Joonas Mikkonen

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.

Biocompatibility of a New Bioabsorbable Radiopaque Stent Material (BaSO4 Containing Poly-L,D-Lactide) in the Rat Pancreas

Background/Aim: During recent years, we have been developing bioabsorbable biliary stents with promising experimental results. In developing pancreatic stents before long-term experiments, the acute toxicity to the pancreas of a bioabsorbable, radiopaque polylactide (PLA 96-barium sulfate, BaSO4) stent material was investigated. Methods: The pancreas of 65 Sprague-Dawley rats was exposed either to radiopaque stent material [PLA 96 with 25% (w/w) of BaSO4], radiolucent stent material (PLA 96), or inert steel by inserting a 5-mm-long (diameter 0.3 mm) fiber/stick of material into the pancreas after laparotomy under general anesthesia. Pancreatic tissue specimens and blood samples were taken after 1, 3, 7, and 21 days for histological examination and amylase activity measurements. Samples were also taken from 5 baseline (control) rats without exposing to any materials. Results: The baseline serum amylase activity was normal, and no histological changes in the pancreas were observed. A significant increase (mean ± SE) in the serum amylase activity was observed only on day 1 in the animals having radiopaque stent material (PLA 96-BaSO4; 5,845 ± 1,135 U/l), steel (4,946 ± 667 U/l), or radiolucent stent material (PLA 96; 7,684 ± 667 U/l) inserted. There was slightly more acinar cell necrosis on day 7 in the steel group than in the radiopaque stent (PLA 96-BaSO4) group (p = 0.028). Conclusions: Radiopaque stent material (PLA 96-BaSO4) was not more toxic than the reference steel material in the rat pancreas during the 21-day observation period and is thus applicable for further in vivo experiments when developing pancreatic bioabsorbable stents.

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.

A novel biodegradable pancreatic stent for human pancreatic applications: a preclinical safety study in a large animal model

BACKGROUND Endoscopic stenting is one treatment method for pancreatic strictures or pseudocysts in patients with symptomatic chronic pancreatitis. With a biodegradable stent, the later removal of the stent could be avoided. OBJECTIVE We investigated the degradation, patency, and toxicity of a novel biodegradable, self-expanding radiopaque polylactide-barium sulfate pancreatic stent in a large animal model. DESIGN Animal study. SETTING AND INTERVENTIONS Five swine had a biodegradable pancreatic stent placed into the pancreatic duct (PD) and were followed-up for 6 months. MAIN OUTCOME MEASUREMENTS Repeated blood tests and radiographs were studied during the follow-up. The animals were euthanized at 6 months, at which time, the PD inner diameter was measured, and histology was analyzed and graded. For comparison, histology from 5 nonstented animals was also analyzed. RESULTS The stent was correctly inserted into the PD in 4 of 5 animals. All the animals remained healthy, gained weight, and showed no signs of pancreatitis. A radiograph showed that the stent was in its original place in all animals at 1 month but had disappeared in all animals by 3 months. At 6 months, the autopsied pancreatic tissue was soft, and the PD was patent in all of the animals. The PD was slightly dilated at the site of the stent in the head of the pancreas compared with the preoperative diameter (5 mm [range 3-6 mm] vs 2 mm [range 1-3 mm], P < .05), but, in the body of the pancreas, no significant dilatation was seen. In the histology of the pancreata, there was no difference between the samples from the exposed parts of the biodegradable pancreatic stent compared with the distal nonexposed parts, or to the samples from the nonstented animals. CONCLUSIONS This novel biodegradable pancreatic stent, studied in these swine, appeared to be safe for use in the PD. These encouraging results warrant further clinical trials with this biodegradable pancreatic stent in pancreatic applications in human beings.

Biodegradable braided poly(lactic-co-glycolic acid) urethral stent combined with dutasteride in the treatment of acute urinary retention due to benign prostatic enlargement: a pilot study.

To evaluate, in a pilot study, the efficacy and safety of combining a braided poly(lactic‐co‐glycolic acid) (PLGA, a copolymer of l‐lactide and glycolide) urethral stent and dutasteride in the treatment of acute urinary retention (AUR) due to benign prostatic enlargement (BPE).

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.

A new biodegradable braided self-expandable PLGA prostatic stent: an experimental study in the rabbit.

PURPOSE The biodegradable PLGA (a copolymer of L-lactide and glycolide) urethral stent with a spiral configuration has been used clinically for the prevention of postoperative urinary retention after different types of thermal therapy for benign prostatic hyperplasia. A new braiding pattern for this stent has recently been developed by our group. The aim here was to investigate the in situ degradation and biocompatibility of the new braided stent in the rabbit urethra. MATERIALS AND METHODS PLGA stents with a one-over-one braiding pattern and steel stents served as controls that were inserted into the posterior urethras of 24 male rabbits using a special delivery instrument. The animals were sacrificed after 1 week, 1 month, 2 months, or 4 months, and light microscopy and histologic analyses were performed. RESULTS The delivery instrument worked well and cystoscopy was not needed in the insertion process. The braided PLGA stents degraded smoothly in 1 to 2 months. The metallic stents induced more epithelial hyperplasia and epithelial changes than the biodegradable stents at all time points analyzed. These differences increased during follow-up. CONCLUSION The degradation process was well controlled and the biodegradable stents were more biocompatible than the metallic stents. The new stent can be inserted into the posterior urethra without cystoscopic aid.

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.