L. Ketner’s research while affiliated with University of Rostock and other places

Metallstents werden zunehmend in der Behandlung von vaskulären Erkrankungen eingesetzt, jedoch mit dem Nachteil eines permanenten Fremdkörpers im Organismus, wodurch die Gefahr einer Spätthrombosierung oder Neointimaausbildung besteht. Das anschließende Remodelling ist jedoch nur ein temporärer Vorgang, weshalb der Stent als Gefäßstütze nur vorübergehend benötigt wird. Ein biodegradierbarer, sich auflösender Stent stellt daher eine Alternative zum herkömmlichen Metallstent dar. Biodegradierbare Polylactidstents haben ihr Potenzial als Alternative zu Metallstents bereits demonstriert, allerdings sind bis zum heutigen Tag klinische Erfahrungen nur sehr begrenzt vorhanden. Die wissenschaftliche Zielsetzung der vorliegenden Arbeit lag daher in der tierexperimentellen Charakterisierung der physikalischen und biologischen Eigenschaften eines biodegradierbaren Röhrchenstents aus Poly-L-Lactid (PLLA) mit und ohne Sirolimusbeschichtung (polymerer Drug-eluting-Stent).

To assess technical feasibility and biocompatibility of a new Sirolimus (SIR)-eluting biodegradable poly-L-lactide (PLLA) stent for peripheral vascular application. In 15 pigs, both common carotid arteries (CCA) were surgically exposed and clamped in the proximal segment. After transverse incision, 12 316L stents, 12 unloaded and 6 SIR-loaded PLLA stents mounted on 6.0 x 40-mm balloon catheters were randomly implanted into the CCA and inflated to 8 bar. Angiographic equipment was not available. Stented CCA were explanted after 1 week (6 pigs; 316L versus PLLA) and 6 weeks (9 pigs; 316L versus PLLA versus SIR-PLLA), and processed for quantitative histomorphometry and estimation of vascular inflammation and injury scores. No animals were lost during follow-up. All stents were patent on histological analysis without any signs of excessive recoiling or collapse. Unloaded PLLA stents showed decreased residual lumen area and increased neointimal area after 1 week (13.16 +/- 0.34, 1.94 +/- 0.26) and 6 weeks (11.57 +/- 0.30, 2.85 +/- 0.24) as compared with 316L stents (15.26 +/- 0.13, 1.27 +/- 0.41 and 13.99 +/- 0.51, 1.54 +/- 0.59). SIR-eluting stents demonstrated comparable neointimal area (1.75 +/- 0.38) and 50% lower intimal thickness as compared with 316L stents after 6 weeks, but a slightly decreased residual lumen (13.06 +/- 0.32) in the consequence of differences in strut thickness (PLLA, 270 microm; 316L, 155 microm). The vascular inflammation score against PLLA-stents could be reduced by Sirolimus. The vascular injury scores were low and similar in all groups. PLLA stents showed sufficient mechanical stability after porcine CCA stenting. By incorporation of Sirolimus, a significant reduction of the inflammatory and neointimal response to the PLLA stent was seen without systemic toxicity or thrombotic complications. These findings need to be assessed with longer follow-up to confirm maintenance of efficacy. The greater strut height of PLLA stents is a major limitation and requires modification.

The purpose of the study was to evaluate the feasibility of anastomotic stent application in a porcine aortoiliac graft model. In a total of 10 pigs, a polytetrafluoroethylene aortobi-iliac graft was implanted through a midline abdominal incision. The lower edge of the iliac vessel was graft-inverted about 1 mm to produce irregularities at the downstream anastomosis. After transverse graft incision, six stainless-steel stents, six poly-L-lactic acid (PLLA) stents and four PLLA stents with 10% polycaprolactone (PCL) were implanted at the iliac anastomotic site using a 6 mm balloon dilatation catheter. Four anastomotic sites were left untreated. After two weeks, the patency of graft limbs was evaluated by contrast-enhanced computed tomography (CT). Both metal and polymeric stent designs provided adequate flexibility to manoeuvre across the anastomotic site for expansion in the chosen position. After deployment, the stent-arterial wall contact was complete on a macroscopic view. On CT scan, all metal and PLLA-stented graft limbs were free of stenosis, whereas all PLLA/PCL stents were occluded. The non-stented graft limbs showed a stenosis of 50-70%. In summary, this model is feasible to assess preclinically the deployment and patency rate of an anastomotic stent and to test future stent developments.

