Regional Deposition Patterns Research Articles

Cellular iron deposition patterns predict clinical subtypes of multiple system atrophy

BackgroundMultiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. Therefore, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology. MethodsIron burden in subcortical and brainstem regions were histologically mapped in human post-mortem brains of 4 MSA-parkinsonian (MSA-P), 4 MSA-cerebellar (MSA-C), and 1 MSA case with both parkinsonian and cerebellar features. We then performed the first cell type-specific evaluation of pathological iron deposition in α-synuclein-affected and -unaffected cells of the globus pallidus, putamen, and the substantia nigra, regions of highest iron concentration, using a combination of iron staining with immunolabelling. Selective regional and cellular vulnerability patterns of iron deposition were compared between disease subtypes. In 7 MSA cases, expression of key iron- and closely related oxygen-homeostatic genes were examined. ResultsMSA-P and MSA-C showed different patterns of regional iron burden across the pathology-related systems. We identified subcortical microglia to predominantly accumulate iron, which was more distinct in MSA-P. MSA-C showed relatively heterogenous iron accumulation, with greater or similar deposition in astroglia. Iron deposition was also found outside cellular bodies. Cellular iron burden associated with oligodendrocytic, and not neuronal, α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen homeostatic genes, rather than of cellular iron. Importantly, hierarchal cluster analysis revealed the pattern of cellular vulnerability to iron accumulation, distinctly to α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes. ConclusionsOur comprehensive evaluation of iron deposition in MSA brains identified distinct regional, and for the first time, cellular distribution of iron deposition in MSA-P and MSA-C and revealed cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes. Our findings suggest distinct iron-related pathomechanisms in MSA clinical subtypes that are therefore not a consequence of a uniform down-stream pathway to α-synuclein pathology, and inform current efforts in iron chelation therapies at the disease and cellular-specific levels.

Cerebral Tau Deposition in Comorbid Progressive Supranuclear Palsy and Amyotrophic Lateral Sclerosis: An [18F]-Flortaucipir and 7T MRI Study

Introduction: Progressive supranuclear palsy (PSP) is a four-repeat tauopathy characterized by multiple clinicopathologic subtypes. Advanced neuroimaging techniques have shown an early ability to distinguish PSP subtypes noninvasively for improved diagnosis. This study utilized tau PET imaging and MRI techniques at 7T to determine the neuroimaging profile of a participant with comorbid PSP and amyotrophic lateral sclerosis (ALS). Method: [18F]-flortaucipir PET imaging was performed on one participant with PSP-ALS, one participant with typical PSP (Richardson’s syndrome; PSP-RS), and 15 healthy control volunteers. Standardized uptake value ratio (SUVR) in each brain region was compared between PSP participants and controls. Quantitative susceptibility mapping (QSM) and inflow-based vascular-space occupancy MRI at 7T were performed on the two PSP participants and on two age-matched healthy controls to evaluate for differences in regional brain iron content and arteriolar cerebral blood volume (CBVa), respectively. Results: In the participant with PSP-ALS, the precentral gyrus demonstrated the highest [18F]-flortaucipir uptake of all brain regions relative to controls (z-score 1.94). In the participant with PSP-RS, [18F]-flortaucipir uptake relative to controls was highest in subcortical regions, including the pallidum, thalamus, hippocampus, and brainstem (z-scores 1.08, 1.41, 1.49, 1.32, respectively). Susceptibility values as a measure of brain iron content were higher in the globus pallidus and substantia nigra than in the midbrain and pons in each participant, regardless of group. CBVa values tended to be higher in the subcortical gray matter in PSP participants than in controls, although large measurement variability was noted in controls across multiple regions. Conclusion: In vivo tau PET imaging of an individual with PSP-ALS overlap demonstrated increased tau burden in the motor cortex that was not observed in PSP-RS or control participants. Consistent with prior PET studies, tau burden in PSP-RS was mainly observed in subcortical regions, including the brainstem and basal ganglia. QSM data suggest that off-target binding to iron may account for some but not all of the increased [18F]-flortaucipir uptake in the basal ganglia in PSP-RS. These findings support existing evidence that tau PET imaging can distinguish among PSP subtypes by detecting distinct regional patterns of tau deposition in the brain. Larger studies are needed to determine whether CBVa is sensitive to changes in brain microvasculature in PSP.

