Physics of Fluids

The Next Generation Impactor (NGI) is one of the regulatory gold standards for characterizing aerodynamic particle size distributions (APSDs) of orally inhaled drug products (OIDPs); however, its reliance on complex, resource-intensive in vitro testing under tightly controlled environmental conditions limits experimental flexibility and introduces variability. In alignment with the growing regulatory emphasis on New Approach Methodologies (NAMs) for drug development, this study presents a rigorously validated computational fluid particle dynamics (CFPD) based virtual NGI (vNGI) as an in silico method complementary to conventional testing. The vNGI replicates a significant portion of the NGI geometry and airflow physics, enabling high-resolution spatiotemporal analysis of aerosol transport and deposition mechanisms that are otherwise inaccessible experimentally. A comprehensive verification and validation framework was implemented, including mesh and particle independence studies, turbulence model assessment, and comparison of stagewise deposition efficiencies with available in vitro data at 30 L/min. The model's capabilities were further extended to low and high flow rates, and two bio-relevant mouth-throat models and polydisperse particle laden aerosol were added. The model demonstrates strong predictive capability for a few stages and provides mechanistic insight into discrepancies in other stages, depending on the type of analysis. Importantly, this work establishes the vNGI as a fit-for-purpose according to NAM by (i) defining a clear context of use for APSD prediction and inhaler performance evaluation, (ii) capturing physically and biologically relevant air-particle interactions, and (iii) demonstrating technical robustness and reproducibility through systematic validation. The platform can potentially further enable simulation of environmental and physiological conditions, such as humidity effects, that are difficult to control experimentally, thereby improving human relevance and reducing reliance on costly and time-consuming in vitro testing. This study positions the vNGI as a scalable, regulatory aligned NAM capable of supporting early stage drug device combination product development, device optimization, and an alternative bioequivalence assessment, contributing to ongoing efforts to enhance predictive performance, reduce experimental burden, and transition toward human centric, inhalation product evaluation.

Control of fluids is a hallmark of microfluidic systems and fundamental for the successful application of microfluidic devices. Trigger valves use geometric features to autonomously control the release of fluids in microfluidic devices. Our previous work has adapted geometries used in closed trigger valve systems to enable use in open systems, allowing for open microfluidic devices with up to three trigger valves. Here, we focus on the parallel co-flows produced by sequential release of trigger valves and present a model that predicts their layer widths as a function of the geometric characteristics of the different side channels of each trigger valve. We show layered co-flows with widths as low as 50 microns. Additionally, we expand the use of trigger valves in open microfluidic devices by incorporating 1) varied step heights, 2) devices with up to seven trigger valves, and 3) use of varied fluids and plastics. To validate the implementation and use of these trigger valves in open systems, we have developed a theoretical framework to compare predicted outcomes (i.e., fluid travel distance, velocity, and layering width) with our experimental values. This theoretical work offers applications in various fields, including hydrogel patterning for 3D cell culture, organ-on-a-chip models, at-home sample preparation, and autonomous microfluidic systems for biosensing.