To assess the technical feasibility, thrombogenicity, and biocompatibility of a new biodegradable poly-L-lactic acid (PLLA) anastomotic stent. A polytetrafluoroethylene bifurcated graft was implanted in 17 pigs through a midline abdominal incision. After transverse graft incision, 17 316L stainless steel stents and 17 PLLA stents were randomly implanted at both iliac anastomotic sites and deployed with a 6-mm balloon under direct vision without angiography. Intended follow-up was 1 week in 6 pigs receiving oral acetylsalicylic acid (ASA) and in 7 pigs receiving ASA/clopidogrel; 4 pigs receiving ASA/clopidogrel were followed for 6 weeks. At the end of the study, the segments containing the stents were surgically explanted and processed for histology to measure the mean luminal diameter, intimal thickness, and the vascular injury and inflammation scores. Initial technical success of stent placement was achieved in all animals without rupture of the suture. Two pigs died (unrelated to the stent) at 3 days after operation (1 in groups A and B). At 1 week, all PLLA stents showed thrombotic occlusion with the use of ASA alone. In contrast, all PLLA stents remained patent with concurrent administration of ASA/clopidogrel. All metal stents were patent regardless of the antiplatelet regimen. The mean luminal diameter of patent PLLA stents (4.13+/-0.17 mm) was comparable to metal stents (4.27+/-0.35 mm, p=0.78) at 1 week, but significantly diminished at 6 weeks (3.21+/-0.44 versus 4.19+/-0.18 mm, p=0.005). Histological analysis showed no signs of excessive recoil. PLLA stents induced a higher inflammation score (1.79+/-0.56) and more intimal hyperplasia (0.34+/-0.11 mm) compared to metal stents [1.27+/-0.44 mm (p<0.001) and 0.18+/-0.04 mm (p=0.006), respectively] at 6 weeks. Vascular injury was comparable between PLLA and metal stents. Biodegradable PLLA stents showed higher thrombogenicity and reduced patency compared to metal stents during early follow-up. Although ASA and clopidogrel prevented thrombotic occlusion, the increased inflammatory response and neointima formation remain major concerns of PLLA stents. A solution to this problem might be the incorporation of anti-inflammatory drugs into the PLLA stent.

Introduction: Instead of vascular metallic stents with their permanent implant nature biodegradable stents can be applied. The aim of the study was to investigate the influence of Acetylsalicylic acid (ASA) versus ASA/Clopidogrel (CLOP) on acute/subacute thrombotic occlusion of a Poly-L-Lactid Acid (PLLA) stent after implantation in a porcine iliac model of stenosis. Materials and methods: A polytetrafluoroethylene (PTFE) aortobi-iliac graft (12/6 mm) was implanted in pigs (body weight bw: 37.4 ± 1.9) with creating of an iliac anastomotic stenosis. PLLA-stents (n=11) were placed across the distal anastomosis unilaterally (right: 6, left: 5) und balloon-dilated to 6 mm. Beginning 1 day before operation and continuing until the end of the study, the pigs received ASA 100mg orally alone (n=5) or in combination with CLOP 75mg orally (n=6). Intravenous heparin (50 IU/kg bw hourly) was administered as a continous infusion during the procedure. Doppler ultrasound (4MHz) was performed at the femoral arteries. After a follow-up aortoiliac CT-scan at 1 week, the segments containing the stents were surgically explanted and processed for histology (HE), and the animals were sacrified. Results: All PLLA-stents were sucessfully delivered at the distal anastomotic region and showed a complete stent-arterial wall contact after deployment on a macroscopically view. Stenting was successful in eliminating the anastomotic stenosis, proved by femoral doppler measurement, i.e. the poststenotic flow was abolished. One animal died 3 days after operation due to distortion of the right colon resulting in gangrene. At 1 week, all PLLA-stents using ASA alone (n=4) were shown to be occluded, whereas all PLLA-stents under the combination of ASA and CLOP (n=6) and all non-stented anastomotic sites (n=4) were patent. The residual lumen diameter was significant higher at the PLLA-stented (4.54 mm ± 0.16) than at the non-stented (1.89 mm ± 0.33) anastomotic site, p<0.001. The percent lumen stenosis of the PLLA-stented group amounted to 28.48% ± 2.98 compared to 61.01% ± 7.02 (p<0.001) of the the non-stented group, related to the inner diameter of the graft (6.35 mm ± 0.11 and 4.85 mm ± 0.03, respectively). The PLLA-stent associated neointimal restenosis was 5.07% ± 1.76, related to the normal lumen diameter (within the internal elastic lamina) of 4.78 mm ± 0.09. Conclusion: Acute/subacute occlusion of the PLLA-stent was prevented by a combination of ASA and CLOP. No significant stent-induced re-stenosis was observed. A longer follow-up period, however, is mandatory to evaluate chronic thrombosis/re-stenosis and the degradation behaviour.