Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=ierd20

Download by: [ JH Libraries] Date: 20 May 2017, At: 07:54

Expert Review of Medical Devices

ISSN: 1743-4440 (Print) 1745-2422 (Online) Journal homepage: http://www.tandfonline.com/loi/ierd20

Tissue engineered vascular grafts: current state ofthe field

Chin Siang Ong, Xun Zhou, Chen Yu Huang, Takuma Fukunishi, HuaitaoZhang & Narutoshi Hibino

To cite this article: Chin Siang Ong, Xun Zhou, Chen Yu Huang, Takuma Fukunishi, HuaitaoZhang & Narutoshi Hibino (2017) Tissue engineered vascular grafts: current state of the field,Expert Review of Medical Devices, 14:5, 383-392, DOI: 10.1080/17434440.2017.1324293

To link to this article: http://dx.doi.org/10.1080/17434440.2017.1324293

Accepted author version posted online: 27Apr 2017.Published online: 09 May 2017.

Submit your article to this journal

Article views: 30

View related articles

View Crossmark data

REVIEW

Tissue engineered vascular grafts: current state of the fieldChin Siang Onga*, Xun Zhoua*, Chen Yu Huangb, Takuma Fukunishia, Huaitao Zhanga and Narutoshi Hibinoa

aDivision of Cardiac Surgery, Johns Hopkins Hospital, Baltimore, MD, USA; bDepartment of Physics & Astronomy, Johns Hopkins University,Baltimore, MD, USA

ABSTRACTIntroduction: Conventional synthetic vascular grafts are limited by the inability to remodel, as well asissues of patency at smaller diameters. Tissue-engineered vascular grafts (TEVGs), constructed frombiologically active cells and biodegradable scaffolds have the potential to overcome these limitations,and provide growth capacity and self-repair.Areas covered: This article outlines the TEVG design, biodegradable scaffolds, TEVG fabrication meth-ods, cell seeding, drug delivery, strategies to reduce wait times, clinical trials, as well as a 5-year viewwith expert commentary.Expert commentary: TEVG technology has progressed significantly with advances in scaffold materialand design, graft design, cell seeding and drug delivery. Strategies have been put in place to reducewait times and improve ‘off-the-shelf’ capability of TEVGs. More recently, clinical trials have beenconducted to investigate the clinical applications of TEVGs.

ARTICLE HISTORYReceived 29 March 2017Accepted 25 April 2017

KEYWORDSTissue engineered vasculargrafts; vascular surgery;vascular grafts; cell seeding;biomaterial

1. Introduction

Vascular grafts fulfill an important role in the contemporarymanagement of a wide range of clinical conditions. In additionto atherosclerotic disease, many vascular pathologies, includ-ing aneurysmal degeneration, congenital malformations, vas-culitis, and traumatic injury, necessitate arterial bypass. Inmost cases, autologous tissue, such as internal thoracic arteryor saphenous vein, is the first choice for small diameter arterialgrafts. However, prior surgeries and comorbid medical condi-tions may limit the availability of a patient’s own vessels, andtheir harvest can be associated with significant morbidity.While synthetic grafts demonstrate good patency and long-term outcomes for management of the aorta and other largearteries, their use for bypass of small diameter vessels hasbeen associated with less than satisfying results [1]. Long-term outcomes are negatively impacted by high rates ofthrombus formation and intimal hyperplasia. Therefore, thereremains a substantial unfulfilled need for readily availablesmall-caliber vascular grafts with good long-term patency [2].For pediatric patients, homografts and synthetic grafts are asource of morbidity, due to the lack of growth potential andinflammatory reactions associated with these grafts. There isan unmet clinical need for new vascular grafts that havegrowth potential.

Langer and Vacanti defined the concept of tissue engineer-ing in 1993 in their seminal Science paper ‘Tissue Engineering’where they defined the term as ‘an interdisciplinary field thatapplies the principles of engineering and life sciences towardthe development of biological substitutes that restore, main-tain, or improve tissue function’ [3].

The principle of ‘tissue engineering’ has been applied tocreate tissue engineered vascular grafts (TEVGs) using a patient’sautologous cells or a patient’s stem-cell-derived cells, in combi-nation with a scaffold [4–6] (Figure 1). Early pioneering work inthis field was performed in the 1980s when Greisler implantedwoven absorbable polyglycolic acid (PGA) grafts into rabbit aor-tas and demonstrated replacement of the prosthesis withendothelialized vessels at 7 months. While nearly a quarter ofthe specimens demonstrated either dilation or intimal hyperpla-sia, all were able to withstand arterial perfusion pressure [7]. Thestrengths and weaknesses of Greisler’s experiment highlightedthe properties that a TEVG should exhibit. At themost basic level,a graft must be biocompatible and not exhibit toxicity or exces-sive immunogenicity. An ideal TEVG [5] should have themechan-ical properties to maintain a balance between degradation andneotissue formation. From a functional standpoint, TEVGs shouldbe biomimetic and resist long-term complications, such as infec-tion, intimal hyperplasia, stenosis, calcification, and aneurysmaldilatation. Logistically, it is also important that themanufacturingprocess for a TEVG be resilient, minimize production time, and, inthe case of unseeded TEVGs, allow for storability in order tooptimize ‘off-the-shelf’ capabilities [8].

2. TEVG design

Most TEVGs seek to replicate the biological and mechanicalproperties of native blood vessels, if not the protein, materials,and cells themselves present in native vascular architecture. Ata histological level, mammalian arteries consist of three layers –intima, media, and adventitia.

CONTACT Narutoshi Hibino nhibino1@jhmi.edu Division of Cardiac Surgery, The Johns Hopkins Hospital, Zayed 7107, 1800 Orleans St, Baltimore,MD 21287, USA,

*These authors contributed equally to this work.

EXPERT REVIEW OF MEDICAL DEVICES, 2017VOL. 14, NO. 5, 383–392https://doi.org/10.1080/17434440.2017.1324293

© 2017 Informa UK Limited, trading as Taylor & Francis Group

The innermost intimal layer consists of endothelial cells(ECs), which provide a tight luminal barrier while also provid-ing cellular signaling that prevents thrombosis, infection, andinflammation. These cells are adhered to a basement mem-brane comprised collagen and laminin. The media comprisessmooth-muscle cells (SMCs) imbedded in a layer of type I andIII collagen. In response to the appropriate signals, these SMCswill contract or relax, resulting in vasoconstriction or vasodila-tion. The media is sandwiched between the internal andexternal elastic lamina, fenestrated layers of elastin whichinterface with the intima and the adventitia, the outermostlayer of the arterial wall. The adventitia consists of fibroblastsin a loose extracellular matrix (ECM) comprised mostly ofcollagen. The ECM of native vessels consists of a network ofmultiple proteins in media and adventitia, which serve distinctmechanical and biochemical purposes.

Collagen is the primary component of ECM, providing ten-sile strength. Thus, it plays an important role in the design ofTEVGs. As it is easily isolated and synthesized, it has beenutilized as a substrate for engineered protein matrices.Elastin is another major component of ECM, providing elasticrecoil to the arterial wall. Its paracrine functions include mod-ulating the proliferation of endothelial and SMCs. Elastin hasbeen used as a coating for synthetic vascular grafts, such asPolytetrafluoroethylene, and has been shown to decrease pla-telet activation, aggregation, and thrombus formation. Likecollagen, elastin has been shown to be synthesized in biolo-gically significant quantities by TEVGs [9]. Finally, fibrin is acomponent of blood vessels that is formed when fibrinogen is

rapidly polymerized by action of thrombin. It recruits cells andis broken down by fibrinolysis. The presence of native proteinsin TEVGs allows for relevant cellular signaling that promotes amore native-like immediate microenvironment, and betterbiomimicry. TEVGs attempt to recapitulate the functions ofeach component in the vessel by promoting cellular infiltra-tion and proliferation to facilitate the synthesis of theseproteins.

