An appropriately sized soft polyester external stent prevents enlargement and neointimal hyperplasia of a saphenous vein graft in a canine model.

Although the efficacy of external stents for vein grafts in coronary artery bypass grafting has been recognized, the ideal diameter and material of the stent remain controversial. We created a new external stent made of soft polyester mesh and performed an animal experiment using canines. Bilateral saphenous vein grafts were interposed in the bilateral common carotid artery of 10 beagles. The grafts in the left carotid artery were designated as the control group, and those in the right rolled by a soft polyester mesh external stent were designated as mesh group. Two of the 10 animals were sacrificed due to severe wound infection. The other eight were observed by echography for 6 months, and then grafts were extracted and thickness of the neointima of the grafts was measured. The control group showed 146% ± 26% postoperative enlargement of the internal diameter of the vein grafts after 6 months, whereas the mesh group showed only 115% ± 15% after the same duration (P = 0.0003). The median thickness of the neointima in the mesh group (170 µm [range: 150-190]) was significantly thinner than that in the control group (260 µm [range: 220-310], P < 0.0001). Some degree of correlation between the thickness of neointima and proportion of enlargement was noted (r = 0.518, P = 0.0024). A soft polyester mesh external stent for vein grafts successfully suppressed the enlargement of the vein grafts and thickness of the neointima after 6 months.

First-in-Man Trial of SiO2 Inert-Coated Bare Metal Stent System in Native Coronary Stenosis　- The AXETIS FIM Trial.

BACKGROUND: A novel bare metal stent with an SiO2coating was developed to prevent excessive neointimal hyperplasia by inertization of the metallic stent surface. The efficacy of the device was demonstrated in a preclinical model. The aim of this first-in-man trial was to assess the safety and feasibility of the new device.Methods and Results:This prospective non-randomized single-arm trial was designed to enroll 35 patients with a de novo coronary lesion. Quantitative coronary angiography and optical coherence tomography (OCT) were performed at the baseline procedure and at the 6-month follow-up. Stent implantation was performed with OCT guidance according to optimal stent implantation criteria. The trial was terminated upon the advice of the data safety monitoring board after enrolling 14 patients due to the high incidence of re-intervention. Optimal OCT implantation criteria were achieved in only 8.3% of lesions. At 6 months, angiographic in-stent late lumen loss as the primary endpoint was 0.77±0.44 mm, and binary restenosis occurred in 33.3% of lesions. At the 6-month OCT, neointimal volume obstruction was 32.8±15.6% with a neointimal thickness of 237±117 µm. At 12 months, the device-oriented composite endpoint (defined as cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization rate) was 33.3%. CONCLUSIONS: In contrast with the preclinical study, the Axetis stent did not efficiently suppress neointimal hyperplasia in humans in this trial.

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.

Inhibition of neo-intimal hyperplasia in porcine coronary arteries utilizing a novel paclitaxel-coated scoring balloon catheter.

OBJECTIVE: Scoring balloons are particularly useful in the acute treatment of fibro-calcific, bifurcation and in-stent restenosis lesions but have not been shown to affect the restenosis rate. Conventional balloons coated with paclitaxel have recently been shown to reduce restenosis rates in certain lesion subsets, but are associated with suboptimal acute results. A novel paclitaxel-coated scoring balloon was developed to overcome these limitations. DESIGN: AngioSculpt(®) scoring balloons (SB) were coated with paclitaxel admixed with a specific excipient. SETTING AND INTERVENTIONS: Four in vitro and in vivo studies were performed: (a) loss of the drug during passage to the lesion, (b) transfer of the drug to the vessel wall; (c) inhibition of neo-intimal proliferation in porcine coronary arteries as compared to uncoated SB and the Paccocath™, and (d) evaluation of the dose-response to 1.5-12 µg of paclitaxel/mm(2) . MAIN OUTCOME MEASURES AND RESULTS: Drug loss during delivery to the lesion was 17% ± 8%, and transfer to the vessel wall was 9% ± 4% of dose on unused balloons. The paclitaxel-coated SB resulted in a lower late lumen loss of 0.27 ± 0.24 mm compared to 1.4 ± 0.7 mm with the uncoated SB (P = 0.001). Histomorphometry revealed larger luminal areas of 6.8 ± 1.6 mm(2) (paclitaxel-coated SB) and 5.8 ± 1.7 mm(2) (Paccocath) as compared to the uncoated SB (2.3 ± 1.5 mm(2) ; P = 0.001). No coating related adverse effects were observed on follow-up angiography or histologic examination at the treatment site or downstream myocardium. CONCLUSION: A novel paclitaxel-coated SB leads to a significant inhibition of neointimal proliferation in the porcine coronary model.

