© 1999 American Heart Association, Inc.
Integrative Physiology |
Novel Vascular Graft Grown Within Recipient’s Own Peritoneal Cavity
From the Centre for Research in Vascular Biology, Department of Anatomical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
Correspondence to Dr Julie Campbell, Centre for Research in Vascular Biology, Department of Anatomical Sciences, The University of Queensland, Brisbane, Queensland, 4072 Australia. E-mail julie.campbell{at}mailbox.uq.edu.au
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Abstract |
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Abstract—A method by which to overcome the clinical symptoms of atherosclerosis is the insertion of a graft to bypass an artery blocked or impeded by plaque. However, there may be insufficient autologous mammary artery for multiple or repeat bypass, saphenous vein may have varicose degenerative alterations that can lead to aneurysm in high-pressure sites, and small-caliber synthetic grafts are prone to thrombus induction and occlusion. Therefore, the aim of the present study was to develop an artificial blood conduit of any required length and diameter from the cells of the host for autologous transplantation. Silastic tubing, of variable length and diameter, was inserted into the peritoneal cavity of rats or rabbits. By 2 weeks, it had become covered by several layers of myofibroblasts, collagen matrix, and a single layer of mesothelium. The Silastic tubing was removed from the harvested implants, and the tube of living tissue was everted such that it now resembled a blood vessel with an inner lining of nonthrombotic mesothelial cells (the "intima"), with a "media" of smooth muscle–like cells (myofibroblasts), collagen, and elastin, and with an outer collagenous "adventitia." The tube of tissue (10 to 20 mm long) was successfully grafted by end-to-end anastomoses into the severed carotid artery or abdominal aorta of the same animal in which they were grown. The transplant remained patent for at least 4 months and developed structures resembling elastic lamellae. The myofibroblasts gained a higher volume fraction of myofilaments and became responsive to contractile agonists, similar to the vessel into which they had been grafted. It is suggested that these nonthrombogenic tubes of living tissue, grown in the peritoneal cavity of the host, may be developed as autologous coronary artery bypass grafts or as arteriovenous access fistulae for hemodialysis patients.
Key Words: artificial artery • autologous transplant • tissue engineering
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Atherosclerosis is the principal cause of coronary occlusion, stroke, aortic aneurysm, and gangrene of the extremities and, as a single disease, is the major cause of mortality and morbidity in the United States, Europe, and other western nations. Atherosclerotic lesions are the result of an inflammatory response and damage of the arterial wall complicated by excessive lipid deposition.1 A method by which to overcome the clinical symptoms of atherosclerosis is the insertion of bypass grafts around an artery blocked or impeded by plaques. The most common vascular graft material in use today is saphenous vein or mammary artery from the patient him/herself (autografts). Both are flexible, viable, nonthrombogenic, and compatible. However, although the mammary artery seldom develops atherosclerosis, it may not always be the proper size or length, and saphenous vein may have varicose degenerative alterations that can lead to aneurysm formation when transplanted to a high-pressure arterial site. Furthermore, the nonthrombogenic surface of endothelial cells of saphenous veins is often damaged during graft preparation. Venous and arterial allografts have also been tried but have generally been abandoned clinically because they show a high incidence of rejection, deterioration, and complications. Similarly, the use of dialdehyde starch–tanned bovine xenografts has been generally abandoned because of a high incidence of aneurysm formation and poor resistance to infection.
For these reasons and because autologous grafts are not always available, synthetic vascular prostheses such as Dacron fabric grafts and expanded polytetrafluoroethylene have been developed. Although they perform reasonably satisfactorily in high-flow low-resistance conditions, these materials are not suitable for small-caliber arterial reconstructions because they are foreign bodies and because blood coagulation can occur on the luminal surface, resulting in occlusion. One innovation designed to improve their patency is the coating of the lumen of the graft with endothelial cells.2 Although flow through the graft is improved and thrombogenesis is reduced, graft failure due to occlusion by cell overgrowth can still occur. Gene therapy has been used to address this overgrowth, but retrovirally transduced cells on the graft are not able to withstand the stresses encountered by the flow of blood and are sheared off. Also, the procedure for obtaining endothelial cells from the patient is invasive, and the cells are hard to propagate in vitro. Attempts have been made to use skin granulation tissue as a vascular graft (the Sparks mandril prosthesis3 ). This process involves the placement of a plastic/glass rod under the skin. With time, cylindrical granulation tissue is formed, the rod is removed, and the tissue is tanned to remove all cellular components, leaving only a skeletonized collagen framework. However, findings of a low bursting strength led to the addition of external and internal synthetic grafts (such as Dacron) to the skeletonized tube, but these grafts were still found to have high rates of complication and low percentages of patency,4 and their usage is limited. Therefore, despite considerable experimental and clinical research, none of the biological and synthetic grafts produced thus far is an ideal substitute for an artery.