Modeling of local and systemic exposure to metals and metalloids after inhalation exposure: Recommended update to the USEPA metals framework.

The USEPA issued the "Framework for Metal Risk Assessment" in 2007, recognizing that human and environmental exposure to metals and metalloids (MMEs) poses challenges risk assessment. Inhalation of aerosols containing MMEs is a primary pathway for exposure in the occupational setting, for consumer exposure, and to general population exposure associated with point-source emissions or ambient sources. The impacts of inhalation can be at the point of deposition (local exposure) or may manifest after uptake into the body (systemic exposure). Both local and systemic exposure can vary with factors that determine the regional deposition of MME-containing aerosols. Aerosol characteristics such as particle size combine with species-specific characteristics of airway morphology and lung function to modulate the deposition and clearance of MME particulates. In contrast to oral exposure, often monitored by measuring MME levels in blood or urine, inhalation exposure can produce local pulmonary impacts in the absence of significant systemic distribution. Exposure assessment for nutritionally essential MMEs can be further complicated by homeostatic controls that regulate systemic MME levels. Predictions of local exposure can be facilitated by computer models that estimate regional patterns of aerosol deposition, permitting calculation of exposure intensity in different regions of the respiratory tract. The utility of deposition modeling has been demonstrated in assessments of nutritionally essential MMEs regulated by homeostatic controls and in the comparison of results from inhalation studies in experimental animals. This facilitates extrapolation from animal data to humans and comparisons of exposures possessing mechanistic linkages to pulmonary toxicity and carcinogenesis. Pulmonary deposition models have significantly advanced and have been applied by USEPA in evaluations of particulate matter. However, regional deposition modeling has yet to be incorporated into the general guidance offered by the agency for evaluating inhalation exposure. Integr Environ Assess Manag 2024;20:952-964. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

The southern Wyoming Laramide basin: implications for long-term tectonic control on uplift and subsidence

ABSTRACTAn evolving tectonic setting during the Late Cretaceous and Paleocene drove the dramatic transformation of southern Wyoming from a broad marine shelf setting to a series of lacustrine basins. Early dominant control of depositional patterns by flexural tectonics gave way to control by dynamic topography and Laramide-style deformation. The southern Wyoming region demonstrates how progressive partitioning by Laramide movements exerted increasingly dominant control on regional depositional patterns. It did this by creating a long-lived, Laramide uplift-bounded fluvial catchment and basin largely controlled by Laramide-driven subsidence. The Rock Springs and Rawlins uplifts underpinned the basin and exerted their influence in the subsurface. Episodes of Laramide-driven subsidence produced a series of embayments, including the large Rusty–Allen Ridge embayment and the very large deepwater Lewis embayment. The degree of eustatic control in the region would have been greatest at short time scales in the low coastal–shallow-marine settings, causing shoreline oscillations. Several long transgressive episodes followed relatively punctuated progradational periods of coastal-plain construction when supply was generally high from the thrust belt and surrounding uplifts. Laramide activity in the Paleocene led to enclosure of the fluvial basin and the development of a series of smaller marine embayments that mark the end of influence in the region by open and coastal marine processes.

Calculation of oil saturation in clay-rich shale reservoirs: A case study of Qing 1 Member of Cretaceous Qingshankou Formation in Gulong Sag, Songliao Basin, NE China

The targeted reservoir, which is referred as the first member of Cretaceous Qingshankou Formation in Gulong Sag, Songliao Basin, NE China, is characterized by the enrichment of clay and lamellation fractures. Aiming at the technical challenge of determining oil saturation of such reservoir, nano-pores were accurately described and located through focused ion beam scanning electron microscopy and quantitative evaluation of minerals by scanning electron microscopy based on Simandoux model, to construct a 4D digital core frame. Electrical parameters of the shale reservoir were determined by finite element simulation, and the oil saturation calculation method suitable for shale was proposed. Comparison between the results from this method with that from real core test and 2D nuclear magnetic log shows that the absolute errors meet the requirements of the current reserve specification in China for clay-rich shale reservoir. Comparison analysis of multiple wells shows that the oil saturation values calculated by this method of several points vertically in single wells and multiple wells on the plane are in agreement with the test results of core samples and the regional deposition pattern, proving the accuracy and applicability of the method model.

