Basic science in vascular surgery
Endothelial Cell Seeding: A Review M. Welch, FRCS, D. Durrans, MS, FRCS, H.M.H. Carr, FRCS, R. Vohra, PhD, FRCS, O.B. Rooney, MI Biol, M.G. Walker, ChM, FRCS, Manchester, United Kingdom
The concept of endothelial cell seeding, designed to provide vascular grafts with a nonthrombogenic lining, has progressed from crude animal experiments during the past two decades to detailed in vitro functional studies using human cells. Although favorable results have been obtained in animal studies this has yet to be translated to humans, where current application of these techniques has been limited to a very few clinical trials. The history, current status and future directions are reviewed herein. (Ann Vasc Surg 1992;6:000-000). KEY WORDS:
Endothelial seeding; grafts.
Interest in the use of prosthetic materials for arterial grafting was first described by Alexis Carrel in 1912, who used solid tubes of glass or metal to bridge arterial defects in dogs . Progress was made following the development of plastic materials, Voorhees' and Harrison's work forming the basis for the development of today's prosthetic grafts [2,3]. Despite advances in design, small diameter prosthetic grafts still represent a poor alternative to autologous vein. The development of a prosthetic graft which is nonthrombogenic remains the ultimate goal. Attempts to improve prosthetic graft performance have progressed broadly along two fronts: mechanical and biological. The latter adopts the concept that improved performance could be achieved if the luminal surface of the graft had biological characteristics of normal vessels, being lined with endothelium capable of resisting platelet From the Department of Vascular Surgery, Manchester Royal Infirmary, Manchester, United Kingdom. Reprint requests: Mr. M.G. Walker, Consultant Vascular Surgeon, Department of Vascular Surgery, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL United Kingdom.
aggregation. While endothelialization of grafts in human beings is usually limited to pannus ingrowth of approximately 1 cm at each anastomosis , endothelium has been observed scattered throughout the length of a Dacron prosthesis . The concept of endothelial cell seeding was first introduced in 1970 by Mansfield , who used granulation tissue from the bed of a pedicled skin flap as a cell source to seed a mixture of endothelial cells, fibroblasts, and macrophages onto patches of Dacron. These were implanted into atrial walls in dogs and removed after three weeks. Inflammatory cell infiltrates were noted in those grafts seeded with homologous and xenogenic cells; those seeded with autologous cells demonstrated no such reaction, exhibiting a complete absence of thrombus from the graft surface. These original experiments have since generated a large volume of research to develop a technique to line prosthetic grafts with a confluent functional endothelial cell monolayer. Progress in endothelial seeding has been made in a number of areas: harvesting, culture, and seeding technique. More recently, advances in genetic engineering have explored the possibility of manipulating genetic expression of seeded endothelial cells
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in order to further promote their antithrombotic functions.
ANIMAL EXPERIMENTS In 1978, Herring published his preliminary results of endothelial cell seeding using a single stage technique . Dacron grafts were seeded with autologous endothelial cells, which had been mechanically scraped from the internal surface of canine saphenous vein using steel wool pledgers. The cells were mixed with blood used to preclot the grafts , which were implanted into dogs. When explanted, the seeded grafts showed a progressive increase in thrombus-free surface with time when compared to control grafts, and also demonstrated significantly thinner inner capsules. The endothelial nature of the lining was confirmed by the identification of endothelial cell-specific WiebeI-Palade bodies and by staining with fluorescent-labeled factor VIII-related (yon Willebrand) antibody [9,10]. Herring's group produced further encouraging results using different graft designs [11-13] and also investigated methods of achieving optimum seeding efficiency, stating that a vein to graft surface area ratio of >0.425 was necessary to produce an endothelialized graft by one month . Later, detailed histological examination of seeded Dacron and expanded polytetrafluoroethylene (ePTFE) aortic grafts in dogs showed that seeded ePTFE grafts developed endothelial linings significantly sooner than Dacron, with limited fibroblast ingrowth and thinner inner capsules . Graham and Stanley described a method of endothelial cell harvesting in which canine external jugular veins were explanted and everted, with the endothelium removed enzymatically [16-18]. Cells were cultured and later added to blood used to preclot Dacron grafts and seeded using the same technique as Herring's. The grafts were interposed in the thoracoabdominal position in dogs; when explanted at four weeks the seeded grafts were 80% endothelialized compared with 10% coverage of sham-seeded control grafts. The nature of the lining was confirmed by scanning and transmission electron microscopy, and by immunofluorescent staining of factor VIII-related antigen. Further encouraging results were reported using immediate seeding of Dacron and ePTFE [19-21]. In 1982 Belden and associates described significantly improved thrombus-free surface and endothelialization at one month, but did not observe improved patency . In an attempt to improve patency, Stanley and colleagues implanting bilateral iliofemoral Dacron grafts with one limb seeded, also administered aspirin and dipyridamole . All grafts remained patent until medication was discontinued at two weeks, after which cumulative pa-
