Ilkka Uurto

Drug-eluting biodegradable poly-D/L-lactic acid vascular stents: an experimental pilot study.

Purpose: To evaluate in vivo a new drug-eluting biodegradable vascular stent with respect to biocompatibility, neointimal hyperplasia formation, and reliability. Methods: Self-expanding biodegradable poly-96L/4D-lactic acid (PLA) stents with 2 drugs (PLA + dexamethasone [DEX] and PLA + simvastatin [SIM]) and 2 different coatings (PLA + P(D,L)LA and PLA + polycaprolactone [PCL]) were compared with a self-expanding stainless steel Wallstent. The stents were implanted in both common iliac arteries of 8 pigs. Prior to sacrifice at 1 month, angiography was performed to determine patency. Specimens were harvested for quantitative histomorphometry; vascular injury and inflammation scores were assigned to the stented iliac segments. Results: All stented arteries were angiographically patent. The mean luminal diameter (3.05 mm) and area (30.36 mm2) of DEX-eluting PLA stents were decreased compared to other stents (PLA + P(D,L)LA: 3.66 mm and 43.92 mm2 PLA + SIM: 4.21 mm and 56.48 mm2 PLA + PCL: 4.19 mm and 54.64 mm2 Wallstent: 5.01 mm and 81.19 mm2). Wallstents and DEX-eluting PLA stents induced minimal intimal hyperplasia: PLA + DEX: 0.16 mm, PLA + P(D,L)LA: 0.35 mm, PLA + SIM: 0.33 mm, PLA + PCL: 0.29 mm, and Wallstent: 0.18 mm. The vascular injury scores demonstrated only mild vascular trauma for all stents. Only mild to moderate inflammatory reaction was noted around stent struts with a vascular inflammation score. Conclusions: Biodegradable polymer stents appear to be biocompatible and reliable, causing minimal neointimal hyperplasia. Furthermore, the new biodegradable poly-D/L-lactic acid stent can be used as a local drug delivery vehicle. The DEX-eluting PLA stent reduces neointimal hyperplasia. The findings show a need for further investigation to prove the efficacy and safety of this new biodegradable drug-eluting stent.

Biodegradable self-expanding poly-L/D-lactic acid vascular stent: a pilot study in canine and porcine iliac arteries.

Purpose: To report results of an in vivo pilot study to evaluate the biocompatibility and delivery system of a new biodegradable vascular stent and validate the study design. Methods: Two self-expanding intravascular stents, a biodegradable poly-D/L-lactic acid (PLA) and a medical stainless steel stent (Wallstent) were implanted in the common iliac arteries of 2 postpuberal female pigs and 3 laboratory-bred beagle dogs. Specimens were harvested after 45 days in the dogs and 32 days in the pigs for histomorphometry of the stented iliac artery segments. Preliminary measurements were made to assess the reliability of the quantitative histomorphometric measurements before final measurements Results: Histomorphometry analyses showed that mean luminal diameter and area were decreased in the PLA stent group (1.97±0.48 mm and 14±6.4 mm2, respectively) compared to the control stent group (4.28±0.83 mm and 61±19 mm2, respectively). The intimal thickness was higher in the PLA stent group (0.65±0.07 mm) than in the control group (0.44±0.21 mm). The mean injury score was 0.19±0.12 in the PLA stent group and 0.78±0.39 in the controls. In the PLA stent group, the mean inflammation score was 1.46±0.78 compared to 0.58±0.40 in the control group. There were no differences observed between the animal models. Conclusions: The PLA stent showed increased neointimal formation and reduced patency during early follow-up. Mechanical properties of the new biodegradable vascular stents are still inadequate, and the stent and the delivery device require modifications. The study methods were assessed as reliable and reproducible.

Drug-eluting bioabsorbable stents – An in vitro study

The aim of this study was to investigate the drug elution properties of novel drug-eluting bioabsorbable stents in vitro with four different drugs: dexamethasone, indomethacin, simvastatin and ciprofloxacin. Braided stents of poly-lactic acid (96l/4d) fibers were coated with a solution containing the appropriate bioabsorbable polymer and drug, with acetone as the solvent. Two different drug concentrations for both non-sterile and gamma sterilized stents were used for dexamethasone and indomethacin. For ciprofloxacin and simvastatin, only one drug dose was used. The stents were placed in sodium-phosphate-buffered saline in a shaking incubator (pH 7.4, +37 degrees C) and the eluted drug was measured periodically using an ultraviolet spectrometer. The drugs were hydrophobic to different degrees, as demonstrated by their various speeds of elution. In general, the higher the drug load in the stent, the faster the drug elution and the more hydrophilic the elution profile. In the cases of dexamethasone, indomethacin and ciprofloxacin, the sterilization decreased the drug elution rate slightly and the elution started earlier. However, in the case of ciprofloxacin, the gamma sterilization increased the drug elution rate slightly. Sustained elution was achieved for all four drugs. It was also evident that both the concentration and the hydrophility of the drug had a great influence on the drug elution profile. Gamma sterilization modified the drug elution profiles of dexamethasone, indomethacin and simvastatin, but had little effect on the drug elution profile of ciprofloxacin compared to three other drugs.

