Nanoparticles are a promising solution for delivery of a wide range of medicines and vaccines. Optimizing their design depends on being able to resolve, understand, and predict biophysical and therapeutic properties, as a function of design parameters. While existing tools have made great progress, gaps in understanding remain because of the inability to make detailed measurements of multiple correlated properties. Typically, an average measurement is made across a heterogeneous population, obscuring potentially important information. In this work, we develop and apply a method for characterizing nanoparticles with single-particle resolution. We use convex lens-induced confinement (CLiC) microscopy to isolate and quantify the diffusive trajectories and fluorescent intensities of individual nanoparticles trapped in microwells for long times. First, we benchmark detailed measurements of fluorescent polystyrene nanoparticles against prior data to validate our approach. Second, we apply our method to investigate the size and loading properties of lipid nanoparticle (LNP) vehicles containing silencing RNA (siRNA), as a function of lipid formulation, solution pH, and drug-loading. By taking a comprehensive look at the correlation between the intensity and size measurements, we gain insights into LNP structure and how the siRNA is distributed in the LNP. Beyond introducing an analytic for size and loading, this work allows for future studies of dynamics with single-particle resolution, such as LNP fusion and drug-release kinetics. The prime contribution of this work is to better understand the connections between microscopic and macroscopic properties of drug-delivery vehicles, enabling and accelerating their discovery and development.

X-ray speckle visibility spectroscopy using X-ray free-electron lasers has long been proposed as a probe of fast dynamics in noncrystalline materials. In this paper, numerical modeling is presented to show how the data interpretation of visibility spectroscopy can be impacted by the nonidealities of real-life X-ray detectors. Using simulated detector data, this work provides a detailed analysis of the systematic errors of several contrast extraction algorithms in the context of low-count-rate X-ray speckle visibility spectroscopy and their origins are discussed. Here, it was found that the finite detector charge cloud and pixel size lead to an unavoidable `degeneracy' in photon position determination, and that the contrasts extracted using different algorithms can all be corrected by a simple linear model. The results suggest that experimental calibration of the correction coefficient at the count rate of interest is possible and essential. This allows computationally lightweight algorithms to be implemented for on-the-fly analysis.

The ability to deliver two coherent X-ray pulses with precise time-delays ranging from a few femtoseconds to nanoseconds enables critical capabilities of probing ultra-fast phenomena in condensed matter systems at X-ray free electron laser (FEL) sources. Recent progress made in the hard X-ray split-and-delay optics developments now brings a very promising prospect for resolving atomic-scale motions that were not accessible by previous time-resolved techniques. Here, we report on characterizing the spatial and temporal coherence properties of the hard X-ray FEL beam after propagating through split-and-delay optics. Speckle contrast analysis of small-angle scattering measurements from nanoparticles reveals well-preserved transverse coherence of the beam. Measuring intensity fluctuations from successive X-ray pulses also reveals that only single or double temporal modes remain in the transmitted beam, corresponding to nearly Fourier transform limited pulses.

We present the concept and a prototypical implementation of a compact x-ray split-delay system that is capable of performing continuous on-the-fly delay scans over a range of ∼10  ps with sub-100 nanoradian pointing stability. The system consists of four channel-cut silicon crystals, two of which have gradually varying gap sizes from intentional 5 deg asymmetric cuts. The delay adjustment is realized by linear motions of these two monolithic varying-gap channel cuts, where the x-ray beam experiences pairs of anti-parallel reflections, and thus becomes less sensitive in output beam pointing to motion imperfections of the translation stages. The beam splitting is accomplished by polished crystal edges. A high degree of mutual coherence between the two branches at the focus is observed by analyzing small-angle coherent x-ray scattering patterns. We envision a wide range of applications including single-shot x-ray pulse temporal diagnostics, studies of high-intensity x-ray-matter interactions, as well as measurement of dynamics in disordered material systems using split-pulse x-ray photon correlation spectroscopy.

Two-time correlations determined by XPCS display anisotropic and heterogeneous dynamics in a stretched silanized silica-elastomer nanocomposite (time scale 70 minutes).

One of the important challenges in condensed matter science is to understand ultrafast, atomic-scale fluctuations that dictate dynamic processes in equilibrium and non-equilibrium materials. Here, we report an important step towards reaching that goal by using a state-of-the-art perfect crystal based split-and-delay system, capable of splitting individual X-ray pulses and introducing femtosecond to nanosecond time delays. We show the results of an ultrafast hard X-ray photon correlation spectroscopy experiment at LCLS where split X-ray pulses were used to measure the dynamics of gold nanoparticles suspended in hexane. We show how reliable speckle contrast values can be extracted even from very low intensity free electron laser (FEL) speckle patterns by applying maximum likelihood fitting, thus demonstrating the potential of a split-and-delay approach for dynamics measurements at FEL sources. This will enable the characterization of equilibrium and, importantly also reversible non-equilibrium processes in atomically disordered materials.