tency rates were 73% in seeded grafts and 27% in controls; seeded grafts were completely endothelialized between two and four weeks. Hunter and Schmidt performed similar studies and also manipulated flow to 30% of normal for a one hour period at three and five weeks after graft implantation [24,25]. During low flow conditions, endothelial cell seeded Dacron grafts retained thrombus-free characteristics, whereas thrombus accumulated in nonseeded grafts, occluding some of them. However, similar flow modifications using ePTFE grafts did not produce such promising results . In 1983 Sharefkin described a method of harvesting endothelial cells in which a segment of canine aorta was clamped, cannulated, and filled with a solution of trypsin and collagenase . The harvested cells were mixed with blood and seeded onto Dacron aortic grafts implanted into dogs. At six weeks the grafts were completely endothelialized with no visible thrombus, compared with widespread luminal fibrin and red thrombus on nonseeded grafts. This cannulation method was later compared with the eversion method of enzymatic harvesting and was found to provide far greater numbers of viable and functional cells [28,29]. Further modifications of this method, using an in situ technique, were published in 1990 . Thus, experiments up to this point suggested that endothelial cell seeding decreased the amount of thrombus on the graft surface by promoting endothelialization. More specific effects were then investigated using an animal model.
The effect of seeding on platelet behavior
Platelet survival decreases following implantation of arterial prostheses in animals, with recovery of survival times to normal levels correlating directly with endothelial cell coverage of the graft luminal surface . Sharefkin and coworkers, using indium-111 oxine isotope labeling, measured platetet survival times in dogs after insertion of Dacron bypass grafts, and found that endothelial cell seeding curtailed the degree of platelet interaction with the grafts, thus restoring a normal platelet survival pattern when endothelialization was complete . It was also noted that seeded grafts produced significantly more prostacyclin (PGI2) than nonseeded grafts. These results were confirmed by other investigators . Sicard and associates examined the relationship of platelet deposition to PGIz and thromboxane (TXAz) production in arterial autografts, paraanastomotic native artery, and endothelial cellseeded and non-seeded small diameter Dacron grafts. When these were implanted into canine carotid and femoral arteries , seeded grafts accumulated significantly fewer platelets than non-
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seeded grafts, but significantly more than arterial autografts. They also found that the PGI2/TXA2 ratio was highest in arterial autografts and lowest in non-seeded Dacron grafts, concluding that the balance between TXA2 and PG~2 in the graft wall may be the best determinant of platelet deposition and possibly long-term patency. Shepard and colleagues studied platelet deposition and healing patterns as influenced by endothelial cell seeding in the baboon, an animal whose coagulation system, platelet behavior, and endothelial cell growth characteristics were thought to closely resemble those of humans [37,38]. They implanted Dacron grafts seeded with autologous venous endothelial cells into carotid arteries and found that, although this accelerated healing, it did not alter early platelet reactivity. In order to reduce this early platelet reactivity, Allen and coworkers studied the effects of aspirin therapy on seeded and non-seeded Dacron grafts implanted into canine carotid and femoral arteries [39,40]. Aspirin reduced platelet deposition and improved early graft patency in both groups, although seeded grafts accumulated significantly more platelets than controls 24 hours after implantation. Two weeks later, however, platelet deposition on seeded prostheses had decreased to a level significantly lower than that on controls, and continued to decline on serial studies up to seven months. Platelet accumulation on control grafts dramatically increased after the withdrawal of aspirin therapy and was associated with a sharp rise in thrombosis; this effect was not seen on seeded grafts. Further studies supported the contention that a combination of endothelial cell seeding and antiplatelet medication produced significantly improved thrombus-free surface and short-term patency , despite the fact that antiplatelet medication significantly reduced mean PG12 production by seeded grafts compared with non-medicated seeded grafts [50,51].