3. Scaffolds

The essential concept driving the field of TEVGs is biomimicry[5]. The scaffold for TEVGs offers the ability of neotissue for-mation. The TEVG undergoes remodeling through the body’sinnate response to foreign material and the scaffold is even-tually replaced by autogenous tissue. There are different typesof scaffolds that can be used for TEVG. Each scaffold hasadvantages and disadvantages. Further research is requiredto improve the material of the scaffolds.

3.1. Synthetic scaffolds

Most scaffolds employed in TEVGs are constructed from bio-degradable polymers (Table 1). These polymers are degradedby hydrolytic cleavage of ester linkages. The rate of degrada-tion can be modulated by multiple factors, including molecu-lar weight, surface-area-to-volume ratio, and crystallinity.When compared to methods that utilize biological proteins,

Figure 1. TEVGs: fabrication methods (Left Top), scaffolds (Top Right), cell types (Left Bottom), clinical application (Bottom Right).

384 C. S. ONG ET AL.

such as collagen, synthetic polymers facilitate less cellularrecruitment, but they allow for improved mechanical proper-ties that make them more feasible for grafts subject to arterialpressure.

One of the most commonly and widely studied polymers isPGA, the material utilized by Greisler in his early studies in the1980s. PGA exhibits rapid degradation within 1 month [10].PGA mesh has been employed in other experimental andclinical applications with US FDA approval, including scaffoldsfor nerve regeneration, repair of dural tears, and in the tissueengineering of liver, bone, cartilage, and intestine. Therefore,its mechanical properties are well-documented and under-stood. Mauri and colleagues demonstrated that a PGA TEVGwith human ECs should be able to withstand mechanicalstress equivalent to aortic pressure by comparing to aortictissue [11].

Polylactic acid (PLA) is similar in structure to PGA, with theaddition of a single methyl group, causing it to be morehydrophilic. Therefore, it degrades more slowly than PGA,taking months to years. PLA is available as either a racemicmixture or a pure enantiomer (poly-L-lactic acid [PLLA]), whichtakes longer to degrade. Like PGA, PLA has also beenemployed in many clinical applications including tissue engi-neering [12]. PLA has three isomeric forms, of which PLLA isthe most studied for cardiovascular tissue engineering appli-cations [13].

Poly-ε-caprolactone (PCL) [14–16] is one of the most hydro-philic and degradation-resistant biodegradable polymers com-monly used, taking more than 1 year to be broken down.When compared to PGA and PLA, PCL is also notable forhaving a lower glass-transition temperature of −60°C, meaningthat it will be remain stable as a polymer at room temperatureand during refrigeration.

Scaffolds can also be constructed from copolymers [26] oftwo or more components, such as copolymer of ε-caprolac-tone and lactic acid (PCLA) and of copolymer of glycolic acidand lactic acid (PLGA), resulting in intermediate properties anddegradation times. By varying the ratio of the componentmonomers, these properties can be finely adjusted. However,immiscibility, reduced polymerization, and crystallinity cancause more rapid degradation times.

Groups have also experimented with using fast-degrading(FD) scaffolds. Wu and colleagues created electrospun poly-

glycerol-sebacate (PGS)/PCL grafts that were used in a rataorta model. No cells were seeded, but 3 months after inter-position grafting in rat abdominal aorta, the grafts rapidlydegraded, forming neoarteries with synchronous pulsation,confluent endothelial, and smooth-muscle layers, expressingelastin, collagen, and glycosaminoglycan, with native-likemechanical properties [15].

Other synthetic polymers used are polyethylene glycol [13],polyurethane (PU) [13,17], polyhydroxy alkanoate [18], polyhy-droxy octanoate [19], poly-diaxanone [20], PGS [21], polyesterurethane urea [22,23], and poly-4-hydroxy-butyrate [24,25].

3.2. Biological scaffolds

There are also a number of strategies for creation of biologicalTEVGs, such as self-assembly, hydrogels, and decellularizedbiological matrices. Biological material, such as collagen [27]and fibrin [28–30], is also frequently used in these constructs.

Hydrogels [31] attempt to directly recapitulate the structureof native vessels by embedding cells within a solubilizedprotein matrix, generally consisting of collagen and/or addi-tional proteins. The solution can then be molded into adesired shape, such as a tubular structure for vascular grafts,and then solidified. Stem cells or other progenitor cells arecommonly used in hydrogels, with the goal of encouragingcellular signaling, proliferation, and recruitment to promoteremodeling into vascular tissue. However, while hydrogelshave been employed broadly in tissue-engineering applica-tions, they often lack the mechanical properties needed forfunctional vascular grafts. Many strategies have been pro-posed to overcome this limitation, such as supplementationwith growth factors, such as vascular endothelial growth fac-tor [32,33], constructing multilayer grafts [34,35], and chemi-cal/enzymatic cross-linking of the protein matrix [36,37].

Intact extracellular matrices can also be obtained by decel-lularizing native vascular tissue, with the goal of removing allimmunogenic components while preserving biological andmechanical properties. For example, Syedain and colleagues[38] also implanted decellularized engineered tissue tubes inlambs and evaluated them to adulthood. The lambs increasedin weight by 366%, and the graft diameter and volumeincreased by 56% and 216%, respectively. Mechanical, chemi-cal, and enzymatic processes can be employed for the decel-lularization process, and, theoretically, both homografts andxenografts from other species can be utilized. The advantagesof this approach include a more natural structure, containingfunctional proteins to promote cellular recruitment. One dis-advantage of this approach is the possibility of immunogeni-city from antigens of retained cellular remnants, whichremains to be determined [39], although the decellularizationprocess seeks to minimize this risk.

Another novel approach toward developing an ECM isthrough cell sheet self-assembly [31,40]. When cultured in amedium enriched with ascorbic acid, the substrate for col-lagen synthesis, SMCs, and fibroblasts can be directed tosynthesize their own ECM. In vitro, this can be performed acylindrical mandrel to generate a tubular structure. Othergroups have also demonstrated that this process can also beperformed in vivo, by implanting synthetic tubing into the

Table 1. Examples of scaffold materials used in TEVG fabrication.

Scaffold material

PGA [10,11]PLA [12,13]PCL [14–16]PEG [13]PU [13,17]PHA [18]PHO [19]PDS [20]PGS [21]PEUU [22,23]P4HB [24,25]Copolymers [26]

PGA: Polyglycolic acid; PLA: polylactic acid; PCL: poly-ε-caprolactone;PEG: polyethylene glycol; PU: polyurethane; PHA: polyhydroxy alkanoate;PHO: polyhydroxy-octanoate; PDS: poly-diaxanone; PGS: polyglycerol seba-cate; PEUU: polyester urethane urea; P4HB: poly-4-hydroxy-butyrate.

