Effect of Aspect Ratio and Deformability on Nanoparticle Extravasation through Nanopores

We describe the fabrication of filamentous hydrogel nanoparticles using a unique soft lithography based particle molding process referred to as PRINT (Particle Replication in Non-wetting Templates). The nanoparticles possess a constant width of 80 nm, and we varied their lengths ranging from 180 nm to 5000 nm. In addition to varying the aspect ratio of the particles, the deformability of the particles was tuned by varying the cross-link density within the particle matrix. Size characteristics such as hydrodynamic diameter and persistence length of the particles were analyzed using dynamic light scattering and electron microscopy techniques, respectively, while particle deformability was assessed by atomic force microscopy. Additionally, the ability of the particles to pass through membranes containing 0.2 μm pores was assessed by means of a simple filtration technique, and particle recovery was determined using fluorescence spectroscopy. The results show that particle recovery is mostly independent of aspect ratio at all cross-linker concentrations utilized, with the exception of 96 wt% PEG diacrylate 80 × 5000 nm particles, which showed the lowest percent recovery

Scalable, Shape-Specific, Top-Down Fabrication Methods for the Synthesis of Engineered Colloidal Particles

The search for a method to fabricate non-spherical colloidal particles from a variety of materials is of growing interest. As the commercialization of nanotechnology continues to expand, the ability to translate particle fabrication methods from a laboratory to an industrial scale is of increasing significance. In this article, we examine several of the most readily scalable top-down methods for the fabrication of such shape specific particles and compare their capabilities with respect to particle composition, size, shape and complexity as well as the scalability of the method. We offer an extensive examination of Particle Replication In Non-wetting Templates (PRINT®) with regards to the versatility and scalability of this technique. We also detail the specific methods used in PRINT particle fabrication, including harvesting, purification and surface modification techniques, with examination of both past and current methods

Low Modulus Biomimetic Microgel Particles with High Loading of Hemoglobin

We synthesized extremely deformable red blood cell-like microgel particles and loaded them with bovine hemoglobin (Hb) to potentiate oxygen transport. With similar shape and size as red blood cells (RBCs), the particles were fabricated using the PRINT® (Particle Replication In Non-wetting Templates) technique. Low crosslinking of the hydrogel resulted in very low mesh density for these particles, allowing passive diffusion of hemoglobin throughout the particles. Hb was secured in the particles through covalent conjugation of the lysine groups of Hb to carboxyl groups in the particles via EDC/NHS coupling. Confocal microscopy of particles bound to fluorescent dye-labeled Hb confirmed the uniform distribution of Hb throughout the particle interior, as opposed to the surface conjugation only. High loading ratios, up to 5 times the amount of Hb to polymer by weight, were obtained, without a significant effect on particle stability, shape, though particle diameter decreased slightly with Hb conjugation. Analysis of the protein by circular dichroism (CD) spectroscopy showed that the secondary structure of Hb was unperturbed by conjugation to the particles. Methemoglobin in the particles could be maintained at a low level and the loaded Hb could still bind oxygen as studied by UV-vis spectroscopy. Hb-loaded particles with moderate loading ratios demonstrated excellent deformability in microfluidic devices, easily deforming to pass through restricted pores half as wide as the diameter of the particles. The suspension of concentrated particles with Hb concentration of 5.2 g/dL showed comparable viscosity to that of mouse blood, and the particles remained intact even after being sheared at a constant high rate (1,000 1/s) for 10 min. Armed with the ability to control size, shape, deformability, and loading of Hb into RBC mimics, we will discuss the implications for artificial blood

Mercury's Sodium Exosphere: Observations during the MESSENGER Orbital Phase

The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft entered into orbit about Mercury on March 18,2011. We now have approximately five Mercury years of data from orbit. Prior to the MESSENGER mission, Mercury's surface-bounded exosphere was known to contain H, He, Na. K, and Ca. The Ultraviolet and Visible Spectrometer (UVVS) began routine orbital observations of both the dayside and nightside exosphere on March 29. 2011, measuring altitude profiles for all previously detected neutral species except for He and K. We focus here on what we have learned about the sodium exosphere: its spatial, seasonal, and sporadic variation. Observations to date permit delineation of the relative roles of photon-stimulated desorption (PSD) and impact vaporization (IV) from seasonal and spatial effects, as well as of the roles of ions both as sputtering agents and in their possible role to enhance the efficiency of PSD. Correlations of Mercury's neutral sodium exosphere with measurements from MESSENGER's Magnetometer (MAG) and Energetic Particle and Plasma Spectrometer (EPPS) provide insight into the roles of ions and electrons. Models incorporating MAG observations provide a basis for identifying the location and area of the surface exposed to solar wind plasma, and EPPS observations reveal episodic populations of energetic electrons in the magnetosphere and the presence of planetary He(+), 0(+), and Na(+)

The effect of particle size on the biodistribution of low-modulus hydrogel PRINT particles

There is a growing recognition that the deformability of particles used for drug delivery plays a significant role on their biodistribution and circulation profile. Understanding these effects would provide a crucial tool for the rational design of drug delivery systems. While particles resembling red blood cells (RBCs) in size, shape and deformability have extended circulation times and altered biodistribution profiles compared to rigid, but otherwise similar particles, the in vivo behavior of such highly deformable particles of varied size has not been explored. We report the fabrication of a series of discoid, monodisperse, low-modulus hydrogel particles with diameters ranging from 0.8 to 8.9 μm, spanning sizes smaller than and larger than RBCs. We injected these particles into healthy mice, and tracked their concentration in the blood and their distribution into major organs. These deformable particles all demonstrated some hold up in filtration tissues like the lungs and spleen, followed by release back into the circulation, characterized by decreases in particles in these tissues with concomitant increases in particle concentration in blood. Particles similar to red blood cells in size demonstrated longer circulation times, suggesting that this size and shape of deformable particle is uniquely suited to avoid clearance