The effect of seeding on graft infection
When dogs with Dacron grafts were challenged with intravenous infusions of S t a p h y l o c o c c u s aureus at various intervals following surgery it was noted that almost 100% became infected up to one month postoperatively . The incidence of infection then progressively decreased but was still 30% in dogs so challenged one year after graft implantation. An important discovery was that all grafts having positive cultures for S t a p h y l o c o c c u s a u r e u s had either an incomplete or absent pseudointimal lining. In a later study where S t a p h y l o c o c c u s aureus was infused one month after implantation of endothelial cell-seeded Dacron grafts , although seeding did not prevent infection, there appeared to
be a relationship between endothelialization and resistance to bacterial adherence and infection. Similar studies with ePTFE demonstrated significantly fewer bacteria adhering to seeded grafts [54,55]. Scanning electron microscopy and autoradiography of seeded grafts confirmed that the sites of bacterial adherence largely corresponded to accumulations of surface thrombus. Endothelial seeding and the leukocyte
Shepard and associates, noting that both seeded and non-seeded grafts explanted within two weeks had a heavy infiltration of polymorphonuclear leukocytes , hypothesized that complement activation might prove a barrier to successful endothelial cell seeding. Plasma from healthy donors was assayed for complement activity following incubation with short segments of Dacron and ePTFE grafts. Substantial complement activation by Dacron and virtually none by ePTFE was observed. It has been well demonstrated that leukocytes are associated with endothelial loss from vein grafts as well as seeded grafts . Emerick and colleagues found significantly improved endothelial retention in animals rendered leukopenic . Seeding of endarterectomized arteries
Bush and coworkers performed bilateral carotid endarterectomy in dogs, seeding one side with autologous venous endothelial cells . The arterial segments explanted at intervals showed greatly accelerated endothelial coverage, reduced neointimal hyperplasia, and more PG~2 production in the seeded group . Cultured homologous aortic endothelial cells or human umbilical venous endothelial cells have been used to seed endarterectomized baboon aortas [61,62]. Platelet deposition was reduced and attached endothelial cells underwent spreading in the presence of high shear blood flow to form a confluent monolayer after only one hour. Seeding of venous prostheses
Although early work on the seeding of prostheses used for canine inferior vena cava replacement produced disappointing results , endothelialization of over 50% of the midgraft surface was observed  and anastomotic subendotheliai hyperplasia was significantly reduced. Improved patency was noted in later studies in which antiplatelet medication was also used [65-67]. T E C H N I C A L IMPROVEMENTS These early experiments showed that endothelial cell seeding in combination with antiplatelet drugs
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could reduce thrombogenicity and thereby improve patency of vascular prostheses. However, further work has been undertaken to maximize the numbers of cells harvested and to improve adherence to grafts. Cell source
While the superiority of autologous cells for seeding is not in doubt [68-72], a major problem is the relatively poor harvest of macrovascular endothelial cells obtained from vein. Several early papers described successful isolation and growth of microvascular endothelial cells [73-77], but prolonged culture was unsuccessful. Progress in this field was made by Kern and associates who used sequential filtration to separate endothelial and stromal cells obtained from subcutaneous and omental fat . Jarrell's group used a Percoll density gradient to obtain a relatively pure endothelial harvest , and later claimed 100% successful pure isolate from liposuction-derived subcutaneous fat . Further modifications of the methods described by Kern and Jarrell have produced enthusiastic reports of improved cell yield, growth, and resistance to shear stress during in vivo and in vitro flow studies [81-89]. Successful purification of microvascular endothelial cells has been reported through incubation of the harvested cell mixture with Ulex europaeus-1 (UEA-l)-coated Dynabeads* . Utex europaeus-1 is a lectin which binds specifically to L-fucose residues on endothelial cells and when fluorescently-labelled is often used as an endothelial marker [91-93]. Endothelial cells selectively bind to the beads while contaminating stromal cells are removed by washing with a saline solution. Despite these reports, relatively little use has been made of this technique because of doubts as to the purity of cells obtained. However Park and associates described the successful endothelialization of a Dacron graft seeded with cells derived from subcutaneous fat . This mesoatrial graft, implanted nine months previously in a patient with Budd-Chiari syndrome, required resection of a mechanical stricture of its mid-portion; a confluent endothelial monolayer was identified by light and electron microscopy and confirmed by staining with anti-factor VIII antibodies. Microvascular endothelial cells derived from omentum are frequently confused with morphologically similar mesothelial cells [95-97], which also synthesize prostacyclin . After the discovery that pieces of mouse mesothelium exposed to invitro blood flow were nonthrombogenic [99,100], autologous mesothelial cells enzymatically harvested from canine omentum were mixed with * Dynal, Oslo, Norway.