Background: Automatic tube compensation (ATC) was designed to compensate for the additional resistive load imposed by the endotracheal tube during spontaneous breathing. In ATC mode, the ventilator adds or subtracts the flow-dependent pressure drop across the tube during both inspiration and expiration so that tracheal pressure remains close to PEEP. Early prototype ventilators achieved true tracheal-pressure control and showed physiological and clinical benefits, but clinical studies with commercial systems have failed to confirm these earlier findings. A 2003 bench study found that commercial ventilators provided, at best, only partial tube compensation, unlikely to result in meaningful clinical benefit. We therefore tested whether this limitation has been remedied in contemporary ICU ventilators. Methods: We performed a bench comparison of five commercial ICU ventilators and an ATC prototype ventilator designed to accurately compensate for the flow-dependent resistance over a wide range of flow rates. An active lung simulator generated spontaneous breathing patterns with weak, moderate, and strong inspiratory efforts at different PEEP levels. We tested each breathing pattern through endotracheal tubes with inner diameters of 7 and 8 mm, and measured airway pressure, tracheal pressure, and flow during CPAP with and without ATC. Breathing through the tube against open atmosphere served as a zero-PEEP/T-piece reference. Results: In CPAP mode, the commercial ventilators showed flow-dependent airway-pressure deviations, amounting to a substantial added resistance of 1.5 - 6.5 mbar/(L/s), whereas the ATC prototype ventilator imposed an added resistance of only 0.6 mbar/(L/s). In ATC mode, the commercial ventilators reduced the resistive load by no more than by 25%, and large tracheal-pressure deviations remained, especially at higher inspiratory effort and during expiration. In some cases, the residual load during ATC was even greater than the load during unsupported breathing through the tube. By contrast, the ATC prototype ventilator maintained tracheal pressure close to PEEP throughout the breathing cycle and eliminated on average 79% of the tube-related resistive load. Conclusions: In the commercial ventilators evaluated in this study, the defining physiological objective of ATC was only partially achieved. Therefore, clinical benefits previously reported for tracheal-pressure control support should be interpreted with caution when applied to commercial ATC implementations, unless effective tube compensation has been demonstrated under relevant conditions. These findings suggest that more advanced control approaches, such as those implemented in the ATC prototype ventilator, may be required to achieve consistent and physiologically accurate tube compensation.

The suspension culture of pluripotent stem (PS) cells in stirred bioreactors poses a delicate balance between maintaining homogeneous cell dispersion and avoiding excessive shear stress that can compromise cell viability and pluripotency. In this study, we used computational fluid dynamics (CFD) coupled with a discrete particle method (DPM) to simulate iPS cell behavior in a 5 mL delta-impeller stirred tank. Our analysis revealed that upward flow at the tank bottom and downward flow at the top are critical for maintaining a stable suspension. To optimize the stirring protocol, we applied Bayesian optimization to identify a time-dependent stirring schedule that begins with a high-speed phase for resuspension, followed by a low-speed phase for sustained suspension with minimal hydrodynamic stress. The optimized schedule demonstrated improved suspension ratio and reduced slip velocity, indicating lower mechanical stress on cells. These findings provide engineering insights into scalable bioreactor operation, contributing to the design of robust iPS cell manufacturing systems.

A wide spectrum of microparticles is inhaled with each breath, deposited on airway surfaces, entrapped in the mucus, and removed by mucociliary transport (MCT). However, the influence of particle size on MCT remains largely unknown. Here, we investigated the MCT of microparticles with a trachea-on-a-chip method that integrates a micro-machined device with a trachea explant from newborn pigs. This method preserves airway structures for mucus secretion and cilia beating (e.g., airway surface epithelia and submucosal glands), maintains physiological air-liquid-interface on the airway surface, and allows tracks motion of microparticles with high resolution. Using this method, we found that, in normal airways, 6 um polystyrene particles clear rapidly, whereas 102 um particles clear slower and require mucus strands for motion. In cystic fibrosis (CF) airways, MCT of microparticles reduces, but particle size-dependence persists. Methacholine increases particle motion in normal airways, but not in CF airways. These findings suggest two distinct MCT processes, in which large particles rely on mucus strands for clearance, small particles can be cleared independent of mucus strands, and CF disrupts both.

The endothelial cells (ECs) that line blood vessels continuously sense and respond to the physical forces exerted by blood flow. In vivo, pulsatile arterial flow interacts with vessel curvature, branching and other anatomical features to generate complex local hemodynamic environments that dictate the magnitude, direction, pulsatility, and oscillatory nature of wall shear stress experienced by ECs. Currently, accessible and reproducible in vitro models of complex pulsatile flow that recapitulate in vivo vascular anatomy remain limited. Here, we combine a novel rotational-flow endothelial culture platform with detailed computational fluid dynamics (CFD) modeling to characterize four well geometries designed to generate distinct hemodynamic environments. CFD analyses demonstrate that these geometries intrinsically generate pulsatile flow and produce reproducible spatially distinct regions of wall shear stress magnitude, pulsatility, and oscillatory shear within a single culture well. Endothelial alignment mapping and functional assays reveal region-specific cellular responses to the predicted local flow conditions that closely corresponded to the predicted local hemodynamic environment, linking complex flow patterns to endothelial adaptation. The technical advancements of our modeling efforts should support a faster, cheaper, simpler, and--importantly--validated framework for future investigation into EC mechanobiology under complex flow conditions. HIGHLIGHTSO_LISimple engineered well geometries generate distinct hemodynamic microenvironments, mimicking in vivo vascular structures, using a conventional orbital shaker. C_LIO_LIComputational fluid dynamics (CFD) reveals spatially distinct patterns of wall shear stress, pulsatility, and oscillatory shear applied to ECs within individual culture wells. C_LIO_LIHigh average wall shear stress and elevated oscillatory shear index induces a unique perpendicular alignment of ECs to the dominant flow vector. C_LI

