Highlights ► We investigated transfollicular vaccination via intact skin using nanoparticles(NP). ► Polymeric NP from PLGA+- chitosan were loaded with ovalbumin (OVA). ► OVA/NP stimulated ...proliferation of CD4+ &/or CD8+ T-cells more than OVA/solution. ► NP improved (×2–3) follicular delivery of OVA on pig ears compared to OVA/solution. ► Consequently using OVA/NP one may reduce the dose compared to OVA/solution.
Abstract Cationically modified poly( d , l -lactide- co -glycolide) (PLGA) nanoparticles have recently been introduced as novel carriers for DNA/RNA delivery. The colloidal characteristics of the ...nanoparticles—particle size and surface charge—are considered the most significant determinants in the cellular uptake and trafficking of the nanoparticles. Therefore, our aim was to introduce chitosan-coated PLGA nanoparticles, whose size and charge are tunable to adapt for a specific task. The results showed that biodegradable nanoparticles as small as 130 nm and adjustable surface charge can be tailored controlling the process parameters. As a proof of concept, the overall potential of these particulate carriers to bind the antisense oligonucleotides, 2′- O -methyl-RNA, and improve their cellular uptake was demonstrated. The study proved the efficacy of chitosan-coated PLGA nanoparticles as a flexible and efficient delivery system for antisense oligonucleotides to lung cancer cells.
In this study we have applied a model to explain the reported subdiffusion of particles in mucus, based on the measured mean squared displacements (MSD). The model considers Brownian diffusion of ...particles in a confined geometry, made from permeable membranes. The applied model predicts a normal diffusive behavior at very short and long time lags, as observed in several experiments. In between these timescales, we find that the “subdiffusive” regime is only a transient effect, MSD∝τα,α<1. The only parameters in the model are the diffusion-coefficients at the limits of very short and long times, and the distance between the permeable membranes L. Our numerical results are in agreement with published experimental data for realistic assumptions of these parameters. Finally, we show that only particles with a diameter less than 40 nm are able to pass through a mucus layer by passive Brownian motion.
Due to the increased demand for reliable data regarding penetration into and permeation across human skin, assessment of the absorption of xenobiotics has been gaining in importance steadily. In ...vitro experiments allow for determining these data faster and more easily than in vivo experiments. However, the experiments described in literature and the subsequent evaluation procedures differ considerably. Here we will give an overview on typical finite and infinite dose experiments performed in fundamental research and on the evaluation of the data. We will point out possible difficulties that may arise and give a short overview on attempts at predicting skin absorption in vitro and in vivo.
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The fate of inhaled particles after deposition onto the pulmonary mucosa is far from being solved, in particular with respect to mucociliary clearance and mucus penetration. Due to the fact that ...these phenomena govern pulmonary residence time and thus bioavailability, they are highly relevant for any kind of controlled release formulation delivered via that route. This study applies ex vivo and in silico approaches to investigate the dependency of muciliary clearance of micro-, submicrometer and nanoparticles on size, shape, charge and surface chemistry of such particles. In addition, measurement of mucociliary clearance of different particles also provided information about their penetration into mucus. Surprisingly, no significant differences in mucociliary clearance could be found for any type of particle under investigation. As revealed by computational modeling, particle penetration into the mucus gel layer was negligible at least within the time frame allowed by horizontal mucus transport. These data suggest that the observed lack of difference in mucociliary clearance is caused by the lack of immediate penetration of deposited aerosol particles through the mucus blanket.
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The conducting airways of the human lungs are lined by mucus, which lubricates the lung epithelium and provides a first-line protection against airborne threats. As a novel approach ...for visualization of the human mucus microstructure, we applied confocal Raman microscopy as a label-free and chemically selective technique. We were successfully able to chemically resolve the pulmonary surfactant from the mucus matrix and show its spatial distribution, as well as to visualize the structural changes within the freeze–dried mucus mesh upon chemical mucolysis. Subsequently, we performed rheological measurements before and after mucolysis and correlated morphology and chemical structure of the mucus with its rheological characteristics. These results do not only enrich the knowledge about the mucus microstructure, but can also, significantly contribute to rational development of future lung therapeutics.