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preclot and seeded onto Dacron grafts [101-103]. One month later the explanted grafts had confluent linings of mesothelial cells, and seeded grafts secreted significantly more prostacyclin than nonseeded controls . Thomson and colleagues compared the ability of adult human endothelial and mesothelial cells to attach and spread on ePTFE [105,106]. Mesothelial attachment, though not improved by precoating grafts, was quantitatively good, but the attached cells remained in a rounded-up state, making them less likely than endothelial cells to withstand shear stress of blood flow. Graft precoating
Labeling endothelial cells with indium-I 11 oxine by a method originally described by Sharefkin [I07], Rosenman and coworkers seeded cells mixed with preclot on to ePTFE interposed as canine arteriovenous shunts , with cell retention determined using a gamma counter. After restoration of flow there was a 30% detachment of cells in the first 30 minutes, which decreased to 2% per hour over the next 24 hours, with negligible loss thereafter. Similar results were obtained by Campbell and Kesler using both ePTFE and polyester elastomer [109-111]. Seeger and associates found that precoating ePTFE with human fibronectin significantly improved endothelial adherence [I 12,113]. However, exposure to flow in an animal model resulted in similar percentage detachment of cells from both coated and uncoated grafts; this may have been related to the very low fibronectin concentration of 5 mcg/ml used for coating. Ramalanjaona and associates seeded indium-111 oxine-labeled autologous endothelial cells on to ePTFE canine carotid interposition grafts and observed a six-fold increase in cell retention on those grafts pretreated with fibronectin at a concentration of 250 mcg/ml . Using preclot to precoat ePTFE, Lindblad and colleagues added a radio-labeled endothelial cell suspension as a second step [115,116]. This produced a seeding efficiency superior to that obtained using fibronectin, although the concentration of fibronectin used was not recorded. Cultured grafts
Early attempts to culture an endothelial lining on Dacron and ePTFE were of limited success ; Herring and coworkers obtained no cellular growth in 41 of 67 seeded grafts cultured from one to four weeks, and only five of these 20 successfully cultured grafts implanted into dogs remained patent after three days. More encouraging results were obtained when ePTFE precoated with 100 mcg/ml fibronectin and seeded with cultured autologous
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endothelial cells was incubated for three hours prior to implantation into canine carotid arteries . Seeded grafts had 75%, 80%, and 95% cell coverage at one, two, and 10 weeks, respectively. Further experiments with cultured endothelial linings demonstrated improved resistance to shear stress , reduced platelet deposition , more complete endothelialization [ 121 ] and improved patency .
