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De Jong R.,Erasmus Medical Center | Van Hout G.P.J.,University Utrecht | Houtgraaf J.H.,Erasmus Medical Center | Kazemi K.,Erasmus Medical Center | And 5 more authors.
Circulation: Cardiovascular Interventions | Year: 2014

Background: Engraftment and survival of stem cells in the infarcted myocardium remain problematic in cell-based therapy for cardiovascular disease. To overcome these issues, encapsulated mesenchymal stem cells (eMSCs) were developed that were transfected to produce glucagon-like peptide-1, an incretin hormone with known cardioprotective effects, alongside MSC endogenous paracrine factors. This study was designed to investigate the efficacy of different doses of intracoronary infusion of eMSC in a porcine model of acute myocardial infarction (AMI). Methods and Results: One hundred pigs were subjected to a moderate AMI (posterolateral AMI; n=50) or a severe AMI (anterior AMI; n=50), whereupon surviving animals (n=36 moderate, n=33 severe) were randomized to receive eitherintracoronary infusion of 3 incremental doses of eMSC or Ringers' lactate control. Cardiac function was assessed using invasive hemodynamics, echocardiography, and histological analysis. A trend was observed in the moderate AMI model, whereas in the severe AMI model, left ventricular ejection fraction improved by +9.3% (P=0.004) in the best responding eMSC group, because of a preservation of left ventricular end-systolic volume. Arteriolar density increased 3-fold in the infarct area (8.4±0.9/mm2 in controls versus 22.2±2.6/mm2 in eMSC group; P<0.001). Although not statistically significant, capillary density was 30% higher in the border zone (908.1±99.7/mm2 in control versus 1209.0±64.6/mm2 in eMSC group; P=ns).. Conclusions-eMSCs enable sustained local delivery of cardioprotective proteins to the heart, thereby enhancing angiogenesis and preserving contractile function in an animal AMI model.. © 2014 American Heart Association, Inc. Source


Levy E.B.,U.S. National Institutes of Health | Gacchina Johnson C.,U.S. National Institutes of Health | Jacobs G.,U.S. National Institutes of Health | Woods D.L.,U.S. National Institutes of Health | And 6 more authors.
Journal of Vascular and Interventional Radiology | Year: 2015

Purpose To evaluate the effect of embolic diameter on achievement of hypoxia after embolization in an animal model of liver tumors. Materials and Methods Inoculation of VX2 tumors in the left liver lobe was performed successfully in 12 New Zealand white rabbits weighing 3.7 kg ± 0.5 (mean ± SD). Tumors were deemed eligible for oxygen measurements when the maximum transverse diameter measured 15 mm or more by ultrasound examination. Direct monitoring of oxygenation of implanted rabbit hepatic VX2 tumors was performed with a fiberoptic electrode during and after transarterial embolization of the proper hepatic artery to angiographic flow stasis with microspheres measuring 70-150 μm, 100-300 μm, or 300-500 μm in diameter. Results Failure to achieve tumor hypoxia as defined despite angiographic flow stasis was observed in 10 of 11 animals. Embolization microsphere size effect failed to demonstrate a significant trend on hypoxia outcome among the diameters tested, and pair-wise comparisons of different embolic diameter treatment groups showed no difference in hypoxia outcome. All microsphere diameters tested resulted in similar absolute reduction (24.3 mm Hg ± 18.3, 29.1 mm Hg ± 1.8, and 19.9 mm Hg ± 9.3, P =.66) and percentage decrease in oxygen (56.0 mm Hg ± 23.9, 56.0 mm Hg ± 6.4, and 35.8 mm Hg ± 20.6, P =.65). Pair-wise comparisons for percent tumor area occupied by embolic agents showed a significantly reduced fraction for 300-500 μm diameters compared with 70-150 μm diameters (P <.05). Conclusions In the rabbit VX2 liver tumor model, three tested microsphere diameters failed to cause tumor hypoxia as measured by a fiberoptic probe sensor according to the adopted hypoxia definitions. © 2015 Published by Elsevier, Inc., on behalf of the SIR. Source


Karaca C.,Massachusetts General Hospital | Cizginer S.,Massachusetts General Hospital | Konuk Y.,Massachusetts General Hospital | Kambadakone A.,Massachusetts General Hospital | And 5 more authors.
Gastrointestinal Endoscopy | Year: 2011

