets.
The authors found that the mechanical properties of the synthesized polymer were similar to those of commercial polyurethane vascular grafts and that nitric oxide was released in two phases: a rapid burst during the first 48 hours, followed by a slower, sustained release over a two-month period. During both phases, endothelial cells exposed to the nitric oxide–eluting polyurethane films showed enhanced rates of proliferation and increased rates of migration and coverage of the synthetic surface, as compared with cells exposed to control polyurethane films. The development of a nascent endothelial lining within vascular conduits forms a physiologically relevant interface between blood and the vessel wall that is similar to that of native vessels and is considered to be a pivotal event required to protect against early thrombosis and graft occlusion. In addition, vascular smooth-muscle cells showed a reduced rate of proliferation when exposed to nitric oxide–eluting polyurethane films during both phases of the release of nitric oxide, indicating that the use of a nitric oxide–eluting polyethylene graft may limit the formation of occlusive scar tissue and neointimal hyperplasia. Finally, the level of platelet adhesion was significantly lower on nitric oxide–eluting polyurethane films than on control polyurethane films during both phases of nitric oxide release. This finding, too, predicts that the use of nitric oxide–eluting polyurethane grafts will inhibit the formation of occlusive thrombus.
The synthesis of a bioactive, nitric oxide–eluting polyurethane serves as a first step toward the generation of a synthetic, small-diameter vascular graft for use in bypass procedures involving small-caliber arteries. The concept is tantalizing, but several questions remain. Will the in vitro effects of nitric oxide–eluting polyurethane be maintained when the films are formed into cylindrical vascular grafts? And what about the effect of the physical forces of the circulation, especially shear stress, on the in vivo antithrombotic and antiocclusive properties of the polymer? Similarly, we need to determine the response of bone marrow–derived endothelial progenitor cells to nitric oxide–eluting polyurethane. These stem cells participate extensively in the reendothelialization of damaged vascular surfaces and actively contribute to the processes of neointimal formation, restenosis, and atherogenesis.3 The sustained release of nitric oxide may favorably influence this cell population, because endothelial nitric oxide synthase is critical for the activity of endothelial progenitor cells.
Will nitric oxide–eluting polyurethane grafts offer enduring vascular benefit? Early reendothelialization and inhibition of platelet aggregation should enhance long-term patency by establishing an endothelial environment resembling that of native vessels, but this possibility will require careful study. In humans, the endothelial cells that overlie atherosclerotic plaques in diseased blood vessels do not produce much biologically active endothelial-derived nitric oxide, in part because they express little endothelial nitric oxide synthase.4 The therapeutic potential of nitric oxide–eluting polyurethane grafts may therefore lie in the hope that they more closely mirror a healthy vascular endothelial phenotype.5
Source Information
From the Divisions of Cardiac Surgery (S.V.) and Nephrology (P.A.M.), St. Michael's Hospital and the University of Toronto, Toronto.
References
Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001;88:756-762.
Jun HW, Taite LJ, West JL. Nitric oxide-producing polyurethanes. Biomacromolecules 2005;6:838-844.
Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;8:403-409.
Wilcox JN, Subramanian RR, Sundell CL, et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 1997;17:2479-2488.
Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease. Circulation 2003;108:2054-2059.(Subodh Verma, M.D., Ph.D.)