IN VITRO EXPERIMENTS While animal studies have shown that endothelial seeding improves graft patency, particularly in combination with antiplatelet medication, a major flaw in this model was substantial cell detachment on exposure to flow, although this was remedied to a certain extent by precoating. A great deal of in vitro work has concentrated on improving harvesting techniques and on more detailed examination of endothelial cell kinetics. The first in vitro system for studying the dynamic response of endothelial cells to controlled levels of fluid shear stress was described by Dewey and associates in 1981  who developed an apparatus capable of producing laminar and turbulent shear stress. Using cultured bovine aortic endothelial cells, moderate levels of shear stress did not alter the basic growth kinetics or population behavior, whereas increasing shear stress caused the cells to assume an ellipsoid configuration by 48 hours, with their major axes aligned in the direction of flow. Less alignment was noted in cell populations close to confluence, suggesting that cell-to-cell contact or secreted cellular substances may influence this phenomenon. Increasing the shear rate was associated with increased fluid endocytosis and platelet reactivity when compared with cultures maintained under static conditions. Although further encouraging results were reported with animal cells [124-128], it became clear that improved endothelial cell adherence and growth required grafts to be precoated with materials such as extracellular matrix, collagen gel, glucosaminoglycan keratin, and human fibronectin [12%132]. Laboratory work confirmed the conclusion from in vivo experiments that precoated the graft surface prior to seeding enabled endothelial cells to withstand the shear stress of flow [133-139]. Preliminary studies using adult human endothelial cells were published in 1984 , by Jarrell and colleagues who enzymatically harvested cells from cadaver arteries and veins. The cells attached rapidly to gelatin-precoated tissue culture polystyrene, but optimal growth required addition to the culture medium of heparin and endothelial cell growth factor. Adult human endothelial cells were subsequently successfully harvested and cultured from
saphenous vein segments obtained from patients undergoing coronary artery bypass  and varicose vein surgery [142,143]. As with animal cells, human endothelial cell adherence and spreading on polystyrene and graft materials has been shown to be dramatically improved by precoating with extracellular matrix, collagen 1/111, human fibronectin, platelet-rich plasma, and fibrin glue [144-162]. Ramalanjaona and coworkers, using a peristaltic pump to precoat ePTFE grafts with different concentrations of fibronectin for varying periods, found that a fibronectin concentration of 250 mcg/ml perfused through the graft for 60 minutes produced the most efficient coating . Studies in our own laboratory have shown a time and concentration-dependent increase in fibronectin attachment to several types of prosthesis [164,I65], with a minimum concentration of 50 mcg/ml necessary for optimal endothelial adherence. Preclot improved endothelial cell adherence [166,167] and also produced significantly better cell retention (75.4 + 9.5%) at flow rates up to 200 ml/min for two hours . Scanning electron microscopy of post-flow specimens revealed well formed endothelial monolayers completely covering the graft in the preclot group, whereas incomplete coverage was evident at 300 ml/minute and at all flows in the fibronectin group. Three phases of cell loss were noted: an immediate loss of 10-30% within five minutes of commencement of flow, 1.5-2% in the next 15 minutes, and 0.5-1% every five minutes up to 60 minutes; loss during the second hour was 3.5-4%. In our laboratory an artificial pulsatile flow circuit was used to study the effect of flow on endothelial retention after immediate seeding of cultured cells, endothelial surveillance being facilitated by indium1 ! 1 oxine labeling. However, it has been reported that substantial amounts of indium-111 oxine may leak from endothelial cells after several hours, leading to underestimation of cell retention during chronic flow . In addition, free indium may bind to the graft precoating thus leading to overestimation of cell retention. Although this isotope obviously has its limitations in chronic flow studies, it does not adversely affect cell viability . Other factors have been shown to affect the success of human endothelial cell seeding. Sharefkin and coworkers demonstrated that the ability of endothelial cells to attach and proliferate may be altered by the particular enzyme preparation used in harvesting . They further reported that particles from surgical glove powder curtailed human endothelial cell growth in culture . Studies comparing the age of cells used to seed grafts demonstrated more successful attachment to Dacron and ePTFE by low passage cells . Cryopreserved saphenous vein endothelial cells attached to grafts but were less able to resist moderate levels
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of shear stress . As with animal studies, in vitro coverage of ePTFE and Dacron has been achieved by culturing seeded grafts, complete endothelialization occurring within nine days [175,176].