We have measured in situ the progression of dewetting from a large number of holes in immiscible polymer bilayer films. Using x-ray photon correlation spectroscopy (XPCS) in grazing incidence we probe independently the evolving dewetting process both at the top surface and the buried interface of the bilayer. At an early stage, differences in the evolution of the velocities measured by XPCS between the surface and buried interface indicate that the holes do not penetrate the bottom layer. The rim velocity at late stages decays according to a wave-vector-dependent power law, which indicates inhomogeneous flows in the film. The changes in the static scattering show that observed slow-down of the dewetting velocity is correlated with the changing roughness at the buried interface of the polymer bilayer.

The Vertically Integrated Photon Imaging Chip (VIPIC) was custom-designed for X-ray photon correlation spectroscopy, an application in which occupancy per pixel is low but high time resolution is needed. VIPIC operates in a sparsified streaming mode in which each detected photon is immediately read out as a time- and position-stamped event. This event stream can be fed directly to an autocorrelation engine or accumulated to form a conventional image. The detector only delivers non-zero data (sparsified readout), greatly reducing the communications overhead typical of conventional frame-oriented detectors such as charge-coupled devices or conventional hybrid pixel detectors. This feature allows continuous acquisition of data with timescales from microseconds to hours. In this work VIPIC has been used to measure X-ray photon correlation spectroscopy data on polystyrene latex nano-colliodal suspensions in glycerol and on colloidal suspensions of silica spheres in water. Relaxation times of the nano-colloids have been measured for different temperatures. These results demonstrate that VIPIC can operate continuously in the microsecond time frame, while at the same time probing longer timescales.

The availability of ultrafast pulses of coherent hard x-rays from the Linac Coherent Light Source opens new opportunities for studies of atomic-scale dynamics in amorphous materials. Here we show that single ultrafast coherent x-ray pulses can be used to observe the speckle contrast in the high-angle diffraction from liquid Ga and glassy Ni2Pd2P and B2O3. We determine the thresholds above which the x-ray pulses disturb the atomic arrangements. Furthermore, high contrast speckle is observed in scattering patterns from the glasses integrated over many pulses, demonstrating that the source and optics are sufficiently stable for x-ray photon correlation spectroscopy studies of dynamics over a wide range of time scales.

X-ray photon correlation spectroscopy is employed to investigate the motion of dilute suspensions of gold nanoparticles in low-molecular-weight polystyrene melts. At high temperatures, the observed motion is diffusive, with a rate that follows a Vogel-Fulcher temperature dependence. Closer to the glass transition temperature Tg, diffusion is superseded by a hyperdiffusive process that first becomes observable near a crossover temperature Tc approximately 1.1Tg and is identified with heterogeneous strain in the melts. Following rapid cooling to temperatures sufficiently below Tc, but still above Tg, the hyperdiffusive dynamics displays a time dependence similar to aging in polymer glasses.

The competitive growth process of ballistic deposition is studied experimentally using x-ray reflectivity characterization of silicon thin films deposited with various vapor incidence angles. Linear profiles of film density with thickness are shown to reproduce the observed reflectivity spectra. A porosity of about 10% was observed in the first few atomic layers atop the substrate, with porosity decreasing with film thickness to near zero for vapor incidence between normal and 60 degrees, and porosity increasing to 50% and above for vapor incidence angles above 70 degrees-the regime of glancing-angle deposition. Our results support the model of glancing deposition as sequential atomic ballistic deposition, where the observed sign change in the slope of the density profile is understood to correspond to the geometric condition where the roughening caused by self-shadowing overtakes the smoothing effects of atomic surface diffusion. From the electron-density profiles derived from x-ray reflectivity measurements, we calculate the average porosity and using data on optical indices of refraction we estimate the amount of silicon oxide.

We investigate lattice orientation and strain fields across ferroelectric domain walls in a single crystal lithium tantalate using x-ray diffraction imaging (topography). The sample is an actual voltage-operated optical switch consisting of a series of triangular polarization-inverted domains formed in an originally poled single crystal. By applying an electric field only about 2% of the coercive field in the forward and reverse directions, we observed asymmetric lattice rotation of about 10−6 rad, and normal strain variation in the order of 10−5 with reference to the zero-field state. Our results confirm that in congruent LiTaO3 crystals there is unexpectedly large strain field expanding several micrometers across the domain walls, in contrast with the widely accepted theoretical fact that in this material the polarization reversal establishes over only a few lattice constants, resulting in small and localized lattice distortions.

