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Artiﬁcial blood vessel: The Holy Grail of peripheral vascular surgery
John D. Kakisis,a,b Christos D. Liapis,b Christopher Breuer,a and Bauer E. Sumpio,a New Haven, Conn; and Athens, Greece
Artiﬁcial blood vessels composed of viable tissue represent the ideal vascular graft. Compliance, lack of thrombogenicity, and resistance to infections as well as the ability to heal, remodel, contract, and secrete normal blood vessel products are theoretical advantages of such grafts. Three basic elements are generally required for the construction of an artiﬁcial vessel: a structural scaffold, made either of collagen or a biodegradable polymer; vascular cells, and a nurturing environment. Mechanical properties of the artiﬁcial vessels are enhanced by bioreactors that mimic the in vivo environment of the vascular cells by producing pulsatile ﬂow. Alternative approaches include the production of ﬁbrocollagenous tubes within the recipient’s own body (subcutaneous tissue or peritoneal cavity) and the construction of an artiﬁcial vessel from acellular native tissues, such as decellularized small intestine submucosa, ureter, and allogeneic or xenogeneic arteries. This review details the most recent developments on vascular tissue engineering, summarizes the results of initial experiments on animals and humans, and outlines the current status and the challenges for the future. ( J Vasc Surg 2005;41:349-54.)
There is a tremendous impetus in the vascular community to develop synthetic small-diameter grafts that have high long-term patency rates. “Off the shelf” availability in various diameters and lengths, uncomplicated storage or preparation requirements, and ease of handling are the main advantages of such grafts; their inherent thrombogenicity and compliance mismatch are the main drawbacks. Synthetic grafts have been associated with excellent longterm results in treating the pathology of large-diameter arteries where the ﬂow is high and the resistance is low. The patency rates have been disappointing when they are used to replace small-diameter ( 6 mm) arteries such as the coronary and the infragenicular vessels.1-3 One strategy to overcome these limitations applies tissue engineering techniques to construct biologic substitutes of diseased native vessels. These artiﬁcial blood vessels should ideally be composed of viable tissue, able to contract in response to hemodynamic forces and chemical stimuli, and secrete normal blood vessel products. Artiﬁcial blood vessels should also allow complete healing without any immunologic reaction, remodeling according to the needs
From the Department of Vascular Surgery,a Yale University School of Medicine, and the 2nd Department of Propedeutic Surgery,b Athens University Medical School, Laiko Hospital. Competition of interest: none. Additional material for this article may be found online at www.mosby.com/jvs. Reprint requests: Bauer E. Sumpio, MD, PhD, Chief, Vascular Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510. 0741-5214/$30.00 Copyright © 2005 by The Society for Vascular Surgery. doi:10.1016/j.jvs.2004.12.026
of the environment, and even have the ability to grow when placed in children. Compliance, lack of thrombogenicity, and resistance to infections are theoretical advantages of such grafts, and burst strength and “off the shelf” availability are additional desirable goals.4 This review summarizes recent developments in vascular tissue engineering and the initial in vivo studies. A Medline search of the English-language literature was performed using the key words artiﬁcial vessels, tissue engineering, and vascular grafts. Reference lists from all relevant articles were reviewed to identify additional studies. Construction of an artiﬁcial vessel. Three basic elements are generally required for the construction of an artiﬁcial vessel: a structural scaffold, cells, and a nurturing environment (Table).5-13 The scaffold provides a temporary skeleton to support the growing tissue and provides the desired shape until the cells produce their own extracellular matrix (ECM). Most scaffolds are based on collagen matrices and biodegradable polymers. Another strategy is to use a tubular mandrel as a supporting device in vitro and remove it prior to implantation of the graft into the host.14 Autologous or allogeneic smooth muscle cells (SMCs), ﬁbroblasts, and endothelial cells (ECs) can then be seeded on the scaffold and cultured until a cellularized vessel with optimal mechanical properties is created. Bioreactors that mimic the in vivo environment of the vascular cells by producing pulsatile ﬂow are being evaluated and may be useful in this process.12,15,16 Artiﬁcial vessels based on collagen scaffolds. Weinberg and Bell5 were the ﬁrst to report the in vitro construction of a vessel; its multilayer structure resembled that of an artery. Collagen and bovine aortic SMCs were 349