Background. Scanning electron microscopy (SEM) is widely used to determine fibrin fiber structural properties such as fiber diameter and fiber length. However, conventional SEM preparation protocols are time-consuming and typically require conductive sputter coating. The coating process introduces an additional layer onto the sample surface and may influence measurements of nanoscale fiber structure. Furthermore, preparation of purified fibrinogen clots often follows protocols originally developed for plasma clots, resulting in unnecessary processing steps. Objective. To evaluate indium tin oxide (ITO) as a flat, conductive substrate for SEM imaging of fibrin fibers, investigate the effects of sputter coating on measured fiber diameter, and develop a simplified SEM preparation protocol for purified fibrinogen clots. Methods. Platelet-poor plasma clots and purified fibrinogen clots were formed on ITO substrates and imaged by SEM following 0 s, 45 s, or 90 s sputter coating. Fibrin fiber diameters were quantified and compared across coating conditions. For purified fibrinogen clots, an ITO-based simplified preparation protocol, in which clots were formed and imaged directly on the conductive ITO surface, was compared with a previously developed, standardized SEM protocol, in which clots were formed in microtube lids and subsequently transferred onto carbon tape for imaging. Results. Fiber diameter measurements were affected by sputter coating duration, with increasing coating time resulting in larger apparent fiber diameters. Plasma and purified fibrinogen clots exhibited distinct fiber diameter distributions and coating responses. For purified fibrinogen clots, the simplified ITO-based protocol produced fiber diameter measurements that were not significantly different from those obtained using the standardized lid-to-carbon-tape workflow when identical coating times were applied. Conclusions. ITO provides a practical conductive substrate for SEM imaging of fibrin fibers and enables substantial simplification of purified fibrinogen clot preparation. When coating conditions are matched, the simplified ITO-based protocol yields fiber diameter measurements comparable to those obtained using the previously standardized lid-to-carbon-tape workflow. These findings support the use of ITO as an alternative conductive imaging substrate and provide a simplified workflow for SEM analysis of purified fibrinogen clots. By reducing washing and transfer steps, this workflow may also provide a useful platform for future controlled studies of fibrin interactions with added proteins or other associated components.

The cytoplasm is a crowded and dynamic fluid within which cellular building blocks such as mRNA, proteins, or organelles undergo transport and mixing. Although small things like proteins can eventually mix through diffusion, the high viscosity of cytoplasm means that it should be difficult to obtain significant mixing for structures in the size range of mRNA, multi-protein complexes or organelles. In large amoeboid cells, the cytoplasm undergoes active streaming coupled to cell motility, but this streaming is laminar flow which should not be effective for mixing. In this work we used a combination of live cell tracking of injected beads and computational analysis of motion and mixing in giant amoeba Chaos carolinensis with the initial goal of testing the possibility that large-scale cellular deformations during pseudopod formation might implement chaotic mixing by a Baker-transform like process. Instead, we found that Chaos carolinensis accelerates cytoplasmic mixing using a novel cytoplasmic gel state capture and release strategy. While it was previously thought that the amoeba sol to gel state transitions only occur at the trailing and leading edge of the cell body, our work indicates that these transitions occur frequently throughout the mid-cell region, driving the cytoplasmic mixing of beads and organelles. These results indicate that amoeba achieves nearly complete mixing between 1 and 2 cytoplasmic stream/flow cycle, effectively approximating the Bernoulli mixing regime and thus representing one of the theoretically fastest possible mixers.

