Treatment of acute pulmonary embolism after catheter-directed thrombolysis with dabigatran vs warfarin: results of a multicenter randomized RE-SPIRE trial.

BACKGROUND: Thrombolytic therapy is effective method in the high-risk acute pulmonary embolism (PE) treatment. Reduced-dose thrombolysis (RDT) plus oral anticoagulation therapy is effective and safe method in the moderate and severe PE treatment. It is leading to good early and intermediate-term outcomes. In the RE-COVER and RE-COVER II studies, dabigatran showed similar effectiveness as warfarin in the treatment of acute PE. Dabigatran leads to fewer hemorrhagic complications and is not inferior in efficacy to warfarin in the prevention of PE after mechanical fragmentation and RDT (catheter-directed treatment [CDT]+RDT) in patients with high and intermediate to high PE risk. We sought to evaluate the efficacy and safety (incidence of clinically significant recurrence of venous thromboembolic complications and deaths) during a 6-month course of treatment with dabigatran or warfarin in patients with high and intermediate to high acute PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT). METHODS: The RE-SPIRE is a prospective, multicenter randomized double-arm study. Over a 5-year period, 66 consecutive patients with symptomatic high and intermediate to high PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT) were randomized into two groups within the next 48 hours. The first group continued treatment with dabigatran 150 mg twice a day for 6 months; the second group continued treatment with warfarin under the control of international normalized ratio (2.0-3.0) for 6 months. Both groups received low molecular weight heparins for 2 days after surgery. Then, group 1 continued to receive low molecular-weight-heparin for 5 to 7 days, followed by a switch to dabigatran at a dosage of 150 mg two times a day. Group 2 received both low-molecular-weight heparin and warfarin up to an international normalized ratio of >2.0, followed by heparin withdrawal. The follow-up period was 6 months. RESULTS: There were 63 patients who completed the study (32 in the dabigatran group and 31 in the warfarin group). In both groups, there was a statistically significant decrease in the mean pulmonary artery pressure. The mean pulmonary artery pressure at the 6-month follow-up after surgery was 24 mm Hg (interquartile range, 20.3-29.25 mm Hg) in the dabigatran group and 23 mm Hg (interquartile range, 20.0-26.3 mm Hg) in the warfarin group. The groups did not differ statistically in the deep vein thrombosis dynamics. Partial recanalization occurred in 52.0% vs 73.1% in the dabigatran and warfarin groups, respectively (P = .15). Complete recanalization occurred in 28.0% vs 19.2% in the dabigatran and warfarin groups, respectively (P = .56). The groups did not differ in the frequency of major bleeding events according to the International Society for Thrombosis and Hemostasis (0% vs 3.2% in the dabigatran and warfarin groups, respectively; P = 1.00). However, there were more nonmajor bleeding events in the warfarin group than in the dabigatran group (16.1% vs 0%, respectively; P = .02). CONCLUSIONS: The results of the study show that dabigatran is comparable in effectiveness to warfarin. Dabigatran has greater safety in comparison with warfarin in the occurrence of all cases of bleeding in the postoperative and long-term periods. Thus, dabigatran may be recommended for the treatment and prevention of PE after CDT with RDT in patients with high and intermediate to high PE risk.

4π light scattering flow cytometry: enhancing the identification and characterization of individual cells.

The analysis of individual particles with complex morphologies from light scattering is crucial in disperse systems studies, such as blood cells. Characterization, which assumes determining particle characteristics, has a higher likelihood of succeeding in solving the inverse light-scattering problem if an instrument provides enough light-scattering data. In this study, we demonstrate how we extend the operating angular interval for the 4π Scanning Flow Cytometer (4πSFC), which measures angle-resolved light-scattering profiles (LSPs) of individual particles. The angular interval is extended by additionally measuring light scattering for the backward hemisphere. Currently, the 4πSFC setup uses three lasers, a single optical cell, and three photomultipliers. It enables the measurement of the LSP of individual particles within the angular interval of 10 to 170° for polar angles with integration over azimuth angles, which covers the spatial angle of 98.5% of the 4π angle. We demonstrate the 4πSFC's performance in measuring LSPs from the analysis of polymer beads, mature and spherized erythrocytes, and platelets. The 4πSFC has the potential to be very useful in identifying platelet dimers and granulocytes without labels, characterizing lymphocytes, monocytes, and abnormal erythrocytes.