Small-diameter vascular graft composing of core-shell structured micro-nanofibers loaded with heparin and VEGF for endothelialization and prevention of neointimal hyperplasia.

Despite the significant progress made in recent years, clinical issues with small-diameter vascular grafts related to low mechanical strength, thrombosis, intimal hyperplasia, and insufficient endothelialization remain unresolved. This study aims to design and fabricate a core-shell fibrous small-diameter vascular graft by co-axial electrospinning process, which will mechanically and biologically meet the benchmarks for blood vessel replacement. The presented graft (PGHV) comprised polycaprolactone/gelatin (shell) loaded with heparin-VEGF and polycaprolactone (core). This study hypothesized that the shell structure of the fibers would allow rapid degradation to release heparin-VEGF, and the core would provide mechanical strength for long-term application. Physico-mechanical evaluation, in vitro biocompatibility, and hemocompatibility assays were performed to ensure safe in vivo applications. After 25 days, the PGHV group released 79.47 ± 1.54% of heparin and 86.25 ± 1.19% of VEGF, and degradation of the shell was observed but the core remained pristine. Both the control (PG) and PGHV groups demonstrated robust mechanical properties. The PGHV group showed excellent biocompatibility and hemocompatibility compared to the PG group. After four months of rat aorta implantation, PGHV exhibited smooth muscle cell regeneration and complete endothelialization with a patency rate of 100%. The novel core-shell structured graft could be pivotal in vascular tissue regeneration application.

Suppression of neointimal hyperplasia by sirolimus-eluting expanded polytetrafluoroethylene (ePTFE) haemodialysis grafts in comparison with paclitaxel-coated grafts.

BACKGROUND: Haemodialysis vascular access dysfunction caused by aggressive venous neointimal hyperplasia is a major problem for haemodialysis patients with synthetic arteriovenous (AV) grafts. Several different strategies to prevent venous stenosis by inhibiting smooth muscle cell proliferation and migration using local delivery of potent antiproliferative agents are currently under investigation. We performed this study to evaluate the efficacy of sirolimus-eluting vascular grafts in preventing stenosis and to compare the effectiveness of sirolimus-coated grafts with that of paclitaxel-coated vascular grafts that we characterized in a previous study. METHODS: AV grafts were implanted laterally between the common carotid artery and external jugular vein of 14 female Landrace pigs. Three types of grafts were implanted: grafts coated with 1.08 µg/mm(2) sirolimus (low dose, n = 6), grafts coated with 2.41 µg/mm(2) sirolimus (high dose, n = 2) and uncoated control grafts (n = 6). Animals were sacrificed 6 weeks after surgery. Cross-sections of the venous anastomoses were analysed to determine the percentage of luminal stenosis in each group, and immunohistochemistry was performed to identify the cellular phenotypes of the neointimal hyperplasia and tissues adjacent to the implanted grafts. RESULTS: Compared with the control group, neointimal hyperplasia in the venous anastomoses of the groups implanted with sirolimus-coated vascular grafts was significantly suppressed without infection. The mean ± standard error values for the percentage of luminal stenosis were 75.7 ± 12.7% in the control group and 22.2 ± 1.41% in the low-dose sirolimus-coated group. Myofibroblasts and fibroblasts were the major cell types found in the neointimal hyperplasia. CONCLUSIONS: Neointimal hyperplasia was effectively suppressed by sirolimus-eluting grafts. However, the inhibitory effects of sirolimus-eluting grafts were weaker than those observed for paclitaxel-coated grafts in our previous study.