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Methods for preparing an artiﬁcial vessel and initial results
Author Weinberg and Bell,5 1986 L’Heureux et al,6 1993 Scaffold Natural (collagen) Collagen Type I and III collagen Cells Bovine aortic SMC, EC and ﬁbroblasts Human umbilical vein SMC and EC Human skin ﬁbroblasts Canine jugular SMC and EC Mechanical properties Poor, necessitating a Dacron mesh Poor Implantation site Not tested Not tested Patency
Hirai et al,7,8 1994
Type I collagen Synthetic (biodegradable polymer) PGA-PHA PGA PGA-CL/LA PGA-P4HB PGA-P4HB None
Poor, necessitating a Dacron mesh
Canine posterior vena cava
65% at 6 months
Shum-Tim et al,9 1999 Niklason et al,10 1999 Watanabe et al,
Hoerstrup et al,12 2001 Hoerstrup et al,13 2002 L’Heureux et al,14 1998
Ovine carotid SMC, EC and ﬁbroblasts Bovine aortic SMC and EC Canine femoral vein SMC and ﬁbroblasts Ovine carotid ﬁbroblasts and EC Human umbilical cord cells Human umbilical vein SMC and EC Human skin ﬁbroblasts
Good Good Moderate Good Good Good
Ovine infrarenal aorta Swine saphenous artery Canine inferior vena cava Not tested Not tested Canine femoral artery
100% at 5 months 100% at 4 weeks 100% at 13 months
50% at 7 days
SMC, Smooth muscle cells; EC, endothelial cells; PGA, polyglycolic acid; PHA, polyhydroxyalkanoate; CL, caprolactone; LA, lactic acid; P4HB, poly-4hydroxybutyrate.
casted together in culture medium to create an annular mold (Fig 1, online only). The inner surface of the graft was seeded with bovine ECs and the outer with bovine adventitial ﬁbroblasts. A Dacron mesh was embedded into the wall to enhance the mechanical strength of the model. Models made without the mesh dilated and ruptured at very low intraluminal pressures ( 10 mm Hg). A model with one mesh had a burst strength of 40 to 70 mm Hg, whereas three layers of collagen lattice alternating with two meshes provided a burst strength of 120 to 180 mm Hg. The absence of elastin, the longitudinal (instead of circular) orientation of the SMCs, and the low densities of the SMCs and collagen accounted for the poor mechanical properties of the model. However, well differentiated SMCs and functional endothelium, which could produce von Willebrand’s factor and prostacyclin, made this blood vessel model attractive and sparked further research into the tissue engineering of blood vessels. A similar technique used by Hirai et al7,8 yielded similar results. Hybrid medial tissue was prepared by pouring a cold solution of canine jugular SMCs and type I collagen into a tubular glass mold. The luminal surface was seeded
with jugular ECs and the resulting graft was implanted in canine vena cava. Despite the low venous pressures, the graft ruptured within a few days of implantation. Subsequent grafts were wrapped with a Dacron mesh to prevent tearing, and the patency rate of the wrapped grafts was 64% at 6 months. Complete remodeling could be documented by a monolayer of longitudinally oriented ECs on the luminal surface, circumferentially oriented SMCs of the contractile phenotype at the subendothelial layer, ingrown ﬁbroblasts throughout the vessel wall, meshes of collagen ﬁbrils in the intercellular space, and sheet-like elastic lamellae in the subendothelial layer. The poor mechanical strength of collagen-based artiﬁcial vessels has been partially attributed to the longitudinal orientation of the SMCs before implantation. Several strategies have been used to stimulate reorientation of the SMCs in a circumferential direction. L’Heureux et al6 hypothesized that SMC orientation is directly inﬂuenced by tensions that oppose cell contraction. In this context, circumferential forces induced during the maturation of the artiﬁcial vessel are favorable, whereas longitudinal forces are not. To minimize longitudinal forces, the adherence of
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media to the glass mandrel was repeatedly broken up by tapping the tube on a hard surface at least once a day. This allowed free longitudinal contraction of the media. The radial forces remained, stimulating reorientation of the SMCs in a circumferential fashion. A collagen gel containing human dermal ﬁbroblasts was added around the media-like structure to simulate an adventitia; an endothelium was established by injecting a solution of human umbilical vein ECs onto the inner lining of the vessel. The structure of the complete model resembled that of an artery, but it still was not able to withstand intraluminal pressure at a physiological level. An innovative technique was introduced