Fibrin Sealant TISSEEL Lyo as a haemostatic agent in vascular surgery: Results of randomized, controlled, patient-blinded, multicentre clinical study in the Russian population.

BACKGROUND: This phase III, controlled, patient-blinded, multicentre study in two parallel, equal-sized treatment groups compared the efficacy and safety of TISSEEL Lyo, fibrin sealant versus Manual Compression (MC) with surgical gauze pads for use as a haemostatic agent in patients who underwent vascular surgery in Russia. METHODS: Adult patients, both genders, who received peripheral vascular expanded polytetrafluoroethylene conduits and had suture line bleeding after surgical haemostasis were enrolled. Patients were randomized to be treated with TISSEEL Lyo or MC. The bleeding needed additional treatment and had to be assessed as grade 1 or 2 bleeding according to the Validated Intraoperative Bleeding scale. The primary efficacy endpoint was the proportion of patients achieving haemostasis at 4 min after treatment application (T4) at the study suture line, which was maintained until the closure of the surgical wound. The secondary efficacy endpoints included the proportion of patients achieving haemostasis at 6 min (T6) and 10 min (T10) after treatment application at the study suture line, which was maintained until closure of the surgical wound, as well as the proportion of patients with intraoperative and postoperative rebleeding. Safety outcomes included incidence of adverse events (AEs), surgical site infections and graft occlusions. RESULTS: A total of 110 patients were screened; 104 patients were randomized: (TISSEEL Lyo: 51 [49%] patients; MC: 53 [51%] patients). T4 haemostasis was achieved in 43 (84.3%) patients in the TISSEEL Lyo group and in 11 (20.8%) patients in the MC group (p < 0.001). Significantly more patients in TISSEEL Lyo group achieved the haemostasis at T6 (relative risk (RR) of achieving haemostasis 1.74 [95% confidence interval (CI) 1.37; 2.35]) and T10 (RR 1.18 [95% CI 1.05; 1.38]) versus MC. No one had intraoperative rebleeding. Postoperative rebleeding was reported only in one patient in the MC group. No treatment-emergent serious AEs (TESAEs) related to TISSEEL Lyo/MC, TESAEs leading to withdrawal and TESAEs leading to death were reported in patients during the study. CONCLUSIONS: Data demonstrated TISSEEL Lyo had clinically and statistically significant superiority to MC as a haemostatic agent in vascular surgery at all measured time points including 4, 6 and 10 min and had proven to be safe.

Ultraviolet light scattering scanning flow cytometry in the characterization of submicron microparticles.

Ultraviolet lasers are commonly used in flow cytometry to excite fluorochrome molecules with subsequent measurement of the specific fluorescence of individual cells. In this study, the performance of the ultraviolet light scattering (UVLS) in the analysis of individual particles with flow cytometry has been demonstrated for the first time. The main advantage of the UVLS relates to the improvement of the analysis of submicron particles due to the strong dependence of the scattering efficiency on the wavelength of the incident light. In this work, submicron particles were analyzed using a scanning flow cytometer (SFC) that allows measurements of light scattering in an angle-resolved regime. The measured light-scattering profiles of individual particles were utilized in solution of the inverse light-scattering problem to retrieve the particle characteristics using a global optimization. The standard polystyrene microspheres were successfully characterized from the analysis of UVLS which provided the size and refractive index (RI) of individual beads. We believe that the main application of UVLS relates to the analysis of microparticles in a serum, in particular in the analysis of chylomicrons (CMs). We have demonstrated the performance of the UVLS SFC in the analysis of CMs of a donor. The RI versus size scatterplot of CMs was successfully retrieved from the analysis. The current set-up of the SFC has allowed us to characterize individual CMs starting from the size of 160 nm that provides determination of the CM concentration in a serum with flow cytometry. This feature of the UVLS should help with the analysis of lipid metabolism measuring RI and size map evolution after lipase action.

Treatment of Long Femoropopliteal Occlusive Lesions With Self-expanding Interwoven Nitinol Stent: 24 Month Outcomes of the STELLA-SUPERA-SIBERIA Register Trial.