Detailed comparative analysis of environmental microparticle deposition characteristics between human and monkey nasal cavities using a surface mapping technique

Inhaled particulate matter is associated with nasal diseases such as allergic rhinitis, rhinosinusitis and neural disorders. Its health risks on humans are usually evaluated by measurements on monkeys as they share close phylogenetic relationship. However, the reliability of cross-species toxicological extrapolation is in doubt due to physiological and anatomical variations, which greatly undermine the reliability of these expensive human surrogate models. This study numerically investigated in-depth microparticle transport and deposition characteristics on human and monkey (Macaca fuscata) nasal cavities that were reconstructed from CT-images. Deposition characteristics of 1–30μm particles were investigated under resting and active breathing conditions. Similar trends were observed for total deposition efficiencies and a single correlation using Stokes Number was fitted for both species and both breathing conditions, which is convenient for monkey-human extrapolation. Regional deposition patterns were carefully compared using the surface mapping technique. Deposition patterns of low, medium and high inertial particles, classified based on their total deposition efficiencies, were further analyzed in the 3D view and the mapped 2D view, which allows locating particle depositions on specific nasal regions. According to the particle intensity contours and regional deposition profiles, the major differences were observed at the vestibule and the floor of the nasal cavity, where higher deposition intensities of medium and high inertial particles were shown in the monkey case than the human case. Comparisons of airflow streamlines indicated that the cross-species variations of microparticle deposition patterns are mainly contributed by two factors. First, the more oblique directions of monkey nostrils result in a sharper airflow turn in the vestibule region. Second, the monkey's relatively narrower nasal valves lead to higher impaction of medium and high inertial particles on the nasal cavity floor. The methods and findings in this study would contribute to an improved cross-species toxicological extrapolation between human and monkey nasal cavities.

Design of In Vivo Deposition and Clearance Experiments.

Experiments designed to image in vivo deposition of radiolabel-drug mixtures are useful for estimating inhaled drug delivery and for assessing bioequivalence of delivery devices. Validation of the radiolabel-drug mixture is vital to ensure that subsequent imaging is reflective of drug deposition. Application of gamma attenuation corrections allows both total and regional lung deposition of drug to be estimated by two-dimensional (2D) imaging. Imaging methods are also useful for measuring in vivo mucociliary clearance (MC) function. Such measures allow assessment of the efficacy of drugs designed to improve clearance of airway secretions in airway disease. MC rates can be measured by controlled inhalation and gamma camera monitoring of radiolabeled aerosols containing non-permeating tracers. While in vivo MC rates reflect the function of the mucociliary apparatus, they are also dependent on regional deposition patterns of the inhaled aerosol.

New REE-Constrained Terrigenous Depositional Changes in the Central Okinawa Trough and their Responses to Climate since 92 Millennia

Abstract The continental margin is one of the major depocenters for terrigenous sediments in the world ocean. Complex interactions between land and sea control the sedimentary processes along the continental margin. The Okinawa Trough (OT) receives huge amounts of terrigenous materials transported by rivers from the adjacent landmass, while the Kuroshio Current (KC) and the North Pacific Intermediate Water jointly play major roles in oceanic climate and regional deposition patterns of terrigenous sediments. Various studies have investigated the changes in terrigenous sediment provenance in the central OT only since the last glacial. Still, few studies focus on more long-term variations in terrigenous deposition over the last few glacial-interglacial cycles. Here, we report a new high-resolution sediment geochemistry record of a well-dated core MD01-2404 taken from the central OT covering a timespan of 92 kyr. Our results show dynamic glacial-interglacial changes in sediment compositions and terrigenous deposition patterns. Bulk sediments in MD01-2404 comprise relatively high biogenic components during interglacials, while higher terrigenous fractions during the last deglacial and glacial periods. We suggest that the provenance of terrigenous sediments is mainly derived from Taiwanese rivers, Yangtze River, and Yellow River with hydrothermal inputs. During the time interval of 37 to 46 kyr, a new finding of “Negative Ce Anomaly Event” in the central OT firstly reported here is attributed to a combination of suboxic conditions in deep and pore waters and the addition of depleted Ce-bearing sediments. Temporal changes of deposition patterns in the central OT are attributed to complex interactions among dynamic glacial-interglacial changes in eustatic sea level, the East Asian summer monsoon, and the KC.