CLINICAL TRIALS The earliest results of endothelial cell seeding in humans were published by Herring in 1984 [177,178], who seeded Dacron grafts with mechanically harvested endothelial cells in the femoropopliteal, axillofemoral and femorofemoral positions. No difference in patency was observed when seeded and non-seeded grafts were compared, though early patency of seeded grafts was substantially worse in those patients who continued to smoke. This may have been partly due to poor harvesting efficiency and reduced reproductive capacity of smokers' cells . They also reported a case of a cell-seeded ePTFE graft in which there was evidence of endothelialization . Although light and electron microscopy revealed an established endothelial surface, this was not confirmed by specific endothelial cell markers. Clinical trials to date have failed to show significant differences in patency between seeded and non-seeded grafts [181,182]. More subtle differences between the two have been sought by performing indium-lll labeled platelet scintiscans at various times after surgery. Zilla and associates found no differences in early or late platelet deposition between seeded and non-seeded fibrin glueprecoated ePTFE femorodistal grafts [183,184]. Conversely, Ortenwall and colleagues found significantly less isotope-labeled platelet deposition in the seeded limbs of aortic bifurcation grafts [185,186]. In a subsequent series of femoropopliteal reconstructions in which they seeded half of each implanted ePTFE graft with autologous endothelial cells, seeded segments accumulated significantly fewer platelets at one and six months after surgery .
THE F U T U R E It is clear that translation of the success achieved in animal studies to humans remains a distant prospect. After more than a decade of intense interest and research, there has been relatively little progress in the clinical field where several major issues require resolution. In particular, the ability to harvest cells and endothelialize the graft in the operating room in a short time demands simple techniques. Whether cell function is significantly altered by harvesting remains largely unanswered as does the question of the ability of such seeded
ANNALS OF VASCULAR SURGERY
cells to resist the shear stress of flowing blood. There has been considerable debate regarding smooth muscle cell contamination at the time of harvesting, since it is known that when such cells are seeded together there is a tendency to realignment which may not be detrimental. The functional properties of seeded endothelial cells have been studied in little detail, and although they have been shown to produce prostacyclin in response to flow  many other products have not been assayed. It has been well documented that endothelial cells are capable of exhibiting pro- and anticoagulant properties, the latter resulting from synthesis and secretion of prostacyclin and adenine nucleotides, cell surface properties related to the presence of heparin-like substances, and also from thrombomodulin-mediated activation of protein C. In addition it has been shown that endothelial cells in culture secrete both urokinase (uPA) and tissuetype (tPA) plasminogen activators [189-196]. Procoagulant properties result from the synthesis and secretion of von Willebrand factor (vWF), fibronectin, and thrombospondin [197-199]; plasminogen activator inhibitor-1 (PAI-1) has also been identified in the media of cultured bovine and human endothelial cells [ 195,196,200]. This inhibitor neutralizes both uPA and tPA, indicating that endothelium may also modulate fibrinolysis in a complex manner. Two more recently discovered vasoactive mediators are also synthesized and secreted by endothelial cells: endothelial-derived relaxing factor (EDRF) not only relaxes vascular smooth muscle through the formation of intracellular cyclic guanosine monophosphate but also acts as a potent inhibitor of platelet adhesion and aggregation ; endothelin-I on the other hand is a polypeptide which exhibits potent vasoconstrictor properties [202,203]. The current method of monitoring the progress of seeded grafts by means of indium- ! 11 labelled platelet scintiscans is a rather crude determinant. A potentially more reliable marker system has recently been developed by transfecting ceils with bacterial genes which can be detected by fluorescently-labeled antibodies , allowing long-term surveillance as the genetic marker is transmitted to the cell progeny. Recombinant technology may allow genetic modification of seeded endothelial cells [205-208], promoting and suppressing genes controlling anticoagulant and procoagulant substances respectively. Such technology could also be used to modify angiogenic or growth factor genes and provide a drug delivery system for treatment of atheromatous disease. Genetically modified endothelial cells have been successfully seeded at angioplasty in recent animal studies . The application of these revolutionary techniques in a clinical setting may have
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profound influence on the future management of vascular disease.
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