We describe here a "designer" artery, produced in the peritoneal cavity from cells of the same animal into which it is grafted. These arterial substitutes are composed of living myofibroblasts and the matrix they have produced, and they are antigenically acceptable and strong, respond to agonists and antagonists similar to blood vessels of the host, and are lined by living, nonthrombogenic, mesothelial (endothelium-like) cells.
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Materials and Methods |
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Tubing Implantation and Harvest and Autologous Tissue Transplantation
Thirty male adult Wistar rats (250 to 350 g) and 20 New Zealand White rabbits (aged 3 to 4 months) were anesthetized with 2.5% halothane (Fluothane; Laser Animal Health, Queensland, Australia) (vol/vol O2). A small incision was made in the shaved abdominal wall, and four 10-mm (for rat) or four 20-mm (for rabbit) lengths of Silastic tubing with outer diameter of 3 mm (rat) and 5 mm (rabbit) were placed inside the peritoneal cavity of each animal.
Two weeks after insertion of the tubing, the rats were premedicated
with atropine (0.25 mg/kg body wt administered
intraperitoneally) and anesthetized with
1% halothane. The 4 implants were harvested from the peritoneal cavity
of each rat, and any implants that had adhered to the wall or bowel
were discarded. Of the free-floating implants, the one with the
thickest capsule was selected for autologous transplantation, and the
others were used for histology or Western analysis (see below).
With the aid of an operating microscope, 2 vascular clamps were placed
on the area above and below the transplant site in the abdominal aorta,
which was then resected. The elastic recoil left a gap of 5 to 10
mm between the cut ends. The Silastic tubing was removed from the
implant selected for autologous transplantation, and at the same time,
the tissue capsule was gently everted such that the mesothelial layer
now lined its inside surface (Figure 1
).
The tube of living tissue was then trimmed and aligned with the gap
ready for suturing. Two stay sutures (9-0 silk) were placed at each
anastomosis to orient the graft and the artery and to facilitate the
placing of other sutures. The mid anastomotic site was sutured with
10-0 (22-µm) Ethilon suture material and with round and nontraumatic
needles (Ethicon, Inc). Suturing was first performed at the distal
anastomosis, followed by the proximal anastomosis. A total of 8
interrupted sutures were placed at each end: one each was placed at the
dorsal, ventral, medial, and lateral aspect of the anastomosis, and 4
more (Ethilon 9-0) interrupted sutures were then placed to fill the
intervals between them. The use of stay sutures was important, because
they prevent accidental suturing of the front and back wall of the same
vessel. The grafts were not preclotted, nor were heparin or
spasmolytics administered.
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Similarly, 2 weeks after insertion of 4 pieces of Silastic tubing into
their peritoneal cavities, 20 rabbits were preanesthetized with
1 mL Saffan (IV, Gloxovet) injected into their marginal ear veins, and
continuous anesthesia was achieved with 2.5% halothane.
The 4 grafts were harvested from each animal, the thickest
free-floating capsule was set aside for autologous transplantation into
the right carotid artery, and the others were fixed for histology. To
expose the right carotid artery, a midline incision (approximately in
line with the trachea) was made, the surrounding connective tissue was
bluntly dissected, and the submandibular glands were clamped and
retracted to one side. The transplantation procedure was similar to
that in the rat, except a 10-mm segment of artery was removed. After
elastic recoil, this left a gap of 
20 mm between the cut ends
into which the trimmed everted tube of tissue (with Silastic tubing
discarded) was sutured.
In both rats and rabbits, after suturing was complete, the distal clamp
was released to allow the graft to fill with blood under low pressure,
and then the proximal clamp was released to allow blood flow under full
arterial pressure through the graft. Light external
pressure with Gelfoam (Upjohn, New South Wales, Australia)
sealant was required at the anastomoses to control initial leakage.
Hemostasis was achieved by 2 to 3 minutes after removal of the
clamps, but the graft was continuously monitored for 10 to 14 minutes
in case of secondary bleeding. Patency was determined by direct
inspection. The wound was irrigated with saline solution and closed
with Dexon (Davis & Geck) 4-0 sutures. The animals had free
access to standard food and water. A graft was deemed successful at the
time of operation if it was fully dilated and pulsating and if a
femoral pulse was present. Unsuccessful grafts were limp and
flaccid, with no detectable pulse.