by Kanda et al16 to induce longitudinal orientation of the ECs, which enhances their stability under ﬂow shear stress, and circumferential orientation of the SMCs, which is expected to increase the mechanical strength of the artiﬁcial vessel and improve its vasomotor reactivity. The investigators hypothesized that by applying pulsatile ﬂow on a collagen-based artiﬁcial vessel, the ECs would orient parallel to the direction of ﬂow and the SMCs would align parallel to the direction of stretch (i.e., circumferentially). They utilized a nondegradable polyurethane graft with a collagen gel embedding canine SMCs. Autologous ECs were then seeded onto the media equivalent to create the framework of an intima, and the graft was subjected to pulsatile ﬂow of culture medium. After 10 days of stress loading, the ECs aligned parallel to the longitudinal axis of the graft and the SMCs were oriented in a circumferential direction. In the initial experiments, the application of direct, pulsatile ﬂow on an immature artiﬁcial vessel necessitated the use of a polyurethane scaffold. To avoid the use of a scaffold, the investigators17 utilized an elastomeric silicon tube in the bioreactor. A hybrid media tissue composed of type I collagen gel and bovine aortic SMCs was constructed around this tube, which was subsequently subjected to periodic cyclic inﬂation. After 5 days of culture under these conditions, both the SMCs and collagen ﬁbers were aligned circumferentially. Another strategy for inﬂuencing reorientation of SMCs within artiﬁcial grafts was developed by Tranquillo et al.18 A strong magnetic ﬁeld was applied during collagen ﬁbrillogenesis, when the media equivalent was ﬁrst created, resulting in circumferential orientation of the collagen ﬁbrils within the collagen scaffold. The entrapped SMCs were subsequently aligned along the circumferentially orientated ﬁbrils through cell contact guidance. The technique appears to be simple, reproducible, and effective, resulting in media equivalents that are stiffer and more viscous than the nonmagnetically orientated controls. Berglund et al19 recently presented the concept of a construct-sleeve hybrid graft composed of an outer collagen layer containing neonatal human dermal ﬁbroblasts and an inner support sleeve fabricated from type I collagen gel and cross-linked with glutaraldehyde, ultraviolet, or dehydrothermal treatment. Although inferior to native arteries, the hybrid grafts approached the mechanical properties that are considered necessary for implantation in
animals. It is expected that as the support sleeve will degrade, the cellular layer will gradually strengthen and eventually become the load-bearing component of the graft. The in vivo performance of the graft remains to be tested, however. Artiﬁcial vessels based on biodegradable scaffolds. Several biocompatible and biodegradable polymers have been used as scaffolds for the construction of artiﬁcial vessels. Polyglycolic acid (PGA)10,20,21 is most commonly used. Its high porosity permits the diffusion of nutrients upon implantation and subsequent neovascularization, and it is easily handled and fabricated into different shapes.19 Unfortunately, PGA meshes are rapidly bioabsorbed (within 6 to 8 weeks) and unable to withstand systemic pressures. To improve the physical properties of PGA, several copolymers have been produced by combining PGA with polyhydroxyalkanoate (PHA),9 poly(lactic acid-colysine),11 poly-4-hydroxybutyrate (P4HB),12,13 poly-Llactic acid (PLLA),21,22 or polyethylene glycol (PEG).23 These combinations not only deﬁne the mechanical characteristics of the scaffold but also regulate the phenotype of the cells grown on them through cellular interactions with the scaffold material.21 Shum-Tim et al9 have seeded a PGA-PHA co-polymer directly with a mixed population of ovine carotid ECs, SMCs and ﬁbroblasts. The PGA inner layer was used to promote cell attachment and tissue formation, whereas the outer PHA layer provided the necessary mechanical strength with a longer degradation period of 52 weeks. The tissue-engineered grafts were used to replace infrarenal aortic segments in seven lambs and all remained patent for up to 5 months. Collagen and DNA content, as well as the mechanical strain-stress curve, approached those of the native aorta over time. Histology revealed elastic ﬁbers in the medial layer and endothelial-speciﬁc von Willebrand factor on the luminal surface. Watanabe et al11 created a hybrid polymer scaffolding composed of a PGA sheet and a co-polymer consisting of L-lactides and -caprolactone. The scaffold was seeded with a mixed cell population obtained from the femoral veins of mongrel dogs and, after 7 days of culture, implanted as an interposition graft