Wet nitrogen (N) deposition to urban Latin America: Filling in the gaps with GEOS-Chem

In Latin America, atmospheric deposition is a major vector of nitrogen (N) input to urban systems. Yet, measurements of N deposition are sparse, precluding analysis of spatial patterns, temporal trends, and ecosystem impacts. Chemical transport models can be used to fill these gaps in the absence of dense measurements. Here, we evaluate the performance of a global 3-D chemical transport model in simulating spatial and interannual variation in wet inorganic N (NH4–N + NO3–N) deposition across urban areas in Latin America. Monthly wet and dry inorganic N deposition to Latin America were simulated for the period 2006–2010 using the GEOS-Chem Chemical Transport Model. Published estimates of observed wet or bulk inorganic N deposition measured between 2006 and 2010 were compiled for 16 urban areas and then compared with model output from GEOS-Chem. Observed mean annual inorganic N deposition to the urban study sites ranged from 5.7 to 14.2 kg ha−1 yr−1, with NH4–N comprising 48–90% of the total. Results show that simulated N deposition was highly correlated with observed N deposition across sites (R2 = 0.83, NMB = −50%). However, GEOS-Chem generally underestimated N deposition to urban areas in Latin America compared to observations. Underestimation due to bulk sampler dry deposition artifacts was considered and improved bias without improving correlation. In contrast to spatial variation, the model did not capture year-to-year variation well. Discrepancies between modeled and observed values exist, in part, because of uncertainties in Latin American N emissions inventories. Our findings indicate that even at coarse spatial resolution, GEOS-Chem can be used to simulate N deposition to urban Latin America, improving understanding of regional deposition patterns and potential ecological effects.

Assessment of the predictive capability of modelling and simulation to determine bioequivalence of inhaled drugs: A systematic review.

There are a multitude of different modelling techniques that have been used for inhaled drugs. The main objective of this review was to conduct an exhaustive survey of published mathematical models in the area of asthma and chronic obstructive pulmonary disease (COPD) for inhalation drugs. Additionally, this review will attempt to assess the applicability of these models to assess bioequivalence (BE) of orally inhaled products (OIPs). PubMed, Science Direct, Web of Science, and Scopus databases were searched from 1996 to 2020, to find studies that described mathematical models used for inhaled drugs in asthma/COPD. 50 articles were finally included in this systematic review. This research identified 22 articles on in silico aerosol deposition models, 20 articles related to population pharmacokinetics and 8 articles on physiologically based pharmacokinetic modelling (PBPK) modelling for inhaled drugs in asthma/COPD. Among all the aerosol deposition models, computational fluid dynamics (CFD) simulations are more likely to predict regional aerosol deposition pattern in human respiratory tracts. Across the population PK articles, body weight, gender, age and smoking status were the most common covariates that were found to be significant. Further, limited published PBPK models reported approximately 29 parameters relevant for absorption and distribution of inhaled drugs. The strengths and weaknesses of each modelling technique has also been reviewed. Overall, while there are different modelling techniques that have been used for inhaled drugs in asthma and COPD, there is very limited application of these models for assessment of bioequivalence of OIPs. This review also provides a ready reference of various parameters that have been considered in various models which will aid in evaluation if one model or hybrid in silico models need to be considered when assessing bioequivalence of OIPs.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease

BackgroundTriple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD.MethodsThis phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs.ResultsThe mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64).ConclusionsRadiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD.Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045

Particle inhalability of a standing mannequin with large airways in a ventilated room

This study presents a series of numerical simulations for airflow field and particle dispersion and deposition around a mannequin inside a ventilated room. A 3-D airway system of a volunteer subject with a large respiratory system was reconstructed from the nostril inlet to the end of the tracheobronchial tree 4th generation and was integrated into a standing mannequin at the center of a room. The room ventilation system supplied air through a diffuser and expelled air via a damper in three modes. The airflow field was first evaluated by solving the governing equations and the k-ω SST transitional turbulence model using the Ansys-Fluent software. Then spherical particles with various diameters were released into the room, and their trajectories were evaluated using the Lagrangian approach. Aspiration fraction and particle deposition for inhalation flow rates of 15 and 30 L/min were analyzed using a modified discrete random walk (DRW) stochastic model using a user-defined function (UDF) coupled to the Ansys-Fluent discrete phase model. For the first ventilation mode, a recirculation flow region formed behind the mannequin that led the airflow streamlines to the breathing zone. A recirculation flow formed in front of the face for the second ventilation mode that led the airflow streamlines out of the mannequin breathing zone. For the third mode, however, there was no strong recirculation flow zone around the mannequin. Simulation results showed that the aspiration fraction in the first ventilation mode was higher than the other modes. In addition, the regional deposition rates and deposition patterns of particles inside the respiratory system were presented for each region. Accordingly, most large particles were trapped in the nasal passage; however, some large particles penetrated deeper into the airway due to the large airway size. For the higher breathing rate, the percentage of large escaped particles from the lobe branches dropped by a factor of 7 compared to the lower breathing rate.