Conventional extrusion-based 3D bioprinting encounters limitations in fabricating intricate tissue architectures due to fixed nozzle diameters and fixed deposition orientations. These constraints restrict conformal printing on curved or non-planar surfaces and often necessitate support-intensive fabrication strategies. This work introduces a mechanically simplified extrusion platform inspired by the swivel jet nozzle, featuring a free-degree-of-orientation extrusion head termed the universal extrusion head (Univ-Ex head), coupled with a modular nozzle architecture. The Univ-Ex head employs a swivel-like mechanical design that enables orientation freedom without external actuation in its current implementation, thereby minimizing mechanical complexity while supporting deposition on physiologically relevant, non-planar geometries. Multiple nozzle concepts were developed through comparative CAD iterations, with two representative geometries--a flat nozzle and a conical nozzle--selected for experimental validation. The platform is evaluated through parametric CAD design, stereolithography-printed prototypes, proof-of-concept extrusion experiments, and fluid dynamics simulations performed using FLOW-3D software. Numerical and experimental results demonstrate stable filament formation and clear diameter-dependent extrusion behavior, while simulations further confirm the feasibility of angled and non-planar deposition. A variable-diameter nozzle concept is proposed as a forward design direction to enable real-time adjustment of bioink flow rate and deposition resolution in principle; however, the present study intentionally validates the system using fixed-diameter nozzle variants to maintain stable numerical and experimental boundary conditions. A gear-integrated Univ-Ex head is also presented as a forward upgrade and demonstrated as a single-piece prototype. Collectively, this work establishes a scalable, hardware-focused pathway toward conformal bio-additive manufacturing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/734010v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@8833caorg.highwire.dtl.DTLVardef@33dforg.highwire.dtl.DTLVardef@14d8d11org.highwire.dtl.DTLVardef@685ef0_HPS_FORMAT_FIGEXP M_FIG C_FIG

Potent antineoplastics, such as afatinib and freebase doxorubicin, are associated with systemic toxicity. To address this issue, we developed a carrier that releases drugs, including afatinib and doxorubicin, specifically at the focus of low-intensity ultrasound. This remotely triggered and focal approach enables the release of drugs specifically at the ultrasound focus, thus mitigating undesirable off-target effects, and at concentrations governed by the duration of the applied ultrasound. We produced ultrasound-sensitive microdroplets with high encapsulation efficiencies (39.6% for afatinib and 46.6% for doxorubicin). The microdroplets consist of an ultrasound-sensitive drug delivery system based on a methoxy poly(ethylene glycol)-poly(D, L-lactide) diblock copolymer (mPEG-PDLLA) and perfluorooctyl bromide (PFOB). Antineoplastic agents were encapsulated within these microdroplets via co-evaporation during particle synthesis. The microdroplets released doxorubicin and afatinib in an ultrasound-pressure-dependent manner, with fitted half-maximal release pressures (P50) of 0.61 MPa and 0.72 MPa, respectively. Together, the effective encapsulation of hydrophobic antineoplastic agents and the dose-dependent ultrasound-triggered release provide a new method for targeted drug delivery and a foundation for future targeted chemotherapies.

Molecular dynamics simulations of nucleic acids are performed using a solvent-buffer distance of 10 [A] between the solute surface and the simulation box boundary. Although this cell size has been extensively explored in protein simulations, its implications for nucleic acid dynamics are not well understood. Nucleic acids are elongated, highly charged, and flexible structures with hydration and dynamical properties distinct from those of proteins and therefore, they may require different solvent-layer considerations in simulations. In this study, we investigated the effect of simulation cell size on nucleic acid dynamics by simulating a 30-base-pair double-helical nucleic acid structure and its two single-stranded forms using solvent-buffer distances of 3, 5, 10, 15, and 20 [A]. Smaller cells may impose restricted hydration, molecular crowding, and periodic image interactions. However, larger cells provide solvent space for conformational relaxation. A total of 45 s of molecular dynamics simulations were performed (3 structures x 5 cell sizes x 3 replicates x 1 s). Our results show that while the commonly used 10 [A] buffer may be sufficient to maintain the stability of the double-stranded nucleic acid, larger cells are required to capture the conformational dynamics of single-stranded structures. In both, increasing the cell size to 15 or 20 [A] enables broader conformational sampling. The first hydration shell exhibits reduced crowding in the 20 [A] cell, consistent with more relaxed conformations. At larger cell sizes, single-stranded nucleic acids adopt compact, self-associated conformations for stability. Together, this study presents physical insight into how simulation cell size and solvent environment influence nucleic acid dynamics.

