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Traumatic brain injury is a major cause of morbidity in civilian as well as military populations. Computational simulations of injurious events are an important tool to understanding the biomechanics of brain injury and evaluating injury criteria and safety measures. However, these computational models are highly dependent on the material parameters used to represent the brain tissue. Reported material properties of tissue from the cerebrum and cerebellum remain poorly defined at high rates and with respect to anisotropy. In this work, brain tissue from the cerebrum and cerebellum of male Göttingen minipigs was tested in one of three directions relative to axon fibers in oscillatory simple shear over a large range of strain rates from 0.025 to 250 s -1 . Brain tissue showed significant direction dependence in both regions, each with a single preferred loading direction. The tissue also showed strong rate dependence over the full range of rates considered. Transversely isotropic hyper-viscoelastic constitutive models were fit to experimental data using dynamic inverse finite element models to account for wave propagation observed at high strain rates. The fit constitutive models predicted the response in all directions well at rates below 100 s -1 , after which they adequately predicted the initial two loading cycles, with the exception of the 250 s -1 rate, where models performed poorly. These constitutive models can be readily implemented in finite element packages and are suitable for simulation of both conventional and blast injury in porcine, especially Göttingen minipig, models., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Traumatic brain injury (TBI), particularly from explosive blasts, is a major cause of casualties in modern military conflicts. Computational models are an important tool in understanding the underlying biomechanics of TBI but are highly dependent on the mechanical properties of soft tissue to produce accurate results. Reported material properties of brain tissue can vary by several orders of magnitude between studies, and no published set of material parameters exists for porcine brain tissue at strain rates relevant to blast. In this work, brain tissue from the brainstem, cerebellum, and cerebrum of freshly euthanized adolescent male Göttingen minipigs was tested in simple shear and unconfined compression at strain rates ranging from quasi-static (QS) to 300 s-1. Brain tissue showed significant strain rate stiffening in both shear and compression. Minimal differences were seen between different regions of the brain. Both hyperelastic and hyper-viscoelastic constitutive models were fit to experimental stress, considering data from either a single loading mode (unidirectional) or two loading modes together (bidirectional). The unidirectional hyper-viscoelastic models with an Ogden hyperelastic representation and a one-term Prony series best captured the response of brain tissue in all regions and rates. The bidirectional models were generally able to capture the response of the tissue in high-rate shear and all compression modes, but not the QS shear. Our constitutive models describe the first set of material parameters for porcine brain tissue relevant to loading modes and rates seen in blast injury., (Copyright © 2023 by ASME.)

Animal studies provide valuable insights on how the interaction of blast waves with the head may injure the brain. However, there is no acceptable methodology to scale the findings from animals to humans. Here, we propose an experimental/computational approach to project observed blast-induced molecular changes in the rat brain to the human brain. Using a shock tube, we exposed rats to a range of blast overpressures (BOPs) and used a high-fidelity computational model of a rat head to correlate predicted biomechanical responses with measured changes in glial fibrillary acidic protein (GFAP) in rat brain tissues. Our analyses revealed correlates between model-predicted strain rate and measured GFAP changes in three brain regions. Using these correlates and a high-fidelity computational model of a human head, we determined the equivalent BOPs in rats and in humans that induced similar strain rates across the two species. We used the equivalent BOPs to project the measured GFAP changes in the rat brain to the human. Our results suggest that, relative to the rat, the human requires an exposure to a blast wave of a higher magnitude to elicit similar brain-tissue responses. Our proposed methodology could assist in the development of safety guidelines for blast exposure., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Computational simulations of traumatic brain injury (TBI) are commonly used to advance understanding of the injury-pathology relationship, tissue damage thresholds, and design of protective equipment such as helmets. Both human and animal TBI models have developed substantially over recent decades, partially due to the inclusion of more detailed brain geometry and representation of tissues like cerebral blood vessels. Explicit incorporation of vessels dramatically affects local strain and enables researchers to investigate TBI-induced damage to the vasculature. While some studies have indicated that cerebral arteries are rate-dependent, no published experimentally based, rate-sensitive constitutive models of cerebral arteries exist. In this work, we characterize the mechanical properties of axially failed porcine arteries, both quasi-statically (0.01 s-1) and at high rate (>100 s-1), and propose a rate-sensitive model to fit the data. We find that the quasi-static and high-rate stress-stretch curves become significantly different (p < 0.05) above a stretch of 1.23. We additionally find a significant change in both failure stretch and stress as a result of strain rate. The stress-stretch curve is then modeled as a Holzapfel-Gasser-Ogden material, with a Prony series added to capture the effects of viscoelasticity. Ultimately, this paper demonstrates that rate dependence should be considered in the material properties of cerebral arteries undergoing high strain-rate deformations and provides a ready-to-use model for finite element implementation., (Copyright © 2022 by ASME.)