A triple crystal x-ray topography technique with sample and analyzer mesh scans has been used to obtain micron resolution lattice orientation and strain maps of a single crystal silicon microcantilever. Both free and slightly bent states of the cantilever have been studied. The results show ∼8 mdeg twist between the cantilever and the supporting base, 0.3 m radius of anticlastic curvature, and strain on the order of −2×10−5 in the direction of surface normal.

A set of algorithms for fast pattern recognition and track reconstruction using 3D space points for the ATLAS Level 2 (LVL2) Trigger at the LHC is described. The presented algorithms work by first identifying the z position along the beamline of any interesting interaction. This allows selection of groups of spacepoints pointing back to this position using a histogramming technique that greatly reduces the combinatorial overhead and execution time before moving on to fitting the tracks and vertices. Results on the timing and performance of the tracking at LVL2 are presented using both simulated data and real test beam data and cosmic data.

We report a study of critical x-ray scattering from SrTiO3 near the antiferrodistortive structural phase transition at T(C) approximately 105 K. A line shape analysis of the thermal diffuse scattering results in the most precise experimental determination to date of the critical exponent gamma. The microscopic mechanism behind the anomalous "central peak" critical scattering component is clarified here by the first-ever observation of a static coherent diffraction pattern (speckle pattern) within the anomalous critical scattering of SrTiO3. This observation allows us to directly attribute the origins of the central peak to Bragg diffraction from remnant static disorder above T(C).

A set of conceptually simple and robust algorithms for fast pattern recognition and track reconstruction using three-dimensional space points developed for the ATLAS level 2 (LVL2) trigger at the LHC is presented. Results on execution time and physics performance demonstrating the effectiveness of this approach in a demanding, online trigger environment are presented. Both this strategy and a complimentary lookup table based strategy provided results appearing in the recent ATLAS High-Level Trigger, Data Acquisition and Controls Technical Design Report and were successfully implemented online during data taking for the recent ATLAS combined test beam.

Consider a model of particles (nucleons) that has a two-body interaction, which leads to bound composites with saturation properties. These properties are: all composites have the same density and the ground-state energies of composites with k nucleons are given by -kW+sigma k(2/3), where W and sigma are positive constants. W represents a volume term and sigma a surface-tension term. These values are taken from nuclear physics. We show that in the large N limit where N is the number of particles, such an assembly in a large enclosure at finite temperature shows properties of liquid-gas phase transition. We do not use the two-body interaction but the gross properties of the composites only. We show that (a) the p-rho isotherms show a region where pressure does not change as rho changes just as in the Maxwell construction of a Van der Waals gas, (b) in this region the chemical potential does not change, and (c) the model obeys the celebrated Clausius-Clapeyron relations. A scaling law for the yields of composites emerges. For a finite number of particles N (up to some thousands) the problem can be easily solved on a computer. This allows us to study finite particle number effects, which modify phase-transition effects. The model is calculationally simple. Monte Carlo simulations are not needed.

ATLAS is one of the four major Large Hadron Collider (LHC) experiments that will start data taking in 2007. It is designed to cover a wide range of physics topics. The ATLAS trigger system has to be able to reduce an initial 40 MHz event rate, corresponding to an average of 23 proton-proton inelastic interactions per every 25 ns bunch crossing, to 200 Hz admissible by the Data Acquisition System. The ATLAS trigger is divided in three different levels. The first one provides a signal describing an event signature using dedicated custom hardware. This signature must be confirmed by the High Level Trigger (HLT) which using commercial computing farms performs an event reconstruction by running a sequence of algorithms. The validity of a signature is checked after every algorithm execution. A main characteristic of the ATLAS HLT is that only the data in a certain window around the position flagged by the first level trigger are analyzed. In this work, the performance of one sequence that runs at the Event Filter level (third level) is demonstrated. The goal of this sequence is to reconstruct and identify high transverse momentum electrons by performing cluster reconstruction at the electromagnetic calorimeter, track reconstruction at the Inner Detector, and cluster track matching.

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The trigger system of the ATLAS experiment at the LHC aims at a high selectivity in order to keep the full physics potential while reducing the 40 MHz initial event rate imposed by the LHC bunch crossing down to /spl sim/100 Hz, as required by the data acquisition system. Algorithms working in the final stage of the trigger environment (Event Filter) are implemented to run both in a "wrapped" mode (reconstructing tracks in the entire Muon Spectrometer) and in a "seeded" mode (according to a dedicated strategy that performs pattern recognition only in regions of the detector where trigger hypotheses have been produced at earlier stages). The working principles of the offline muon reconstruction and identification algorithms (MOORE and MuId) implemented and used in the framework of the Event Filter are discussed in this paper. The reconstruction performance of these algorithms is presented for both modes in terms of efficiency, momentum resolution, rejection power and execution times on several samples of simulated single muon events, also taking into account the high background environment expected for ATLAS.