Thermal sensitivity of endothelial cells on synthetic vascular graft material.

PURPOSE: The goal is to identify thermal exposures capable of reducing or eliminating cell survival on expanded polytetrafluoroethylene (ePTFE), in an effort to develop a mild hyperthermia treatment of neointimal hyperplasia in ePTFE vascular grafts. MATERIALS AND METHODS: Viable and dead bovine aortic endothelial cells were quantified following different thermal exposure conditions: cells on collagen-coated ePTFE sheets or tissue culture polystyrene dishes were heated at 42° and 45°C to determine their thermal sensitivity on different surfaces, and cells cultured on collagen-coated ePTFE sheets were heated at 43-50°C for various durations, followed by incubation at 37°C for 0 and 20 h, respectively. Significant cell death was set to be 50%. Two types of cell death, apoptosis and necrosis, were distinguished by cell morphology and membrane integrity assessments. RESULTS: The attachment and survival of cells on ePTFE sheets were more sensitive to inhibition by mild heating than those on tissue culture dishes. Exposure to 45°C for 90 min and 50°C for 30 min caused significant necrotic cell death on ePTFE (65% and 75%, respectively). A 37°C/20-h incubation following 30-min exposures at 47° and 50°C increased total cell death (necrosis + apoptosis) from 20% to 50% and 75% to 100%, respectively. CONCLUSION: Cells grown on ePTFE were more susceptible to mild hyperthermia-induced death, compared to those on tissue culture dishes. Significant cell death on ePTFE mainly via apoptosis can be achieved by optimising temperature and duration of exposure.

[Histological character of intimal hyperplasia post jugular vein grafts and the protective effect of lovastatin].

OBJECTIVE: To investigate the characteristics of intimal hyperplasia and lovastatin's effects on canine jugular venous prosthesis bypass grafting. METHODS: In the study, 12 adult mistus dogs were randomly divided into 2 groups: lovastatin group and control group. All the dogs were performed with jugular venous prosthesis bypass grafting (ePTFE, 6 mm in diameter, and 5 cm in length). Four weeks later, all the 12 specimens were harvested. The patency and mural thrombus of grafts were evaluated. The characteristics of intimal hyperplasia were described and measured by HE staining and endothelial nitric oxide synthase (eNOs) immunohistochemical method. The differences between the two groups were compared. RESULTS: Four weeks later, 3 grafts with complete occlusion were found in the two groups separately. Apparent intimal hyperplasia was observed in all the grafts. The neointima of proximal and distal part in lovastatin group were thinner than in control group respectively (proximal P=0.045, distal P=0.040). The endothelial cells were found in the surface of neointima. Newly born vessels could be found in the neointima and the new vessels were more in lovastatin group than in control group (proximal P=0.041, distal P=0.031). CONCLUSION: At the end of 4 weeks, the intimal hyperplasia with neovascularization was obviously near the anastomosis. Lovastatin showed the ability to inhibit the intimal hyperplasia and promote the neovascularization.

[Unilateral condylar hyperactivity]. / Unilaterale condylaire hyperactiviteit.

Unilateral condylar hyperactivity is a growth disorder which is characterised by a progressive asymmetry in the mandibula and in some cases also secondarily in the maxilla. Various forms are hemimandibular hyperplasia, hemimandibular elongation and a hybridform. In deciding on a plan of treatment, it is important to determine whether there is a question of continuous and/or excessive condylar activity, possibly with the help of a skeletal scintigraphy.

