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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Regen Med. Author manuscript; available in PMC 2010 November 1.
Published in final edited form as:
PMCID: PMC2822541

Biomaterials for vascular tissue engineering


Cardiovascular disease is the leading cause of mortality in the USA. The limited availability of healthy autologous vessels for bypass grafting procedures has led to the fabrication of prosthetic vascular conduits. While synthetic polymers have been extensively studied as substitutes in vascular engineering, they fall short of meeting the biological challenges at the blood–material interface. Various tissue engineering strategies have emerged to address these flaws and increase long-term patency of vascular grafts. Vascular cell seeding of scaffolds and the design of bioactive polymers for in situ arterial regeneration have yielded promising results. This article describes the advances made in biomaterials design to generate suitable materials that not only match the mechanical properties of native vasculature, but also promote cell growth, facilitate extracellular matrix production and inhibit thrombogenicity.

Keywords: biomaterials, biopolymers, degradable polymer scaffolds, endothelialization, in situ vascular regeneration, tissue engineering, vascular grafts

Coronary and peripheral vascular bypass graft procedures are performed in approximately 600,000 patients annually in the USA, most commonly with the saphenous vein or the internal mammary artery [201]. Although the use of autogenous vascular substitutes has had a major impact on advancing the field of reconstructive arterial surgery, these tissue sources may be inadequate or unavailable. Moreover, their harvest adds time, cost and the potential for additional morbidity to the surgical procedure [13]. Currently, expanded polytetrafluoroethylene (ePTFE), polyethylene terephthalate (Dacron®) and polyurethane are used to fabricate synthetic vascular grafts [4]. However, owing to thrombus formation and compliance mismatch, none of these materials have proved suitable for generating grafts less than 6 mm in diameter that would be required to replace the saphenous vein, internal mammary or radial artery as a vascular substitute [58].

The functional importance of normal physiologic responses of the vascular wall in controlling thrombosis and inflammation has guided attempts to closely mimic the native arterial wall in the design of a new generation of vascular prostheses. These features include the structural components collagen and elastin, which are responsible for the tensile strength and viscoelasticity of the blood vessel, and create a fatigue-resistant tissue with long-term durability [9]. Furthermore, the endothelial lining in the native vasculature not only serves as a protective, thromboresistant barrier between blood and the surrounding tissue, but also controls vessel tone, platelet activation and leukocyte adhesion. Other elements that define an ideal biomaterial necessary to the design of a vascular graft are bio-compatibility, infection resistance, suturability and off-the-shelf availability.

The first tissue-engineered blood vessel substitute was created by Weinberg and Bell in 1986 [10]. They generated cultures of bovine endothelial cells, smooth muscle cells (SMCs) and fibroblasts in layers of collagen gel supported by a Dacron mesh. Although physiologic pressures were sustained for only 3–6 weeks, they did demonstrate the feasibility of a tissue-engineered graft with human cells. Since then, strategies to create a suitable material for a vascular graft have focused on three areas of research: coatings and surface chemical modifications of synthetic materials, biodegradable scaffolds and biopolymers. Each group can be further organized into tissue-engineering strategies for in situ vascular regeneration, in which the body's natural healing response is modulated by material design and fabrication, or strategies for ex vivo formation of a blood vessel substitute, whereby in vitro culture of human cells on polymer substrates before implantation defines their mechanical and biological properties.

Synthetic nondegradable polymers

ePTFE, Dacron & polyurethanes

Synthetic materials have been employed in vascular graft design for a variety of reasons, mainly due to the ease and flexibility of tailoring their mechanical properties. One such example is ePTFE, a porous polymer with an electronegative luminal surface that is not degradable. However, only 45% of standard ePTFE grafts are patent as femoropopliteal bypass grafts at 5 years, while autologous vein grafts display a 60–80% patency [11,12]. In standard ePTFE grafts, the fibril length or intermodal distance measures approximately 30 μm and neither transanastomotic nor transmural endothelialization occurs to any significant extent. Experimental ePTFE variants with a larger fibril length of 60 μm have been produced, which in animal models have facilitated luminal endothelialization [13]. Nonetheless, these observations have not been replicated in clinical studies. Currently, Dacron is most commonly used for aortic replacement and to a lesser extent as a conduit for femoropopliteal bypass surgery. Characteristically, knitted grafts incorporate a velour finish, which orients the loops of yarn upward, perpendicular to the fabric surface, thereby increasing available surface area and enhancing the anchorage of fibrin and cells to promote tissue integration. The preference for a velour finish has been primarily motivated by improved handling characteristics, with few data demonstrating that internal, external or double velour grafts exhibit greater patency rates [14]. Dacron grafts are often crimped longitudinally to increase flexibility, elasticity and kink resistance. However, these properties are lost soon after implantation, as a consequence of tissue ingrowth. Despite some evidence that suggests that platelet deposition and complement activation [1518] are lower on ePTFE than Dacron prostheses, the patency rates of Dacron and ePTFE grafts are similar [19]. Polyurethane is a copolymer that consists of three different monomer types: a diisocyanate hard domain, a chain extender and a diol soft domain. At physiological temperatures, the soft domains provide flexibility while the hard domains impart strength. The most common medical-grade polyurethanes are based on soft domains made from polyester, polyether or polycarbonate. Various components have been added to the graft design to improve synthetic graft function and yield biohybrid conduits. For example, Nakagawa et al. developed a poly(ether-urethane) graft reinforced with knitted polyester fibers for hemodialysis, which was found to be more durable than ePTFE [20]. Further development has yielded a poly(carbonate-urea)urethane vascular graft that exhibits a compliance profile similar to human arteries [21].

Polymer functionalization

The poor patency rates of synthetic polymers have motivated further strategies to functionalize the luminal surface of grafts and direct tissue regeneration. Coatings, chemical and protein modifications, and endothelial cell seeding on otherwise inert materials have been employed to improve endothelialization and inhibit inflammation. As a result, carbon deposition, photo-discharge and plasma discharge technologies have been utilized to deposit reactive groups onto polymer surfaces to interact with cell-specific peptides and influence protein adsorption to the surface [22]. For example, Nishibe and colleagues found that in a dog carotid implant model, fibronectin bonding improved graft healing in high-porosity ePTFE grafts [23]. Recent studies have documented that cell adhesion peptide sequences, such as the P15 peptide found in type I collagen, increase endothelial cell adhesion to ePTFE in vivo via integrin-specific binding [24]. Endothelial cell attachment can be significantly improved on surfaces coupled with another potent adhesion peptide, RGD, when compared with fibronectin-coated grafts [25,26]. To this end, Zilla and colleagues were able to improve cell retention on shear stressed grafts by precoating them with RGD-crosslinked fibrin [27]. In addition, delivery of growth factors from polymer surfaces has also facilitated the rate of in situ endothelialization [28,29]. For example, ePTFE grafts impregnated with fibrin glue containing FGF-1 and heparin has promoted transmural endothelialization and SMC proliferation in a dog model [3032].

Several investigators have endeavored to endothelialize the luminal surfaces of synthetic vascular grafts to mimic the biologic responsiveness of the native vasculature [27,3237], as seen in Table 1 & 2. The success of cell transplantation is limited because of difficulties in cell sourcing and attachment, and retention during pulsatile flow conditions [38]. Strategies that promote in situ regeneration of a functional endothelial lining have also met with difficulties owing to chronic inflammatory and prothrombotic responses to the synthetic polymeric materials [39]. Endothelial cells growing onto prosthetic graft surfaces that display a procoagulant phenotype can, in principle, promote rather than retard thrombosis [40]. Furthermore, activated endothelial cells may increase growth factor production and secretion that encourages SMC proliferation. Indeed, subintimal SMC proliferation occurs predominantly in areas that have an overlying endothelium [41]. This response can be seen with ePTFE grafts coated with anti-CD34 antibodies and implanted in pigs [42]. While the antibodies are able to capture endothelial progenitor cells and increase endothelial cell coverage, intimal hyperplasia at the distal anastomosis is significantly increased at 4 weeks.