The impact of weather on the health of Americans and the American health system is substantial. Using available health and economic data, we developed a data-driven scenario that describes a compounded heat emergency in an archetypal community in the United States. We then characterize the potential human and economic costs of such a heat emergency to demonstrate the widespread impact on health outcomes, health systems, and society.

Exposure to higher levels of ambient air pollution during pregnancy has been linked to multiple adverse pregnancy outcomes. However, studies on acute exposures and reduced gestation length have reported inconsistent findings. This project aims to examine the acute association between ambient air pollution and preterm (28-36 gestational weeks) or early-term (37-38 gestational weeks) births. Daily concentrations of 12 air pollutants, based on bias-corrected numerical model outputs, were linked to vital records of singleton live preterm and early-term births from 2005-2017 in California, Florida, Georgia, Kansas, Nevada, New Jersey, North Carolina (2005-2015), and Oregon. Under a time-stratified case-crossover design, odds ratios (OR) were estimated via conditional logistic regression with adjustment for risks among ongoing pregnancies, meteorology, time trends and federal holidays. We estimated cumulative associations up to a 6-day lag using distributed lag models. Risk estimates per interquartile range (IQR) increase in exposure were pooled across states using inverse-variance weighting. Our study included 1,085,162 preterm and 3,901,185 early-term births. We observed positive associations between 0-2 day cumulate exposure to several air pollutants and early-term births, including NO2 (OR: 1.0023, 95% CI:1.0010, 1.0037 per 7.1 g/m3 increase), PM2.5 (OR=1.0022, 95% CI: 1.006, 1.0038 per 4.6 g/m3 increase), PM2.5 organic carbon (OR= 1.0026, 95% CI: 1.0013, 1.0039 per 1.7 g/m3 increase) and PM2.5 elemental carbon (OR=1.0025, 95% CI: 1.0014, 1.0035 per 0.26 g/m3 increase). Associations with preterm birth were mostly null. In conclusion, we found positive associations between short-term air pollution exposure, including PM and major PM2.5 components, and risks of early-term birth.

Poly-L-Lysine (PLL) mediates the non-specific adhesion of cells and is commonly used in Atomic Force Microscopy (AFM) measurements, to ensure that cells remain attached to the substrate. However, it is acknowledged that adhesion affects the measured mechanical properties, in particular in the case Red Blood Cells (RBCs). This results in a wide range of Youngs modulus E reported in the literature. The present study aims at providing a systematic approach to the impact of non-specific adhesion on the rheology of RBCs. It provides a correlation between the topography profile of adherent RBCs and their rheology, from weak (cPLL = 10-3 mg/mL) to strong-adhesion (cPLL = 100 mg/mL) regimes. Using RICM and AFM, we find that there is a continuum of RBC shapes promoted by adhesion, from concave to dome-shaped, as predicted by the theory of vesicle adhesion. Their elastic properties discriminate them into two populations depending on adhesion strength, where stiffer RBCs (E {gtrsim} 100 Pa) correlate with dome-shaped cells. These findings are supported by rheology measurements of the dynamic complex shear modulus G*(f): while the storage modulus increases with cell-substrate adhesion, reflective of an increased membrane shear modulus, the loss modulus remains unchanged. Finally, further analysis inspired by membrane theory shows that different deformation modes may be triggered during indentation of either weakly or strongly adhering RBCs, illustrating the limits of the Hertz model.