EXPERT REVIEW OF MEDICAL DEVICES 385

peritoneal cavity and relying on the body’s inflammatoryresponse to form a layer of granulation tissue around thestructure. Once explanted, this granulation tissue can be har-vested and everted to obtain a mesothelialized sleeve ofcollagen ECM and fibroblasts [41].

3.3. Hybrid scaffolds

Building scaffolds that combine degradable synthetic and nat-ural polymers may provide good mechanical properties whilealso enhancing biocompatibility and cellular recruitment.Hajiali and colleagues created electrospun PGA scaffoldsblended with different concentrations of gelatin and foundthat increased gelatin consult improved biological andmechanical properties [42]. Similarly, Xie and colleagues cre-ated PLA/PLCL (poly(L-lactide-co-ε-caprolactone)) graftsimpregnated with collagen/elastin [43]. Gong and colleagueselectrospun a biodegradable polymer around decellularizedrat aortas to create a hybrid scaffold TEVG [44].

TEVGs can also be combined with stents to create hybridstent grafts. Takeuchi and colleagues created a stent graft withdouble-layered polyethylene terephthalate/PGA that was usedin a dog aorta model of endovascular aneurysm repair. Itdemonstrated similar tensile strength and flexibility as a tradi-tional polyester graft, with PGA degradation and replacementby host tissue in vivo 2 months postimplantation [45].

4. TEVG fabrication methods

One of the most popular techniques for creating a degradablepolymer scaffold is electrospinning. The process uses an elec-tric field to direct a jet of polymer solution from a capillary tiptoward a target for deposition. In order to create a tubularstructure such as an arterial scaffold, a rapidly rotating man-drel is used as a target [46]. By varying parameters such as theflow rate, voltage, polymer concentration, distance, surfacespeed, and solvent, the thickness, density, and physical prop-erties of the resulting scaffold can be altered. Studies havedemonstrated that high burst pressures and tensile strengthakin to physiological parameters can be obtained by simplyvarying deposition time [47].

Another common method is particulate or porogen leach-ing [48], where particulates or porogens (salt, sugar, wax)serve as placeholders for pore formation in the actual scaffold,before being leached by evaporation, cross linking, or byanother chemical reaction.

Freeze drying (lyophilization) [15,49,50] is based on theprinciple of sublimation, where a polymer is first dissolved ina solvent. This solution is frozen and the solvent is allowed tosublime during the drying process. Pore size [51] can becontrolled by changing conditions, such as freezing rate andsolute concentration.

Other techniques to fabricate scaffolds [52] include solventcasting, foaming, phase separation, fiber mesh, fiber bonding,self-assembly, rapid prototyping, melt molding, and mem-brane lamination. Bioreactors may also be used; for example,Gui and colleagues used a pulsatile bioreactor to culture SMCson PGA scaffolds on silicone backbones [53], and Syedain and

colleagues used custom pulsed-flow-stretch bioreactors toengineer tissue tubes prior to decellularization [38].

Im and colleagues demonstrated a novel technique of solid-state drawing to produce a TEVG with good mechanical proper-ties without the need for solvents or additional treatments. Theirmethodology consisted of dual rotary motors on either side of aheating oven to mechanically stretch a biodegradable polymer.Functional studies demonstrated that their resulting productexhibited improved tensile strength and hydrophobicity.Additionally, spectroscopy demonstrated increased molecularorientation, which translates into a smoother surface that isless likely to cause platelet aggregation [54].

Scaffolds can also be made of customized graft materialand graft designs. Sugiura and colleagues developed twoversions of bilayer copolymeric grafts, one FD and the otherslow degrading (SD). The SD grafts consisted of a double-layerof PLA/PLCL. The outer layer of the FD grafts consisted of ablend of PLA–PGA. In a mouse aorta model, the FD grafts hadbetter cellular infiltration, and less calcification [55]. Otherattempts at multilayer grafts include adding a thick poroushydrogel sleeve to a dense nanofibrous core (PCL) [35] andadding hydrogel solutions between a mandrel and a hydratedPU mesh [34]. In an attempt to emulate the J-shaped mechan-ical behavior of a two-component elastin/collagen system,Rapoport and colleagues electrospun PU with PGA to form acorrugated graft [56].

5. Cell seeding for TEVG

5.1. Cell seeding techniques

There are numerous techniques [57] to perform cell seeding.Passive seeding (static seeding and gravitational seeding) [58] isthe most common approach but also the least efficient approachand involves direct application of the cell suspension into thescaffold, either luminally or from the outside. Fibronectin or otheradhesive biological glues may also be used as well [59].

Dynamic seeding uses various systems to increase seedingefficiency, uniformity, and penetration of the scaffold. Generally,the two main types are rotational seeding [60] that induceshydrostatic forces and vacuum seeding [61] that creates pressuregradients to draw cells in through the micropores of the TEVG.

Electrostatic cell seeding and magnetic cell seeding aim toincrease seeding efficiency through the use of a temporarypositive charge on the typically negatively charged TEVG lumi-nal surface for the former [62], and the use of magnets andmagnetite nanoparticles for the latter [63]. Other techniques[57] include photopolymerized hydrogels [64] for cell seeding,sheet-based cell seeding [65], and hybrid systems [66].

Assessment of cell seeding can be performed by cell count-ing, quantitative histology, scanning electron microscopy, andpicogreen (DNA) detection assay, followed by assessment ofviability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetraso-dium bromide assay and live–dead assays.

5.2. Cell types used in seeding

There have been a number of different cell types used in cellseeding [67], such as adult blood vessel cell types, endothelial

386 C. S. ONG ET AL.

progenitor cells (EPCs), stem cells, and stem-cell-derived vas-cular cells [68].

Adult blood vessel cell types include ECs, SMCs, and fibro-blasts, but these cell types involve a blood vessel biopsy whichmay result in morbidity during harvesting at the donor sites [69]and have limited replicative ability due to patient’s age [70]. Thiscell source is usually autologous, though nonautologous sourcesutilizing allogeneic cells have been described [71].

EPCs may also be used for cell seeding and can be obtainedusing far less invasive methods than adult blood vessel cell types,by extraction from peripheral blood. Asahara and colleaguesisolated EPCs from human peripheral blood using cell surfaceantigen expression and magnetic bead selection [72]. Shirota andcolleagues collected human peripheral blood samples, excludedmonocytes and macrophages, and expanded EPCs in vitro. Theythen seeded these cells into a small diameter vascular grafts anddemonstrated elongation and alignment of EPCs along the direc-tion of blood flow [73]. However, it is important to note that EPCsrepresent a relatively heterogeneous cell population [74].

Mesenchymal stem cells (MSCs) are adult stem cells that havethe capability to form a variety of connective tissue phenotypes,including blood vessels. They are readily isolatable from bonemarrow, peripheral blood, skeletal muscle, and adipose tissue[75]. While bone marrow aspiration has historically been the pre-ferred method for obtaining MSCs from bone marrow mononuc-lear cells [76–78], liposuction [79] or skeletalmuscle biopsy [22] arealso adequate, even from the hair follicle in the skin dermis [80].MSCs obtained through each of these techniques have beensuccessfully utilized in TEVGs, although there is evidence thatthe source of MSCs may affect the biomechanical properties ofthe resulting grafts. Potentially, MSCs could be harvested from apatient, expanded in vitro, and used for a personalized TEVGwithout the need for additional cell culture [81].

