Rationale and Objectives
To evaluate the efficacy of a self-expanding metal stent seeded with autologous endothelial progenitor cells (EPCs) for preventing in-stent stenoses in transjugular intrahepatic portosystemic shunt (TIPS) in a swine model.
Materials and Methods
TIPS was performed in 18 young adult pigs, using a self-expanding nitinol stent (control, n = 8) and an autologous EPC-seeded stent (treatment, n = 10). All pigs were sacrificed at 2 weeks post-TIPS procedure. Portography was performed immediately before the euthanasia. Gross, microscopic, and immunohistochemistry of the TIPS tract specimens were examined. The proliferative response of the shunt was quantified histologically.
Results
TIPS was performed successfully in 16 swine, 2 animals died during the procedure. Another pig died of unknown causes 2 days post-procedure. At day 14 follow-up, portography and necropsy of the 15 remaining swine demonstrated that five shunts occluded and one shunt was stenotic (80%) in the control group ( n = 6). Five shunts remained patent, two shunts were stenosed (50%, 70%), and the remaining two shunts were occluded in the treatment group ( n = 9). The patency rate was significantly lower in the control group than in the treatment group, 0% versus 55.6% ( P = .03). Histological analyses showed a significantly greater pseudointimal hyperplasia in the TIPS track of the control group than that of the treatment group ( P < .05). Intact endothelium was documented in the lumina of all the EPC-implanted stent group.
Conclusions
The EPC-seeded metal stent is feasibly fabricated in vitro and improves the patency in TIPS in a porcine model.
Transjugular intrahepatic portosystemic shunt (TIPS) has been in use for more than 20 years to treat recurrent variceal hemorrhage and refractory ascites caused by portal hypertension . However, shunt stenosis or occlusion remains a major obstacle to the utility of TIPS . Several investigators have suggested that bile leakage is inevitable during a TIPS procedure and there may be small bile ducts in communication with the TIPS tract that may account for the neointimal overgrowth . Bile leak inhibits smooth muscle cell proliferation instead of promoting their growth in an in vitro cell culture, and further study shows that such bile leakage may promote in-stent stenosis in a TIPS shunt by inhibiting endothelial cell proliferation . Using a physical barrier to block bile and cytokine leakage between the circulation and the injured hepatic parenchyma has been shown to prevent in-stent stenosis of TIPS . Another potential method to prevent in-stent stenosis is the induction of rapid endogenous reendothelialization of the tract to inhibit the bile leakage that is associated with early stage thrombosis and late stage pseudointimal overgrowth within a TIPS shunt . The design of an autologous endothelialized stent graft to prevent post-TIPS in-stent stenosis holds great promise. Although Zhuang showed that the TIPS shunt patency improves significantly at 2 weeks in a swine model with an autologous vein-covered stent, such a technique does not seem practical in routine clinical use.
It is known that endothelial progenitor cells (EPCs) can differentiate into endothelial cells in vivo and can easily be harvested from peripheral blood . In this study, we designed a novel endoprosthesis for TIPS that was seeded with autologous EPCs to test that the shunt patency would be improved with this device when compared with a bare metal self-expanding stent.
Materials and methods
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Preparation of EPC-seeded Stent
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TIPS Creation
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Follow-up
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Statistical Analysis
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Results
EPC-seeded Stent Fabrication in vitro
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TIPS Procedure
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Follow-up Portography and Histopathology
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Table 1
Results of the TIPS Creation in a Swine Model with Bare or EPC-seeded Stent
Animal No. Gender Weight (kg) Stent Type Follow-up Duration Tract Status 1 F 20 Bare 14 Occlusion 2 F 30 EPC-seeded 15 Occlusion 3 M 25 Bare 15 Occlusion 4 M 25 EPC-seeded 14 Patent 5 F 32 EPC-seeded 14 Stenosis 50% 6 F 25 EPC-seeded 14 Occlusion 7 F 20 EPC-seeded 13 Patent 8 F 20 Bare 14 Occlusion 9 F 20 Bare 14 Occlusion 10 F 20 EPC-seeded 14 Stenosis 70% 11 ∗ F 25 Bare 2 Stenosis 60% 12 M 25 EPC-seeded 15 Patent 13 M 25 EPC-seeded 14 Patent 14 F 23 EPC-seeded 13 Patent 15 M 25 Bare 15 Stenosis 80% 16 F 20 Bare 14 Occlusion
F, female; M, male; bare, bare metal stent; EPC-seeded, endothelial progenitor cell–seeded metal stent with fibrin gel.
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Table 2
Morphometry Analysis of the TIPS Shunts
PIH Area (mm 2 ) PIH Thickness(mm) Sites Bare Stent EPC-seeded Bare Stent EPC-seeded Hepatic vein segment 14.3 ± 6.53 11.1 ± 5.66 1.20 ± 0.37 0.97 ± 0.56 ∗ Central segment 12.0 ± 4.57 9.68 ± 5.46 ∗ 1.26 ± 0.45 0.85 ± 0.47 ∗ Portal vein segment 12.1 ± 5.56 10.5 ± 5.2 1.50 ± 0.36 0.98 ± 0.44 ∗
PIH, pseudointimal hyperplasia; PIH thickness, distance from the stent wires to lumen; TIPS, transjugular intrahepatic portosystemic shunt.
PIH area not including thrombus.
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Discussion
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Acknowledgment
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