Table 1
Synthetic polymers: in vivo vascular regeneration
Table 2
Ex vivo engineering of synthetic polymers

The high rates of thrombus formation on vascular substitutes have led researchers to focus on modulating adverse inflammatory responses. One such example is the creation of nitric oxide-producing polyurethanes, in which the nitric oxide donor diazeniumdiolate is covalently bound to a polyurethane backbone [43]. Nitric oxide is produced by endothelial cells and functions to regulate vascular tone, prevent platelet aggregation and inhibit smooth muscle hyperplasia. Consequently, in vitro studies investigating the release of nitric oxide from modified polyurethane films have determined that the material does reduce platelet adhesion and vascular SMC growth, while stimulating endothelial cell growth [44]. Furthermore, the elastomeric copolymer, poly(1,8-octanediol citrate), with mechanical and degradation properties suitable for vascular tissue engineering, has exhibited decreased platelet adhesion and clotting relative to ePTFE [45]. In vitro studies evaluating the biocompatibility of these materials have demonstrated the potential for further application as vascular graft coatings, but require more robust in vivo test beds in order to determine their success.

Degradable scaffolds

The use of biodegradable polymers as scaffolds on which layers of cells are grown is an alternate tissue-engineering approach for the development of a functional vascular graft. The scaffold degrades and is replaced and remodeled by the extracellular matrix (ECM) secreted by the cells. Polyglycolic acid (PGA) is commonly used in tissue-engineering applications as it degrades through hydrolysis of its ester bonds, and glycolic acid, in turn, is metabolized and eliminated as water and carbon dioxide. PGA loses its strength in vivo within 4 weeks and is completely absorbed by 6 months. Biodegradation rates can be controlled by copolymerization with other polymers, such as poly-l-lactic acid (PLLA), polyhydroxyalkanoate, polycaprolactone-copolylactic acid and polyethylene glycol [4648].

Several investigators have explored the potential of PGA composite scaffolds in fabricating vascular conduits in situ and ex vivo. For example, partially resorbable Dacron grafts have facilitated infiltration and proliferation of vascular cells and promotion of capillary growth [49]. The regenerative potential of these conduits has led to further PGA and Dacron fiber blends with the purpose of optimizing compositional ratios for in vivo healing responses and graft strength maintenance [50,51]. As in situ regeneration via polymer degradation limits exact control over the remodeling process, other groups have demonstrated the ability to construct functional grafts ex vivo. Mooney and colleagues have seeded cells onto a PLLA/polylactide-coglycolide (PLGA) copolymer-coated PGA mesh [47,52]. Similarly, Vacanti and colleagues used PLGA to generate capillary networks for artificial microvasculature applications [53]. Furthermore, Niklason and colleagues have developed a pulsatile bioreactor to remodel PGA scaffolds seeded with bovine smooth muscle and endothelial cells [54]. After a 10-week culture period, the resulting tissue-engineered vessel displayed a burst pressure of up to 2300 mm Hg. After 5 weeks, the PGA scaffold had degraded to 15% of its initial mass. Consequently, mechanical stability was dependent on SMC production of collagen and culture medium supplements that promoted collagen crosslinking. Although the lumen of the graft did not present a confluent endothelium lining, vessels did display contractile responses to serotonin, prostaglandin and endothelin-1, and implants remained patent for 1 month in a swine model. Attempts to translate this approach to human cells have led to poor mechanical properties due to the limited proliferative capacity of human SMCs, especially when harvested from elderly patients. In addition, the notable absence of elastic fibers could limit fatigue resistance and predispose the vessels to subsequent aneurysmal degeneration.

Polyhydroxyalkanoates, linear polyesters that are produced by bacterial fermentation of sugar or lipids, have also been employed in graft design, as they can be modified to display a wide range of degradation rates and mechanical properties. Shum-Tim et al. engineered an aortic graft consisting of a polymer scaffold of PGA and polyhydroxyoctanoate (PHO) seeded with bovine carotid artery cells [55]. The inner layer of the construct was made of nonwoven mesh of PGA fibers, while the outer layers were composed of nonporous PHO. The PGA scaffold promoted cellular growth and ECM production, while the slower degradation rate of PHO provided mechanical support as this remodeling occurred. Significantly, the graft did not require extensive in vitro conditioning. The construct was implanted directly in the abdominal aorta of lambs with 100% patency noted at 5 months. Histological analysis revealed that the remodeled graft contained uniform collagen and elastin fibers that had aligned in the direction of blood flow. The mechanical stress–strain curve of the engineered construct approached that of the native vessel, although some permanent deformation was observed 6 months after implantation, indicating either insufficient or noncrosslinked elastin. Fu and colleagues investigated the effects of ascorbic acid and basic FGF, which stimulated cells on a PGA-poly(4-hydroxybutyrate) construct to proliferate and generate large quantities of collagen, thereby accelerating the improvement in mechanical integrity [56].

Yet another versatile polymer, polycaprolactone (PCL), slowly degrades by hydrolysis of ester linkages, with elimination of the resultant fragments by macrophages and giant cells. Shin'oka et al. reported the use of PCL-based scaffolds to engineer venous blood vessels [57,58]. The PCL–polylactic acid copolymer was reinforced with woven PGA and seeded with autologous smooth muscle and endothelial cells harvested from a peripheral vein. After 10 days, the construct was implanted as a pulmonary bypass graft into a 4-year-old child [59]. Subsequent studies with autologous bone marrow cells on the constructs have reported greater than 95% patency at a mean follow-up of 16 months [60]. Further evaluation of endothelial cell function and mechanical properties of vascular grafts constructed with autologous bone marrow cells was conducted with a canine inferior vena cava model [61]. Interestingly, the biochemical properties and wall thickness of cell-seeded scaffolds were similar to those of the vena cava 6 months after implantation.

Biodegradable polymer systems provide the opportunity for spatial and temporal release of various growth factors to promote vascular wall regeneration. For example, VEGF release from PLGA scaffolds has been shown to promote angiogenesis in situ [62]. Likewise, FGF-2 release from poly(ester urethane) urea (PEUU) scaffolds amalgamates the favorable mechanical properties of polyurethanes with the bioactivity of an angiogenic protein [63]. While degradation via hydrolysis serves as a powerful tool in vascular tissue engineering to control the release of bioactive molecules from the polymer matrix, incorporation of proteolytic sites into the material can further optimize presentation of these molecules to the surrounding environment via cell-mediated degradation.

Although tissue-engineered vascular grafts based on biodegradable scaffolds have yielded promising results, some drawbacks exist. Challenges of cell sourcing are compounded by long culture periods that range between 2 and 6 months, and the proliferative capacity of cells isolated from elderly patients is limited. The mechanical strength of the materials may be comparable to that of native vessels, but compliance mismatch limits long-term patency. Table 3 summarizes other notable work with degradable scaffolds.

Table 3
Biodegradable scaffolds


An alternative strategy to synthetic and degradable scaffold-based vascular grafts is the manipulation of proteins that constitute the architecture of native ECM. The generation of protein polymers that mimic native structural proteins and adopt the characteristics of the arterial wall offers a unique approach to develop a vascular graft. Ultimately, the success of this approach is dependent on appropriate cell migration, adhesion and proliferation, as well as ECM production, on the biomimetic surfaces.

One such protein is type I collagen, a major ECM component in the blood vessel [64]. Collagen fibers function to limit high strain deformation, thereby preventing critical rupture of the vascular wall [65,66]. Collagen gels and fibers reconstituted from purified collagen are ideal in artificial blood vessel development due to their low inflammatory and antigenic responses [67]. Furthermore, integrin-binding sequences in collagen allow for cell adhesion during fibrillogenesis. As mentioned previously, Weinberg and Bell first reported the use of collagen gels as substrates for cells in vascular tissue engineering. Since then, Habermehl and colleagues have developed a process to obtain large quantitites of collagen from rat tail tendons to scale-up production [68].

Variables such as fiber orientation, crosslinking conditions and cell seeding techniques have been explored to improve the mechanical integrity of collagen-based constructs. A wide range of crosslinking agents can enhance covalent links between the collagen fibers, the most efficient of which is glutaraldehyde [69]. The cytotoxicity of this chemical, however, has led to the development of alternative crosslinking mechanisms, such as the enzymatic reactions of lysyl oxidase and transglutaminase, as well as photocrosslinking [7072]. Various groups have investigated fiber orientation and SMC alignment as a means to increase mechanical properties in the circumferential direction of a tubular construct [7375]. Preconditioning treatments involve applying mechanical strain or shear stress to the construct and compaction of SMC-containing collagen gels around a mandrel in order to increase mechanical strength [7678].