Embryonic stem cells (ESCs) have the potential to differ-entiate into any adult cell type. For the purposes of TEVG, theyare appealing because of their proliferative capability andversatility but also pose numerous concerns. In addition toethical considerations, there are substantial biological con-cerns regarding potential tumorigenicity and stability interms of lineage commitment during differentiation. Onestudy of vascular grafts constructed with human ESCs foundevidence of bone and cartilage markers, suggesting that someof the cells in the mature graft have differentiated into toosteoblasts and chondrocytes and that stringency in analyzingdifferentiating cell population is warranted [82].

As an alternative to ESCs, groups have investigated the useof induced pluripotent stem cells (iPSCs) [83]. These cells aregenerated by dedifferentiating mature adult cells, often fromskin or blood. iPSCs were then differentiated into vascularSMCs via an embryoid body approach [53,84] or in a definedmedium in the presence of Wnt3a for 10–12 days for neuralcrest induction, before further induction into a mesenchymallineage and confirmation of MSC phenotype [85].

Hibino and colleagues demonstrated that mouse iPSCscould be seeded on PLGA and PCLA scaffolds in a mouseinferior vena cava model with good endothelialization [86].Gui, Sundaram, and colleagues used human iPSCs in an aorticinterposition model in nude mice with good outcomes (noruptures, stenosis, or teratomas at 2 weeks) [53,85]. However,

the number of seeded differentiated iPSCs decreased overtime (42% at 1 week, 10% at 4 and 10 weeks) [86].

5.3. Effect of cell seeding

The use of cell seeding remains controversial [57], with unan-swered questions regarding the necessity and clinical relevanceof high-efficiency cell seeding, quantification method of cellseeding, optimal cell type for seeding, and the fate and functionof seeded cells. The fate of the seeded cells remains uncertain,with Cho and colleagues showing decreasing cell density byfluorescence intensity over 8 weeks [69]. It has been proposedthat seeded cells are lost due to cell death or lack of cellularattachment with resultant embolization to the distal end organs[57]. Studies performed by Lee and colleagues, to investigatethe duration of incubation and cell dose, on seeding efficiencyand cellular attachment, showed that incubation time does notaffect TEVG patency, cell attachment, and seeding efficiency andthat macrophage infiltration and inhibition of critical stenosisoccur in a cell dose-dependent manner [87].

6. Drug delivery

Various groups have investigated strategies for delivering orembedding pharmacological agents within the graft toenhance their biocompatibility and functional properties.There are generally two approaches, direct addition of druginto the material used for vascular graft creation and drugloading into the vessels or grafts.

Examples of drug addition into the material for graft crea-tion include Lee and colleagues, who applied a polymeric localdrug delivery technique by electrospinning PLGA with epigal-locatechin-3-O-gallate, a green tea polyphenol, to preventintimal hyperplasia in a rabbit aorta model [88]. Centola,Spadaccio, and colleagues developed a heparin-releasingpoly-L-lactide (PLLA) scaffold using electrospinning. Heparinin the graft helps to guide MSC differentiation toward the ECtype (determined by CD31 positivity and morphology) andalso as a postoperative drug [89,90].

In terms of drug loading into the vessel or grafts, Zou andcolleagues created treated rat internal jugular veins with rapa-mycin-containing PLGA nanoparticles and used them for car-otid interposition grafts, finding that they inhibited neointimalhyperplasia [91]. Similarly, Duncan and colleagues used PLGAnanoparticles to deliver a TGF-β inhibitor to prevent TEVGstenosis in their mouse model [92]. Dimitrievska and collea-gues used a novel method of ‘click chemistry’ to conjugateoriented heparin moieties onto decellularized aortas in orderto improve blood compatibility [93].

7. Strategies to reduce wait times

One major impediment to the clinical implementation ofTEVGs is the waiting time for graft creation. The use of auto-logous cells requires longest wait times, up to months [94]. Inlow-pressure systems, Hibino and colleagues demonstrate atechnique for harvesting bone marrow, isolating cells, seedingthem, and implanting them on the same day [95]. Dahl, Quint,and colleagues cultured human/dog SMCs on a PGA scaffold

EXPERT REVIEW OF MEDICAL DEVICES 387

that was subsequently decellularized and tested them in mod-els of coronary bypass and AV grafts which demonstratedgood functional outcomes and showed progress toward ‘off-the-shelf’ [96,97]. Krawiec and colleagues developed a culture-free method of differentiating MSCs obtained from liposuctioninto SMCs that were used in TEVGs [75]. Acellular grafts [8],such as the Humacyte Acellular Vessel [96], are also helpful indecreasing waiting times.

8. Clinical trials

There are several reports of clinical trials for TEVGs. Shin’oka,Hibino, and colleagues reported a clinical trial of PGA/PCL orPLA grafts used for extracardiac cavopulmonary shunts inchildren. At a mean follow-up interval of 5 years, there is noevidence of aneurysm, rupture, or calcification, although graftstenosis is the primary mode of graft failure [98–100]. Lawsonand colleagues performed two phase 2 studies of their decel-lularized PGA scaffold TEVG (seeded with SMCs from donors)as upper limb arteriovenous (AV) grafts in 60 renal patientsrequiring hemodialysis and demonstrated safety (1 infection in82 patient-years of follow-up) and efficacy (patency) [101].Bockeria and colleagues also performed a clinical trial of vas-cular grafts (PCL with 2-ureido-4[1H]-pyrimidinone motif) asextracardiac cavopulmonary conduits in five pediatric patientsundergoing Fontan surgery [102]. At 1 year, there were nodevice-related adverse events and the implanted graftsdemonstrated stable conduit diameters, lengths, wall thick-nesses, and blood-flow patterns. McAllister and colleagueshave also conducted a multicenter cohort study of the effec-tiveness of hemodialysis access for renal patients using TEVGsand found that their primary patency rate approaches estab-lished quality objectives for AV fistulas [103]. More recently,the group followed up with a study using TEVGs built fromallogeneic fibroblasts implanted as brachial-axillary AV shuntsfor three patients requiring hemodialysis access [71]. Variousbiodegradable scaffolds are currently undergoing clinical eva-luation for the treatment of coronary artery disease [104].

9. Expert commentary

The short supply of autologous grafts and the limitations ofsynthetic grafts, especially for small-diameter arterial applica-tions, will ensure the continued need for TEVGs.

As discussed in this review, TEVG technology has improvedmarkedly, with advances made in scaffold material (synthetic,biological, hybrid), TEVG design, and TEVG fabrication meth-ods. In addition, many different types of cells have beenseeded into TEVGs, using a variety of seeding techniques.Drug delivery in the TEVGs has also been attempted, eitheras a component of the material used to create the TEVGs ordrug loading after TEVG creation. To decrease wait time andimprove the ‘off-the-shelf’ capability of TEVGs, the use ofsame-day harvesting, seeding, and implantation and use ofdecellularized or acellular TEVGs show promise. Finally, clinicaltrials investigating TEVGs have been successfully conducted.

However, it is still challenging to develop ideal materials forTEVGs. First, stenosis caused by excessive inflammatory

reaction to graft materials is the primary mode of graft failureand needs to be addressed. In particular, the development ofsmall diameter grafts is still challenging, due to graft stenosis.