Abstract Background Few studies have evaluated the clinical outcomes of transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (AS). Particularly, limited data ...exist comparing the results of TAVR with new-generation devices versus early-generation devices. Objectives This study sought to evaluate the clinical outcomes of TAVR for bicuspid AS with early- and new-generation devices. Methods The Bicuspid TAVR Registry is an international multicenter study enrolling consecutive patients with bicuspid AS undergoing TAVR between April 2005 and May 2015. Results Of 301 patients, 199 patients (71.1%) were treated with early-generation devices (Sapien XT Edwards Lifesciences Corporation, Irvine, California: n = 87; CoreValve Medtronic, Minneapolis, Minnesota: n = 112) and 102 with new-generation devices (Sapien 3 Edwards Lifesciences Corporation: n = 91; Lotus Boston Scientific Corporation, Marlborough, Massachusetts: n = 11). The mean Society of Thoracic Surgeons score was 4.7 ± 5.2 without significant differences between groups (4.6 ± 5.1 vs. 4.9 ± 5.4; p = 0.57). Overall, all-cause mortality rates were 4.3% at 30 days and 14.4% at 1 year. Moderate or severe paravalvular leak was absent and significantly less frequent with new-generation compared to early-generation devices (0.0% vs. 8.5%; p = 0.002), which resulted in a higher device success rate (92.2% vs. 80.9%; p = 0.01). There were no differences between early- and new-generation devices in stroke (2.5% vs. 2.0%; p > 0.99), life-threatening bleeding (3.5% vs. 2.9%; p > 0.99), major vascular complication (4.5% vs. 2.9%; p = 0.76), stage 2 to 3 acute kidney injury (2.5% vs. 2.9%; p > 0.99), early safety endpoints (15.1% vs. 10.8%; p = 0.30), and 30-day all-cause mortality (4.5% vs. 3.9%; p > 0.99). Conclusions The clinical outcomes of TAVR in patients with bicuspid AS were favorable. New-generation devices were associated with less paravalvular leak and, hence, a higher device success rate than early-generation devices. (The Bicuspid Aortic Stenosis Following Transcatheter Aortic Valve Replacement Registry Bicuspid TAVR; NCT02394184 )
To adjust Raman signal attenuation in human skin depth profiling, an artificial skin surrogate is developed and a methematical correction algorithm is derived.
Understanding the penetration behaviour ...of drugs into human skin is a prerequisite for the rational development and evaluation of effective dermal drug delivery.
The general procedure for the acquisition of quantitative drug penetration profiles in human skin is performed by sequential segmentation and extraction. Unfortunately, this technique is destructive, laborious and lacks spatial resolution. Confocal Raman microscopy bares the potential of a chemically selective, label free and nondestructive analysis. However, the acquisition of quantitative drug depth profiles within skin by Raman microscopy is impeded by imponderable signal attenuation inside the tissue.
In this study, we present a chemical semi-solid matrix system simulating the optical properties of human skin. This system serves as a skin surrogate for investigation of Raman signal attenuation under controlled conditions. Caffeine was homogeneously incorporated within the skin surrogate, and Raman intensity depth profiles were acquired. A mathematical algorithm describing the Raman signal attenuation within the surrogate was derived from these profiles. Human skin samples were incubated with caffeine, and Raman intensity depth profiles were similarly acquired. The surrogate algorithm was successfully applied to correct the drug profiles in human skin for signal attenuation. For the first time, a mathematical algorithm was established, which allows correction of Raman signal attenuation in human skin, thus facilitating reliable drug quantification in human skin by confocal Raman spectroscopy.
The penetration and storage behavior of dye-containing nanoparticles (diameter 320
nm) into the hair follicles was investigated. The results were compared to the findings obtained with the same ...amount of dye in the non-particle form.
In the first part of the experiments, the penetration of the dye into the hair follicles was investigated in vitro on porcine skin, which is an appropriate model for human tissue. It was found that the nanoparticles penetrate much deeper into the hair follicles than the dye in the non-particle form, if a massage had been applied. Without massage, similar results were obtained for both formulations.
Subsequently, the storage behavior of both formulations in the hair follicles was analyzed in vivo on human skin by differential stripping. Using the same application protocol, the nanoparticles were stored in the hair follicles up to 10 days, while the non-particle form could be detected only up to 4 days.
Taking into consideration the surface structure of the hair follicles, it was assumed that the movement of the hairs may act as a pumping mechanism pushing the nanoparticles deep into the hair follicles.
Abstract Understanding the bio-nano interactions in the lungs upon the inhalation of nanoparticles is a major challenge in both pulmonary nanomedicine and nanotoxicology. To investigate the effect of ...pulmonary surfactant protein A (SP-A) on the interaction between nanoparticles and alveolar macrophages, we used magnetite nanoparticles (110–180 nm in diameter) coated with different polymers (starch, carboxymethyldextran, chitosan, poly-maleic-oleic acid, phosphatidylcholine). Cellular binding and uptake of nanoparticles by alveolar macrophages was increased for nanoparticles treated with SP-A, whereas albumin, the prevailing protein in plasma, led to a significant decrease. A significantly different adsorption pattern of SP-A, compared to albumin was found for these five different nanomaterials. This study provides evidence that after inhalation of nanoparticles, a different protein coating and thus different biological behavior may result compared to direct administration to the bloodstream. From the Clinical Editor In this nano-toxicology study of inhaled nanoparticles, the authors investigated the effect of pulmonary surfactant protein A on the interaction between nanoparticles and alveolar macrophages utilizing magnetite nanoparticles coated with different polymers (starch, carboxymethyldextran, chitosan, poly-maleic-oleic acid, phosphatidylcholine). Cellular binding and uptake of nanoparticles increased for nanoparticles treated with SP-A, whereas albumin, the prevailing protein in plasma, led to a significant decrease.
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