The 30 rats were randomly divided into 5 groups (n=6 per group) and euthanized at 1, 1.5, 2, 3, and 4 months after transplantation. The 20 rabbits were divided randomly into 4 groups (n=5 per group) and euthanized at 1, 2, 3, and 4 months after transplantation.
Tissue Analysis
Free-floating implants from the rat and rabbit not used for
autologous transplantation were processed for light microscopy,
immunohistochemistry,5 and transmission electron
microscopy.6 In addition, fresh implants from the rat
(n=6) were used for organ bath experiments (see below). Total protein
was extracted from another 6 rat implants and subjected to Western blot
analysis7 using antibodies to cytoskeletal markers
and contractile filaments. In both cases, rat aorta was used as a
control. Antibodies used for Western blotting were 
-smooth muscle
actin (1-A4, mouse IgG2a, 42 kDa, Sigma Chemical
Co), ß-actin (AC-74, 44 kDa, Sigma), smooth muscle myosin heavy chain
(mouse IgG1, hSM-V, 204 and 202 kDa, Sigma),
vimentin (V9, mouse Ig G2a, 57 kDa, Sigma), and
desmin (D33, mouse IgG1, 250 kDa, Dako), as well
as collagen I (C-1926, Sigma), collagen IV (epitopes
1 and 2, Sigma),
elastin (Sigma), and ED1 for macrophages (Dako). Densitometric
analysis was performed on the bands by use of image
analysis software (Mocha, Jandel Scientific), and values for
each implant protein were expressed as a percentage of that expressed
in the aorta. For light microscopy, sections were stained with
hematoxylin and eosin and with both Weigert’s and Hart’s
stains for elastin. For immunohistochemistry, sections were stained
with antibodies to -smooth muscle actin, smooth muscle myosin heavy
chain, and von Willebrand factor (Serotec) by use of the
biotin/streptavidin system. Negative controls were obtained by omitting
the primary antibody or staining with an irrelevant monoclonal antibody
of the same isotype. The volume fraction of myofilaments
(Vvmyo) of cells of the "media" was
determined as previously described.6
Rats and rabbits at 1, 2, 3, and 4 months after transplantation were euthanized with pentobarbital (Lethobarb, Provet Supplies) and perfusion-fixed. Wall thickness of the transplants was measured, and cell density was calculated by image analysis (modification of the method of Kleinert et al2 ). Sections were taken for light microscopy, electron microscopy, and immunohistochemistry of the tissue before transplantation. Transplants taken from the rat group killed at 1.5 months were taken for standard organ bath experiments to determine the response of the tissue to contracting and relaxing agents and were compared with 2-week implants and normal rat aorta.
All statistical analyses were performed by use of the statistical software package SIGMASTAT (Jandel Scientific).
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Results |
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Formation of a Granulation Tissue Tube in the Peritoneal Cavity
In both the rat and rabbit, an average of 2 of 4 pieces of Silastic tubing implanted in the peritoneal cavity remained free-floating and had become completely encased in a capsule of granulation tissue by 2 weeks (Figure 2a
). However, in 2 rats and 1 rabbit, all
4 harvested tubes had adhesions. These were removed, discarded, and
replaced by fresh tubing. After 2 weeks, 3 of the 4 new implants in
each of the 3 animals remained free-floating and by 2 weeks had
developed a capsule of granulation tissue. The tissue was removed from
the Silastic tubing of all free-floating implants by trimming one end
and then pealing it back over the tubing, a procedure similar to taking
off a sock (see Figure 1
). This caused little or no damage and,
at the same time, everted the tube of living tissue. The Silastic
tubing functioned only as an irritant and molding and was now
discarded.
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Light microscopy of the capsule from both the rat and rabbit showed
that close to where the Silastic tubing had been was a layer of
connective tissue covered by several layers of cell-rich granulation
tissue (Figure 2b). There was concentric layering of collagen
bundles, and the spindle-shaped cells contained large amounts of
synthetic organelles and abundant focal/dense bodies in myofilament
bundles (Figure 2c and 2d). Vvmyo in these
cells of the rat tube was 35.7±1.6% compared with 63.7±5.7%
(P<0.05) for smooth muscle cells in the aorta of the same
animals (Table 1).
Macrophages, readily distinguished by their irregular shape and
high vesicle content, were commonly seen. The inside lining of the
everted tubes consisted of a single layer of cells that stained
positively for von Willebrand Factor,8 and
transmission electron microscopy confirmed their identification as
mesothelial cells (Figure 2c). The hollow tubes of living tissue
thus resembled normal blood vessels, with an inner
"endothelium" (mesothelium in this case),
"media" of myofibroblasts, and a thin outer "adventitia" of
connective tissue.