PURPOSE: The efficacy and safety of the Supera stent in superficial femoral artery (SFA) have been reported mostly in shorter lesions with relatively low proportion of occlusions. There are little data on the effectiveness of the Supera stent in long lesions. The aim of this study was to assess the clinical safety and efficiency of the Supera stent in the treatment of long femoropopliteal occlusive lesions (Trans-Atlantic Inter-Society Consensus [TASC] C/D) in patients with symptomatic peripheral artery disease. MATERIALS AND METHODS: The STELLA-SUPERA-SIBERIA is a prospective, single-center, single-arm study. Patients with symptomatic (Rutherford stages 3-6) de novo and TASC C/D occlusive lesions of the femoropopliteal segment were treated with Supera stent. The primary endpoint was the 12 month rate of primary sustained clinical improvement (upward shift on the Rutherford classification to a one level without the need for repeated target lesion revascularization (TLR) in surviving patients without the need for unplanned amputation). Secondary endpoints were the 24 month of primary sustained clinical improvement, MALE, limb salvage, the primary patency, the secondary patency, 24 month MACE. Follow-up included clinical examination, duplex scan, and biplane x-ray up to 24 months. RESULTS: Between April 2019 and January 2020, 52 symptomatic patients with 55 long femoropopliteal occlusive lesions (52.7% TASC D lesions and 47.3% TASC C lesions) were treated. The mean target lesion length was 205±72 mm. All patients had total occlusions. The mean lesion length of the implanted Supera stents was 198±82 mm. At 12 and 24 months, the primary sustained clinical improvement rate was 80.2% and 63.6%, respectively. The Rutherford category assessment was significantly improved at 24 months compared with baseline (p=0.02). The primary patency rate at 12 and 24 months was 78.1% and 60.0%, respectively. At 12 and 24 months, freedom from TLR was 83.5% and 81.8%, respectively. There were no stent fractures at 24 months. CONCLUSION: Supera Stent implantation for TASC C/D femoropopliteal lesions revascularization appears to be a safe and efficient implant given the complexity of the treated lesions. Head-to-head studies are mandatory to establish Supera Stent as an alternative tool to open surgery for long femoropopliteal lesions. CLINICAL IMPACT: Our study indicated, that using self-expanding interwoven nitinol stent for TASC C/D femoropopliteal lesions revascularization appears to be a safe and efficient implant given the complexity of the treated lesions. Although bypass grafting is recommended for prolonged femoropopliteal lesions, open surgery is more traumatic and is associated with greater risks than endovascular procedures. Our findings suggest that the use of interwoven nitinol stents can overcome the disadvantages of traditional stents in such cases, which may help to improve patients' outcomes and reduce the risk of adverse events.

A light scatter based model relating erythrocyte vesiculation to lifetime in circulation.

Methods for measuring erythrocyte age distribution are not available as a simple analytical tool. Most of them utilize the fluorescence or radioactive isotopes labeling to construct the age distribution and support physicians with aging indices of donor's erythrocytes. The age distribution of erythrocyte may be a useful snapshot of patient state over 120-days period of life. Previously, we introduced the enhanced assay of erythrocytes with measurement of 48 indices in four categories: concentration/content, morphology, aging and function (10.1002/cyto.a.24554). The aging category was formed by the indices based on the evaluation of the derived age of individual cells. The derived age does not exactly mean the real age of erythrocytes and its evaluation utilizes changes of cellular morphology during a lifespan. In this study, we are introducing the improved methodological approach that allows us to retrieve the derived age of individual erythrocytes, to construct the aging distribution, and to reform the aging category consisting of eight indices. The approach is based on the analysis of the erythrocyte vesiculation. The erythrocyte morphology is analyzed by scanning flow cytometry that measures the primary characteristics (diameter, thickness, and waist) of individual cells. The surface area (S) and sphericity index (SI) are calculated from the primary characteristics and the scattering diagram SI versus S is used in the evaluation of the derived age of each erythrocyte in a sample. We developed the algorithm to evaluate the derived age that provides eight indices in the aging category based on a model using light scatter features. The novel erythrocyte indices were measured for simulated cells and blood samples of 50 donors. We determined the first-ever reference intervals for these indices.

Activated Carbon-Enriched Electrospun-Produced Scaffolds for Drug Delivery/Release in Biological Systems.