Drivers of Dissolved Organic Carbon Mobilization From Forested Headwater Catchments: A Multi Scaled Approach

Understanding and predicting catchment responses to a regional disturbance is difficult because catchments are spatially heterogeneous systems that exhibit unique moderating characteristics. Changes in precipitation composition in the Northeastern U.S. is one prominent example, where reduction in wet and dry deposition is hypothesized to have caused increased dissolved organic carbon (DOC) export from many northern hemisphere forested catchments; however, findings from different locations contradict each other. Using shifts in acid deposition as a test case, we illustrate an iterative “process and pattern” approach to investigate the role of catchment characteristics in modulating the steam DOC response. We use a novel dataset that integrates regional and catchment-scale atmospheric deposition data, catchment characteristics and co-located stream Q and stream chemistry data. We use these data to investigate opportunities and limitations of a pattern-to-process approach where we explore regional patterns of reduced acid deposition, catchment characteristics and stream DOC response and specific soil processes at select locations. For pattern investigation, we quantify long-term trends of flow-adjusted DOC concentrations in stream water, along with wet deposition trends in sulfate, for USGS headwater catchments using Seasonal Kendall tests and then compare trend results to catchment attributes. Our investigation of climatic, topographic, and hydrologic catchment attributes vs. directionality of DOC trends suggests soil depth and catchment connectivity as possible modulating factors for DOC concentrations. This informed our process-to-pattern investigation, in which we experimentally simulated increased and decreased acid deposition on soil cores from catchments of contrasting long-term DOC response [Sleepers River Research Watershed (SRRW) for long-term increases in DOC and the Susquehanna Shale Hills Critical Zone Observatory (SSHCZO) for long-term decreases in DOC]. SRRW soils generally released more DOC than SSHCZO soils and losses into recovery solutions were higher. Scanning electron microscope imaging indicates a significant DOC contribution from destabilizing soil aggregates mostly from hydrologically disconnected landscape positions. Results from this work illustrate the value of an iterative process and pattern approach to understand catchment-scale response to regional disturbance and suggest opportunities for further investigations.

Unique regional patterns of amyloid burden predict progression to prodromal and clinical stages of Alzheimer's disease

Although beta-amyloid (Aβ) positivity has shown to be associated with higher risk of progression to Alzheimer's disease (AD) in mild cognitive impairment (MCI), information on the time to conversion to manifest dementia cannot be readily deduced from this binary classification. Here, we assessed if regional patterns of Aβ deposition measured with 18F-florbetapir may serve as biomarker for progression risk in Aβ-positive cognitively normal (CN) and MCI patients, including clinical follow-up data and cerebrospinal fluid (CSF) biomarkers. Voxel-wise group comparisons between age and sex-matched Aβ-positive groups (i.e., CN-stables [n = 38] vs. CN-to-MCI/AD progressors [n = 38], MCI-stables [n = 104] versus MCI-to-AD progressors [n = 104]) revealed higher Aβ burden in precuneus, subcortical, and parietal regions in CN-to-MCI/AD progressors and cingulate, temporal, and frontal regions in MCI-to-AD progressors. Importantly, these regional patterns predicted progression to advanced stages on the AD spectrum in the short and the long-term beyond global Aβ burden and CSF biomarkers. These results suggest that distinct regional patterns of Aβ burden are a valuable biomarker for risk of disease progression in CN and MCI.