Background: LC beads (Biocompatibles International plc) are designed for the time-released delivery of the chemotherapeutic agent irinotecan into focal, hypervascularized, hepatic tumors. Objective: To determine the feasibility of EUS-guided injection of LC beads (with/without irinotecan) into the swine pancreas. Design: Survival animal study. Setting: Academic center. Subjects: This study involved 12 Yorkshire swine. Intervention: LC beads without irinotecan and loaded with up to 300 mg of irinotecan were injected under EUS guidance with a 19-gauge needle into the tail of the pancreas. CT scanning and necropsy with histology were performed at day 7. Main Outcome Measurements: Feasibility of the injections, gross and microscopic evidence of pancreatic inflammation, and clinical tolerance by the animals. Results: After injection of LC beads with/without irinotecan, in 10 of 12 animals an intrapancreatic, hyperechoic focus with an average diameter of 2.2 cm was visible by EUS, and a hypodense area in the tail of the pancreas was visible by contrast CT. In 2 animals (1 with irinotecan and 1 without) no beads were seen on CT. In 10 of 12 animals, a depot of beads was located in the tail of the pancreas on gross inspection and histology. Drug depot with only localized pancreatic tissue reactions was seen on histopathologic review. Limitations: Animal study. Conclusion The EUS-guided injection of LC beads (with/without irinotecan) into the pancreas of the pig is feasible and safe. This technique is a potential minimally invasive local treatment option for locally advanced pancreatic cancer. © 2011 American Society for Gastrointestinal Endoscopy. Source


Carugo D.,University of Southampton | Ankrett D.N.,University of Southampton | Zhao X.,University of Southampton | Zhang X.,University of Southampton | And 6 more authors.
Phlebology | Year: 2015

Objective: To compare foam bubble size and bubble size distribution, stability, and degradation rate of commercially available polidocanol endovenous microfoam (Varithena®) and physician-compounded foams using a number of laboratory tests. Methods: Foam properties of polidocanol endovenous microfoam and physician-compounded foams were measured and compared using a glass-plate method and a Sympatec QICPIC image analysis method to measure bubble size and bubble size distribution, Turbiscan™ LAB for foam half time and drainage and a novel biomimetic vein model to measure foam stability. Physician-compounded foams composed of polidocanol and room air, CO2, or mixtures of oxygen and carbon dioxide (O2:CO2) were generated by different methods. Results: Polidocanol endovenous microfoam was found to have a narrow bubble size distribution with no large (>500 µm) bubbles. Physician-compounded foams made with the Tessari method had broader bubble size distribution and large bubbles, which have an impact on foam stability. Polidocanol endovenous microfoam had a lower degradation rate than any physician-compounded foams, including foams made using room air (p < 0.035). The same result was obtained at different liquid to gas ratios (1:4 and 1:7) for physician-compounded foams. In all tests performed, CO2 foams were the least stable and different O2:CO2 mixtures had intermediate performance. In the biomimetic vein model, polidocanol endovenous microfoam had the slowest degradation rate and longest calculated dwell time, which represents the length of time the foam is in contact with the vein, almost twice that of physician-compounded foams using room air and eight times better than physician-compounded foams prepared using equivalent gas mixes. Conclusion: Bubble size, bubble size distribution and stability of various sclerosing foam formulations show that polidocanol endovenous microfoam results in better overall performance compared with physician-compounded foams. Polidocanol endovenous microfoam offers better stability and cohesive properties in a biomimetic vein model compared to physician-compounded foams. Polidocanol endovenous microfoam, which is indicated in the United States for treatment of great saphenous vein system incompetence, provides clinicians with a consistent product with enhanced handling properties. © 2015, © The Author(s) 2015. Source


Carugo D.,University of Southampton | Ankrett D.N.,University of Southampton | O'Byrne V.,Biocompatibles International | Wright D.D.I.,BTG | And 3 more authors.
Journal of Materials Science: Materials in Medicine | Year: 2015

We have recently reported on the development of a biomimetic vein model to measure the performance of sclerosing foams. In this study we employed the model to compare the commercially-available Varithena® (polidocanol injectable foam) 1 % varicose vein treatment (referred to as polidocanol endovenous microfoam, or PEM) with physician compounded foams (PCFs) made using different foam generation methods (Double Syringe System and Tessari methods) and different foam formulations [liquid to gas ratios of 1:3 or 1:7; gas mixtures composed of 100 % CO2, various CO2:O2 mixtures and room air (RA)]. PCFs produced using the DSS method had longer dwell times (DTs) (range 0.54–2.21 s/cm in the 4 mm diameter vein model) than those of the corresponding PCFs produced by the Tessari technique (range 0.29–0.94 s/cm). PEM had the longest DT indicating the best cohesive stability of any of the foams produced (2.92 s/cm). Other biomimetic model variables investigated included effect of vessel size, delayed injection and rate of plug formation (injection speed). When comparing the 4 and 10 mm vessel diameters, the DTs seen in the 10 mm vessel were higher than those observed for the 4 mm vessel, as the vein angle had been reduced to 5° to allow for foam plug formation. PCF foam performance was in the order RA > CO2:O2 (35:65) ≅ CO2:O2 (65:35) > CO2; PEM had a longer DT than all PCFs (22.10 s/cm) except that for RA made by DSS which was similar but more variable. The effect of delayed injection was also investigated and the DT for PEM remained the longest of all foams with the lowest percentage deviation with respect to the mean values, indicating a consistent foam performance. When considering rate of plug formation, PEM consistently produced the longest DTs and this was possible even at low plug expansion rates (mean 29.5 mm/s, minimum 20.9 mm/s). The developed vein model has therefore demonstrated that PEM consistently displays higher foam stability and cohesiveness when compared to PCFs, over a range of clinically-relevant operational variables. © 2015, The Author(s). Source

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