Some mechanisms have been proposed for immuneresponse to materials, such as pathways involving inflamma-tion [105], the innate immune system [106], and upregula-tion of TEVG matrix metalloproteinase activity [25]. Inaddition, it has been demonstrated that ECs and SMCsmigrated from adjacent tissue play an important role inpreventing graft stenosis [107]. Second, proper ECM forma-tion is key for balanced neotissue formation. Successful for-mation of ECM requires the degradation and remodeling ofgraft materials by infiltrating host cells. Rapid degradation ofgrafts does not allow sufficient time for the deposition ofadequate ECM, resulting in aneurysm formation or graftrupture. While slow degradation materials can providemechanical support and prevent rupture of the grafts, theyalso prevent ECM formation and cause long-lasting foreignbody material reaction, which promotes calcification withinthe grafts. Thus, there is a need to discover and developgrafts that are optimized for degradation kinetics and ECMdeposition. More basic science research into TEVGs can aidin improving the understanding of the process of TEVGremodeling, leading to development of better and moreoptimized TEVGs.

In terms of clinical trials, the regulatory hurdle remains highand there is a need for new materials to demonstrate provenbiocompatibility with human tissues before approval isgranted. This process frequently takes a very long time. It isalso difficult to accurately predict TEVG degradation andinflammatory response in humans, based on data from pre-clinical animal studies. Despite these, clinical trials must con-tinue; so, the ultimate aim of conducting TEVG research for theadvancement in human health care and the medical sciencesmay be fulfilled. TEVG research has clinical implications thatcan be applied broadly in the fields of vascular surgery andheart surgery and can be applied to patients of all age groups,from pediatric patients undergoing congenital heart surgery,to elderly patients with end-stage renal disease requiringvascular access for hemodialysis.

10. Five-year view

TEVG technology will improve, with the use of innovativetechniques to overcome limitations, advances in nanotechnol-ogy [108], electrospinning [109], and refinement in decellular-ization techniques [108]. Materials and biomaterials willimprove, with investigators seeking ‘ideal’ TEVGs that will beincreasingly ‘off-the-shelf,’ more cost-effective, with better bio-compatibility, in terms of long-term patency and neotissueformation [110,111]. In addition, these TEVGs will haveimproved mechanical strength and better ability to withstandarterial pressures [14,109], better cellular infiltration by con-trolling pore size and optimizing speed of scaffold degrada-tion [110].

In addition, TEVGs will be more patient specific. This will likelybe due to the increasing use of stem cells and stem-cell-derivedvascular cells [68], and supporting cells such as pericytes [112],thus promoting patient-specific vascular regeneration, as well as

388 C. S. ONG ET AL.

the use of 3D bioprinting and 3D printing technologies[111,113] and innovative new systems to allow for ease andsafety of cell seeding without specialized equipment [110].

Finally, the clinical use of TEVGs will increase. There are anumber of preclinical large animal studies and some clinicaltrials [98–101], and it is likely that there will be more studies inlarge animal models to assess clinical applicability [110], lead-ing to more widespread clinical use [5].

11. Conclusions

TEVGs have significant benefits over conventional grafts byallowing for growth, tissue remodeling, and self-repair. TEVGsshow great promise in all fields of vascular surgery, but espe-cially so in pediatric cardiac surgery, where patients have toundergo repeated surgeries as their circulation systems outgrowimplanted conventional grafts of fixed diameters [102]. In TEVGcreation, there are many different cell types that can be used,including regenerative stem cells, and many different scaffoldswith synthetic, biological, and hybrid scaffolds. Drugs can bedelivered by impregnating TEVG material such as nanofibers orloading post-TEVG creation. The major limitations at themoment include limited experience with arterial grafts andclinical trials. The search for the ideal TEVG continues.

Key issues

● TEVGs offer significant benefits by allowing for growth,tissue remodeling, and self-repair, compared to conven-tional vascular grafts.

● TEVGs have shown promise in all fields of vascular surgery,especially in pediatric surgery.

● There are many different types of scaffolds that can be usedto create TEVGs, i.e. synthetic, biological, or hybrid scaffolds.

● TEVGs can be seeded with many different cell types, ran-ging from mature somatic cells, stem cells, to stem cell-derived cells.

● Drug delivery can be done, by impregnating TEVG materialbefore TEVG creation or drug loading after TEVG creation.

● While some clinical trials have been conducted, TEVGs havenot been widely used clinically.

● There is limited use of TEVGs clinically due to the timeconsuming process of TEVG fabrication, costs, as well aslimitations with respect to cell sources and graft materials.

● The search for the ideal TEVG remains.

Funding

This paper was not funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.

References

Papers of special note have been highlighted as either of interest (•) or ofconsiderable interest (••) to readers.

1. Esquivel CO, Blaisdell FW. Why small caliber vascular grafts fail: areview of clinical and experimental experience and the significanceof the interaction of blood at the interface. J Surg Res. 1986;41(1):1–15.

2. Greenwald SE, Berry CL. Improving vascular grafts: the importanceof mechanical and haemodynamic properties. J Pathol. 2000;190(3):292–299.

3. Langer R, Vacanti JP. Tissue engineering. Science (New York, N.Y.).1993;260(5110):920–926.

•• This is a seminal paper defining the concept of tissueengineering.

4. L’Heureux N, Dusserre N, Marini A, et al. Technology Insight: theevolution of tissue-engineered vascular grafts - from research toclinical practice. Nat Clin Pract Cardiovasc Med. 2007;4(7):389–395.

5. Benrashid E, McCoy CC, Youngwirth LM, et al. Tissue engineeredvascular grafts: origins, development, and current strategies forclinical application. Methods (San Diego, Calif.). 2016;99:13–19.

6. Langer R, Vacanti J. Advances in tissue engineering. J Pediatr Surg.2016;51(1):8–12.

7. Greisler HP. Arterial regeneration over absorbable prostheses. ArchSurg. 1982;117:1425–1431.

8. Manson RJ, Unger JM, Ali A, et al. Tissue-engineered vascular grafts:autologous off-the-shelf vascular access? Semin Nephrol. 2012;32(6):582–591.

9. Lee K-W, Stolz DB, Wang Y. Substantial expression of mature elastinin arterial constructs. Proc Natl Acad Sci U S A. 2011;108:2705–2710.

10. Mooney DJ, Mazzoni CL, Breuer C, et al. Stabilized polyglycolic acidfibre-based tubes for tissue engineering. Biomaterials: Silver JubileeCompendium. 2006;17:129–138.

11. Mauri A, Zeisberger SM, Hoerstrup SP, et al. Analysis of the uniaxialand multiaxial mechanical response of a tissue-engineered vasculargraft. Tissue Eng Part A. 2013;19:583–592.

12. Kurobe H, Maxfield MW, Tara S, et al. Development of smalldiameter nanofiber tissue engineered arterial grafts. PlosOne. 2015;10(4):e0120328. doi:10.1371/journal.pone.0120328.eCollection 2015. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25830942

13. Liu X,Wang S. Tissue engineering, cardiovascular: biodegradable poly-mers. In: Mishra M, ed. Encyclopedia of biomedical polymers andpolymeric biomaterials. 1st ed. Oxfordshire, United Kingdom: Taylor& Francis; 2015. p. 7957–7971. Available from: http://www.crcnetbase.com/doi/abs/10.1081/E-EBPP-120051253

14. Fukunishi T, Best CA, Sugiura T, et al. Tissue-Engineered smalldiameter arterial vascular grafts from cell-free nanofiber PCL/Chitosan scaffolds in a sheep model. Plos One. 2016;11:e0158555.

15. Wu W, Allen RA, Wang Y. Fast-degrading elastomer enables rapidremodeling of a cell-free synthetic graft into a neoartery. Nat Med.2012;18:1148–1153.

