Hans J. Kreutzer

A biodegradable stent based on poly(L-lactide) and poly(4-hydroxybutyrate) for peripheral vascular application: preliminary experience in the pig.

Purpose: To assess the technical feasibility and biocompatibility of a novel stent based on poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P4HB) for peripheral vascular applications. Methods: A polytetrafluoroethylene aortobi-iliac graft was implanted in 5 pigs through a midline abdominal incision. After transverse graft limb incision, 5 PLLA/P4HB stents and 5 metal stents (316L stainless steel) were randomly deployed at both iliac anastomotic sites with 6-mm balloon catheters. Angiography was performed to determine patency prior to sacrifice at 6 weeks. Stented segments were surgically explanted and processed for quantitative histomorphometry. Vascular injury and inflammation scores were assigned to the stented iliac segments. Results: No animals were lost during follow-up. All PLLA/P4HB stents were deployed within 2 minutes by balloon inflation to 8 bars without rupture of the stent struts or anastomotic suture. All stents were patent on postprocedural angiography. Histological analysis showed no signs of excessive recoiling or collapse. PLLA/P4HB stents demonstrated decreased residual lumen area and increased neointimal area after 6 weeks (12.27±0.62 and 8.40±1.03 mm2, respectively) compared to 316L stents (13.54±0.84 and 6.90±1.11 mm2, respectively) as the result of differences in stent areas (PLLA/P4HB: 4.31±0.15 mm2; 316L: 2.73±0.29 mm2). Vascular injury scores showed only mild vascular trauma for all stents (PLLA/P4HB: 0.41±0.59; 316L: 0.32±0.47). Inflammatory reaction was slightly higher around PLLA/P4HB stent struts (1.39±0.52) compared to 316L (1.09±0.50). Conclusion: Rapid balloon expansion of PLLA/P4HB stents is feasible without risk of strut rupture. PLLA/P4HB stents provide adequate mechanical stability after iliac anastomotic stenting in pigs. Smaller residual luminal areas in the PLLA/P4HB stents might have been caused by tissue ingrowth into the larger strut interspaces due to higher strut thickness (stent area) in this group. This limitation needs to be addressed in future work on the stent design.

Iliac Anastomotic Stenting with a Sirolimus-Eluting Biodegradable Poly-L-Lactide Stent: A Preliminary Study after 6 Weeks

Purpose: To assess technical feasibility and biocompatibility of a new biodegradable sirolimus-eluting poly-L-lactide (PLLA) vascular anastomotic stent. Methods: A polytetrafluoroethylene bifurcated graft was implanted in 9 pigs through a midline abdominal incision. After transverse graft limb incision, 6 unloaded PLLAs, 6 sirolimus-loaded PLLAs, and 6 unloaded stainless steel (316L) stents were randomly implanted at both iliac anastomotic sites. Stents were deployed with a 6-mm balloon under direct vision without the use of angiography. Prior to sacrifice after 6 weeks, contrast-enhanced computed tomography (CT) was performed to determine patency of the target vessels. Stented segments were surgically explanted and processed for histology to measure the mean luminal diameter and intimal thickness and to assign vascular injury and inflammation scores. Results: No animals were lost during the study period. All stented graft limbs were patent on CT and histology. At the anastomotic sites and iliac arteries, the mean luminal diameter of SIR-PLLA stents (4.11±0.15 and 4.08±0.13 mm, respectively) were comparable to metal stents (4.23±0.35 and 4.21±0.26 mm, respectively), but significantly higher compared to unloaded PLLA stents [3.32±0.56 mm (p<0.001) and 3.29±0.39 mm (p=0.013), respectively]. At the iliac arteries, the mean intimal thickness was significantly lower with SIR-PLLA stents (0.09±0.02 mm) compared to unloaded PLLA stents (0.31±0.15 mm, p<0.001) and metal stents (0.19±0.04 mm, p=0.004). Vascular injury scores demonstrated only mild vascular trauma for all stents (SIR-PLLA: 0.42±0.63, PLLA: 0.51±0.62, metal: 0.50±0.62). Only mild inflammatory reaction was noted around SIR-PLLA stent struts (1.14±0.46), which was comparable to metal stents (1.27±0.45) but significantly lower than PLLA stents (1.79±0.56, p<0.001). Conclusion: SIR-PLLA stents showed comparable luminal diameter compared to metal stents, so incorporating sirolimus could reduce the inflammatory and neointimal response to PLLA stents. These findings need to be assessed with longer follow-up to confirm maintenance of efficacy.

Extracorporeal cell therapy with granulocytes in a pig model of Gram-positive sepsis.

Objectives:Granulocyte transfusions have been used to treat immune cell dysfunction in sepsis. As granulocyte transfusions can trigger tissue injury via local effects of neutrophils, we hypothesized that extracorporeal treatment of plasma using granulocytes would prove beneficial while having less side effects. Design:Prospective controlled three-armed animal study. Setting:Research laboratory. Subjects:Twenty-one female immature pigs (7.5–12 kg, 7–9 weeks old). Interventions:Three groups of spontaneously breathing, sedated pigs (n = 7 each) received an intravenous lethal dose of live Staphylococcus aureus over 1 hour. Although group I had no specific treatment (control), group II and III were subsequently treated for 4 hours with an extracorporeal device containing either no cells (sham control, group II) or human cell line-derived granulocytic cells (group III). Survival time and physiologic, biochemical, and hematologic parameters were monitored for 7 days. Measurements and Main Results:All animals of group I died during the observation time (mean survival time: 70 hours). In group II, two of seven and in group III, six of seven animals survived the observation time (mean survival: 75 and 168 hours, respectively). Survival differences were significant between group I and III (p < 0.001) and between group II and III (p < 0.05) but not between group I and II (p = 0.43). Furthermore, group differences in bacterial blood concentrations, differential blood count, blood gases, lactate, and interleukins were observed. The extracorporeal cell treatment was well tolerated by the animals. Conclusions:Extracorporeal therapy with granulocytic cells significantly improved survival in a pig model of sepsis. Further studies with this approach are encouraged.