To vectorize drug delivery from electrospun-produced scaffolds, we introduce a thin outer drug retention layer produced by electrospinning from activated carbon nanoparticles (ACNs)-enriched polycaprolacton (PCL) suspension. Homogeneous or coaxial fibers filled with ACNs were produced by electrospinning from different PCL-based suspensions. Stable ACN suspensions were selected by sorting through solvents, stabilizers and auxiliary components. The ACN-enriched scaffolds produced were characterized for fiber diameter, porosity, pore size and mechanical properties. The scaffold structure was analyzed by scanning electron microscopy and X-ray photoelectron spectroscopy. It was found that ACNs were mainly coated with a polymer layer for both homogeneous and coaxial fibers. Drug binding and release from the scaffolds were tested using tritium-labeled sirolimus. We showed that the kinetics of sirolimus binding/release by ACN-enriched scaffolds was determined by the fiber composition and differed from that obtained with a free ACN. ACN-enriched scaffolds with coaxial and homogeneous fibers had a biocompatibility close to scaffold-free AC, as was shown by the cultivation of human gingival fibroblasts and umbilical vein cells on scaffolds. The data obtained demonstrated that ACN-enriched scaffolds had good physico-chemical properties and biocompatibility and, thus, could be used as a retaining layer for vectored drug delivery.

Erythrocyte lysis and angle-resolved light scattering measured by scanning flow cytometry result to 48 indices quantifying a gas exchange function of the human organism.

Molecular/cell level of gas exchange function assumes the accurate measurement of erythrocyte characteristics and rate constants concerning to molecules involved into the CO2 /O2 transport. Unfortunately, common hematology analyzers provide the measurement of eight indices of erythrocytes only and say little about erythrocyte morphology and nothing about rate constants of cellular function. The aim of this study is to demonstrate the ability of the Scanning Flow Cytometer (SFC) in the complete morphological analysis of mature erythrocytes and characterization of erythrocyte function via measurement of lysing kinetics. With this study we are introducing 48 erythrocyte indices. To provide the usability of application of the SFC in clinical diagnosis, we formed four categories of indices which are as follows: content/concentration (9 indices), morphology (26 indices), age (5 indices), and function (8 indices). The erythrocytes of 39 healthy volunteers were analyzed with the SFC to fix the first-ever reference intervals for the new indices introduced. The essential measurable reliability of the presented method is expressed in terms of errors of characteristics of single erythrocytes retrieved from the solution of the inverse light-scattering problem and errors of parameters retrieved from the fitting of the experimental kinetics by molecular-kinetics model of erythrocyte lysis.

One-Year Results of Long femoropopliteal Lesions Stenting with Fasciotomy Lamina Vastoadductoria.

BACKGROUND: Fasciotomy can increase the mobility of the superficial femoral artery and decrease the incidence of stent fractures. This study aimed to compare the long-term patency of drug-eluting nitinol stents with and without fasciotomy in patients with prolonged superficial femoral artery occlusions. METHODS: A randomized clinical trial was conducted in 60 (1:1) patients with long femoropopliteal steno-occlusive lesions >200 mm. Patients in group 1 (Zilver) underwent recanalization of femoropopliteal artery occlusion with stenting. In group 2 (ZilverFas), the femoropopliteal occlusion was recanalized with stenting and fasciotomy of Gunter's canal. The follow-up assessment of the patency took place after 6-12 months. RESULTS: Twelve-month primary patency in Zilver and ZilverFas groups was 51% and 80%, respectively (P = 0.02). The freedom from target lesion revascularization in the Zilver and ZilverFas groups was 50% and 76%, respectively (P = 0.04). At 1 year, primary-assisted patency and secondary patency for the ZilverFas and Zilver groups were 83% vs. 62% (P = 0.07) and 86% vs. 65% (P = 0.05), respectively. In the Zilver and ZilverFas groups, the number of stent fractures was 14 and 7, respectively (P = 0.05). The multivariable Cox regression indicated that the stent fracture and diabetes mellitus were independent predictors of restenosis and reocclusion. Fasciotomy reduced the risk of reocclusion and restenosis by 2.94 times. CONCLUSIONS: Our study has shown that decompressing the stented segment with fasciotomy significantly improves the patency of the femoropopliteal segment and significantly reduces the number and severity of stent fractures.

Activated Carbon for Drug Delivery from Composite Biomaterials: The Effect of Grinding on Sirolimus Binding and Release.