The mosquito Aedes albopictus is a competent vector for the transmission of several arboviruses and is currently spreading across many continents. Since conventional control methods, like insecticides, often lead to environmental problems and the emergence of resistance, scientists developed alternative mosquito control strategies. One of the most used is the Sterile Insect Technique (SIT), which involves the mass release of males sterilized through irradiation. The Toxic Male Technique (TMT) is instead based on the release of genetically modified males expressing toxic proteins that kill females when they mate. Control strategies are often intended as methods to eradicate mosquito populations, yet a less ambitious and more cost-effective task is to reduce them such that the probability of transmission of viruses to humans becomes negligible. To compare the efficacy of these control strategies, we develop a mathematical model with two communicating compartments: a mosquito population and epidemiological model coupled with a human epidemiological model. As a proof-of-concept, we test the model using meteorological and entomological data for the Emilia-Romagna region. Our results indicate that the TMT strategy is more effective in lowering the probability of transmission and provides indication for the deployment of control strategies.

Minimally invasive surgery is a powerful technique that enables operations deep within the body while minimizing patient trauma and recovery time. Optical endoscopes are key to providing intraoperative vision but still face challenges due to the loss of essential senses, including depth perception and tactile feedback for tissue evaluation. Thus, it is critical to develop endoscopic imaging technologies that can augment operators with critical information. In this work, we explore a prototype multimodal 3D imaging endoscope that integrates volumetric light-field imaging with laser-speckle contrast imaging to simultaneously capture 3D structure and blood-flow information in a clinically relevant form factor.

The global coral reef crisis has prompted restoration initiatives worldwide. Targeting the coral larval stage is among the most scalable approaches as recruitment operates over large spatial scales. It thus represents one of the best levers for coral population recovery. Active coral larval seeding has shown considerable success, and passive substrate engineering has emerged as a promising complementary strategy. Coral settlement modules featuring helix recesses have increased settlement and survival by up to 80-fold on small experimental units, but whether these results translate to tools deployable at the scale of thousands of units, remains yet an open question. Here, we transferred structural features from successful experimental coral settlement designs into production-ready concrete modules to (i) evaluate coral recruitment on five designs at four reef sites differing in flow regime and coral cover over one year; (ii) compare production-scale performance against experimental clay modules and natural reef substrate; and (iii) identify key parameters for large-scale production. The helix recess geometry of coral settlement modules outperformed the featureless control design approximately 20-fold and exceeded natural reef recruitment at least 3- to 32-fold. The helix features were successfully transferred from experimental clay to production-scale concrete modules, yielding comparable settlement densities when standardized to crevice length, which proved to be the biologically relevant unit of available habitat. Production feasibility was demonstrated by producing 690 modules for deployment on a hybrid reef on the west side of Oahu, Hawaii. The passive coral larval recruitment approach presented here could substantially improve the logistical and economic feasibility of large-scale coral reef restoration. This approach requires neither coral larval rearing, handling, nor coral fragmenting, and is compatible with active larval seeding where genetic diversity or larvae supply are limiting factors. The coral settlement modules can be cast in standardized concrete molds at precast facilities. Modules have demonstrated consistent coral recruitment enhancement across reef environments with contrasting flow and coral cover. Deploying mixed arrays of helix-recess structures with designs offering multi-level complexity and three-dimensional rugosity maximizes outcomes for coral, fish, and invertebrate communities simultaneously. Site selection is the most critical deployment decision and should consider larval supply, hydrodynamics, and substrate stability which drive recruitment outcomes more than design choice alone. The modules offer a range of application potential, ranging from integration into existing coastal infrastructure over stand-alone reef restoration approaches, to substrate-consolidating interconnected arrangements.