Iliac Anastomotic Stenting with a Biodegradable Poly-L-Lactide Stent: A Preliminary Study after 1 and 6 Weeks

Purpose: To assess the technical feasibility, thrombogenicity, and biocompatibility of a new biodegradable poly-L-lactic acid (PLLA) anastomotic stent. Methods: 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. Results: 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. Conclusion: 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.

Anastomotic stenting in a porcine aortoiliac graft model

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.

Plasma separation by centrifugation and subsequent plasma filtration: impact on survival in a pig model of sepsis.

The impact on survival of a combination of plasma separation by centrifugation and subsequent plasma filtration was tested in a bacterial sepsis model in pigs. In this animal study 19 pigs were included. Groups II and III received an intravenous lethal dose of live Staphylococcus aureus over 1 h; group I received saline (non‐septic control—NC). Groups I and II were treated by an extracorporeal circuit consisting of online centrifugation and subsequent plasma filtration (group II: treated group—TG) for 4 h; group III had no specific treatment (septic control, SC). The observation time was 7 days. All animals of group I (NC) and group II (TG) survived, while all animals of group III (SC) died during the observation time. Extracorporeal therapy with online centrifugation and plasma filtration significantly improved survival in a pig model of sepsis. Further studies with this approach are encouraged.

Role of different replacement fluids during extracorporeal treatment in a pig model of sepsis.

In an extracorporeal combination therapy, the impact of different replacement fluids on survival was tested in a bacterial sepsis model in pigs. In an animal study 19 pigs, weighing 7.5–11.1 kg, were included. All groups received an intravenous lethal dose of live Staphylococcus aureus over 1 h. The animals were treated by an extracorporeal circuit consisting of online centrifugation and subsequent plasma filtration for 4 h. The extracorporeal circuit was pre‐filled with 400 mL replacement fluid. In the P0 group 100% hydroxyethyl starch 130/0.4 was used as replacement fluid; in the P30 group 30% pig plasma and 70% hydroxyethyl starch; and in the P100 group 100% pig plasma. The observation time was 7 days. All animals of the group P100 survived, while all animals of group P0 and five out of seven animals of the P30 group died during the observation time. Extracorporeal therapy consisting of online centrifugation and plasma filtration with 100% pig plasma as replacement fluid significantly improved survival in a pig model of sepsis. Further studies with this approach are encouraged.

Temporäre Implantate für die endovaskuläre Applikation

ZusammenfassungMetallstents 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).AbstractAlthough vascular intervention using metal stents has become the gold standard of care for stenotic vessels, the lifelong persistence of metal stents within the arteries might induce long-term effects, bearing the risk of late thrombosis finally resulting in neointimal hyperplasia. However, since the vessel wall may undergo positive remodeling after stenting, the need for mechanical scaffolding of an artery may be only temporary. Thus, the use of biodegradable devices, which eventually degrade and leave only the remodeled vessel, might decrease restenosis rates. Polymeric biodegradable polylactide stents have demonstrated this potential as an alternative to standard metal stents, but to date, the human experiences with these devices are limited. The aim of this study was therefore to summarize our experiences in dealing with a biodegradable slotted tube stent made of poly-L-lactide (PLLA) with incorporation of Sirolimus (polymeric drug eluting stent).

Temporäre Implantate für die endovaskuläre ApplikationTemporary devices for endovascular application

ZusammenfassungMetallstents 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).AbstractAlthough vascular intervention using metal stents has become the gold standard of care for stenotic vessels, the lifelong persistence of metal stents within the arteries might induce long-term effects, bearing the risk of late thrombosis finally resulting in neointimal hyperplasia. However, since the vessel wall may undergo positive remodeling after stenting, the need for mechanical scaffolding of an artery may be only temporary. Thus, the use of biodegradable devices, which eventually degrade and leave only the remodeled vessel, might decrease restenosis rates. Polymeric biodegradable polylactide stents have demonstrated this potential as an alternative to standard metal stents, but to date, the human experiences with these devices are limited. The aim of this study was therefore to summarize our experiences in dealing with a biodegradable slotted tube stent made of poly-L-lactide (PLLA) with incorporation of Sirolimus (polymeric drug eluting stent).

Temporäre Implantate für die endovaskuläre Applikation@@@Temporary devices for endovascular application: Biodegradierbarer Polylactidstent@@@Biodegradable polylactide stents

ZusammenfassungMetallstents 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).AbstractAlthough vascular intervention using metal stents has become the gold standard of care for stenotic vessels, the lifelong persistence of metal stents within the arteries might induce long-term effects, bearing the risk of late thrombosis finally resulting in neointimal hyperplasia. However, since the vessel wall may undergo positive remodeling after stenting, the need for mechanical scaffolding of an artery may be only temporary. Thus, the use of biodegradable devices, which eventually degrade and leave only the remodeled vessel, might decrease restenosis rates. Polymeric biodegradable polylactide stents have demonstrated this potential as an alternative to standard metal stents, but to date, the human experiences with these devices are limited. The aim of this study was therefore to summarize our experiences in dealing with a biodegradable slotted tube stent made of poly-L-lactide (PLLA) with incorporation of Sirolimus (polymeric drug eluting stent).