Mir-22-incorporated polyelectrolyte coating prevents intima hyperplasia after balloon-induced vascular injury.

Drug-coated balloons (DCBs) offer potential to deliver drugs to treat coronary lesions but without leaving permanent implants behind. Paclitaxel and sirolimus are anti-proliferation drugs that are commonly used in commercially available DCBs. However, these drugs present significant cytotoxicity concern and low efficacy in vivo. Here, we use microRNA-22 (miR-22) as balloon loaded drugs and polyelectrolyte complexes (PECs) polyethyleneimine/polyacrylic acid (PEI/PAA) as balloon coatings to establish a new DCB system through the ultrasonic spray method. The PEI/PAA forms a stable and thin coating on the balloon, which resulted in a good transfer capacity to the vessel wall both in vitro and in vivo. miR-22 that could modulate smooth muscle cell (SMC) phenotype switching is incorporated into the PEI/PAA coating and shows a sustained release profile. The PEI/PAA/miR-22 coated balloon successfully inhibits intima hyperplasia after balloon-induced vascular injury in a rat model through decreasing proliferative SMCs via the miR-22-methyl-CpG binding protein 2 (MECP2) axis. Our findings indicate that balloons coated with PEI/PAA/miR-22 have great potential to be promising DCBs in the treatment of cardiovascular disease.

Sirolimus-eluting cobalt-chrome alloy stent suppresses stent-induced tissue hyperplasia in a porcine Eustachian tube model.

Various preclinical studies with developed Eustachian tube (ET) stents are in progress but have not yet been clinically applied. ET stent is limited by stent-induced tissue hyperplasia in preclinical studies. The effectiveness of sirolimus-eluting cobalt-chrome alloy stent (SES) in suppressing stent-induced tissue hyperplasia after stent placement in the porcine ET model was investigated. Six pigs were divided into two groups (i.e., the control and the SES groups) with three pigs for each group. The control group received an uncoated cobalt-chrome alloy stent (n = 6), and the SES group received a sirolimus-eluting cobalt-chrome alloy stent (n = 6). All groups were sacrificed 4 weeks after stent placement. Stent placement was successful in all ETs without procedure-related complications. None of the stents was able to keep its round shape as original, and mucus accumulation was observed inside and around the stent in both groups. On histologic analysis, the tissue hyperplasia area and the thickness of submucosal fibrosis were significantly lower in the SES group than in the control group. SES seems to be effective in suppressing stent-induced tissue hyperplasia in porcine ET. However, further investigation was required to verify the optimal stent materials and antiproliferative drugs.

Coating small-diameter ePTFE vascular grafts with tunable poly(diol-co-citrate-co-ascorbate) elastomers to reduce neointimal hyperplasia.

Lack of long-term patency has hindered the clinical use of small-diameter prosthetic vascular grafts with the majority of these failures due to the development of neointimal hyperplasia. Previous studies by our laboratory revealed that small-diameter expanded polytetrafluoroethylene (ePTFE) grafts coated with antioxidant elastomers are a promising localized therapy to inhibit neointimal hyperplasia. This work is focused on the development of poly(diol-co-citrate-co-ascorbate) (POCA) elastomers with tunable properties for coating ePTFE vascular grafts. A bioactive POCA elastomer (@20 : 20 : 8, [citrate] : [diol] : [ascorbate]) coating was applied on a 1.5 mm diameter ePTFE vascular graft as the most promising therapeutic candidate for reducing neointimal hyperplasia. Surface ascorbate density on the POCA elastomer was increased to 67.5 ± 7.3 ng mg-1 cm-2. The mechanical, antioxidant, biodegradable, and biocompatible properties of POCA demonstrated desirable performance for in vivo use, inhibiting human aortic smooth muscle cell proliferation, while supporting human aortic endothelial cells. POCA elastomer coating number was adjusted by a modified spin-coating method to prepare small-diameter ePTFE vascular grafts similar to natural vessels. A significant reduction in neointimal hyperplasia was observed after implanting POCA-coated ePTFE vascular grafts in a guinea pig aortic interposition bypass graft model. POCA elastomer thus offers a new avenue that shows promise for use in vascular engineering to improve long-term patency rates by coating small-diameter ePTFE vascular grafts.