Intrathecal (IT) drug delivery, i.e., the infusion of substances directly into cerebrospinal fluid (CSF) by lumbar, ventricular, or cisternal access points, is one method that can be used to bypass the blood brain barrier (BBB), however, IT-administered substances also suffer from rapid turnover and poor tissue penetration. Although nanoparticles and colloids can circulate within the subarachnoid space to sustain the levels of encapsulated drug in CSF, their access to deep tissue regions remains incomplete. Here, we present a new method for enhancing CNS delivery of IT-administered nanoparticles. CSF Flow Enhancement (CFE) refers to the manipulation of CSF production, distribution, and clearance for therapeutic purposes. We tested the overarching hypothesis that infusion of hypertonic fluid adjacent to the choroid plexus would enhance fluid production and movement to improve the CNS delivery of IT-administered nanoparticles. Model polystyrene nanoparticles (100nm) were solubilized in aCSF of increasing tonicity (1-9X tonicity) and infused into the cisterna magna, after which tissues were removed to examine delivery to CNS tissues and peripheral organs. Our results demonstrate that an infusion of up to 4X hypertonic aCSF in 10uL is well tolerated and yields significant improvements in CNS localization of co-administered nanoparticles, more than doubling the delivery of nanoparticles to the ventral surfaces of the brain and sometimes dramatic (up to 10-fold) increases in delivery to specific tissue regions and surfaces of the CNS. Significantly, we provide early evidence that modulation of tonicity can define the parenchymal fate of IT administered colloids: while nanoparticles were not detected in the brain parenchyma of mice that received a standard infusion, parenchymal delivery was observed for the 2X condition, and extensive perivascular infiltration of nanoparticles was observed for the 4X condition. Lastly, we show that the delivery improvements achieved by CFE are generalizable across multiple sizes of polystyrene nanoparticle (20, 40, or 100nm). Collectively, this work describes a tonicity-based approach for achieving CFE by the intrathecal route, which we posit is a useful and potentially generalizable approach for improving CNS drug delivery.

Urinary stone disease is a common urological condition with increasing incidence, particularly in developed countries. Laser lithotripsy (LL) has become a preferred minimally invasive treatment due to its high precision and low tissue damage. Recent studies suggest that cavitation plays a critical role in stone damage during LL, and three-dimensional passive cavitation mapping (3D-PCM) has emerged as a promising tool for detecting these events. However, clinical translation of 3D-PCM remains challenging due to limitations in imaging depth, field of view (FOV), and procedural compatibility. Here, we present a large-FOV dual-modality imaging system (3D-PCM and B-mode ultrasound) based on a large-aperture planar ultrasound array. Through array optimization and model-based reconstruction, our system achieves an expanded FOV of ~40*40mm^2 at a clinically relevant imaging depth of ~110mm, while maintaining high spatial resolution of ~0.6 mm laterally and ~0.4 mm axially. In vivo experiments in a porcine model demonstrate that the reconstructed cavitation distribution correlates well with stone damage. Our technology has the potential to provide real-time treatment feedback during LL without disrupting the standard workflow.

Vodobatinib (VBN) is a weakly basic (pKa {approx} 2.3), anticancer treatment with poor enteric solubility and low oral bioavailability. This study demonstrates how an emerging polymeric amorphization technique, slurry conversion, can yield amorphous drug-polymer salts with enhanced dissolution rates. The technique had not previously been applied to a weakly basic drug, so design rules for this class of active were unknown. Two acidic polymers, poly(styrene sulfonic acid) (PSSA) and poly(acrylic acid) (PAA), were individually evaluated for salt formation with VBN. Formulation involved blending the drug and polymer in a 1:2 (v/v) ratio of a protic liquid to solvent and a 1:9 (w/w) ratio of solid to solvent. Design rules for effective combinations of solvents and protic liquids were developed and optimized to thread the needle between dissolution of all species and acid-base interactions, both of which were required to form amorphous salts. Drug loadings of 10%, 20%, and 40% by mass were tested. X-ray photoelectron spectroscopy was employed to evaluate protonation of the quinoline nitrogen atoms on VBN, a key indicator of successful salt formation. Powder X-ray diffraction was used to confirm that the resulting slurry contained amorphous VBN, and 1H NMR spectroscopy indicated residual solvent remained after drying, which remains an area for improvement. In dissolution kinetics tests in FeSSIF, the lead drug-polymer salt formulation achieved a concentration of dissolved VBN up to 140 {micro}g/mL, an improvement of >35-fold compared to <4 {micro}g/mL (LLD) for crystalline VBN. These results demonstrate that slurry conversion is a viable polymeric amorphization technique even for weakly basic drugs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/734800v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1812ceforg.highwire.dtl.DTLVardef@1ad06dcorg.highwire.dtl.DTLVardef@9d8bb7org.highwire.dtl.DTLVardef@13fcbe8_HPS_FORMAT_FIGEXP M_FIG C_FIG