The shortcomings of a stiff collagen-based scaffold have motivated researchers to explore the potential of more elastic fibrin gels in vascular tissue engineering [79]. Fibrin is formed when fibrinogen polymerizes into a fibrillar mesh with the addition of thrombin. An advantage of this biopolymer is the ability to produce it with the patient's own blood, thereby preventing an inflammatory response upon implantation [80]. Fibrin also binds to critical proteins that direct cell fate, such as fibronectin and VEGF [81]. In vivo degradation can be controlled with the proteinase inhibitor aprotonin and crosslinking agents, although there are concerns that the concentrated presence of these natural proteins may interfere with local coagulation cascades [82].

Interestingly, SMCs embedded in fibrin gels produce more collagen and ECM than cells that are entrapped in collagen gels [83]. One such example is the fibrin-based vascular graft developed by Swartz and colleagues, who incorporated ovine SMCs and endothelial cells into the gel [84]. The grafts were implanted in the jugular veins of lambs, and remained patent for 15 weeks. Upon histologic examination, the constructs were found to contain both collagen and elastin, with the mechanical integrity comparable to that of native coronary arteries. Furthermore, Tranquillo and colleagues demonstrated that the enmeshed SMCs directed compaction and alignment of both the fibrin fibers and the cell-synthesized collagen fibers in a circumferential orientation around a nonadhesive mandrel [85].

The elasticity afforded by fibrin-based grafts is a critical factor in vascular tissue-engineering design. Researchers have also explored the potential of incorporating scaffolds with more extensible proteins such as elastin, a key structural element in native vasculature. Crosslinked elastic fibers form concentric rings around the medial layer of arteries, providing elasticity to the vascular graft by stretching under a stress and recoiling back to the original dimensions as the load is released [8689]. In addition, elastin regulates vascular SMC activity by inhibiting SMC proliferation. Unlike collagen, the stable crosslinked fiber network of native elastin makes isolation and purification techniques difficult. Therefore, different strategies have emerged to incorporate elastin into tubular constructs. Whereas some investigators have attempted to promote elastogenesis in vascular grafts indirectly with SMC culture techniques [9092], others have developed protocols to process insoluble and soluble elastin [93]. One such example includes a freeze-drying protocol for collagen and elastin to produce a porous scaffold [94].

More recently, the development of recombinant genetic and protein engineering has enabled the synthesis of bioinspired protein polymers that not only mimic structural proteins but also direct cellular fate by emulating the ECM in vivo [9598]. Specifically, polymers with pentapeptide repeat motifs similar to VPGVG exhibit elastic behavior with features that are consistent with native elastin, including a mobile backbone and the presence of β turns [99102]. The biosynthetic machinery of microorganisms can be exploited to produce significant quantities of these recombinant protein polymers that have been designed from primary amino acid sequences and self-assemble into a distinct 3D folded structure [100,103]. These elastin-mimetic biopolymers, in turn, can be cast as hydrogels or electrospun into nanofibrous scaffolds [104108].


Recent developments in the field of nanotechnology have facilitated vascular tissue-engineering efforts in mimicking the nanostructure of native vasculature, thereby directing mechanical and biologic performance of the bulk material. One such application is electropinning of synthetic polymers and naturally occurring materials into nanofibers [109112]. The advantages of this strategy include the ability to form scaffolds with high porosity as well as high surface area-to-volume ratio, thus simulating the dimensions and structure of native collagen and elastin fibrils [113,114]. In particular, He and colleagues have demonstrated the utility of electrospinning with the generation of a nanofibrous scaffold composed of collagen-blended degradable poly(l-lactic acid)-co-poly(ε-caprolactone) [115]. Results indicated that the blended nanofibers supported endothelial cell attachment and spreading, and preserved the endothelial cell phenotype.

Enhancement of base material properties with the addition of fillers has resulted in various nanocomposites. In general, these materials have demonstrated a reduction in thrombogenicity while improving mechanical properties. For example, Kannan and colleagues have generated a polymer based on poly(carbonate-urea)urethane and polyhedral oligomeric silsesquioxane nanoparticles, and have reported the nanocomposite's heparin-like behavior at the blood–material interface [116,117]. Furthermore, the polymer displayed a greater degree of compliance match to natural arteries compared with ePTFE and Dacron. Other groups have utilized the strength and flexibility of carbon nanotubes as fillers to enhance base polymer properties [118,119]. These efforts have indicated that although the composite polymers decrease thrombogenicity on their surfaces, toxicity of carbon nanotubes remains a concern [120,121].

Alternative tissue sources

Decellularized allogeneic or xenogenic tubular tissues that contain an intact and structurally organized ECM have been investigated as vascular conduits, which include human umbilical vein and bovine and porcine carotid arteries. Although a readily available supply of artificial arteries is attractive, drawbacks include the inability to tailor matrix content and architecture, progressive biodegradation and the risk of viral transmission from animal tissue. Decellularization removes most cellular antigenic components in allogeneic and xenogeneic tissue. A combination of physical agitation, chemical surfactant removal and enzymatic digestion disrupts cells and removes protein, lipids and nucleotide remnants [122125]. Following decellularization, chemical crosslinking is used to enhance mechanical strength and reduce immunogenicity [126,127]. The addition of an external support such as a Dacron mesh is also common to provide mechanical strength and prevent late dilation. Efforts to improve the durability and healing response of decellularized scaffolds have included coating with heparin and FGF, as well as seeding with endothelial cells, bone marrow-derived cells, and adipose-derived stem cells [128136].

Alternative tubular tissue sources have been utilized as vascular substitutes as well. For example, decellularized small intestinal submucosa is composed of collagen, fibronectin, proteoglycans, growth factors, glycosaminoglycans and glycoproteins [137]. Consequently, implantation of the small intestinal submucosa construct as a vascular graft leads to neovascularization, host cell migration and adhesion, and matrix remodeling [138141]. The development of a tissue-engineered vascular conduit from yet another avascular tissue source has been documented by Campbell and colleagues [142]. The intraperitoneal graft model employs the peritoneal cavity as an in situ bioreactor for the creation of a tubular construct seeded with layers of host cells. The investigators observed that foreign objects implanted into the peritoneal cavity became encapsulated by a fibrous capsule containing myofibroblasts and a surrounding layer of mesothelial cells [143]. They then inserted silastic tubing into the peritoneal cavities of dogs, rabbits and rats. After 2–3 weeks, the tubing was removed, and the cell-encapsulated construct was grafted into the carotid artery (rabbit), abdominal aorta (rat) and femoral artery (dog) of the animal in which it was grown [144,145]. Remodeling of the autologous grafts included differentiation of myofibroblasts to smooth muscle-like cells, increased wall thickness, elastin and collagen production, and circumferential alignment of cells and matrix proteins [146]. The constructs displayed endothelium-dependent relaxation when stimulated with acetylcholine and were patent in rabbits for at least 16 months and in dogs for 6.5 months.

Recently, sheet-based tissue engineering and bioreactor conditions have enabled the expansion of in vitro culture of cells into a cohesive cell sheet comprised of various cell types and endogenously expressed ECM. Thermoresponsive polymers, such as poly N-isopropylacrylamide and methyl cellulose, have served as coatings on culture flasks in order to facilitate the removal of cultured cells and underlying ECM as a uniform sheet. These sheets have been further processed into blood vessels by layering and wrapping them around a mandrel for incubation [147149]. While this maturation period can be as extensive as 10 weeks, the resulting graft does not require exogenous biomaterials for mechanical support. L'Heureux et al. have demonstrated the utility of assembling arterial bypass grafts exclusively from a patient's own cells by implanting the substitutes into primate models [150]. In vivo results indicated that the grafts were antithrombogenic and mechanically stable for 8 months, with histology and microscopy displaying complete tissue integration, regeneration of a vascular media, as well as elastogenesis and a collagen fiber network.