Urethral in situ biocompatibility of new drug‐eluting biodegradable stents: an experimental study in the rabbit

To assess the effect of drug‐eluting properties on the degradation process and the biocompatibility of biodegradable drug‐eluting urethral stents.

Biocompatibility of new drug-eluting biodegradable urethral stent materials.

OBJECTIVES To investigate the effects of biodegradable stent material (poly-96L/4D-lactic acid [PLA]) on the production of cytokines and other inflammatory mediators in vitro and the biocompatibility of new drug-eluting biodegradable urethral stent materials in vivo. Indomethacin, dexamethasone, and simvastatin were used in the materials. METHODS The effects of the biodegradable stent material on cytokines and other inflammatory mediators were measured using the Human Cytokine Antibody Array and enzyme-linked immunosorbent assay in THP-1 cells, with bacterial lipopolysaccharide as a positive control. To assess the biocompatibility of the stent materials, we used muscle implantation. Biodegradable stent materials without drug-eluting properties and silicone and latex were used as controls. The measurements were done at 3 weeks and 3 months. RESULTS The PLA stent material induced production of inflammatory mediators, especially interleukin-8, tumor necrosis factor-alpha, and transforming growth factor-beta, in vitro. The increase in the production of these mediators with the PLA stent material was smaller than in the cells treated with lipopolysaccharide. In vivo, the effects of the biodegradable materials did not differ at 3 weeks, although, at 3 months, dexamethasone had induced more tissue reactions than had the other materials. At 3 months, fibrosis and chronic inflammatory changes were decreased in the biodegradable material groups compared with the positive control. CONCLUSIONS PLA stent material increased the production of cytokines and other inflammatory mediators less than did positive controls in vitro. The in vivo biocompatibility of the drug-eluting biodegradable materials was better than that of the positive controls. Drug-eluting biodegradable urethral stents could potentially offer a new treatment modality in the future.

Preclinical Evaluation of New Indomethacin-Eluting Biodegradable Urethral Stent

PURPOSE To evaluate the effect of an indomethacin-eluting biodegradable urethral stent on the production of inflammatory cytokines in vitro and the degradation and biocompatibility of the new stent in vivo. MATERIALS AND METHODS The effects of an indomethacin and indomethacin-eluting biodegradable stent on monocyte chemoattractant protein (MCP)-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and transforming growth factor-ß were measured in THP-1 cells by enzyme-linked immunosorbent assay. Stents (copolymer of L-lactide and glycolide acid) that were coated with 50L/50D polylactic acid and two different concentrations of indomethacin were inserted into the rabbit urethra. Stents without the drug were used as controls. Scanning electron microscopy (SEM) was used to assess the degradation of the stents. Biocompatibility was evaluated using histologic analyses of the urethral specimen. The measurements were performed at 3 weeks and 3 months. RESULTS Indomethacin and indomethacin-releasing stent material inhibited MCP-1 and RANTES production in activated THP-1 macrophages. SEM analysis revealed that indomethacin coating had no effect on the degradation process of the stents and less epithelial polyposis had developed in the indomethacin stent group. In histologic analyses at 3 weeks, indomethacin-eluting stents caused more calcification but no significant differences in other tissue reactions. At 3 months, the indomethacin-eluting stents caused less inflammatory reaction and calcification compared with the control stents. CONCLUSION Indomethacin-eluting property can be safely added to biodegradable stents without major influence on the degradation time. The development of epithelial polyposis in the urethra can be potentially reduced by the new indomethacin-eluting urethral stents.

Dexamethasone-eluting Vascular Stents

Percutaneous transluminal angioplasty (PTA) with stenting is widely used in the treatment of vascular disorders, but restenosis remains a significant problem. Drug-eluting stents (DES) have been developed as an attempt to reduce the intimal response leading to restenosis. Drugs used in DES include mainly immunosuppressive and anti-proliferative compounds. Glucocorticoids are also an interesting possibility for those purposes because they have anti-proliferative effects in vascular smooth muscle cells and down-regulate the production of cytokines and growth factors driving inflammation and fibrosis. In this MiniReview, feasibility and safety of drug-eluting metal and biodegradable vascular stents are discussed with special emphasis on dexamethasone-eluting stents.