Comparison of thin-strut cobalt-chromium stents and stainless steel stents in a porcine model of neointimal hyperplasia.

BACKGROUND: The high radial force and durability of cobalt-chromium alloy enable the construction of low-profile stents with thin struts, which improves their elasticity and may play a key role in reducing the incidence of neointimal hyperplasia as well as allow faster endothelialization. The aim of this study was to compare cobalt-chromium (CoCr) and stainless steel (SS) coronary stents in a pig model of neointimal hyperplasia. MATERIAL/METHODS: Eighteen stents were implanted into the coronary arteries of nine pigs. Control coronarography was performed 28 days after stent implantation. The animals were then sacrificed, their hearts explanted, and the coronary arteries isolated for further histopathological analysis. RESULTS: Quantitative coronary angiography and histomorphometric analysis revealed no statistically significant difference between the two groups of stents. However, there was a trend toward greater late lumen loss (p=0.09) and neointimal area in the CoCr stents (p=0.08). The qualitative histopathology of the CoCr stents revealed findings typical of bare metal stents reviewed in the literature and approved for use in clinical practice. No signs of stent thrombosis, necrosis, or fibrin deposits were observed nor signs of excessive inflammatory reaction. Endothelialization was complete within 28 days. CONCLUSIONS: Despite thinner struts, CoCr stents have no advantage over stainless steel stents in terms of neointimal hyperplasia inhibition. However, their positive safety results together with their high radial strength, low profile, and excellent elasticity can ensure their usage, especially in lesions of complex morphology.

Novel biodegradable polymer-coated, paclitaxel-eluting stent inhibits neointimal formation in porcine coronary arteries.

BACKGROUND: Biodegradable polymer-coated stents may have positive effects on arterial healing, and reduce the need for prolonged antiplatelet therapy. AIM: To assess the vascular effects of the biodegradable polymer proposed as a stent coating, as well as to evaluate inhibition of intimal hyperplasia by Biodegradable Polymer-Coated Paclitaxel-Eluting Stents (BP-PES, LUC-Chopin, Balton) in porcine coronary arteries. METHODS: A total of 19 stents were implanted into the coronary arteries of 13 pigs: seven bare metal stents (BMS), six biodegradable polymer-coated stents (PCS) and six BP-PES. Animals were followed up for 28 days. Additionally, 11 BP-PES were implanted in four pigs which were followed for 90 days. Twenty eight and 90 days after stent implantation, the control coronary angiography was performed. Subsequently, the animals were sacrificed, their hearts were extracted and the coronary arteries were isolated for further histopathological analysis. RESULTS: After 28 days, BP-PES stents effectively limited neointimal hyperplasia in comparison to the control group (LL = 0.48 +/- 0.06 for BMS vs 0.87 +/- 0.16 for PCS vs 0.15 +/- 0.05 mm for BP-PES; p < 0.05). However, at three months, a 'catch-up' effect in neointimal formation was observed. Histopathology demonstrated favourable safety, with complete endothelialisation and inflammation significantly decreased between one and three months. CONCLUSIONS: It seems that the biodegradable polymer-coated, paclitaxel-eluting stent examined in the present study is both safe and feasible. This supports the first such study in humans being conducted.

Inhibition of hyperplasia during the implantation of the puborectalis-like artificial anal sphincter.