Conclusion & future perspective

The development of a synthetic arterial substitute represents a major milestone of 20th century medicine, yielding technology that has saved the lives of millions of patients. Nonetheless, a durable small-caliber (diameter: <6 mm) conduit remains elusive, and patency rates for infrainguinal revascularization through the use of a prosthetic graft have changed little over the past 30 years. The challenges of creating the ideal tissue-engineered vascular substitute are numerous, but significant progress has been made towards understanding the importance of both the mechanical and biologic requirements of biomaterials for this application. Investigators continue to strive for the generation of multifunctional materials with optimized release and presentation of bioactive molecules in order to guide in situ vascular regeneration. For example, the challenges of sufficiently balancing polymer degradation rates with ECM production and cellular infiltration has resulted in polymers designed with cell-binding sequences, enzymatic cleavage sites, and tethering of chemoattractant molecules [151,152]. This ‘bottom-up’ approach to materials design enables researchers to finely modulate the nanostructure of a material in order to influence its bulk properties. The success of these efforts will depend on the generation of composite scaffolds that mimic the complexity of native vascular matrix in order to improve elasticity and compliance of the native blood vessel while inhibiting adverse responses at the blood–material interface. In vitro, in vivo and computational models are also providing new insights into the complex interplay of cellular, biochemical and biomechanical processes that lead to graft failure. However, a better understanding of vascular progenitor cell biology is required to harness the potential of progenitor cells in endothelialization of arterial grafts. Through continued collaboration among vascular surgeons, biologists, material scientists and biomedical engineers, existing barriers in the creation of an arterial substitute will undoubtedly be broken.

Executive summary

Synthetic polymers

  • Nondegradable materials
    • Expanded polytetrafluoroethylene, Dacron® and polyurethane are currently used as synthetic vascular grafts.
    • Polyurethane is better able to match the compliance of native vasculature, but the patency rates of grafts composed of synthetic, nondegradable materials is relatively poor.
    • Functionalization of the polymer surfaces via chemical modification and coatings enables improved endothelialization and thromboresistance of the materials.
  • Degradable scaffolds
    • Biodegradable polymers act as scaffolds upon which cells and the surrounding environment can modulate vascular remodeling.
    • Degradable polymers, including polyglycolic acid, polyhydroxyalkanoates, polycaprolactone and polyethylene glycol, have been utilized in generating cell-seeded scaffolds for vascular substitutes.
    • Degradable scaffolds have been further functionalized with proteolytic sites for the controlled release of bioactive molecules from the polymer matrix and optimized presentation of these factors to the surrounding environment via cell-mediated degradation.
    • While degradable polymers have enabled improved extracellular matrix (ECM) production and vascular cell infiltration into the graft site, compliance mismatch, prolonged cell culture periods and the challenges of cell sourcing remain significant obstacles in utilizing biodegradable materials in the clinical setting.


  • The generation of protein polymers that mimic native structural proteins and adopt the characteristics of the arterial wall offers a unique approach to develop a vascular graft.
  • Collagen and fibrin gels and fibers are able to bind to critical proteins that direct cell fate, and are therefore ideal in the formation of artificial blood vessels. While aligned, crosslinked collagen fibers contribute to the mechanical integrity of the graft, the more elastic fibrin mimics the role of elastin in native vasculature.
  • ECM production and mechanical integrity can be further modulated by smooth muscle cell seeding, culture techniques and preconditioning treatments.
  • The biosynthetic machinery of microorganisms can be exploited to produce significant quantities of recombinant protein polymers that have been designed from primary amino acid sequences and self-assemble into a distinct 3D folded structure. The generation of elastin-mimetic protein polymers is one such example of a vascular tissue-engineering application.
  • Decellularized allogeneic or xenogenic tubular tissues that contain an intact and structurally organized ECM have been investigated as vascular conduits, which include human umbilical vein and bovine and porcine carotid arteries. These grafts have met with some success, but drawbacks include the inability to tailor matrix content and architecture, progressive biodegradation and the risk of viral transmission from animal tissue.


Financial & competing interests disclosure The authors' research is funded by NIH grants R01 HL083867, RO1HL56819, RO1HL60464 and NSF EEC-9731643. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.


Papers of special note have been highlighted as:

[filled square] of interest

[filled square][filled square] of considerable interest

1. Berger PB, Alderman EL, Nadel A, Schaff HV, International Multicenter Aprotinin Graft Patency Experience (IMAGE) Investigators Frequency of early occlusion and stenosis in a left internal mammary artery to left anterior descending artery bypass graft after surgery through a median sternotomy on conventional bypass: benchmark for minimally invasive direct coronary artery bypass. Circulation. 1999;100(23):2353–2358. [PubMed]
2. McKee JA, Banik SSR, Boyer MJ, et al. Human arteries engineered in vitro. EMBO Rep. 2003;4(6):633–638. [PubMed]
3. Verma S, Szmitko PE, Weisel RD, et al. Should radial arteries be used routinely for coronary artery bypass grafting? Circulation. 2004;110(5):e40–e46. [PubMed]
4. Kannan RY, Salacinski HJ, Butler PE, Hamilton G, Seifalian AM. Current status of prosthetic bypass grafts: a review. J Biomed Mater Res B Appl Biomater. 2005;74(1):570–581. [PubMed]
5. Abbott WM, Megerman J, Hasson JE, L'Italien G, Warnock DF. Effect of compliance mismatch on vascular graft patency. J Vasc Surg. 1987;5(2):376–382. [PubMed]
6. Conte MS. The ideal small arterial substitute: a search for the Holy Grail? FASEB J. 1998;12(1):43–45. [PubMed]
7. Greisler HP. Interactions at the blood/material interface. Ann Vasc Surg. 1990;4(1):98–103. [PubMed]
8. Wittemore AD, Kent KC, Donaldson MC, Couch NP, Mannick JA. What is the proper role of polytetrafluoroethylene grafts in infrainguinal reconstruction? J Vasc Surg. 1989;10:299–305. [PubMed]
9. Humphrey JD. Mechanics of the arterial wall: review and directions. Crit Rev Biomed Eng. 1995;23(1–2):1–162. [PubMed]
10. Weinberg CB, Bell E. A blood vessel model constructed from collagen and cultured vascular cells. Science. 1986;231(4736):397–400. [PubMed]
11. Johnson WC, Lee KK. A comparative evaluation of polytetrafluoroethylene, umbilical vein, and saphenous vein bypass grafts for femoral-popliteal above-knee revascularization: a prospective randomized Department of Veterans Affairs cooperative study. J Vasc Surg. 2000;32(2):268–277. [PubMed]
12. Xue L, Greisler HP. Biomaterials in the development and future of vascular grafts. J Vasc Surg. 2003;37(2):472–480. [PubMed]
13. Clowes AW, Kirkman TR, Reidy MA. Mechanisms of arterial graft healing. Rapid transmural capillary ingrowth provides a source of intimal endothelium and smooth muscle in porous PTFE prostheses. Am J Pathol. 1986;123(2):220–230. [PubMed]
14. Goldman M, McCollum CN, Hawker RJ, Drolc Z, Slaney G. Dacron arterial grafts: the influence of porosity, velour, and maturity on thrombogenicity. Surgery. 1982;92(6):947–952. [PubMed]
15. Allen BT, Mathias CJ, Sicard GA, Welch MJ, Clark RE. Platelet deposition on vascular grafts. The accuracy of in vivo quantitation and the significance of in vivo platelet reactivity. Ann Surg. 1986;203(3):318–328. [PubMed]
16. Goldman M, Hall C, Dykes J, Hawker RJ, McCollum CN. Does 111indium-platelet deposition predict patency in prosthetic arterial grafts? Br J Surg. 1983;70(10):635–638. [PubMed]
17. Hamlin GW, Rajah SM, Crow MJ, Kester RC. Evaluation of the thrombogenic potential of three types of arterial graft studied in an artificial circulation. Br J Surg. 1978;65(4):272–276. [PubMed]
18. Shepard AD, Gelfand JA, Callow AD, O'Donnell TF., Jr Complement activation by synthetic vascular prostheses. J Vasc Surg. 1984;1(6):829–838. [PubMed]
19. Abbott W, Green R, Matsumoto T, et al. Prosthetic above-knee femoropopliteal bypass grafting: results of a multicenter randomized prospective trial. Above-Knee Femoropopliteal Study Group. J Vasc Surg. 1997;25(1):19–28. [PubMed]
20. Nakagawa Y, Ota K, Sato Y, Teraoka S, Agishi T. Clinical trial of new polyurethane vascular grafts for hemodialysis: compared with expanded polytetrafluoroethylene grafts. Artif Organs. 1995;19(12):1227–1232. [PubMed]
21. Seifalian AM, Salacinski HJ, Tiwari A, Edwards A, Bowald S, Hamilton G. In vivo biostability of a poly(carbonate-urea)urethane graft. Biomaterials. 2003;24(14):2549–2557. [PubMed]
22. Kapfer X, Meichelboeck W, Groegler FM. Comparison of carbon-impregnated and standard ePTFE prostheses in extra-anatomical anterior tibial artery bypass: a prospective randomized multicenter study. Eur J Vasc Endovasc Surg. 2006;32(2):155–168. [PubMed]
23. Nishibe T, O'Donnel S, Pikoulis E, et al. Effects of fibronectin bonding on healing of high porosity expanded polytetrafluoroethylene grafts in pigs. J Cardiovasc Surg (Torino) 2001;42(5):667–673. [PubMed]
24. Li C, Hill A, Imran M. In vitro and in vivo studies of ePTFE vascular grafts treated with P15 peptide. J Biomater Sci Polym Ed. 2005;16(7):875–891. [PubMed]
25. Krijgsman B, Seifalian AM, Salacinski HJ, et al. An assessment of covalent grafting of RGD peptides to the surface of a compliant poly(carbonate-urea)urethane vascular conduit versus conventional biological coatings: its role in enhancing cellular retention. Tissue Eng. 2002;8(4):673–680. [PubMed][filled square] Demonstrates the use of ex vivo cell seeding mechanisms in promoting endothelialization with endothelial progenitor cells and improving patency of expanded polytetrafluoroethylene grafts.
26. Walluscheck KP, Steinhoff G, Kelm S, Haverich A. Improved endothelial cell attachment on ePTFE vascular grafts pretreated with synthetic RGD-containing peptides. Eur J Vasc Endovasc Surg. 1996;12(3):321–330. [PubMed]
27. Meinhart JG, Deutsch M, Fischlein T, Howanietz N, Fröschl A, Zilla P. Clinical autologous in vitro endothelialization of 153 infrainguinal ePTFE grafts. Ann Thorac Surg. 2001;71(Suppl 5):S327–S331. [PubMed]
28. Greisler HP, Klosak JJ, Dennis JW, Karesh SM, Ellinger J, Kim DU. Biomaterial pretreatment with ECGF to augment endothelial cell proliferation. J Vasc Surg. 1987;5(2):393–399. [PubMed]
29. Randone B, Cavallaro G, Polistena A, et al. Dual role of VEGF in pretreated experimental ePTFE arterial grafts. J Surg Res. 2005;127(2):70–79. [PubMed]
30. Gray JL, Kang SS, Zenni GC, et al. FGF-1 affixation stimulates ePTFE endothelialization without intimal hyperplasia. J Surg Res. 1994;57(5):596–612. [PubMed]
31. Greisler HP, Cziperle DJ, Kim DU, et al. Enhanced endothelialization of expanded polytetrafluoroethylene grafts by fibroblast growth factor type 1 pretreatment. Surgery. 1992;112(2):244–254. discussion 254–255. [PubMed]
32. Greisler HP, Gosselin C, Ren D, et al. Biointeractive polymers and tissue engineered blood vessels. Biomaterials. 1996;17(3):329–336. [PubMed]
33. Clagett GP, Burkel WE, Sharefkin JB, et al. Platelet reactivity in vivo in dogs with arterial prostheses seeded with endothelial cells. Circulation. 1984;69(3):632–639. [PubMed]
34. Gosselin C, Vorp DA, Warty V, et al. ePTFE coating with fibrin glue, FGF-1, and heparin: effect on retention of seeded endothelial cells. J Surg Res. 1996;60(2):327–332. [PubMed]
35. Herring MB, Dilley R, Jersild RA, Jr, Boxer L, Gardner A, Glove J. Seeding arterial prostheses with vascular endothelium. The nature of the lining. Ann Surg. 1979;190(1):84–90. [PubMed]
36. Hubbell JA, Massia SP, Desai NP, Drumheller PD. Endothelial cell-selective materials for tissue engineering in the vascular graft via a new receptor. Biotechnology (NY) 1991;9(6):568–572. [PubMed]
37. Seifalian AM, Tiwari A, Hamilton G, Salacinski HJ. Improving the clinical patency of prosthetic vascular and coronary bypass grafts: the role of seeding and tissue engineering. Artif Organs. 2002;26(4):307–320. [PubMed]
38. Zilla P, Deutsch M, Meinhart J. Endothelial cell transplantation. Semin Vasc Surg. 1999;12(1):52–63. [PubMed]
39. Hedeman Joosten PP, Verhagen H, Heijnen-Snyder G, et al. Thrombogenesis of different cell types seeded on vascular grafts and studied under blood-flow conditions. J Vasc Surg. 1998;28(6):1094–1103. [PubMed]
40. Pearson JD. Endothelial cell function and thrombosis. Baillieres Best Pract Res Clin Haematol. 1999;12(3):329–341. [PubMed]