Activated carbon (AC) could be potentially useful as a drug carrier in fiber polymer scaffolds destined for prolonged drug delivery. To be introduced, AC must be ground into smaller-sized particles to be introduced in scaffolds, as most biocompatible scaffolds consist of fibers with a diameter of less than 1 µm. In this study, the adsorption of sirolimus (SRL) from phosphate-buffered saline (PBS) solution and blood plasma (BP) onto AC of AX-21 type, as well as the release of SRL from AC depending on its fragmentation, were studied. Two-stage grinding of the AC, first with a ball mill, and then with a bead mill, was performed. Grinding with a bead mill was performed either in water or in polyvinylpyrrolidone to prevent aggregation of AC particles. Dynamic light scattering and scanning electron microscopy (SEM) demonstrated that the size of the particles obtained after grinding with a ball mill was 100-10,000 nm, and after grinding with a bead mill, 100-300 nm. Adsorption in PBS was significantly higher than in BP for all fractions, and depended on SRL concentration. The fraction obtained after grinding with a ball mill showed maximal SRL adsorption, both in PBS and BP, and slow SRL release, in comparison with other fractions. The 100-300 nm AC fractions were able to adsorb and completely release SRL into BP, in contrast to other fractions, which strongly bound a significant amount of SRL. The data obtained are to be used for controlled SRL delivery, and thus in the modification of drug delivery in biological media.

Correction: Gostev et al. In Vivo Stability of Polyurethane-Based Electrospun Vascular Grafts in Terms of Chemistry and Mechanics. Polymers 2020, 12, 845.

The authors wish to make a change to the published paper [...].

Bypass Versus Interwoven Nitinol Stents for Long Femoro-Popliteal Occlusions: A Propensity Matched Analysis.

PURPOSE: To compare femoro-popliteal bypass and interwoven nitinol stenting for long occlusions of the femoro-popliteal segment. MATERIALS AND METHODS: Single center retrospective propensity matching analysis of the symptomatic patients with long occlusion of the femoro-popliteal segment (> 20 cm), who underwent stenting with interwoven nitinol stent or femoro-popliteal bypass from 2012 to 2020. PRIMARY ENDPOINTS: primary patency, primary-assisted patency, secondary patency. Secondary endpoints: major adverse cardiovascular events, major adverse limb events, primary sustained clinical improvement, survival. RESULTS: A total of 437 patients were enrolled: 294 in the bypass group and 143 in the endovascular therapy (EVT) group. After propensity score matching, 264 and 113 patients remained in the groups, respectively. A median occlusion length was 250 mm. One-year and two-year primary and secondary patency rates were comparable in both groups (two-year primary patency: 68.5% for bypass vs. 68.9% for EVT, p = 1.00). In the "above the knee" subgroup analysis, two-year secondary patency was higher in the EVT group than in the bypass group (90.9% vs. 77.5%, p = 0.048). In "below-the-knee" subgroup analysis, primary and primary assisted patency were statistically significantly higher in the EVT group than in artificial bypass subgroup (66.7% vs. 42.4%, p = .046 and 76.7% vs. 45.5%, p = .011, respectively). However, compared to autovenous bypass, the EVT group showed lower primary patency rates, although the differences are not significant. CONCLUSION: A nonselective endovascular strategy can allow for regular successful treatment of femoro-popliteal lesions longer than 25 cm.

Influence of lamina vastoadductoria dissection on the outcomes of femoral artery extensive lesion stenting: A pilot randomised investigation.

OBJECTIVE: Aim of the study was to improve the immediate and long-term results of stenting of the superficial femoral artery in extended lesions with the changing of the biomechanics of superficial ffemoral artery and of the first portion of the popliteal artery. METHODS: Pilot randomized prospective single-center study were included 70 patients. Patients were randomized into two groups in 1 × 1 format for 35 people using the envelope method. Self-expanding bare metal stents were used in all cases. At the first group standard revascularization procedures with SFA stenting were performed; in the second group, the superficial femoral artery stenting was supplemented with fasciotomy in the Hunter's canal with the superficial femoral artery intersection. The total observation period was 2 years. During the observation period an assessment of the clinical symptoms of the lower extremities, measurement of the ankle-brachial index and ultrasound duplex scanning of the operated segment were performed. RESULTS: All procedures in both groups were successfully performed. Primary patency through 24 months was 28.5% (10 of 35) in group 1 and 60% (21 of 35) in group 2 (p = 0,015). CONCLUSIONS: Changing the biomechanical properties of the distal of the superficial femoral artery segment and of the first portion of the popliteal artery is safe and contributes to the primary patency improvement during the stenting of extended of the superficial femoral artery lesions compared to standard SFA stenting. Dissection of the lamina vastoadductoria with transection of the collateral branches of the knee joint network reduces frequent and severe damages of stents after the stenting of the superficial femoral artery extended lesion. According to the frequency of complications in the early and mid-term postoperative period, limb salvage, mortality and the secondary patency rates, the new method is comparable with standard of the superficial femoral artery stenting.