Observations of Mercury's Exosphere: Composition and Structure

Mercury is surrounded by a tenuous exosphere in which particles travel on ballistic trajectories under the influence of a combination of gravity and solar radiation pressure. The densities are so small that the surface forms the exobase and particles in the exosphere are more likely to collide with it rather than with each other. For a planet with a more substantial collision-dominated atmosphere, a population of particles that enters from below the exobase supplies the exosphere. In contrast Mercury's exosphere is supplied both by incoming sources including the solar wind (hydrogen and helium), micrometeoroids (dust), meteoroids and cornets, and by particles released from the surface through a variety of processes that include sputtering by solar wind ions, desorption by solar photons and electrons, impacts by micrometeoroids, and thermal desorption of surface materials. These source processes are balanced by loss processes, which include impact with and sticking to the surface, Jeans (or thermal) escape, ionization followed by transport along magnetic field lines, and acceleration by solar radiation pressure to escape velocity. Ground-based attempts to detect an atmosphere around Mercury before Mariner 10 first visited the planet in 1974 were unsuccessful and led only to increasingly tight upper limits, culminating in a limiting value for surface atmospheric pressure of 0.015 Pascal (Pa) determined by Fink et al. (1974)

Solar wind forcing at Mercury: WSA‐ENLIL model results

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97237/1/jgra50070.pd

Solar wind forcing at Mercury: WSA-ENLIL model results

Analysis and interpretation of observations from the MESSENGER spacecraft in orbit about Mercury require knowledge of solar wind “forcing” parameters. We have utilized the Wang-Sheeley-Arge (WSA)-ENLIL solar wind modeling tool in order to calculate the values of interplanetary magnetic field (IMF) strength (B), solar wind velocity (V) and density (n), ram pressure (~nV2), cross-magnetosphere electric field (V × B), Alfvén Mach number (MA), and other derived quantities of relevance for solar wind-magnetosphere interactions. We have compared upstream MESSENGER IMF and solar wind measurements to see how well the ENLIL model results compare. Such parameters as solar wind dynamic pressure are key for determining the Mercury magnetopause standoff distance, for example. We also use the relatively high-time-resolution B-field data from MESSENGER to estimate the strength of the product of the solar wind speed and southward IMF strength (Bs) at Mercury. This product VBs is the electric field that drives many magnetospheric dynamical processes and can be compared with the occurrence of energetic particle bursts within the Mercury magnetosphere. This quantity also serves as input to the global magnetohydrodynamic and kinetic magnetosphere models that are being used to explore magnetospheric and exospheric processes at Mercury. Moreover, this modeling can help assess near-real-time magnetospheric behavior for MESSENGER or other mission analysis and/or ground-based observational campaigns. We demonstrate that this solar wind forcing tool is a crucial step toward bringing heliospheric science expertise to bear on planetary exploration programs

Combined rotation scarf and Akin osteotomies for hallux valgus: a patient focussed 9 year follow up of 50 patients

<p>Abstract</p> <p>Background</p> <p>The Cochrane review of hallux valgus surgery has disputed the scientific validity of hallux valgus research. Scoring systems and surrogate measures such as x-ray angles are commonly reported at just one year post operatively but these are of dubious relevance to the patient. In this study we extended the follow up to a minimum of 8 years and sought to address patient specific concerns with hallux valgus surgery. The long term follow up also allowed a comprehensive review of the complications associated with the combined rotation scarf and Akin osteotomies.</p> <p>Methods</p> <p>Between 1996 and 1999, 101 patients underwent rotation scarf and Akin osteotomies for the treatment of hallux valgus. All patients were contacted and asked to participate in this study. 50 female participants were available allowing review of 73 procedures. The average follow up was over 9 years and the average age at the time of surgery was 57. The participants were physically examined and interviewed.</p> <p>Results</p> <p>Post-operatively, in 86% of the participants there were no footwear restrictions. Stiffness of the first metatarsophalangeal joint was reported in 8% (6 feet); 10% were unhappy with the cosmetic appearance of their feet, 3 feet had hallux varus, and 2 feet had recurrent hallux valgus. There were no foot-related activity restrictions in 92% of the group. Metatarsalgia occurred in 4% (3 feet). 96% were better than before surgery and 88% were completely satisfied with their post-operative result. Hallux varus was the greatest single cause of dissatisfaction. The most common adverse event in the study was internal fixation irritation. Hallux valgus surgery is not without risk and these findings could be useful in the informed consent process.</p> <p>Conclusions</p> <p>When combined the rotation scarf and Akin osteotomies are an effective treatment for hallux valgus that achieves good long-term correction with a low incidence of recurrence, footwear restriction or metatarsalgia. The nature of the osteotomies allows early return to normal shoes and activity without the need for postoperative immobilisation in a plaster cast.</p

Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization.

We have previously demonstrated that Stat3 regulates lysosomal-mediated programmed cell death (LM-PCD) during mouse mammary gland involution in vivo. However, the mechanism that controls the release of lysosomal cathepsins to initiate cell death in this context has not been elucidated. We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride. Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness. Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3-ablated mammary glands and loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo. We propose that Stat3 regulates LM-PCD in mouse mammary gland by switching cellular function from secretion to uptake of MFGs. Thereafter, perturbation of lysosomal vesicle membranes by high levels of free fatty acids results in controlled leakage of cathepsins culminating in cell death.This work was supported by a grant from the Medical Research Council programme grant no. MR/J001023/1 (T.J.S. and B. L-L.) and a Cancer Research UK Cambridge Cancer Centre PhD studentship (H.K.R.).This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3043.html