41. Greisler HP, Wise D, Trantolo D, et al. Regulation of vascular graft healing by induction of tissue incorporation. In: Wise D, editor. Human Biomaterials Applications. Vol. 227. Humana Press; Totowa, NJ, USA: 1996.
42. Rotmans JI, Heyligers JM, Verhagen HJ, et al. In vivo cell seeding with anti-CD34 antibodies successfully accelerates endothelialization but stimulates intimal hyperplasia in porcine arteriovenous expanded polytetrafluoroethylene grafts. Circulation. 2005;112(1):12–18. [PubMed]
43. Reynolds MM, Hrabie JA, Oh BK, et al. Nitric oxide releasing polyurethanes with covalently linked diazeniumdiolated secondary amines. Biomacromolecules. 2006;7(3):987–994. [PubMed]
44. Taite LJ, Yang P, Jun HW, West JL. Nitric oxide-releasing polyurethane–PEG copolymer containing the YIGSR peptide promotes endothelialization with decreased platelet adhesion. J Biomed Mater Res B Appl Biomater. 2008;84(1):108–116. [PubMed]
45. Motlagh D, Allen J, Hoshi R, Yang J, Lui K, Ameer G. Hemocompatibility evaluation of poly(diol citrate) in vitro for vascular tissue engineering. J Biomed Mater Res A. 2007;82A(4):907–916. [PubMed]
46. Kim BS, Mooney DJ. Engineering smooth muscle tissue with a predefined structure. J Biomed Mater Res. 1998;41(2):322–332. [PubMed]
47. Mooney DJ, Mazzoni CL, Breuer C, et al. Stabilized polyglycolic acid fibre-based tubes for tissue engineering. Biomaterials. 1996;17(2):115–124. [PubMed][filled square] This strategy highlights the use of antibody coatings for in situ regeneration of a functional endothelial lining.
48. Wake MC, Gupta PK, Mikos AG. Fabrication of pliable biodegradable polymer foams to engineer soft tissues. Cell Transplant. 1996;5(4):465–473. [PubMed]
49. Greisler HP, Schwarcz TH, Ellinger J, Kim DU. Dacron inhibition of arterial regenerative activities. J Vasc Surg. 1986;3(5):747–756. [PubMed]
50. Yu TJ, Chu CC. Bicomponent vascular grafts consisting of synthetic absorbable fibers. I. In vitro study. J Biomed Mater Res. 1993;27(10):1329–1339. [PubMed]
51. Yu TJ, Ho DM, Chu CC. Bicomponent vascular grafts consisting of synthetic absorbable fibers: part II: in vivo healing response. J Invest Surg. 1994;7(3):195–211. [PubMed]
52. Mooney DJ, Organ G, Vacanti JP, Langer R. Design and fabrication of biodegradable polymer devices to engineer tubular tissues. Cell Transplant. 1994;3(2):203–210. [PubMed]
53. Fidkowski CW, Kaazempur-Mofrad MR, Borenstein J, Vacanti JP, Langer R, Wang Y. Endothelialized microvasculature based on a biodegradable elastomer. Tissue Eng. 2005;11(1–2):302–309. [PubMed]
54. Niklason LE, Gao J, Abbott WM, et al. Functional arteries grown in vitro. Science. 1999;284(5413):489–493. [PubMed]
55. Shum-Tim D, Stock U, Hrkach J, et al. Tissue engineering of autologous aorta using a new biodegradable polymer. Ann Thorac Surg. 1999;68(6):2298–2304. discussion 2305. [PubMed]
56. Fu P, Sodian R, Lüders C, et al. Effects of basic fibroblast growth factor and transforming growth factor-β on maturation of human pediatric aortic cell culture for tissue engineering of cardiovascular structures. ASAIO J. 2004;50(1):9–14. [PubMed]
57. Shinoka T, Shum-Tim D, Ma PX, et al. Creation of viable pulmonary artery autografts through tissue engineering. J Thorac Cardiovasc Surg. 1998;115(3):536–545. discussion 545–546. [PubMed]
58. Watanabe M, Shin'oka T, Tohyama S, et al. Tissue-engineered vascular autograft: inferior vena cava replacement in a dog model. Tissue Eng. 2001;7(4):429–439. [PubMed][filled square] Nanofibrous scaffolds with aligned fibers were used to mimic native collagen fibrils and guide mesenchymal stem cell organization in vascular grafts. The results suggest that the long-term patency of cellular grafts may be attributed to the antithrombogenic property of mesenchymal stem cells and the organization of the supporting scaffold.
59. Shin'oka T, Imai Y, Ikada Y. Transplantation of a tissue-engineered pulmonary artery. N Engl J Med. 2001;344(7):532–533. [PubMed]
60. Shin'oka T, Matsumura G, Hibino N, et al. Midterm clinical result of tissue-engineered vascular autografts seeded with autologous bone marrow cells. J Thorac Cardiovasc Surg. 2005;129(6):1330–1338. [PubMed]
61. Matsumura G, Ishihara Y, Miyagawa-Tomita S, et al. Evaluation of tissue-engineered vascular autografts. Tissue Eng. 2006;12(11):3075–3083. [PubMed]
62. Ennett AB, Kaigler D, Mooney DJ. Temporally regulated delivery of VEGF in vitro and in vivo. J Biomed Mater Res A. 2006;79(1):176–184. [PubMed]
63. Guan J, Stankus JJ, Wagne WR. Biodegradable elastomeric scaffolds with basic fibroblast growth factor release. J Control Release. 2007;120(1–2):70–78. [PMC free article] [PubMed]
64. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson J. In: Molecular Biology of the Cell. 3rd. Anderson M, Granum S, editors. Garland Publishing; NY, USA: 1994.
65. Buttafoco L, Kolkmana G, Engbers-Buijtenhuijs P, et al. Electrospinning of collagen and elastin for tissue engineering applications. Biomaterials. 2006;27(5):724–734. [PubMed]
66. Ottani V, Raspanti M, Ruggeri A. Collagen structure and functional implications. Micron. 2001;32(3):251–260. [PubMed]
67. Nicolas FL, Gagnieu CH. Denatured thiolated collagen. II. Cross-linking by oxidation. Biomaterials. 1997;18(11):815–821. [PubMed]
68. Habermehl J, Skopinska J, Boccafoschi F, et al. Preparation of ready-to-use, stockable and reconstituted collagen. Macromol Biosci. 2005;5(9):821–828. [PubMed]
69. Charulatha V, Rajaram A. Influence of different crosslinking treatments on the physical properties of collagen membranes. Biomaterials. 2003;24(5):759–767. [PubMed]
70. Brinkman WT, Nagapudi K, Thomas BS, Chaikof EL. Photo-cross-linking of type I collagen gels in the presence of smooth muscle cells: mechanical properties, cell viability, and function. Biomacromolecules. 2003;4(4):890–895. [PubMed]
71. Elbjeirami WM, Yonter EO, Starcher BC, West JL. Enhancing mechanical properties of tissue-engineered constructs via lysyl oxidase crosslinking activity. J Biomed Mater Res A. 2003;66(3):513–521. [PubMed]
72. Orban JM, Wilson LB, Kofroth JA, El-Kurdi MS, Maul TM, Vorp DA. Crosslinking of collagen gels by transglutaminase. J Biomed Mater Res A. 2004;68(4):756–762. [PubMed][filled square][filled square] Degradable polymers allow for spatial and temporal release of growth factors to influence the angiogenic response in a localized region.
73. Hirai J, Matsuda T. Self-organized, tubular hybrid vascular tissue composed of vascular cells and collagen for low-pressure-loaded venous system. Cell Transplant. 1995;4(6):597–608. [PubMed]
74. Nerem RM, Ensley AE. The tissue engineering of blood vessels and the heart. Am J Transplant. 2004;4(Suppl 6):36–42. [PubMed]
75. Nerem RM, Seliktar D. Vascular tissue engineering. Annu Rev Biomed Eng. 2001;3:225–243. [PubMed]
76. Baguneid M, Murray D, Salacinski HJ, et al. Shear-stress preconditioning and tissue-engineering-based paradigms for generating arterial substitutes. Biotechnol Appl Biochem. 2004;39(Pt 2):151–157. [PubMed]
77. L'Heureux N, Germain L, Labbé R, Auger FA. In vitro construction of a human blood vessel from cultured vascular cells: a morphologic study. J Vasc Surg. 1993;17(3):499–509. [PubMed]
78. Seliktar D, Black RA, Vito RP, Nerem RM. Dynamic mechanical conditioning of collagen-gel blood vessel constructs induces remodeling in vitro. Ann Biomed Eng. 2000;28(4):351–362. [PubMed]
79. Cummings CL, Gawlittaa D, Nerema RM, Stegemann JP. Properties of engineered vascular constructs made from collagen, fibrin, and collagen–fibrin mixtures. Biomaterials. 2004;25(17):3699–3706. [PubMed]
80. Ye Q, Zünda G, Benedikta P, et al. Fibrin gel as a three dimensional matrix in cardiovascular tissue engineering. Eur J Cardiothorac Surg. 2000;17(5):587–591. [PubMed]
81. Clark RA. Fibrin glue for wound repair: facts and fancy. Thromb Haemost. 2003;90(6):1003–1006. [PubMed]
82. Jockenhoevel S, Zund G, Hoerstrup SP, et al. Fibrin gel – advantages of a new scaffold in cardiovascular tissue engineering. Eur J Cardiothorac Surg. 2001;19(4):424–430. [PubMed]