Blood platelet quantification by light scattering: from morphology to activation.

Analysis of blood platelets encounters a number of different preanalytical issues, which greatly decrease the reliability and accuracy of routine clinical analysis. Modern hematology analyzers determine only four parameters relating to platelets. Platelet shape and dose-dependent activation parameters are outside the scope of commercial instruments. We used the original scanning flow cytometer for measurement of angle-resolved light scattering and the discrete dipole approximation for simulation of light scattering from a platelet optical model, as an oblate spheroid, and global optimization with two algorithms: the DATABASE algorithm to retrieve platelet characteristics from light scattering and the DIRECT algorithm to retrieve dose-dependent activation parameters. We developed the original sampling protocol to decrease spontaneous platelet activation. The new protocol allows us to keep most of the platelets in resting and partially activated states before analysis. The analysis delivers 13 content and morphological parameters of the platelets. To analyze platelet shape change during ADP activation we developed a phenomenological model. This model was applied to the analysis of ADP activation of platelets to give 8 dose-dependent activation parameters. To demonstrate the applicability of the developed protocol and analytical method, we analyzed platelets from five donors. This novel approach to the analysis of platelets allows the determination of 21 parameters relating to their content, morphology and dose-dependent activation.

Influence of Elongation of Paclitaxel-Eluting Electrospun-Produced Stent Coating on Paclitaxel Release and Transport through the Arterial Wall after Stenting.

It was previously shown that polycaprolactone (PCL)-based electrospun-produced paclitaxel (PTX)-enriched matrices exhibit long-term drug release kinetics and can be used as coatings for drug-eluting stents (DES). The installation of vascular stents involves a twofold increase in stent diameter and, therefore, an elongation of the matrices covering the stents, as well as the arterial wall in a stented area. We studied the influence of matrix elongation on its structure and PTX release using three different electrospun-produced matrices. The data obtained demonstrate that matrix elongation during stent installation does not lead to fiber breaks and does not interfere with the kinetics of PTX release. To study PTX diffusion through the expanded artery wall, stents coated with 5%PCL/10%HSA/3%DMSO/PTX and containing tritium-labeled PTX were installed into the freshly obtained iliac artery of a rabbit. The PTX passing through the artery wall was quantified using a scintillator ß-counter. The artery retained the PTX and decreased its release from the coating. The retention of PTX by the arterial wall was more efficient when incubated in blood plasma in comparison with PBS. The retention/accumulation of PTX by the arterial wall provides a prolonged drug release and allows for the reduction in the dose of the drugs in electrospun-produced stent coatings.

Vascular Stents Coated with Electrospun Drug-Eluting Material: Functioning in Rabbit Iliac Artery.

A stenting procedure aimed at blood flow restoration in stenosed arteries significantly improves the efficiency of vascular surgery. However, the current challenge is to prevent neointimal growth, which reduces the vessel lumen, in the stented segments in the long run. We tested in vivo drug-eluting coating applied by electrospinning to metal vascular stents to inhibit the overgrowth of neointimal cells via both the drug release and mechanical support of the vascular wall. The blend of polycaprolactone with human serum albumin and paclitaxel was used for stent coating by electrospinning. The drug-eluting stents (DESs) were placed using a balloon catheter to the rabbit common iliac artery for 1, 3, and 6 months. The blood flow rate was ultrasonically determined in vivo. After explantation, the stented arterial segment was visually and histologically examined. Any undesirable biological responses (rejection or hemodynamically significant stenosis) were unobservable in the experimental groups. DESs were less traumatic and induced weaker neointimal growth; over six months, the blood flow increased by 37% versus bare-metal stents, where it increased by at least double the rate. Thus, electrospun-coated DESs demonstrate considerable advantages over the bare-metal variants.

Sirolimus-Eluting Electrospun-Produced Matrices as Coatings for Vascular Stents: Dependence of Drug Release on Matrix Structure and Composition of the External Environment.