OBJECTIVES: This study aims to extend the implantation lifetime of the puborectalis-like artificial anal sphincter by inhibiting the occurrence of hyperplasia following the implantation process. METHOD: A new transmission structure was designed inside the puborectalis-like artificial anal sphincter to generate an adequate torque to maintain the feces, even if hyperplasia developed around the prosthetic sphincter. An outer shell was added to the prosthetic sphincter to decelerate the occurrence of hyperplasia on the outer shell side. Medical titanium alloy was tested to replace the nylon-12 prosthetic sphincter, while polyetheretherketone was used for the construction of the power supply unit in the puborectalis-like artificial anal sphincter system instead of nylon-12. In vivo experiments were conducted to evaluate all the methods presented in this study with 10 Pa Ma piglets, 1 domestic pig, and 1 beagle dog during the past 2 years. RESULTS: Compared with the previous prosthetic sphincter that was equipped with a fixed-axle gear transmission, the new transmission structure is equipped with a planet-gear train managed to generate a prosthetic sphincter output with a 53% larger torque but with the same size and type of motor as that used previously and increase the implantation lifetime by 56%. After the replacement of the nylon-12, the new prosthetic sphincter made of medical titanium alloy succeeded in extending the implanted lifetime by 83%. In addition, the lifetime was increased by 143%, when an outer shell was added to the prosthetic sphincter. Polyetheretherketone significantly decreased the growth rate of hyperplasia around the power supply unit by 44% after the replacement of the power supply unit material. After the combination of all the improvements, the longest implantation lifetime of the puborectalis-like artificial anal sphincter during the in vivo experiments was 7 months and 10 days, which reflected an improvement of 249%. CONCLUSION: All methods posted in this study were evaluated to be effective to prolong the implantation lifetime of the puborectalis-like artificial anal sphincter. Among the methods proposed, the most effective was the addition of the outer shell to the puborectalis-like artificial anal sphincter. The least effective method was the improvement of the transmission structure. Medical titanium alloy and polyetheretherketone were good replacements for nylon-12 that managed to extend the implantation lifetime and yield a moderate improvement.

Arsenic trioxide-eluting electrospun nanofiber-covered self-expandable metallic stent reduces granulation tissue hyperplasia in rabbit trachea.

Stent-related granulation tissue hyperplasia is a major complication that limits the application of stents in airways. In this study, an arsenic trioxide-eluting electrospun nanofiber-covered self-expandable metallic stent (ATO-NFCS) was developed. Poly-L-lactide-caprolactone (PLCL) was selected as the drug-carrying polymer. Stents with two different ATO contents (0.4% ATO/PLCL and 1.2% ATO/PLCL) were fabricated. The in vitro release in simulated airway fluid suggested that the total ATO release time was 1 d. The growth of human embryonic pulmonary fibroblasts (CCC-HPF-1), normal human bronchial epithelial cells and airway smooth muscle cells was inhibited by ATO. When embedded in paravertebral muscle, the nanofiber membrane showed good short-term and long-term biological effects. In an animal study, placement of the ATO-NFCS in the trachea through a delivery system under fluoroscopy was feasible. The changes in liver and kidney function 1 and 7 d after ATO-NFCS placement were within the normal range. On pathological examination, the heart, liver, spleen, lungs and kidneys were normal. The effectiveness of the ATO-NFCS in reducing granulation tissue hyperplasia and collagen deposition was demonstrated in the rabbit airway (n = 18) at 4 weeks. The present study preliminarily investigated the efficacy of the ATO-NFCS in reducing granulation tissue formation in the trachea of rabbits. The results suggest that the ATO-NFCS is safe in vivo, easy to place, and effective for the suppression of granulation tissue formation.

Antibiotic-coated ePTFE decreases graft colonization and neointimal hyperplasia.