16. Iwasaki K, Kojima K, Kodama S, et al. Bioengineered three-layeredrobust and elastic artery using hemodynamically-equivalent pulsa-tile bioreactor. Circulation. 2008;118(14 Suppl):S52–57.

17. Sharifpoor S, Simmons CA, Labow RS, et al. Functional character-ization of human coronary artery smooth muscle cells under cyclicmechanical strain in a degradable polyurethane scaffold.Biomaterials. 2011;32(21):4816–4829.

18. Shum-Tim D, Stock U, Hrkach J, et al. Tissue engineering of auto-logous aorta using a new biodegradable polymer. Ann ThoracSurg. 1999;68(6):2298–2304. discussion 2305.

19. Marois Y, Zhang Z, Vert M, et al. In vivo biocompatibility anddegradation studies of polyhydroxyoctanoate in the rat: a newsealant for the polyester arterial prosthesis. Tissue Eng. 1999;5(4):369–386.

20. Sell SA, McClure MJ, Barnes CP, et al. Electrospun polydioxanone-elastin blends: potential for bioresorbable vascular grafts. BiomedMater. 2006;1(2):72–80.

EXPERT REVIEW OF MEDICAL DEVICES 389

21. Lee KW, Johnson NR, Gao J, et al. Human progenitor cell recruit-ment via SDF-1alpha coacervate-laden PGS vascular grafts.Biomaterials. 2013;34(38):9877–9885.

22. Nieponice A, Soletti L, Guan J, et al. In vivo assessment of a tissue-engineered vascular graft combining a biodegradable elastomericscaffold and muscle-derived stem cells in a rat model. Tissue EngPart A. 2010;16(4):1215–1223.

23. Soletti L, Hong Y, Guan J, et al. A bilayered elastomeric scaffold fortissue engineering of small diameter vascular grafts. Acta Biomater.2010;6(1):110–122.

24. Hoerstrup SP, Cummings Mrcs I, Lachat M, et al. Functional growthin tissue-engineered living, vascular grafts: follow-up at 100 weeksin a large animal model. Circulation. 2006;114(1 Suppl):I159–166.

25. Cummings I, George S, Kelm J, et al. Tissue-engineered vasculargraft remodeling in a growing lamb model: expression of matrixmetalloproteinases. Eur J Oncol Nurs Title(S). 2012;41(1):167–172.

26. Matsumura G, Isayama N, Matsuda S, et al. Long-term results ofcell-free biodegradable scaffolds for in situ tissue engineering ofpulmonary artery in a canine model. Biomaterials. 2013;34(27):6422–6428.

27. Schmedlen RH, Elbjeirami WM, Gobin AS, et al. Tissue engineeredsmall-diameter vascular grafts. Clin Plast Surg. 2003;30(4):507–517.

28. Koch S, Flanagan TC, Sachweh JS, et al. Fibrin-polylactide-basedtissue-engineered vascular graft in the arterial circulation.Biomaterials. 2010;31(17):4731–4739.

29. O’Cearbhaill ED, Murphy M, Barry F, et al. Behavior of humanmesenchymal stem cells in fibrin-based vascular tissue engineeringconstructs. Ann Biomed Eng. 2010;38(3):649–657.

30. Li Y, Meng H, Liu Y, et al. Fibrin gel as an injectable biodegradablescaffold and cell carrier for tissue engineering. The Scientific WorldJournal. 2015;2015:10.

31. Stegemann JP, Kaszuba SN, Rowe SL. Review: advances in vasculartissue engineering using protein-based biomaterials. Tissue Eng.2007;13:2601–2613.

32. Iijima M, Aubin H, Steinbrink M, et al. Bio-active coating of decel-lularized vascular grafts with a temperature-sensitive VEGF-conju-gated hydrogel accelerates autologous endothelialization in vivo. JTissue Eng Regen Med. 2016. [Epub ahead of print]. Available from:https://www.ncbi.nlm.nih.gov/pubmed/27689942

33. Zisch AH, Lutolf MP, Ehrbar M, et al. Cell-demanded release of VEGFfrom synthetic, biointeractive cell ingrowth matrices for vascular-ized tissue growth. Faseb J. 2003;17(15):2260–2262.

34. Browning MB, Dempsey D, Guiza V, et al. Multilayer vascular graftsbased on collagen-mimetic proteins. Acta Biomater. 2012;8(3):1010–1021.

35. Madhavan K, Elliott WH, Bonani W, et al. Mechanical and biocom-patible characterizations of a readily available multilayer vasculargraft. J Biomed Mater Res B Appl Biomater. 2013;101(4):506–519.

36. Kuo KC, Lin RZ, Tien HW, et al. Bioengineering vascularized tissueconstructs using an injectable cell-laden enzymatically crosslinkedcollagen hydrogel derived from dermal extracellular matrix. ActaBiomater. 2015;27:151–166.

37. Concheiro A, Alvarez-Lorenzo C. Chemically cross-linked andgrafted cyclodextrin hydrogels: from nanostructures to drug-elut-ing medical devices. Adv Drug Deliv Rev. 2013;65(9):1188–1203.

38. Syedain Z, Reimer J, Lahti M, et al. Tissue engineering of acellularvascular grafts capable of somatic growth in young lambs. NatCommun. 2016;7:12951.

39. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and wholeorgan decellularization processes. Biomaterials. 2011;32(12):3233–3243.

40. Seifu DG, Purnama A, Mequanint K, et al. Small-diameter vasculartissue engineering. Nat Rev Cardiol. 2013;10(7):410–421.

41. Campbell JH, Efendy JL, Campbell GR. Novel vascular graft grownwithin recipient’s own peritoneal cavity. Circ Res. 1999;85:1173–1178.

42. Hajiali H, Shahgasempour S, Naimi-Jamal MR, et al. Electrospun PGA/gelatin nanofibrous scaffolds and their potential application in vas-cular tissue engineering. Int J Nanomedicine. 2011;6:2133–2141.

43. Xie Y, Guan Y, Kim SH, et al. The mechanical performance of weft-knitted/electrospun bilayer small diameter vascular prostheses. JMech Behav Biomed Mater. 2016;61:410–418.

44. Gong W, Lei D, Li S, et al. Hybrid small-diameter vascular grafts:anti-expansion effect of electrospun poly epsilon-caprolactone onheparin-coated decellularized matrices. Biomaterials. 2016;76:359–370.

45. Takeuchi M, Kuratani T, Miyagawa S, et al. Tissue-engineered stent-graft integrates with aortic wall by recruiting host tissue into graftscaffold. J Thorac Cardiovasc Surg. 2014;148:1719–1725.

46. Mooney D, Vacanti JP. Tissue engineering using cells and syntheticpolymers. Transplantation Reviews. 1993;7:153–162. Available from:https://secure.jbs.elsevierhealth.com/action/showCitFormats?pii=S0955-470X%2805%2980014-X&doi=10.1016%2FS0955-470X%2805%2980014-X&code=ytrre-site

47. Drilling S, Gaumer J, Lannutti J. Fabrication of burst pressurecompetent vascular grafts via electrospinning: effects of micro-structure. J Biomed Mater Res. 2009;88:923–934.

48. Hou Q, Grijpma DW, Feijen J. Porous polymeric structures for tissueengineering prepared by a coagulation, compression mouldingand salt leaching technique. Biomaterials. 2003;24(11):1937–1947.