Flow Structure and Particle Deposition Analyses for Optimization of a Pressurized Metered Dose Inhaler (pMDI) in a Model of Tracheobronchial Airway

Inhalation therapy plays an important role in management or treatment of respiratory diseases such asthma and chronic obstructive pulmonary diseases (COPDs). For decades, pressurized metered dose inhalers (pMDIs) have been the most popular and prescribed drug delivery devices for inhalation therapy. The main objectives of the present computational work are to study flow structure inside a pMDI, as well as transport and deposition of micron-sized particles in a model of human tracheobronchial airways and their dependence on inhalation air flow rate and characteristic pMDI parameters. The upper airway geometry, which includes the extrathoracic region, trachea, and bronchial airways up to the fourth generation in some branches, was constructed based on computed tomography (CT) images of an adult healthy female. Computational fluid dynamics (CFD) simulation was employed using the k−ω model with low-Reynolds number (LRN) corrections to accomplish the objectives. The deposition results of the present study were verified with the in vitro deposition data of our previous investigation on pulmonary drug delivery using a hollow replica of the same airway geometry as used for CFD modeling. It was found that the flow structure inside the pMDI and extrathoracic region strongly depends on inhalation flow rate and geometry of the inhaler. In addition, regional aerosol deposition patterns were investigated at four inhalation flow rates between 30 and 120 L/min and for 60 L/min yielding highest deposition fractions of 24.4% and 3.1% for the extrathoracic region (EX) and the trachea, respectively. It was also revealed that particle deposition was larger in the right branches of the bronchial airways (right lung) than the left branches (left lung) for all of the considered cases. Also, optimization of spray characteristics showed that the optimum values for initial spray velocity, spray cone angle and spray duration were 100 m/s, 10° and 0.1 sec, respectively. Moreover, spray cone angle, more than any other of the investigated pMDI parameters can change the deposition pattern of inhaled particles in the airway model. In conclusion, the present investigation provides a validated CFD model for particle deposition and new insights into the relevance of flow structure for deposition of pMDI-emitted pharmaceutical aerosols in the upper respiratory tract.

Differences between cigarette smoking and biomass smoke exposure: An in silico comparative assessment of particulate deposition in the lungs

Cigarette smoking and biomass smoke are the two main environmental risk factors of chronic obstructive pulmonary disease (COPD) worldwide. However, it remains unclear why these exposures result in two different disease phenotypes. In this study, we assessed the lung deposition from biomass and cigarette smoke exposures and examined whether differences due to inherently different particle size distributions and inhalation conditions may contribute to the differences between biomass- and tobacco-related COPD phenotypes. Using high-fidelity three-dimensional computational fluid-particle dynamics in a representative upper airway geometry, coupled to one-dimensional models of the lower airways, we computed total deposited doses and examined regional deposition patterns based on exposure data from a randomized control trial in Peru and from the literature for biomass and mainstream cigarette smoke, respectively. Our results showed that intrathoracic deposition was higher in cigarette smoking, with 36.8% of inhaled biomass smoke particles and 57.7% of cigarette smoke particles depositing in the intrathoracic airways. We observed higher fractions of cigarette smoke particles in the last few airway generations, which could explain why cigarette smoking is associated with more emphysema than biomass smoke exposure. Mean daily deposited dose was two orders of magnitude higher in cigarette smoking. Lobar distributions of the deposited dose also differed, with the left lower and right upper lobes receiving the highest doses of biomass and cigarette smoke particles, respectively. Our findings suggest that the differences between biomass- and tobacco-related COPD could, at least in part, be due to differences in total and regional lung deposition of biomass and cigarette smoke.

Influence of aerodynamic particle size on botulinum neurotoxin potency in mice

Objective For many agents, the aerodynamic particle size can affect both the virulence and disease course in animal models. Botulinum neurotoxins (BoNTs), which are widely known as potential bioterrorism agents, have been shown to be toxic via multiple routes of exposure, including small particle inhalation (1–3 µm MMAD). However, the impact of larger particle sizes on the potency of BoNT has not been previously reported. In this study, we compared the potency of BoNT in small and large particle aerosols. Materials and methods Outbred mice (ICR (CD-1®)) were exposed to BoNT-containing aerosols with differing mass median aerodynamic diameters (MMADs) of 1.1, 4.9, and 7.6 microns. The effects of bioaerosol sampler and inhalation exposure modality were studied. Results and discussion Collecting aerosolized BoNT onto gelatin filters or into liquid impingers resulted in equivalent estimates of aerosol concentration. Nose-only and whole-body inhalation exposure resulted in nearly identical estimates of the median lethal dose (LD50). The LD50 for inhaled BoNT increased approximately 50-fold when the median aerodynamic particle size was increased from 1.1 to 4.9 µm, from 139 (95% CI: 111–185) to 7324 (95% CI: 4287–10 891) mouse intraperitoneal median lethal doses (MIPLD50). These results demonstrate the importance of aerodynamic particle size and regional deposition patterns with regards to BoNT inhalational toxicity. Conclusions These data will be useful for medical countermeasure development, as well as biodefense preparedness modeling by demonstrating that the estimates of dose and toxicity of an inhaled aerosol containing BoNT can be significantly affected by a range of factors.