Despite years of research, it is still unknown whether the interaction of explosion-induced blast waves with the head causes injury to the human brain. One way to fill this gap is to use animal models to establish "scaling laws" that project observed brain injuries in animals to humans. This requires laboratory experiments and high-fidelity mathematical models of the animal head to establish correlates between experimentally observed blast-induced brain injuries and model-predicted biomechanical responses. To this end, we performed laboratory experiments on Göttingen minipigs to develop and validate a three-dimensional (3-D) high-fidelity finite-element (FE) model of the minipig head. First, we performed laboratory experiments on Göttingen minipigs to obtain the geometry of the cerebral vasculature network and to characterize brain-tissue and vasculature material properties in response to high strain rates typical of blast exposures. Next, we used the detailed cerebral vasculature information and species-specific brain tissue and vasculature material properties to develop the 3-D high-fidelity FE model of the minipig head. Then, to validate the model predictions, we performed laboratory shock-tube experiments, where we exposed Göttingen minipigs to a blast overpressure of 210 kPa in a laboratory shock tube and compared brain pressures at two locations. We observed a good agreement between the model-predicted pressures and the experimental measurements, with differences in maximum pressure of less than 6%. Finally, to evaluate the influence of the cerebral vascular network on the biomechanical predictions, we performed simulations where we compared results of FE models with and without the vasculature. As expected, incorporation of the vasculature decreased brain strain but did not affect the predictions of brain pressure. However, we observed that inclusion of the cerebral vasculature in the model changed the strain distribution by as much as 100% in regions near the interface between the vasculature and the brain tissue, suggesting that the vasculature does not merely decrease the strain but causes drastic redistributions. This work will help establish correlates between observed brain injuries and predicted biomechanical responses in minipigs and facilitate the creation of scaling laws to infer potential injuries in the human brain due to exposure to blast waves., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sundaramurthy, Kote, Pearson, Boiczyk, McNeil, Nelson, Subramaniam, Rubio, Monson, Hardy, VandeVord, Unnikrishnan and Reifman.)

Multiple finite-element (FE) models to predict the biomechanical responses in the human brain resulting from the interaction with blast waves have established the importance of including the brain-surface convolutions, the major cerebral veins, and using non-linear brain-tissue properties to improve model accuracy. We hypothesize that inclusion of a more detailed network of cerebral veins and arteries can further enhance the model-predicted biomechanical responses and help identify correlates of blast-induced brain injury. To more comprehensively capture the biomechanical responses of human brain tissues to blast-wave exposure, we coupled a three-dimensional (3-D) detailed-vasculature human-head FE model, previously validated for blunt impact, with a 3-D shock-tube FE model. Using the coupled model, we computed the biomechanical responses of a human head facing an incoming blast wave for blast overpressures (BOPs) equivalent to 68, 83, and 104 kPa. We validated our FE model, which includes the detailed network of cerebral veins and arteries, the gyri and the sulci, and hyper-viscoelastic brain-tissue properties, by comparing the model-predicted intracranial pressure (ICP) values with previously collected data from shock-tube experiments performed on cadaver heads. In addition, to quantify the influence of including a more comprehensive network of brain vessels, we compared the biomechanical responses of our detailed-vasculature model with those of a reduced-vasculature model and a no-vasculature model for the same blast-loading conditions. For the three BOPs, the predicted ICP values matched well with the experimental results in the frontal lobe, with peak-pressure differences of 4-11% and phase-shift differences of 9-13%. As expected, incorporating the detailed cerebral vasculature did not influence the ICP, however, it redistributed the peak brain-tissue strains by as much as 30% and yielded peak strain differences of up to 7%. When compared to existing reduced-vasculature FE models that only include the major cerebral veins, our high-fidelity model redistributed the brain-tissue strains in most of the brain, highlighting the importance of including a detailed cerebral vessel network in human-head FE models to more comprehensively account for the biomechanical responses induced by blast exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Subramaniam, Unnikrishnan, Sundaramurthy, Rubio, Kote and Reifman.)

The objective of this study was to perform finite element analysis (FEA) of cuff inflation within an anatomically accurate model of an adult trachea in four different cuffed-tracheostomy tube designs. The leakage quantified by the distance between the cuff and trachea was largest for the Tracoe cuff and smallest for the Portex cuff. The smooth muscle stresses were greatest for the Portex and least for the Distal cuff, respectively. The proposed FEA model offers a promising approach to virtually evaluate the sealing efficacy of cuffed-tracheostomy tubes and the tracheal wall stresses induced by cuff inflation, prior to application.