83. Long JL, Tranquillo RT. Elastic fiber production in cardiovascular tissue-equivalents. Matrix Biol. 2003;22(4):339–350. [PubMed]
84. Swartz DD, Russell JA, Andreadis ST. Engineering of fibrin-based functional and implantable small-diameter blood vessels. Am J Physiol Heart Circ Physiol. 2005;288(3):H1451–H1460. [PubMed]
85. Grassl ED, Oegema TR, Tranquillo RT. A fibrin-based arterial media equivalent. J Biomed Mater Res A. 2003;66(3):550–561. [PubMed]
86. Patel A, Fine B, Sandig M, Mequanint K. Elastin biosynthesis: The missing link in tissue-engineered blood vessels. Cardiovasc Res. 2006;71(1):40–49. [PubMed]
87. Lillie MA, Gosline JM. The viscoelastic basis for the tensile strength of elastin. Int J Biol Macromol. 2002;30(2):119–127. [PubMed]
88. Silver FH, Horvath I, Foran DJ. Viscoelasticity of the vessel wall: the role of collagen and elastic fibers. Crit Rev Biomed Eng. 2001;29(3):279–301. [PubMed]
89. Silver FH, Snowhill PB, Foran DJ. Mechanical behavior of vessel wall: a comparative study of aorta, vena cava, and carotid artery. Ann Biomed Eng. 2003;31(7):793–803. [PubMed]
90. Isenberg BC, Tranquillo RT. Long-term cyclic distention enhances the mechanical properties of collagen-based media-equivalents. Ann Biomed Eng. 2003;31(8):937–949. [PubMed]
91. Ramamurthi A, Vesely I. Evaluation of the matrix-synthesis potential of crosslinked hyaluronan gels for tissue engineering of aortic heart valves. Biomaterials. 2005;26(9):999–1010. [PubMed]
92. Stock UA, Wiederschain D, Kilroy SM, et al. Dynamics of extracellular matrix production and turnover in tissue engineered cardiovascular structures. J Cell Biochem. 2001;81(2):220–228. [PubMed]
93. Daamen WF, Hafmans T, Veerkamp JH, van Kuppevelt TH. Comparison of five procedures for the purification of insoluble elastin. Biomaterials. 2001;22(14):1997–2005. [PubMed]
94. Buijtenhuijs P, Buttafoco L, Poot AA, et al. Tissue engineering of blood vessels: characterization of smooth-muscle cells for culturing on collagen-and-elastin-based scaffolds. Biotechnol Appl Biochem. 2004;39(Pt 2):141–149. [PubMed]
95. Nagapudi K, Brinkmana WT, Thomasa BS, et al. Viscoelastic and mechanical behavior of recombinant protein elastomers. Biomaterials. 2005;26(23):4695–4706. [PubMed]
96. Cappello J, Crissman J, Dorman M, et al. Genetic engineering of structural protein polymers. Biotechnol Prog. 1990;6(3):198–202. [PubMed]
97. McGrath KP, Tirrell DA, Kawai M, Mason TL, Fournier MJ. Chemical and biosynthetic approaches to the production of novel polypeptide materials. Biotechnol Prog. 1990;6(3):188–192. [PubMed]
98. Meyer DE, Chilkoti A. Genetically encoded synthesis of protein-based polymers with precisely specified molecular weight and sequence by recursive directional ligation: examples from the elastin-like polypeptide system. Biomacromolecules. 2002;3(2):357–367. [PubMed]
99. Chang DK, Urry DK. Molecular dynamics calculations on relaxed and extended states of the polypentapeptide of elastin. Chem Phys Lett. 1988;147(4):395–400.
100. Petka WA, Harden JL, McGrath KP, Wirtz D, Tirrell DA. Reversible hydrogels from self-assembling artificial proteins. Science. 1998;281(5375):389–392. [PubMed]
101. Urry DW. Physical chemistry of biological free energy transduction as demonstrated by elastin protein-based polymers. J Phys Chem B. 1997;101:11007–11028.
102. Urry DW. Five axioms for the functional design of peptide-based polymers as molecular machines and materials: principles for macromolecular assembly. Biopolymers. 1998;47:167–178.
103. Nagarsekar A, Crissman J, Crissman M, Ferrari F, Cappello J, Ghandehari H. Genetic engineering of stimuli-sensitive silkelastin-like protein block copolymers. Biomacromolecules. 2003;4(3):602–607. [PubMed]
104. Kwon IK, Kidoaki S, Matsuda T. Electrospun nano- to microfiber fabrics made of biodegradable copolyesters: structural characteristics, mechanical properties and cell adhesion potential. Biomaterials. 2005;26(18):3929–3939. [PubMed]
105. Li M, Mondrinos MJ, Gandhi MR, Ko FK, Weiss AS, Lelkes PI. Electrospun protein fibers as matrices for tissue engineering. Biomaterials. 2005;26(30):5999–6008. [PubMed][filled square] The synthesis of bioinspired protein copolymers has a potential utility in a variety of soft prosthetic and tissue-engineering applications.
106. van Hest JC, Tirrell DA. Protein-based materials, toward a new level of structural control. Chem Commun (Camb) 2001;2001(19):1897–1904. [PubMed]
107. Wright ER, McMillan RA, Cooper A, et al. Thermoplastic elastomer hydrogels via self-assembly of an elastin-mimetic triblock polypeptide. Adv Funct Mater. 2002;12(2):1–6.
108. Wright ER, Conticello VP. Self-assembly of block copolymers derived from elastinmimetic polypeptide sequences. Adv Drug Deliv Rev. 2002;54(8):1057–1073. [PubMed]
109. Lee SJ, Yoo JJ, Lim GJ, Atala A, Stitzel J. In vitro evaluation of electrospun nanofiber scaffolds for vascular graft application. J Biomed Mater Res A. 2007;83(4):999–1008. [PubMed]
110. Stankus JJ, Soletti L, Fujimoto K, Hong Y, Vorp DA, Wagner WR. Fabrication of cell microintegrated blood vessel constructs through electrohydrodynamic atomization. Biomaterials. 2007;28(17):2738–2746. [PMC free article] [PubMed]
111. Barnes CP, Sell SA, Boland ED, Simpson DG, Bowlin GL. Nanofiber technology: designing the next generation of tissue engineering scaffolds. Adv Drug Deliv Rev. 2007;59(14):1413–1433. [PubMed]
112. Pham QP, Sharma U, Mikos AG. Electrospinning of polymeric nanofibers for tissue engineering applications: a review. Tissue Eng. 2006;12(5):1197–1211. [PubMed]
113. de Mel A, Bolvin C, Edirisinghe M, Hamilton G, Seifalian AM. Development of cardiovascular bypass grafts: endothelialization and applications of nanotechnology. Expert Rev Cardiovasc Ther. 2008;6(9):1259–1277. [PubMed]
114. Li D, Xia YN. Electrospinning of nanofibers: reinventing the wheel? Adv Funct Mater. 2004;16(14):1151–1170.
115. He W, He W, Yong T, Teo WE, Ma Z, Ramakrishna S. Fabrication and endothelialization of collagen-blended biodegradable polymer nanofibers: potential vascular graft for blood vessel tissue engineering. Tissue Eng. 2005;11(9–10):1574–1588. [PubMed]
116. Kannan RY, Salacinski HJ, De Groot J, et al. The antithrombogenic potential of a polyhedral oligomeric silsesquioxane (POSS) nanocomposite. Biomacromolecules. 2006;7(1):215–223. [PubMed]
117. Kannan RY, Salacinski HJ, Sales KM, Butler PE, Seifalian AM. The endothelialization of polyhedral oligomeric silsesquioxane nanocomposites: an in vitro study. Cell Biochem Biophys. 2006;45(2):129–136. [PubMed]
118. Endo M, Koyama S, Matsuda Y, Hayashi T, Kim YA. Thrombogenicity and blood coagulation of a microcatheter prepared from carbon nanotube-nylon-based composite. Nano Lett. 2005;5(1):101–105. [PubMed]
119. Meng J, Kong H, Xu HY, Song L, Wang CY, Xie SS. Improving the blood compatibility of polyurethane using carbon nanotubes as fillers and its implications to cardiovascular surgery. J Biomed Mater Res A. 2005;74(2):208–214. [PubMed]
120. Kim JY, Khang D, Lee JE, Webster TJ. Decreased macrophage density on carbon nanotube patterns on polycarbonate urethane. J Biomed Mater Res A. 2009;88(2):419–426. [PubMed]
121. Hurt RH, Monthioux M, Kane A. Toxicology of carbon nanomaterials: status, trends, and perspectives on the special issue. Carbon. 2006;44(6):1028–1033.
122. Dahl SL, Koh J, Prabhakar V, Niklason LE. Decellularized native and engineered arterial scaffolds for transplantation. Cell Transplant. 2003;12(6):659–666. [PubMed]
123. Schmidt CE, Baier JM. Acellular vascular tissues: natural biomaterials for tissue repair and tissue engineering. Biomaterials. 2000;21(22):2215–2231. [PubMed]
124. Tamura N, Nakamura T, Terai H, et al. A new acellular vascular prosthesis as a scaffold for host tissue regeneration. Int J Artif Organs. 2003;26(9):783–792. [PubMed]
125. Uchimura E, Sawa Y, Taketani S, et al. Novel method of preparing acellular cardiovascular grafts by decellularization with poly(ethylene glycol) J Biomed Mater Res A. 2003;67(3):834–837. [PubMed]