BACKGROUND: Synthetic vascular conduits used in traumatic or infected fields have a high failure rate leading to catastrophic consequences including amputation and death. Although efforts to coat vascular grafts with antibiotics have had varying results, we developed a novel coating technique for expanded-polytetrafluoroethylene (ePTFE), which has proven to be effective in vitro. Thus, we hypothesized that the coated grafts would resist infection and have decreased neointimal hyperplasia when used in vivo in a large animal model. METHODS: Minocycline and rifampin suspended in a mixture of methacrylates were coated onto a 3cm segment of 6mm ePTFE (Bard, Tempe, AZ). An antibiotic-coated (ABX), adhesive-coated (AC), or control (C) ePTFE graft was then placed as an end-to-side graft into the left iliac artery of a male mongrel pig. Sterile saline or innoculum containing 3x10(8)Staphylococcus aureus (SA) or Staphylococcus epidermidis (SE) was then placed directly on the graft and the reflected peritoneum re-approximated to confine the bacteria. After 6 wk, the graft was harvested, cultured, and morphometric analyses of neointimal hyperplasia were performed. RESULTS: Twenty-seven pigs had grafts placed (9 ABX, 9 AC, 9 C) and harvested. Of the nine grafts exposed to SA, the uncoated and adhesive-coated grafts averaged greater than 50,000 colonies of SA while the antibiotic-coated grafts averaged less than 50 colonies. Although not statistically significant, neointimal hyperplasia was decreased by 15% to 20% when using an ABX graft in an infected field. CONCLUSIONS: The coated grafts appeared to decrease NIH formation although not significantly in this small pilot study. The methacrylate antibiotic-coated ePTFE graft did provide resistance to infection when used in infected fields.

[Controlled release of siRNA nanoparticles loaded in a novel external stent prepared by emulsion electrospinning attenuates neointima hyperplasia in vein grafts].

OBJECTIVE: To evaluate a strategy of using TF siRNA loaded in a novel external stent prepared by hybrid ultrafine fibrous membrane consisting of PLGA/Chitosan nanoparticles as a therapy for vein graft disease. METHODS: Hybrid ultrafine fibrous membranes consisting of PLGA/Chitosan nanoparticles were fabricated via a specially designed electrospinning setup. After soaking in chloroform to dissolve PLGA, the amount of chitosan in the hybrid membranes was determined. The water uptake of the hybrid ultrafine fibrous membranes was investigated by incubation in phosphate buffer solution. Right jugular vein-carotid artery interposition grafting models in Sprague-Dawley rats were randomly divided into five groups:Group A (external stent consisting of PLGA/CS-TFsiRNA nanoparticles), Group B (external stent consisting of PLGA/CS-Stealth(TM) RNAi negative control nanoparticles), Group C (external stent consisting of PLGA/CS blank nanoparticles), Group D (external stent consisting of PLGA), Group E (without perivenous external stent). BLOCK-iT(TM) Fluorescent Oligo was used to confirm its stability and successful transfer into the vein graft wall. The vein grafts were harvested at 1, 3, 7, 14, 28 d after operation, respectively. The TF protein expression of vein grafts was analyzed by Western blot and immunochemistry at 1, 3, 7 d after operation, respectively. The expression of proliferating cell nuclear antigen (PCNA) was identified by immunochemistry methods. The thickness of neointima at 28 d was calculated by computer imaging analysis system. RESULTS: The PLGA and CS amount in PLGA/Chitosan nanoparticles membranes could be well controlled by adjusting the flow rate for electrospinning of PLGA and chitosan nanoparticles, respectively. Because of the introduction of chitosan, which is a naturally hydrophilic polymer, the hybrid membranes exhibited good water absorption properties. BLOCK-iT(TM) Fluorescent Oligo could be detected in the graft wall even 12 days after operation. The expression of TF protein in Group A was significantly less than that in control groups at 3 d after operation (P < 0.05, 0.40 +/- 0.03 vs 0.75 +/- 0.01, 0.75 +/- 0.05, 0.77 +/- 0.07) and at 7 d after operation (P < 0.05, 0.30 +/- 0.03 vs 0.84 +/- 0.05, 0.86 +/- 0.06, 0.85 +/- 0.06). The expression of PCNA in Group A decreased significantly in comparison with control groups at 14 d after operation (P < 0.01, 13.0% +/- 2.6% vs 25.0% +/- 2.8%, 24.2% +/- 3.9%, 24.0% +/- 4.1%, 44.8% +/- 3.7%). The thickness of neointima at 28 d after grafting in Group A was significantly less than the untreated group (P < 0.01, 18.8 microm +/- 2.9 microm vs 38.7 microm +/- 5.0 microm, 37.3 microm +/- 3.6 microm, 37.2 microm +/- 2.6 microm, 67.5 microm +/- 4.8 microm). CONCLUSION: The novel external stent prepared by hybrid ultrafine fibrous membrane consisting of PLGA/Chitosan nanoparticles inhibits early neointima formation in rat vein grafts. This strategy may be a practicable and promising form of gene delivery against vein graft failure.