into the inferior vena cava of the same dog. The graft remained patent for up to 13 months, with no evidence of stenosis or dilatation. The scaffold was completely degraded by 3 months, and the overall gross appearance of the artiﬁcial vein was similar to that of the native inferior vena cava. Niklason et al10 used a PGA scaffold and a biomimetic system similar to that described by Kanda et al.17 However, instead of pulsatile ﬂow at 60 beats per minute, the frequency of cyclic stretch was set at 165 to mimic the fetal environment in large mammals and, presumably, facilitate in vitro vasculogenesis. Bovine aortic SMCs were seeded on tubular biodegradable PGA scaffolds and placed around highly distensible silicon tubes. After 8 weeks of pulsatile stretch in the bioreactor, the silicon tubing was removed, and the luminal surfaces of the grafts were seeded with bovine aortic ECs. Continuous perfusion was instituted for
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another 3 days, imposing shear stress to the endothelialized vessel lumen. The resulting graft had a wall thickness and collagen content comparable to native arteries and a rupture strength of 2150 709 mm Hg, which is greater than the 1680 307 mm Hg reported for native human saphenous veins. Engineered vessels showed measurable contractions to pharmacologic agents such as serotonin, endothelin-1 and prostaglandin F2a and contained well-differentiated SMCs, as displayed by the expression of calponin and myosin heavy chains. The initial experience with two of these grafts implanted into the saphenous artery of miniature swine was promising. They were patent for up to 4 weeks, in contrast to two nonpulsed grafts that thrombosed. Hoerstrup et al12 applied direct ﬂow of culture medium with a bioreactor through the vascular lumen, thereby generating signiﬁcant shear on the luminal surface and pulsatile stretch to the vessel wall. A co-polymer of PGAP4HB was used as the scaffold material because its strength, pliability, and thermoplastic characteristics allowed fabrication into almost any shape using a heat-welding technique. Grafts were sequentially seeded with ovine vascular myoﬁbroblasts and ECs and placed in the pulse duplicator system for up to 4 weeks. Increased cell mass and collagen content, well organized in a layered fashion, was achieved in the pulsed vascular grafts, resulting in supraphysiologic burst pressures and suture retention strength appropriate for surgical implantation within 3 weeks of culture. The burst pressure (262 26 mm Hg), however, was still signiﬁcantly lower than that obtained by Niklason et al10 at 8 weeks of culture. In addition to ovine vascular cells, Hoerstrup et al13 also demonstrated the feasibility of seeding the grafts with human umbilical cord cells. These cells exhibit myoﬁbroblast-like characteristics and have the advantage of being readily available and easy to obtain, without necessitating the sacriﬁce of intact donor vessels. In addition, the authors suggest that individual cell pools could be created from a person’s own umbilical cord for potential future use. This technique would eliminate the need to harvest autologous cells and the problem of immunogenicity of heterogenic cells. The ﬁrst clinical application of an artiﬁcial vessel based on a biodegradable scaffold was reported by Shin’oka et al in 2001.24 Cells isolated from a peripheral vein were seeded on a polycaprolactone-polylactic acid co-polymer tube reinforced with woven PGA. The graft was used for the reconstruction of an occluded pulmonary artery in a 4-year-old girl. Seven months after implantation, the patient was doing well, with no evidence of graft occlusion or aneurysm formation. An alternative approach to the use of synthetic biodegradable scaffolds is to implant an acellular native tissue and let the body act as a bioreactor and cell source to seed the acellular matrix. Several tissues, including skin, fascia, peritoneum, muscle, small intestine submucosa, and ureter, have been used for this purpose with various outcomes.4 It has been well-established, however, that the mechanical properties of uncross-linked, cell-extracted tissues are remarkably similar to those of fresh tissue.25 Therefore, it