49. Kumar TR, Krishnan LK. A stable matrix for generation of tissue-engineered nonthrombogenic vascular grafts. Tissue Eng. 2002;8(5):763–770.

50. Jeong SI, Kim SY, Cho SK, et al. Tissue-engineered vascular graftscomposed of marine collagen and PLGA fibers using pulsatileperfusion bioreactors. Biomaterials. 2007;28(6):1115–1122.

51. Schoof H, Apel J, Heschel I, et al. Control of pore structure and sizein freeze-dried collagen sponges. J Biomed Mater Res. 2001;58(4):352–357.

52. Kundu BSJ, Kundu SC. Biomaterial scaffold fabrication techniquesfor potential tissue engineering applications. In: Eberli D, ed. TissueEngineering. Croatia: InTech; 2010. Available from: https://www.intechopen.com/books/tissue-engineering

53. Gui L, Dash BC, Luo J, et al. Implantable tissue-engineered bloodvessels from human induced pluripotent stem cells. Biomaterials.2016;102:120–129.

54. Im SH, Jung Y, Jang Y, et al. Poly(L-lactic acid) scaffold withoriented micro-valley surface and superior properties fabricatedby solid-state drawing for blood-contact biomaterials.Biofabrication. 2016;8(4):045010. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27775924

55. Sugiura T, Tara S, Nakayama H, et al. Fast-degrading bioresorbablearterial vascular graft with high cellular infiltration inhibits calcifica-tion of the graft. J Vasc Surg. 2016. pii: S0741-5214(16)30823-0. doi:10.1016/j.jvs.2016.05.096. [Epub ahead of print]. Available from:https://www.ncbi.nlm.nih.gov/pubmed/27687327

56. Rapoport HS, Fish J, Basu J, et al. Construction of a tubular scaffoldthat mimics J-shaped stress/strain mechanics using an innovativeelectrospinning technique. Tissue Eng Part C Methods.2012;18:567–574.

57. Villalona GA, Udelsman B, Duncan DR, et al. Cell-Seeding techni-ques in vascular tissue engineering. Tissue Eng Part B Rev. 2010;16(3):341–350.

58. Pawlowski KJ, Rittgers SE, Schmidt SP, et al. Endothelial cell seedingof polymeric vascular grafts. Front Biosci. 2004;9:1412–1421.

59. Salacinski HJ, Tiwari A, Hamilton G, et al. Cellular engineering ofvascular bypass grafts: role of chemical coatings for enhancingendothelial cell attachment. Med Biol Eng Comput. 2001;39(6):609–618.

60. Hsu SH, Tsai IJ, Lin DJ, et al. The effect of dynamic culture condi-tions on endothelial cell seeding and retention on small diameterpolyurethane vascular grafts. Med Eng Phys. 2005;27(3):267–272.

61. Van Wachem PB, Stronck JW, Koers-Zuideveld R, et al. Vacuum cellseeding: a new method for the fast application of an evenlydistributed cell layer on porous vascular grafts. Biomaterials.1990;11(8):602–606.

62. Bowlin GL, Meyer A, Fields C, et al. The persistence of electrostati-cally seeded endothelial cells lining a small diameter expandedpolytetrafluoroethylene vascular graft. J Biomater Appl. 2001;16(2):157–173.

63. Shimizu K, Ito A, Arinobe M, et al. Effective cell-seeding techniqueusing magnetite nanoparticles and magnetic force onto

390 C. S. ONG ET AL.

decellularized blood vessels for vascular tissue engineering. J BiosciBioeng. 2007;103(5):472–478.

64. Mann BK, Gobin AS, Tsai AT, et al. Smooth muscle cell growth inphotopolymerized hydrogels with cell adhesive and proteolyticallydegradable domains: synthetic ECM analogs for tissue engineering.Biomaterials. 2001;22(22):3045–3051.

65. Shimizu T, Yamato M, Kikuchi A, et al. Cell sheet engineeringfor myocardial tissue reconstruction. Biomaterials. 2003;24(13):2309–2316.

66. Sodian R, Lemke T, Fritsche C, et al. Tissue-engineering bioreactors:a new combined cell-seeding and perfusion system for vasculartissue engineering. Tissue Eng. 2002;8(5):863–870.

67. Pashneh-Tala S, MacNeil S, Claeyssens F. The tissue-engineeredvascular graft—past, present, and future. Tissue Eng B: Rev. 2015.[Epub ahead of print]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26447530

68. Wang L, Hu J, Sorek CE, et al. Fabrication of tissue-engineeredvascular grafts with stem cells and stem cell-derived vascularcells. Expert Opin Biol Ther. 2016;16:317–330.

69. Cho S-W, Lim SH, Kim I-K, et al. Small-Diameter blood vesselsengineered with bone marrow–derived cells. Ann Surg. 2005;241(3):506–515.

70. Poh M, Boyer M, Solan A, et al. Blood vessels engineeredfrom human cells. Lancet (London, England). 2005;365(9477):2122–2124.

• This paper showed that human telomerase expression led tothe successful culture of engineered blood vessels.

71. Wystrychowski W, McAllister TN, Zagalski K, et al. First human useof an allogeneic tissue-engineered vascular graft for hemodialysisaccess. J Vasc Surg. 2014;60(5):1353–1357.

72. Asahara T, Murohara T, Sullivan A, et al. Isolation of putativeprogenitor endothelial cells for angiogenesis. Science (New York,N.Y.). 1997;275(5302):964–967.

73. Shirota T, He H, Yasui H, et al. Human endothelial progenitor cell-seeded hybrid graft: proliferative and antithrombogenic potentialsin vitro and fabrication processing. Tissue Eng. 2003;9(1):127–136.

74. Brandes RP, Ushio-Fukai M. Endothelial progenitorcells=EPC=elemental pernicious complexity. Antioxid RedoxSignal. 2011;15(4):911–914.

75. Krawiec JT, Liao H-T, Kwan LL, et al. Evaluation of the stromalvascular fraction of adipose tissue as the basis for a stem cell-based tissue-engineered vascular graft. J Vasc Surg. 2016. pii:S0741-5214(16)31277-0. doi: 10.1016/j.jvs.2016.09.034. [Epubahead of print]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28017585

76. Mirensky TL, Hibino N, Sawh-Martinez RF, et al. Tissue-engineeredvascular grafts: does cell seeding matter? J Pediatr Surg. 2010;45(6):1299–1305.

77. Hibino N, Shin’oka T, Matsumura G, et al. The tissue-engineeredvascular graft using bone marrow without culture. J ThoracCardiovasc Surg. 2005;129(5):1064–1070.

78. Matsumura G, Miyagawa-Tomita S, Shin’oka T, et al. First evidencethat bone marrow cells contribute to the construction of tissue-engineered vascular autografts in vivo. Circulation. 2003;108(14):1729–1734.

79. Heydarkhan-Hagvall S, Schenke-Layland K, Yang JQ, et al. Humanadipose stem cells: a potential cell source for cardiovascular tissueengineering. Cells Tissues Organs. 2008;187(4):263–274.

80. Peng HF, Liu JY, Andreadis ST, et al. Hair follicle-derived smoothmuscle cells and small intestinal submucosa for engineeringmechanically robust and vasoreactive vascular media. Tissue EngPart A. 2011;17(7–8):981–990.