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Western analysis showed that the rat granulation tissue tube
contained a similar content of -smooth muscle and desmin as the rat
aorta, with less smooth muscle myosin heavy chain and much greater
levels of ß-actin and vimentin (Table 2). The levels of collagen types I and IV
were similar to levels in the aorta, but elastin levels were low.
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Granulation Tissue Tube as Autologous Vascular Graft
(Artificial Artery)
The potential usefulness of the granulation tissue–derived tube
as vascular graft material was demonstrated in both the rat and rabbit.
The rabbit had a 10-mm segment of its right carotid artery removed and
replaced with 20 mm of everted granulation tissue lined with
mesothelial cells grown for 2 weeks in the peritoneal cavity of the
same animal. The rat had its abdominal aorta cut, but no segment
removed, and 10 mm of autologous granulation tissue inserted at
the cut ends. After 1, 2, 3, and 4 months after implant, the presence
or absence of a pulse through the transplant was evaluated, then the
proximal site of the vessel was clamped, and the graft was
perfusion-fixed followed by postdrop fixation.
One month after transplantation, grafts in all 6 rats of group 1 had a
pulse and were patent. At 2 months, 4 of 6 grafts were patent, and at 3
and 4 months, 3 of 6 grafts were patent, giving an overall patency rate
of 67%. None of the grafts had been preclotted, nor had heparin or
spasmolytics been administered to the animals at the time of
transplantation because we wished to test the antithrombotic benefits
of the mesothelial lining. Nonpatent grafts had their lumens blocked by
incorporated thrombi and by -smooth muscle actin–stained cells.
Signs of recanalization were sometimes seen. The
patent rat grafts possessed a normal intact wall and a strong pulse.
Mesothelium (or migrated endothelium), which stained
for von Willebrand factor,8 constituted the inner
lining. The average wall thickness of the graft increased from
0.18±0.02 mm (pretransplant) to 0.25±0.02 mm by 1 month,
after which no further change was observed. No significant
(P<0.1) increase in cell number was evident in the
"media," with the increase in graft thickness being due to the
large amount of extracellular matrix, mainly collagen, that developed
on the outer surface of the wall (Figure 3a). This "adventitia" contained vasa
vasorum as seen with antibodies to -smooth muscle actin (Figure 3b). Similar results were found for rabbit granulation tissue
tubes grafted into the carotid artery, with an overall patency rate of
70% (14 of 20 at the different time points).
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The cells within the wall of the grafts in both the rat and rabbit
stained intensely for -smooth muscle actin (Figure 3b) and
smooth muscle myosin (Figure 3c). By 3 months, the
Vvmyo of the cells in the rat transplant had
increased to 58.7±1.4%, which was not significantly different from
smooth muscle cells in the rat aorta near to the transplant site (Table 1). Structures that resembled elastic lamellae and stained with
both Hart’s and Weigert’s elastic stain began to appear in both rat
and rabbit grafts by 1 month; at first they were found only near the
lumen and then throughout the "media."
To determine whether the graft responded to contractile and relaxing
agents, organ bath experiments were carried out on grafts transplanted
to the rat aorta for 6 weeks (n=6); these grafts were compared with
rings of aorta from the same animal. First, 10-1
mol/L KCl was administered to determine whether the transplanted graft
had any contractile activity. Rings from the aorta had an increase in
contraction of 16 mN, whereas the transplanted graft contracted to 3 mN
(Figure 4a). Both contracted tissues
relaxed in response to (10-5 mol/L)
acetylcholine. Both tissues were then exposed to the contractile
agonists 5-hydroxytryptamine
(10-9 to 10-5 mol/L) and
phenylephrine (10-9 to
10-4 mol/L). The transplant showed no
contractile response to 5-hydroxytryptamine; however,
it did respond to phenylephrine, with a contractile
response of 1.5 mN at 10-5 mol/L compared with a
response of 15.5 mN exhibited by the aorta at the same concentration
(Figure 4b). Before grafting into the host artery, the tubes of
granulation at 2 weeks had no response to contractile or relaxing
agents (n=6).
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Discussion |
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It has previously been observed that small foreign bodies (such as plastic disk, boiled liver, agar, gelatin, egg white, filter membranes, and boiled blood clot) introduced into the peritoneal cavity of the rat, rabbit, or mouse initiate an inflammatory response, with the resultant granulation tissue covered by a layer of mesothelium.9 10 11 We speculated that if a tube of tissue could be grown and then freed from the molding and everted, this process might be used to develop an autologous vascular substitute.