Although a number of drug-eluting coatings for vascular stents (VSs) have been developed and are in commercial use, more efficient stent coatings and drug delivery systems are needed. Sirolimus (SRL) is a clinically important drug with antiproliferative and immunosuppressive activities that is widely used for coating stents. Here, we characterized SRL-enriched matrices, intended for coating vascular stents, that were produced by electrospinning (ES) on a drum collector from a solution of polycaprolactone (PCL) and human serum albumin (HSA), 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), dimethyl sulfoxide (DMSO), and SRL. The release of tritium-labeled SRL (3H-SRL) from matrices in phosphate-buffered saline (PBS) or human blood plasma (BP) was studied. The introduction of DMSO in the ES blend decreased SRL release. The use of BP significantly accelerated SRL release through binding with serum biomolecules. The exchange of PBS or BP after every time point also increased SRL release. The maximum SRL release in BP was observed at 3 days. The matrices produced from the ES solution with DMSO and HSA released no more than 80% SRL after 27 days in BP, even under medium exchange conditions. Therefore, PCL-based matrices containing HSA, SRL, and DMSO can be used for coating VSs with prolonged SRL delivery.

In Vivo Stability of Polyurethane-Based Electrospun Vascular Grafts in Terms of Chemistry and Mechanics.

The biostability of the polyurethanes Tecoflex EG-80A and Pellethane 2363-80A, used as basic polymers of the vascular grafts (VGs) produced by electrospinning, as well as the tensile strength of Tecoflex VGs, are studied. Solutions of Tecoflex or Pellethane with gelatin and bivalirudin in 1,1,1,3,3,3-hexafluoroisopropanol are used for VG production. After 1, 12, and 24 weeks of VG implantation in the infrarenal position of the abdominal aorta of Wistar rats, VGs are explanted, fixed in formalin, freed from outer tissues, dialyzed, and dried. The polyurethanes are extracted from VGs by dispersion/extraction in tetrahydrofuran (THF) and freed from the excess of THF-insoluble biopolymers. The stability of polyurethanes is assessed by IR spectroscopy and gel permeation chromatography. Pellethane has emerged to be stable at all experimental points. Tecoflex loses approximately 10% of its molecular weight (both Mn and Mw) after 3 months and restored its initial value within 6 months of its functioning as a graft. Mechanical testing demonstrates a 30% reduction in the tensile strength after 3 months in VG and a 10% increase after 6 months. The stability and mechanical properties of polyurethane-based VGs demonstrate their utility for the reconstitution of damaged arteries.

Comparative gene expression profiling of human primary endotheliocytes cultivated on polyurethane-based electrospun 3D matrices and natural decellularized vein.

The formation of a continuous layer of normally functioning endothelium on the lumen surface of small diameter vascular grafts is considered a prerequisite of their long-term functioning without stenosis. Thus, materials supporting not only endothelialization but also the normal functioning state of endotheliocytes are demanded. In this study, we have evaluated the functional state of human umbilical vein endothelial cells (HUVEC) cultivated on the surface of autologous decellularized human umbilical vein and electrospun polyurethane-based matrices by next generation sequencing gene expression profiling. Three types of matrices produced by electrospinning from hexafluoroisopropanol solutions of pure TECOFLEX™ EG-80A polyurethane, polyurethane with gelatin and polyurethane with gelatin and bivalirudin were studied. Cells cultivated on different supports were subjected to RNA-Seq profiling on an Illumina HiSeq platform. The data demonstrated that the structure of 3D matrices and the chemical composition of the fibers have a significant effect on the gene expression profiles of HUVEC. The results suggest that protein-enriched polyurethane-based 3D matrices represent a convenient surface for obtaining a normally functioning endothelial layer.

Electrospun polyurethane-based vascular grafts: physicochemical properties and functioning in vivo.

General physicochemical properties of the vascular grafts (VGs) produced from the solutions of Tecoflex (Tec) with gelatin (GL) and bivalirudin (BV) by electrospinning are studied. The electrospun VGs of Tec-GL-BV and expanded polytetrafluoroethylene (e-PTFE) implanted in the abdominal aorta of 36 Wistar rats have been observed over different time intervals up to 24 weeks. A comparison shows that 94.5% of the Tec-GL-BV VGs and only 66.6% of e-PTFE VGs (р = 0.0438) are free of occlusions after a 6 month implantation. At the intermediate observation points, Tec-GL-BV VGs demonstrate severe neovascularization of the VG neoadventitial layer as compared with e-PTFE grafts. A histological examination demonstrates a small thickness of the neointima layer and a low level of calcification in Tec-GL-BV VGs as compared with the control grafts. Thus, polyurethane-based protein-enriched VGs have certain advantages over e-PTFE VGs, suggesting their utility in clinical studies.