126. Courtman DW, Errett BF, Wilson GJ. The role of crosslinking in modification of the immune response elicited against xenogenic vascular acellular matrices. J Biomed Mater Res. 2001;55(4):576–586. [PubMed]
127. Khor E. Methods for the treatment of collagenous tissues for bioprostheses. Biomaterials. 1997;18(2):95–105. [PubMed]
128. Amiel GE, Komura M, Shapira O, et al. Engineering of blood vessels from acellular collagen matrices coated with human endothelial cells. Tissue Eng. 2006;12(8):2355–2365. [PubMed]
129. Cho SW, Lim SH, Kim IK, et al. Small-diameter blood vessels engineered with bone marrow-derived cells. Ann Surg. 2005;241(3):506–515. [PubMed]
130. Conklin BS, Richter ER, Kreutziger KL, Zhong DS, Chena C. Development and evaluation of a novel decellularized vascular xenograft. Med Eng Phys. 2002;24(3):173–183. [PubMed]
131. Conklin BS, Wu H, Lin PH, Lumsden AB, Chen C. Basic fibroblast growth factor coating and endothelial cell seeding of a decellularized heparin-coated vascular graft. Artif Organs. 2004;28(7):668–675. [PubMed]
132. DiMuzio P, Fischer L, McIlhenny S, et al. Development of a tissue-engineered bypass graft seeded with stem cells. Vascular. 2006;14(6):338–342. [PubMed]
133. Holdsworth RJ, Naidu S, Gervaz P, McCollum P. Glutaraldehyde-tanned bovine carotid artery graft for infrainguinal vascular reconstruction: 5-year follow-up. Eur J Vasc Endovasc Surg. 1997;14(3):208–211. [PubMed]
134. Kaushal S, Amiel GE, Guleserian KJ, et al. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat Med. 2001;7(9):1035–1040. [PMC free article] [PubMed]
135. McFetridge PS, Bodamyali T, Horrocks M, Chaudhuri JB. Endothelial and smooth muscle cell seeding onto processed ex vivo arterial scaffolds using 3D vascular bioreactors. ASAIO J. 2004;50(6):591–600. [PubMed]
136. Shimizu K, Ito A, Arinobe M, et al. Effective cell-seeding technique using magnetite nanoparticles and magnetic force onto decellularized blood vessels for vascular tissue engineering. J Biosci Bioeng. 2007;103(5):472–478. [PubMed]
137. Voytik-Harbin SL, Brightman AO, Kraine MR, Waisner B, Badylak SF. Identification of extractable growth factors from small intestinal submucosa. J Cell Biochem. 1997;67(4):478–491. [PubMed]
138. Badylak SF, Record R, Lindberg K, Hodde J, Park K. Small intestinal submucosa: a substrate for in vitro cell growth. J Biomater Sci Polym Ed. 1998;9(8):863–878. [PubMed]
139. Huynh T, Abraham G, Murray J, Brockbank K, Hagen PO, Sullivan S. Remodeling of an acellular collagen graft into a physiologically responsive neovessel. Nat Biotechnol. 1999;17(11):1083–1086. [PubMed]
140. Marshall SE, Tweedt SM, Greene CH, et al. An alternative to synthetic aortic grafts using jejunum. J Invest Surg. 2000;13(6):333–341. [PubMed]
141. Robotin-Johnson MC, Swanson P, Johnson D, Schuessler R, Cox J. An experimental model of small intestinal submucosa as a growing vascular graft. J Thorac Cardiovasc Surg. 1998;116(5):805–811. [PubMed]
142. Campbell GR, Ryan GB. Origin of myofibroblasts in the avascular capsule around free-floating intraperitoneal blood clots. Pathology. 1983;15(3):253–264. [PubMed]
143. Campbell JH, Efendy JL, Han CL, Girjes AA, Campbell GR. Haemopoietic origin of myofibroblasts formed in the peritoneal cavity in response to a foreign body. J Vasc Res. 2000;37(5):364–371. [PubMed]
144. Campbell JH, Efendy JL, Campbell GR. Novel vascular graft grown within recipient's own peritoneal cavity. Circ Res. 1999;85(12):1173–1178. [PubMed]
145. Chue WL, Campbell G, Caplice N, et al. Dog peritoneal and pleural cavities as bioreactors to grow autologous vascular grafts. J Vasc Surg. 2004;39(4):859–867. [PubMed]
146. Efendy JL, Campbell GR, Campbell JH. The effect of environmental cues on the differentiation of myofibroblasts in peritoneal granulation tissue. J Pathol. 2000;192(2):257–262. [PubMed]
147. Chen CH, Tsai CC, Chen W, et al. Novel living cell sheet harvest system composed of thermoreversible methylcellulose hydrogels. Biomacromolecules. 2006;7(3):736–743. [PubMed]
148. Sekine H, Shimizu T, Yang J, Kobayashi E, Okano T. Pulsatile myocardial tubes fabricated with cell sheet engineering. Circulation. 2006;114(Suppl 1):I87–I93. [PubMed]
149. Yang J, Yamatoa M, Shimizu T, et al. Reconstruction of functional tissues with cell sheet engineering. Biomaterials. 2007;28(34):5033–5043. [PubMed]
150. L'Heureux N, Dusserre N, Konig G, et al. Human tissue-engineered blood vessels for adult arterial revascularization. Nat Med. 2006;12(3):361–365. [PMC free article] [PubMed]
151. Chan G, Mooney DJ. New materials for tissue engineering: towards greater control over the biological response. Trends Biotechnol. 2008;26(7):382–392. [PubMed]
152. Rizzi SC, Ehrbar M, Halstenberg S, et al. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part II: biofunctional characteristics. Biomacromolecules. 2006;7(11):3019–3029. [PubMed]
153. Doi K, Matsuda T. Enhanced vascularization in a microporous polyurethane graft impregnated with basic fibroblast growth factor and heparin. J Biomed Mater Res. 1997;34(3):361–370. [PubMed]
154. Chen L, Yu H, Dai N, Tao SF, Gong WH. Dual cell seeding to improve cell retention on polytetrafluoroethylene grafts. Zhonghua Wai Ke Za Zhi. 2003;41(2):143–145. [PubMed]
155. Bhattacharya V, McSweeney PA, Shi Q, et al. Enhanced endothelialization and microvessel formation in polyester grafts seeded with CD34+ bone marrow cells. Blood. 2000;95(2):581–585. [PubMed]
156. Fields C, Cassano A, Makhoul RG, et al. Evaluation of electrostatically endothelial cell seeded expanded polytetrafluoroethylene grafts in a canine femoral artery model. J Biomater Appl. 2002;17(2):135–152. [PubMed]
157. Griese DP, Ehsan A, Melo LG, et al. Isolation and transplantation of autologous circulating endothelial cells into denuded vessels and prosthetic grafts: implications for cell-based vascular therapy. Circulation. 2003;108(21):2710–2715. [PubMed]
158. Izhar U, Schwalb Herzl, Borman JB. Novel synthetic selectively degradable vascular prostheses: a preliminary implantation study. J Surg Res. 2001;95(2):152–160. [PubMed][filled square][filled square] Presents a novel cell sheet engineering approach for the development of pulsatile myocardial blood vessels. Temperature-responsive polymer coatings were utilized to layer cardiomyocyte sheets into a tube, which was then examined for in vivo function.
159. Iwai S, Sawa Y, Ichikawa H, et al. Biodegradable polymer with collagen microsponge serves as a new bioengineered cardiovascular prosthesis. J Thorac Cardiovasc Surg. 2004;128(3):472–479. [PubMed]
160. Pektok E, Nottelet B, Tille JC, et al. Degradation and healing characteristics of small-diameter poly(ε-caprolactone) vascular grafts in the rat systemic arterial circulation. Circulation. 2008;118(24):2563–2570. [PubMed][filled square][filled square] Demonstrates the ability to construct arterial grafts exclusively from an individual's own cells without relying on exogenous scaffolding. Most importantly, the mechanical properties of the grafts matched those of native vasculature, which allowed for long-term mechanical stability and tissue integration.
161. Hashi CK, Zhu Y, Yang GY, et al. Antithrombogenic property of bone marrow mesenchymal stem cells in nanofibrous vascular grafts. Proc Natl Acad Sci USA. 2007;104(29):11915–11920. [PubMed]
162. Hoerstrup SP, Cummings Mrcs I, Lachat M, et al. Functional growth in tissue-engineered living, vascular grafts: follow-up at 100 weeks in a large animal model. Circulation. 2006;114(Suppl 1):I159–I166. [PubMed][filled square] This strategy demonstrates the utility of incorporating specific features of the natural extracellular matrix into a crosslinked hydrogel system. Specifically, the protein polymers contain the cell adhesion motif RGD and degradation sites for plasmin and matrix-metalloproteinases, which are key in cell-mediated matrix remodeling.


201. Association AH. Heart Disease and Stroke Statistics – 2008 update.