Indeed, it was shown that tubes of granulation tissue can be grown within an animal’s own peritoneal cavity by using moldings of Silastic tubing of different lengths and diameters. These tubes of tissue possess a lining of mesothelial cells and a living contractile wall composed of myofibroblasts with tensile strength provided by collagen type I. The mesothelial layer is extremely important because it possesses fibrinolytic and anticoagulant activity,12 and synthetic grafts seeded with mesothelium are known to have a high patency rate similar to grafts seeded with endothelium.13
We also showed that the artificial artery can be used successfully as an autologous arterial transplant and remain patent for at least 4 months, with constituent cells becoming more smooth muscle—like, with a Vvmyo similar to smooth muscle cells of the adjacent arterial wall. By 6 weeks after transplantation, the cells have begun to respond to the contractile agents phenylephrine and KCl and to relax in response to acetylcholine. However, we have not yet determined whether all the cells in the transplant come from the original myofibroblasts or whether some are derived from the transmural ingrowth of smooth muscle cells or "fallout" hemopoietic cells, as has been reported for vascular and synthetic grafts.14 Also, it is not known whether the mesothelium is sloughed off the grafts and replaced by local endothelium after their transplantation to high-pressure (rat abdominal aorta and rabbit carotid) arterial sites. The source of the lining cells will be determined in future experiments by staining sections with endothelium-specific antibodies (ED31) throughout the length of the transplants over time. Because the patency of the transplants reported in the present study was high, even though they were not preclotted nor had heparin or spasmolytics been administered to the animals, the source of the lining cells was not considered essential information for this initial study.
After the present study was complete, a report15
appeared in Science (April) describing the in vitro
development of vascular grafts from cells isolated from biopsied pig
carotid artery or bovine aorta grown for 8 weeks on pulsed or nonpulsed
biodegradable polymer matrices. The engineered grafts responded to
contractile agonists at a magnitude of 5% of control rabbit
abdominal aorta. One pig had a pulsed xenograft transplanted into the
right saphenous artery; 3 others had autologous grafts (1 pulsed and 2
nonpulsed) into the same site. The pulsed grafts remained patent for
4 weeks, whereas the nonpulsed grafts thrombosed after 3 weeks.
There are several advantages of our grafts compared with those
described above: our grafts are developed entirely in vivo over only 2
weeks by the donor/host themselves; they need no artificial mesh as
part of the wall; and they develop elastic lamellae and have a
demonstrated patency for at least 4 months. Their grafts before
transplantation had contractile responses of 5% of control artery,
whereas our tissue at 6 weeks after transplantation had a 10% to 20%
response.
Although our results are preliminary and more extensive experiments are required before such grafts can be used in humans, we believe that this new type of graft material may open new perspectives in the field of arterial reconstructive surgery. These grafts may be developed to replace or bypass pieces of diseased artery for coronary artery bypass, thus avoiding the removal of saphenous vein (which is often varicose in the elderly) or mammary artery for this purpose. They may also be useful as readily replaceable arteriovenous access fistulae for hemodialysis patients. The grafts are biocompatible, have a nonthrombogenic surface, develop elastic fibers, exhibit a pulse, and contract and relax in response to exogenous agents, making them superior to synthetic grafts. Because they are grown inside the subject’s own body, there is no tissue rejection and limited graft complication. By altering the diameter and/or length of tubing used as a molding, grafts of different sizes can be produced. The procedure also allows for multiple or repeat grafting, because several tubes of tissue can be grown in the peritoneal cavity at the same or a later time.
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Acknowledgments |
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This study was supported in part by a grant from the National Health and Medical Research Council of Australia and by a postgraduate award (to Dr Efendy) from The University of Queensland. This study is the subject of Australian Provisional Patent Application No. PP5422/98, filed August 21, 1998, with extra data added December 22, 1998 (PP7859/98). We thank Dr Lindsay Brown for his expertise with the organ bath experiments and Anita Thomas, Steve Stamatiou, Nathalie Worth, and Nicole Smith for technical assistance.
Received May 3, 1999; accepted September 8, 1999.
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S. Cebotari, T. Walles, S. Sorrentino, A. Haverich, and H. Mertsching Guided Tissue Regeneration of Vascular Grafts in the Peritoneal Cavity Circ. Res., May 3, 2002; 90 (8): e71 - e71. [Full Text] [PDF]
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C. A Thompson and S. N Oesterle Biointerventional cardiology: the future interface of interventional cardiovascular medicine and bioengineering Vascular Medicine, May 1, 2002; 7(2): 135 - 140. [Abstract] [PDF]
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E. R. Edelman Vascular Tissue Engineering : Designer Arteries Circ. Res., December 3, 1999; 85(12): 1115 - 1117. [Full Text] [PDF]
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