Evaluation of Intranasal Vaccine Delivery Using Anatomical Replicas of Infant Nasal Airways.

Nasal delivery is a favorable route for vaccination against most respiratory infections, as antigen deposited in the nasal turbinate and Waldeyer's ring areas induce mucosal and systemic immune responses. However, little is known about the nasal distribution of the vaccines, specifically for infants. Anatomical nasal replicas of five subjects, 3-24months, were developed to assess local intranasal vaccine delivery using MAD Nasal™ device, and understand impact of breathing conditions and administration parameters. High performance liquid chromatography was used to quantify the deposition pattern and determine the delivery efficiency. The delivery efficiency on average for all models was found to be 86.57±14.23%. There were no significant differences in the total delivery efficiency between the models in all cases. However, the regional deposition pattern was altered based on the model and subsequent administration. Furthermore, removing the foam tip from the MAD Nasal™ device, to study the impact of insertion length, did not significantly increase the efficiency within the two models tested, 5- and 16-month. Incorporating nasal replicas in testing provided a benchmark to determine the efficiency of a common intranasal vaccine delivery combination product. This proposed platform would allow comparing other potential nasal vaccine delivery devices.

Regional Deposition: Targeting.

Patterns of regional aerosol deposition within the lungs are known to vary in a predictable manner with a number of factors, most notably aerodynamic particle size and inhalation pattern. Targeting deposition involves the intentional manipulation of one or more of these factors to promote aerosol deposition in certain locations within the respiratory tract. This section will begin by exploring existing evidence supporting the need to target regional deposition. Thereafter, various approaches to targeting will be introduced. In addition to control of aerodynamic particle size and inhalation pattern, a collection of approaches are available through which to passively target deposition to more central or peripheral lung regions. These include the delivery of short aerosol boluses at prescribed time points in inhalation, control of transient hygroscopic aerosol size changes during transport through the respiratory tract, and use of alternative carrier gas mixtures such as helium/oxygen mixtures. Comparatively, targeting aerosol deposition locally to very precise, spatially-defined lung regions is in its infancy. Early, exploratory techniques used for local targeting will be described. The continued evolution of deposition targeting towards ever more specific locations within the lungs is required to explore fundamental research questions in aerosol medicine: namely, how precise does targeting need to be before additional refinement fails to produce appreciably different therapeutic effects, and which nascent applications of aerosols in medicine might benefit from more selective regional targeting?

Breath Hold Facilitates Targeted Deposition of Aerosolized Droplets in a 3D Printed Bifurcating Airway Tree.

The lungs have long been considered a desired route for drug delivery but, there is still a lack of strategies to rationally target delivery sites especially in the presence of heterogeneous airway disease. Furthermore, no standardized system has been proposed to rapidly test different ventilation strategies and how they alter the overall and regional deposition pattern in the airways. In this study, a 3D printed symmetric bifurcating tree model mimicking part of the human airway tree was developed that can be used to quantify the regional deposition patterns of different delivery methodologies. The model is constructed in a novel way that allows for repeated measurements of regional deposition using reusable parts. During ventilation, nebulized ~3-micron-sized fluid droplets were delivered into the model. Regional delivery, quantified by precision weighing individual airways, was highly reproducible. A successful strategy to control regional deposition was achieved by combining an inspiratory wave form with a "breath hold" pause after each inspiration. Specifically, the second generation of the tree was successfully targeted, and deposition was increased by up to four times in generation 2 when compared to a ventilation without the breath hold (p < 0.0001). Breath hold was also demonstrated to facilitate deposition into blocked regions of the model, which mimic airway closure during an asthma that receive no flow during inhalation. Additionally, visualization experiments demonstrated that in the absence of fluid flow, the deposition of 3-micron water droplets is dominated by gravity, which, to our knowledge, has not been confirmed under standard laboratory conditions.