Rapamycin-loaded nanoparticles for inhibition of neointimal hyperplasia in experimental vein grafts

<p>Abstract</p> <p>Background</p> <p>Nanoparticles possess several advantages as a carrier system for intracellular delivery of therapeutic agents. Rapamycin is an immunosuppressive agent which also exhibits marked antiproliferative properties. We investigated whether rapamycin-loaded nanoparticles(NPs) can reduce neointima formation in a rat model of vein graft disease.</p> <p>Methods</p> <p>Poly(lactic-co-glycolic acid) (PLGA) NPs containing rapamycin was prepared using an oil/water solvent evaporation technique. Nanoparticle size and morphology were determined by dynamic light scattering methodology and electron microscopy. In vitro cytotoxicity of blank, rapamycin-loaded PLGA (RPLGA) NPs was studied using MTT Assay. Excised rat jugular vein was treated ex vivo with blank-NPs, or rapamycin-loaded NPs, then interposed back into the carotid artery position using a cuff technique. Grafts were harvested at 21 days and underwent morphometric analysis as well as immunohistochemical analysis.</p> <p>Results</p> <p>Rapamycin was efficiently loaded in PLGA nanoparticles with an encapsulation efficiency was 87.6%. The average diameter of NPs was 180.3 nm. The NPs-containing rapamycin at 1 ng/ml significantly inhibited vascular smooth muscular cells proliferation. Measurement of rapamycin levels in vein grafts shown that the concentration of rapamycin in vein grafts at 3 weeks after grafting were 0.9 ± 0.1 μg/g. In grafted veins without treatment intima-media thickness was 300.4 ±181.5 μm after grafting 21 days. Whereas, Veins treated with rapamycin-loaded NPs showed a reduction of intimal-media thickness of 150.2 ± 62.5 μm (p = 0.001). CD-31 staining was used to measure luminal endothelial coverage in grafts and indicated a high level of endothelialization in 21 days vein grafts with no significant effect of blank or rapamycin-loaded NPs group.</p> <p>Conclusions</p> <p>We conclude that sustained-release rapamycin from rapymycin loaded NPs inhibits vein graft thickening without affecting the reendothelialization in rat carotid vein-to-artery interposition grafts and this may be a promising therapy for the treatment of vein graft disease.</p

Delivery Site of Perivascular Endothelial Cell Matrices Determines Control of Stenosis in a Porcine Femoral Stent Model

PURPOSE: High restenosis rates are a major limitation of peripheral interventions. Endothelial cells, grown within gelatin matrices and implanted onto the adventitia of injured vessels, inhibit stenosis in experimental models. To determine if this technology could be adapted for minimally invasive procedures, we compared the effects of cells in an implantable sponge to an injectable formulation and investigated the importance of delivery site in a stent model. MATERIALS AND METHODS: Stents were implanted in the femoral arteries of 30 pigs followed by perivascular implantation of sponges or injection of particles containing allogeneic endothelial cells. Controls received acellular matrices or nothing. The effects of delivery site were assessed by injecting cellular matrices into or adjacent to the perivascular tissue, or into the neighboring muscle. Animals were sacrificed after 28 days. Pre-sacrifice angiograms and tissue sections were evaluated for stenosis. RESULTS: Arteries treated with cellular matrices had a 55 – 63% decrease in angiographic stenosis (P<0.05) and a 38 – 43% reduction (P<0.05) in histologic stenoses compared to controls. Intimal area was greatest when cellular matrices were delivered into the muscle (6.35 ± 0.95 mm2) compared to into or adjacent to the perivascular tissue (4.05 ± 0.56 mm2 and 4.73 ± 0.53 mm2, respectively, P < 0.05). CONCLUSIONS: Perivascular endothelial-cell matrices reduced stenosis after stent-induced injury. The effects were not dependent on the formulation but appeared to be dependent upon delivery site. Minimally invasive injections of endothelial-cell matrices to the adventitia of arteries following peripheral interventions may decrease restenosis rates.National Institutes of Health (U.S.) (Grant GM 49039

Malignant Biliary obstruction: treatment with ePTFE-FEP-covered endoprostheses initial technical and clinical experinces in a multicenter trial.

To determine and present the initial technical and clinical results of using an expanded polytetrafluoroethylene-fluorinated ethylene propylene (ePTFE-FEP)-covered biliary endoprosthesis to treat malignant biliary obstruction. MATERIALS AND METHODS: This prospective nonrandomized study included 42 patients with malignant obstruction of the common bile duct, common hepatic duct, and hilar confluence. Unilateral (n = 38) or bilateral (n = 4) bile duct drainage was performed by using fully covered endoprostheses with anchoring fins. To avoid branch duct blockage, endoprostheses with drainage holes at the proximal end were available. Procedure- and device-related complications were recorded. Patient survival and stent patency rates were calculated with Kaplan-Meier survival analysis. Mean follow-up bilirubin and alkaline phosphatase levels were calculated, and differences in means were evaluated with a paired t test. RESULTS: Successful deployment, correct positioning, and patency of the device were achieved in all patients. Procedure-related complications occurred in two (5%) patients. Thirty-day mortality rate was 20% (eight of 41 patients), and median survival time was 146 days. Laboratory values decreased significantly after the procedure (P <.001). Recurrent obstructive jaundice occurred in six (15%) patients. Primary patency rates at 3, 6, and 12 months were 90%, 76%, and 76%, respectively. Calculation of the composite end point of death or obstruction revealed a median patency duration of 138 days. No endoprosthesis migration was observed. Branch duct obstruction was observed in four (10%) patients. Postmortem examination of one stent revealed a widely patent endoprosthesis with intact covering. CONCLUSION: Initial results of percutaneous treatment of malignant biliary obstructions with fully covered ePTFE-FEP endoprostheses suggest that they are safe and potentially clinically effective

Determination of Heat and Mass Transport Correlations for Hollow Membrane Distillation Modules

Development and optimization of the membrane distillation (MD) process are strongly associated with better understanding of heat and mass transport across the membrane. The current state-of-the-art on heat and mass transport in MD greatly relies upon the use of various empirical correlations for the Nusselt number (Nu), tortuosity factor (τ), and thermal conductivity (κm) of the membrane. However, the current literature lacks investigations about finding the most representative combination of these three parameters for modeling transport phenomena in MD. In this study, we investigated 189 combinations of Nu, κm, and τ to assess their capability to predict the experimental flux and outlet temperatures of feed and permeate streams for hollow fiber MD modules. It was concluded that 31 out of 189 tested combinations could predict the experimental flux with reasonable accuracy (R2 > 0.95). Most of the combinations capable of predicting the flux reasonably well could predict the feed outlet temperature well; however, the capability of the tested combinations to predict the permeate outlet temperatures was poor, and only 13 combinations reasonably predicted the experimental temperature. As a generally observed tendency, it was noted that in the best-performing models, most of the correlations used for the determination of κm were parallel models. The study also identified the best-performing combinations to simultaneously predict flux, feed, and permeate outlet temperatures. Thus, it was noted that the best model to simultaneously predict flux, feed, and permeate outlet temperatures consisted of the following correlations for τ, Nu, and κm: =ε1−1−ε1/3, Nu=0.13Re0.64Pr0.38, κm=1−εκpol+εκair where ε, Re, Pr, κpol, and κair represent membrane porosity, Reynolds number, Prandtl number, thermal conductivities of polymer and air, respectively