81. Krawiec JT, Vorp DA. Adult stem cell-based tissue engineeredblood vessels: A review. Biomaterials. 2012;33:3388–3400.

82. Sundaram S, Echter A, Sivarapatna A, et al. Small-diameter vasculargraft engineered using human embryonic stem cell-derivedmesenchymal cells. Tissue Eng Part A. 2014;20:740–750.

83. Takahashi K, Yamanaka S. Induction of pluripotent stem cells frommouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006;126(4):663–676.

84. Dash BC, Levi K, Schwan J, et al. Tissue-Engineered vascular ringsfrom human iPSC-Derived smooth muscle cells. Stem Cell Reports.2016;7(1):19–28.

85. Sundaram S, One J, Siewert J, et al. Tissue-engineered vasculargrafts created from human induced pluripotent stem cells. StemCells Transl Med. 2014;3(12):1535–1543.

86. Hibino N, Duncan DR, Nalbandian A, et al. Evaluation of the use ofan induced puripotent stem cell sheet for the construction oftissue-engineered vascular grafts. J Thorac Cardiovasc Surg.2012;143:696–703.

87. Lee Y-U, Mahler N, Best CA, et al. Rational design of an improvedtissue-engineered vascular graft: determining the optimal cell doseand incubation time. Regen Med. 2016;11(2):159–167.

88. Lee MH, Kwon B-J, Koo M-A, et al. Exovascular application ofepigallocatechin-3-O-gallate-releasing electrospun poly(L-lactideglycolic acid) fiber sheets to reduce intimal hyperplasia in injuredabdominal aorta. Biomed Mater. 2015;10:55010.

89. Centola M, Rainer A, Spadaccio C, et al. Combining electrospinningand fused deposition modeling for the fabrication of a hybridvascular graft. Biofabrication. 2010;2:014102.

90. Spadaccio C, Rainer A, Centola M, et al. Heparin-releasing scaffoldfor stem cells: a differentiating device for vascular aims. RegenMed. 2010;5:645–657.

91. Zou J, Zhang X, Yang H, et al. Rapamycin-loaded nanoparticles forinhibition of neointimal hyperplasia in experimental vein grafts.Ann Vasc Surg. 2011;25:538–546.

92. Duncan DR, Chen PY, Patterson JT, et al. TGFβR1 inhibition blocksthe formation of stenosis in tissue-engineered vascular grafts. J AmColl Cardiol. 2015;65:512–514.

93. Dimitrievska S, Cai C, Weyers A, et al. Click-coated, heparinized,decellularized vascular grafts. Acta Biomater. 2015;13:177–187.

94. Dahl SLM, Blum JL, Niklason LE. Bioengineered vascular grafts: canwe make them off-the-shelf? Trends Cardiovasc Med. 2011;21:83–89.

95. Hibino N, Nalbandian A, Devine L, et al. Comparison of humanbone marrow mononuclear cell isolation methods for creatingtissue-engineered vascular grafts: novel filter system versus tradi-tional density centrifugation method. Tissue Eng Part C Methods.2011;17:993–998.

96. Dahl SLM, Kypson AP, Lawson JH, et al. Readily available tissue-engineered vascular grafts. Sci Transl Med. 2011;3:68ra69–68ra69.

97. Quint C, Arief M, Muto A, et al. Allogeneic human tissue-engi-neered blood vessel. J Vasc Surg. 2012;55:790–798.

98. Shin’oka T, Matsumura G, Hibino N, et al. Midterm clinical result oftissue-engineered vascular autografts seeded with autologousbone marrow cells. J Thorac Cardiovasc Surg. 2005;129(6):1330–1338. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15942574

99. Shinoka T, Breuer C. Tissue-engineered blood vessels in pediatriccardiac surgery. Yale J Biol Med. 2008;81:161–166.

100. Hibino N, McGillicuddy E, Matsumura G, et al. Late-term results oftissue-engineered vascular grafts in humans. J Thorac CardiovascSurg. 2010;139:431–436.e432.

• This paper discussed the late-term results of patients, whounderwent implantation of TEVGs as extracardiac cavopul-monary conduits.

101. Lawson JH, Glickman MH, Ilzecki M, et al. Bioengineered humanacellular vessels for dialysis access in patients with end-stage renaldisease: two phase 2 single-arm trials. The Lancet. 2016;387:2026–2034.

• This paper tested bioengineered human acellular vessels asconduits for hemodialysis assess in a clinical trial.

102. Bockeria LA, Svanidze O, Kim A, et al. Total Cavo-Pulmonary con-nection with a new bio-absorbable vascular graft first clinicalexperience. J Thorac Cardiovasc Surg. 2017. pii: S0022-5223(17)30163-0. doi: 10.1016/j.jtcvs.2016.11.071. [Epub ahead of print].

103. McAllister TN, Maruszewski M, Garrido SA, et al. Effectiveness ofhaemodialysis access with an autologous tissue-engineered vascu-lar graft: a multicentre cohort study. Lancet (London, England).2009;373(9673):1440–1446.

EXPERT REVIEW OF MEDICAL DEVICES 391

• This paper reported the clinical trial results of completelybiological and autologous TEVGs implanted for hemodialysisassess.

104. Kraak RP, Grundeken MJ, Koch KT, et al. Bioresorbable scaffolds forthe treatment of coronary artery disease: current status and futureperspective. Expert Rev Med Devices. 2014;11:467–480.

105. Roh JD, Sawh-Martinez R, Brennan MP, et al. Tissue-engineeredvascular grafts transform into mature blood vessels via an inflam-mation-mediated process of vascular remodeling. Proc Natl AcadSci. 2010;107(10):4669–4674.

106. Hibino N, Mejias D, Pietris N, et al. The innate immune systemcontributes to tissue-engineered vascular graft performance.Faseb J. 2015;29(6):2431–2438.

107. Hibino N, Villalona G, Pietris N, et al. Tissue-engineered vasculargrafts form neovessels that arise from regeneration of the adjacentblood vessel. FASEB J. 2011;25(8):2731–2739. Available from:https://www.ncbi.nlm.nih.gov/pubmed/21566209

108. G N, Tan A, Gundogan B, et al. Tissue engineering vascular grafts afortiori: looking back and going forward. Expert Opin Biol Ther.

2015;15:231–244. Available from: http://www.tandfonline.com/doi/abs/10.1517/14712598.2015.980234?journalCode=iebt20

109. Rocco KA, Maxfield MW, Best CA, et al. In vivo applications ofelectrospun tissue-engineered vascular grafts: a review. TissueEng Part B Rev. 2014;20:628–640.

110. Fukunishi T, Shoji T, Shinoka T. Nanofiber composites in vasculartissue engineering. Nanofiber Composite Mater Biomed Appl.2017;455–481. Available from: http://www.sciencedirect.com/science/article/pii/B9780081001738000181

111. Jaspan VN, Hines GL. The current status of tissue-engineered vas-cular grafts. Cardiol Rev. 2015;23:236–239.

112. Gökçinar-Yagci B, Uçkan-Çetinkaya D, Çelebi-Saltik B. Pericytes:properties, functions and applications in tissue engineering. StemRev Rep. 2015;11:549–559.

113. Fukunishi T, Best CA, Sugiura T, et al. Preclinical study of patient-specific cell-free nanofiber tissue-engineered vascular grafts using3-dimensional printing in a sheep model. J Thorac CardiovascSurg. 2017;153(4):924–932. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27938900

392 C. S. ONG ET AL.