Rapamycin Combined with α-Cyanoacrylate Contributes to Inhibiting Intimal Hyperplasia in Rat Models.

BACKGROUND: Vein graft restenosis has an adverse impact on bridge vessel circulation and patient prognosis after coronary artery bypass grafting. OBJECTIVES: We used the extravascular supporter α-cyanoacrylate (α-CA), the local application rapamycin/sirolimus (RPM), and a combination of the two (α-CA-RPM) in rat models of autogenous vein graft to stimulate vein graft change. The aim of our study was to observe the effect of α-CA, RPM, and α-CA-RPM on vein hyperplasia. METHODS: Fifty healthy Sprague Dawley (SD) rats were randomized into the following 5 groups: sham, control, α-CA, RPM, and α-CA-RPM. Operating procedure as subsequently described was used to build models of grafted rat jugular vein on carotid artery on one side. The level of endothelin-1 (ET-1) was determined by enzyme-linked immunosorbent assay (ELISA). Grafted veins were observed via naked eye 4 weeks later; fresh veins were observed via microscope and image-processing software in hematoxylin-eosin (HE) staining and immunohistochemistry after having been fixed and stored" (i.e. First they were fixed and stored, and second they were observed); α-Smooth Muscle Actin (αSMA) and von Willebrand factor (vWF) were measured with reverse transcription-polymerase chain reaction (RT-PCR). Comparisons were made with single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant. RESULTS: We found that intimal thickness of the α-CA, RPM, and α-CA-RPM groups was lower than that of the control group (p < 0.01), and the thickness of the α-CA-RPM group was notably lower than that of the α-CA and RPM groups (p < 0.05). CONCLUSION: RPM combined with α-CA contributes to inhibiting intimal hyperplasia in rat models and is more effective for vascular patency than individual use of either α-CA or RPM.

Selective endothelialization and alleviation of neointimal hyperplasia by functionalizing the Ti-O surface with l-selenocystine and KREDVC.

Due to their relatively good biocompatibility and inactivity, titanium oxide films (Ti-O) are used in the coating of coronary stents, which reduces metal corrosion, slows metal ion release, and improves endothelial cell (EC) compatibility. Here, we report further functionalizing Ti-O with biological cues for selective endothelialization. Selenocystine with an l- or a d-enantiomer was first immobilized on the Ti-O film via polydopamine to generate nitric oxide (NO) endogenously, which inhibited smooth muscle cell (SMC) proliferation, followed by the grafting of a functional KREDVC peptide to induce EC adhesion. The synergistic effects of the immobilized KREDVC, surface chirality, and NO generation on selective endothelialization were investigated. The results showed that the surface chirality of the l-enantiomer and KREDVC grafting significantly enhanced the attachment and growth of ECs compared to SMCs. An in vivo study showed von Willebrand factor expression was increased and neointimal hyperplasia was significantly decreased in samples with l-selenocystine immobilization and KREDVC grafting. In summary, these findings provide new insights on the surface modification of cardiovascular implants with selective endothelialization.