would be reasonable to expect that decellularized allogeneic or xenogeneic arteries would give the best biomechanical proﬁle for vascular tissue engineering. Nevertheless, decellularized canine arteries did not appear to perform well when implanted as interposition carotid or coronary artery bypass grafts in dogs, with an early thrombosis rate of 20% to 56%.26,27 The thrombogenicity of decellularized xenogeneic vessels is mainly due to the lack of EC lining of the luminal surface of the vessel. Bader et al28 have tried to overcome this problem by reseeding decellularized porcine aortas with pre-expanded human ECs and myoﬁbroblasts harvested from saphenous vein biopsy specimens. Apart from demonstrating the feasibility of reseeding decellularized vessels with vascular cells, these experiments also revealed that the in vivo immune response was greatly reduced after such processing. Ex vivo reseeding of decellularized vascular matrix scaffolds could therefore be the answer to thrombogenicity, immunologic rejection, and lack of healing, which are the three main problems of cryopreserved or glutaraldehyde-ﬁxed grafts. Artiﬁcial vessels without the use of a scaffold. L’Heureux et al14 have investigated a novel technique for the production of artiﬁcial vessels, based exclusively on cultured human cells, without the use of a scaffold (Fig 2, online only). Human umbilical vein SMCs and skin ﬁbroblasts were cultured for 30 days, at which time both cell types had formed cohesive cellular sheets composed of cells and ECM, which could be manually peeled from the culture ﬂasks. The SMC sheet was then wrapped around a tubular support to produce the media of the vessel. After 1 week of media maturation, the ﬁbroblast sheet was rolled around the media to provide the adventitia. After a 7-week maturation period, the mandrel was removed and human umbilical vein ECs were seeded in the lumen and allowed to grow for another week. The end product was a well-organized, three-layer wall vessel resembling a human artery. The tissue-engineered graft had burst strength of 2594 501 mm Hg and demonstrated good handling and suturability characteristics. It showed no signs of degradation, tearing, or dilatation when implanted as an interposition femoral artery graft in mongrel dogs. On the other hand, intramural blood inﬁltration was observed between the vessel wall layers and the patency rate was only 50% at 7 days of implantation. Current status and future perspectives. The ability to apply tissue engineering techniques to construct autologous vascular grafts for surgical reconstruction is now a clinical reality. Shin’oka’s group24,29,30 have reported their clinical experience using tissue-engineered vessels as venous conduits for reoperative reconstructive cardiovascular surgical procedures in 40 children with varying forms of congenital heart disease. They report 95% patency at 1 year, without evidence of stenosis or aneurysm formation despite the small caliber of these vessels in the setting of a re-do surgical environment. Although signiﬁcant advances have already been made, the construction of a synthetic graft with mechanical prop-
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erties identical to those of native arteries remains an elusive goal. It should be emphasized, however, that a major advantage of an artiﬁcial vessel is that it does not need to have mechanical properties identical to those of a native artery at implantation.31 Being composed of viable tissue with the potential to remodel, repair, and grow, an artiﬁcial vessel is theoretically able to completely adapt to local hemodynamic conditions and acquire the structural and mechanical characteristics of the vessel it replaces, whether this is an artery or a vein. Although some authors are optimistic enough to believe that we are only a decade away from United States Food and Drug Administration (FDA) approval of a tissueengineered blood vessel substitute,32 certain problems need to be addressed: 1. Grafts currently being investigated require an extended period of preparation, usually 1 to 3 months, so they cannot be used in emergency situations. 2. The prolonged duration of culture increases the risk of infection and raises the cost in terms of manpower, equipment, and materials needed. 3. Most of the biodegradable polymers currently in use as scaffolds for the construction of artiﬁcial vessels already have FDA approval. This could actually be a step backwards. We need a biopolymer appropriate for use as a vascular conduit, not one that is off the shelf. Alternative types of cells are already being used in animal models to eliminate the need for surgical harvest of ECs from large veins or tissue microvessels of patients with atherosclerosis.33 Endothelial progenitor cells (EPCs) provide a valuable cell source for cardiovascular tissue engineering, because they are present in peripheral blood and can differentiate into ECs with comparable antithrombogenic potential. Shirota et al34 have shown that the production rate of endothelial-type nitric oxide synthase and 6keto-prostaglandin-F1-a by EPCs are approximately one third and one half of mature ECs, respectively, whereas the tissue-type plasminogen activator production rate of EPCs is