The interaction of explosion-induced blast waves with the head (i.e., a direct mechanism) or with the torso (i.e., an indirect mechanism) presumably causes traumatic brain injury. However, the understanding of the potential role of each mechanism in causing this injury is still limited. To address this knowledge gap, we characterized the changes in the brain tissue of rats resulting from the direct and indirect mechanisms at 24 h following blast exposure. To this end, we conducted separate blast-wave exposures on rats in a shock tube at an incident overpressure of 130 kPa, while using whole-body, head-only, and torso-only configurations to delineate each mechanism. Then, we performed histopathological (silver staining) and immunohistochemical (GFAP, Iba-1, and NeuN staining) analyses to evaluate brain-tissue changes resulting from each mechanism. Compared to controls, our results showed no significant changes in torso-only-exposed rats. In contrast, we observed significant changes in whole-body-exposed (GFAP and silver staining) and head-only-exposed rats (silver staining). In addition, our analyses showed that a head-only exposure causes changes similar to those observed for a whole-body exposure, provided the exposure conditions are similar. In conclusion, our results suggest that the direct mechanism is the major contributor to blast-induced changes in brain tissues., (© 2021. The Author(s).)

In this study, we investigated how animal orientation within a shock tube influences the biomechanical responses of the brain and cerebral vasculature of a rat when exposed to a blast wave. Using three-dimensional finite element (FE) models, we computed the biomechanical responses when the rat was exposed to the same blast-wave overpressure (100 kPa) in a prone (P), vertical (V), or head-only (HO) orientation. We validated our model by comparing the model-predicted and the experimentally measured brain pressures at the lateral ventricle. For all three orientations, the maximum difference between the predicted and measured pressures was 11%. Animal orientation markedly influenced the predicted peak pressure at the anterior position along the midsagittal plane of the brain (P = 187 kPa; V = 119 kPa; and HO = 142 kPa). However, the relative differences in the predicted peak pressure between the orientations decreased at the medial (21%) and posterior (7%) positions. In contrast to the pressure, the peak strain in the prone orientation relative to the other orientations at the anterior, medial, and posterior positions was 40-88% lower. Similarly, at these positions, the cerebral vasculature strain in the prone orientation was lower than the strain in the other orientations. These results show that animal orientation in a shock tube influences the biomechanical responses of the brain and the cerebral vasculature of the rat, strongly suggesting that a direct comparison of changes in brain tissue observed from animals exposed at different orientations can lead to incorrect conclusions., (Copyright © 2021 by ASME.)

Background: Multiple studies describing human head finite element (FE) models have established the importance of including the major cerebral vasculature to improve the accuracy of the model predictions. However, a more detailed network of cerebral vasculature, including the major veins and arteries as well as their branch vessels, can further enhance the model-predicted biomechanical responses and help identify correlates to observed blunt-induced brain injury., Methods: We used an anatomically accurate three-dimensional geometry of a 50th percentile U.S. male head that included the skin, eyes, sinuses, spine, skull, brain, meninges, and a detailed network of cerebral vasculature to develop a high-fidelity model. We performed blunt trauma simulations and determined the intracranial pressure (ICP), the relative displacement (RD), the von Mises stress, and the maximum principal strain. We validated our detailed-vasculature model by comparing the model-predicted ICP and RD values with experimental measurements. To quantify the influence of including a more comprehensive network of brain vessels, we compared the biomechanical responses of our detailed-vasculature model with those of a reduced-vasculature model and a no-vasculature model., Results: For an inclined frontal impact, the predicted ICP matched well with the experimental results in the fossa, frontal, parietal, and occipital lobes, with peak-pressure differences ranging from 2.4% to 9.4%. For a normal frontal impact, the predicted ICP matched the experimental results in the frontal lobe and lateral ventricle, with peak-pressure discrepancies equivalent to 1.9% and 22.3%, respectively. For an offset parietal impact, the model-predicted RD matched well with the experimental measurements, with peak RD differences of 27% and 24% in the right and left cerebral hemispheres, respectively. Incorporating the detailed cerebral vasculature did not influence the ICP but redistributed the brain-tissue stresses and strains by as much as 30%. In addition, our detailed-vasculature model predicted strain reductions by as much as 28% when compared to current reduced-vasculature FE models that only include the major cerebral vessels., Conclusions: Our study highlights the importance of including a detailed representation of the cerebral vasculature in FE models to more accurately estimate the biomechanical responses of the human brain to blunt impact.