Long-Term Experience of Endovascular Repair for Thoracic Aortic Aneurysms and Dissections

Purpose: To report the long-term results of thoracic endovascular aortic repair (TEVAR) in both elective and emergency cases of thoracic aortic aneurysm (TAA) and type B dissection. Material and Methods: A prospective single-center study of 78 TEVAR patients treated between February 1998 and February 2013. Stent-graft implantation was performed in 51 (65%) patients for TAA (43 elective and 8 emergency cases) and in 27 (35%) patients for type B dissection (11 elective and 16 emergency cases). Short- and long-term results were evaluated, and a subgroup of patients with left subclavian artery (LSA) coverage was also analyzed. Results: The patients were followed for a mean of 55 months (1-160 months). The technical success rate was 81% and 30-day mortality 6.4% (n = 5). The stroke rate was 7.7% (n = 6) and permanent paraparesis 2.6% (n = 2). In follow-up, there were 28 (36%) primary (15 type I and 13 type II) and 10 secondary endoleaks (8 type I and 2 type II). Multivariate analysis showed no significant predictive factors for developing a type I endoleak. Secondary interventions were required in 24% of the patients. There was 1 late thoracic aortic rupture and 1 late conversion (1.3%). Patients with LSA coverage had a higher incidence of stroke (12.5% vs 4.3%, P = .18) and paraparesis (3.1% vs 2.2%, P = .79) compared to those without LSA coverage, although this difference was not statistically significant. Stroke rates were significantly higher in patients treated in an emergency setting (P = .048). Conclusion: Thoracic endovascular aortic repair is a relatively safe and effective therapy for different aortic pathologies with good long-term success. The risk of stroke and paraparesis is notable whether the LSA is covered, and strokes clearly accumulate in the emergency setting. A type I endoleak is the most common complication, but there are no predictive factors for its development.

Hybrid Repair of Thoracoabdominal Aortic Aneurysms Is a Durable Option for High-Risk Patients in the Endovascular Era:

Objective: To report our long-term experience in using the hybrid technique in complex thoracoabdominal aortic aneurysms (TAAAs). Methods: Between March 2005 and September 2013, 10 patients with TAAA underwent hybrid procedures with open renovisceral revascularization and thoracoabdominal aortic endografting. Patients were analyzed retrospectively. Results: Six men and 4 women with a mean age of 66 years (range 54-81 years) were treated electively during the study period. All 4 visceral vessels were revascularized in 8 patients, whereas 1 patient underwent 3-vessel revascularization and another 2-vessel revascularization. The primary technical success rate was 100%. Eight of the procedures were single staged, and the 2 most recent cases were performed in 2 stages. Perioperative and 30-day mortality was 0%. The mean follow-up was 55 months (4-133 months). None of the patients died due to aortic complications. Major complications included paraplegia (10%, n = 1) and bowel ischemia (n = 1). Postoperative cerebrospinal fluid (CSF) pressure and mean arterial pressure measurements were systematically monitored and corrected. The CSF drainage solved another 4 cases of paraparesis. Three patients required postoperative dialysis, but none of them required permanently. Postoperative spinal cord ischemia and renal complications accumulated in extensive TAAA cases. One renal graft was occluded 45 days after the initial procedure but was successfully treated with thrombolysis. One type I and 1 type III endoleak were noted and successfully treated with an additional stent graft. Two cases of type II endoleak were detected—one with a growing aneurysm sac was treated successfully and another showed no growth and further procedures were abandoned after 2 embolization attempts. In long-term follow-up, 90% of the aneurysms showed shrinkage by a mean of 23 mm (range 7-45 mm). Conclusion: The results of hybrid repair on high-risk patients with complex TAAAs are encouraging, and this approach is a valuable alternative when branched and fenestrated endovascular techniques are not considered an option.

Muraglitazar-eluting bioabsorbable vascular stent inhibits neointimal hyperplasia in porcine iliac arteries.

PURPOSE To evaluate the biocompatibility of a new muraglitazar-eluting polylactide copolymer stent and investigate its ability to prevent the formation of intimal hyperplasia. MATERIALS AND METHODS Ten self-expandable muraglitazar-eluting poly-96 L/4D-lactic acid (PLA96) stents and 10 self-expandable control PLA96 stents were implanted into porcine common iliac arteries. After 28 days follow-up, all stent-implanted iliac arteries were harvested and prepared for quantitative histomorphometric analysis. RESULTS Angiographic analysis revealed that one control PLA96 stent had occluded and one had migrated. Histomorphometric analysis demonstrated that, with the control PLA96 stent, the luminal diameter and area were decreased versus the muraglitazar-eluting PLA96 stents (means ± standard error of the mean, 3.58 mm ± 0.34 vs 4.16 mm ± 0.14 and 9.83 mm(2) ± 2.41 vs 13.75 mm(2) ± 0.93, respectively). The control PLA96 stent induced more intimal hyperplasia than the bioactive muraglitazar-eluting PLA96 stent (557 µm ± 122 vs 361 µm ± 32). Vascular injury scores demonstrated only mild vascular trauma for both stents (muraglitazar-eluting, 0.68 ± 0.07; control, 0.75 ± 0.08). Inflammation scores also showed mild inflammation for both stents (muraglitazar-eluting, 1.05 ± 0.17; control, 1.23 ± 0.19). CONCLUSIONS This new muraglitazar-eluting PLA96 stent was shown to be biocompatible with a tendency for better patency and less intimal hyperplasia compared with the control PLA96 stents.