almost the same as that of ECs. Moreover, EPC-seeded decellularized porcine iliac vessels implanted in sheep exhibited high patency, rapid vascular wall regeneration, contractile activity, and nitric oxide-induced vasodilation similar to those of native carotid arteries.35 Apart from EPCs, smooth muscle progenitor cells (SPCs) have also been identiﬁed in peripheral blood.36 Ex vivo expansion of these cells has been achieved and may be exploited for the construction of an artiﬁcial vessel in the lab. Even more exciting is that in vivo recruitment of SPCs to an implanted construct seems feasible, because these cells show increased integrin 5 1 expression, which allows them to attach to ﬁbronectin or other 5 1 adhesive matrices. Signiﬁcant advancements in the properties of artiﬁcial vessels can be expected in the foreseeable future with the combination of tissue engineering and gene therapy. For instance, the incorporation in the vessel wall of SMCs transfected with the tropoelastin gene may result in increased elastin synthesis and deposition,37 whereas transfection of
SMCs with the cyclic guanosine monophosphate-dependent protein kinase gene may enhance the contractile characteristics of the cells and, consequently, of the graft.38 In this context, Matsuda39 harvested ﬁbroblasts from skin tissue and transfected them with a triple-gene-encoding adenovirus to express a tissue factor pathway inhibitor, C-type natriuretic peptide, and vascular endothelial growth factor. The transfected ﬁbroblasts were incorporated into a collagen gel wrapped with a polyurethane ﬁlm, and the construct was implanted into canine carotid arteries. The grafts exhibited 100% patency at 1 month and 70% patency at 3 months, whereas all of the nontransfected ﬁbroblastinoculated grafts occluded 2 days after implantation. Genetic and molecular engineering can also be applied to scaffold technology to improve its mechanical and biologic properties. Modiﬁcation of chain length and location of crosslink junctions in the polymer allow for the preparation of materials with well-deﬁned mechanical characteristics.40 The application of nanoﬁbrous technology to create scaffolds that mimic the natural extracellular matrix enhances the ability to achieve ingrowth of vascular cells,41 whereas incorporation of adhesion peptides or growth factors will improve the capacity of the scaffold to support the attachment of vascular cells and their production of ECM.42-45 It should be noted, however, that the incorporation of cell adhesion peptides in polymer scaffolds is a double-edge sword. Several peptides, such as the RGDS (Arg-Gly-AspSer), KQAGDV (Lys-Gln-Ala-Gly-Asp-Val) and VAPG (Val-Ala-Pro-Gly), have been shown to promote cell attachment to collagen-based, PEG, or poly(lactic acid-colysine) scaffolds and prevent cell wash-out after exposure to shear.42-44 On the other hand, increased cell adhesion results in decreased ECM protein synthesis by the cells.43 This may lead to graft failure because the mechanical integrity of the tissue construct will depend entirely on the ECM density after the degradation of the scaffold. This problem may be overcome by tethering growth factors to the scaffold. For example, as reported by Mann et al,45 transforming growth factor- 1 attached to a PGA scaffold increases the production of ECM proteins by vascular SMCs, thus counteracting the effects of adhesive ligands on ECM production, but it does not increase SMC proliferation. This is particularly important in artiﬁcial vessels, as proliferation of SMCs could lead to narrowing of the vessel lumen. Drug-eluting scaffolds are another revolutionary development in the fabrication of artiﬁcial vessels. Yoon et al46 have incorporated dexamethasone, a steroidal anti-inﬂammatory drug, into the polymer phase of a PLGA scaffold. Dexamethasone was slowly released in a controlled manner for over 30 days, leading to a drastic suppression in the proliferation of lymphocytes and SMCs in vitro. Although not yet tested in vivo, such scaffolds show promise for the prevention of intimal hyperplasia. In conclusion, initial results show that the construction of an artiﬁcial vessel that combines desirable biologic and mechanical characteristics is feasible. The incorporation of recent advances in molecular and genetic engineering to the already developed techniques is expected to aid in the
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solution of the problems that have emerged. The clinical imperative for better vascular grafts, the great scientiﬁc challenge, and the large commercial opportunity for such a graft guarantee that signiﬁcant developments are to be anticipated in this ﬁeld in the near future.
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