The risk of type-A dissection is increased in subjects with connective tissue disorders and dilatation of the proximal aorta. The location and extents of vessel wall tears in these patients could be potentially missed during prospective imaging studies. The objective of this study is to estimate the distribution of systolic wall stress in two exemplary cases of proximal dissection using finite element analysis (FEA) and evaluate the sensitivity of the distribution to the choice of anisotropic material model and root motion. FEA was performed for predissection aortas, without prior knowledge of the origin and extents of vessel wall tear. The stress distribution was evaluated along the wall tear in the postdissection aortas. The stress distribution was compared for the Fung and Holzapfel models with and without root motion. For the subject with spiral dissection, peak stress coincided with the origin of the tear in the sinotubular junction. For the case with root dissection, maximum stress was obtained at the distal end of the tear. The FEA predicted tear pressure was 20% higher for the subject with root dissection as compared to the case with spiral dissection. The predicted tear pressure was higher (9-11%) for root motions up to 10 mm. The Holzapfel model predicted a tear pressure that was lower (8-15%) than the Fung model. The FEA results showed that both material response and root motion could potentially influence the predicted dissection pressure of the proximal aorta at least for conditions tested in this study., (Copyright © 2021 by ASME.)

The interaction of explosion-induced blast waves with the torso is suspected to contribute to brain injury. In this indirect mechanism, the wave-torso interaction is assumed to generate a blood surge, which ultimately reaches and damages the brain. However, this hypothesis has not been comprehensively and systematically investigated, and the potential role, if any, of the indirect mechanism in causing brain injury remains unclear. In this interdisciplinary study, we performed experiments and developed mathematical models to address this knowledge gap. First, we conducted blast-wave exposures of Sprague-Dawley rats in a shock tube at incident overpressures of 70 and 130 kPa, where we measured carotid-artery and brain pressures while limiting exposure to the torso. Then, we developed three-dimensional (3-D) fluid-structure interaction (FSI) models of the neck and cerebral vasculature and, using the measured carotid-artery pressures, performed simulations to predict mass flow rates and wall shear stresses in the cerebral vasculature. Finally, we developed a 3-D finite element (FE) model of the brain and used the FSI-computed vasculature pressures to drive the FE model to quantify the blast-exposure effects in the brain tissue. The measurements from the torso-only exposure experiments revealed marginal increases in the peak carotid-artery overpressures (from 13.1 to 28.9 kPa). Yet, relative to the blast-free, normotensive condition, the FSI simulations for the blast exposures predicted increases in the peak mass flow rate of up to 255% at the base of the brain and increases in the wall shear stress of up to 289% on the cerebral vasculature. In contrast, our simulations suggest that the effect of the indirect mechanism on the brain-tissue-strain response is negligible (<1%). In summary, our analyses show that the indirect mechanism causes a sudden and abundant stream of blood to rapidly propagate from the torso through the neck to the cerebral vasculature. This blood surge causes a considerable increase in the wall shear stresses in the brain vasculature network, which may lead to functional and structural effects on the cerebral veins and arteries, ultimately leading to vascular pathology. In contrast, our findings do not support the notion of strain-induced brain-tissue damage due to the indirect mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Rubio, Skotak, Alay, Sundaramurthy, Subramaniam, Kote, Yeoh, Monson, Chandra, Unnikrishnan and Reifman.)

Objectives: The aim of this study was to perform computational simulations of airflow within an anatomically accurate model of an adult trachea in different tracheostomy tube designs. We hypothesized that tracheal airflow in patients is significantly influenced by the geometry and size of these devices., Methods: The three-dimensional (3D) geometry of the trachea was reconstructed using computed tomography scans for an adult with no history of lung disease. 3D models of four cuffed tube designs, namely Tracoe, Portex, and Shiley Proximal and Distal tracheostomy tubes were generated using geometric modeling software. Transient simulations of airflow in the tube-airway assembly were performed for each tube using computational fluid dynamics (CFD)., Results: Airflow velocity was higher for the Shiley tubes compared with Portex and Tracoe tubes. For all designs, the largest magnitude of inspiratory airflow turbulence was obtained midway in the trachea. The work of breathing, quantified by the resistance of the tracheostomy tube, was lowest for Tracoe. Maximum airway wall shear stress (WSS), defined as flow-induced frictional forces, occurred at the same spatial location in all cases. Low inspiratory WSS at the carina and high expiratory airway WSS at the cuff-airway interface were observed for the Tracoe and Portex tubes., Conclusion: Our CFD model offers a promising approach not only for choosing a tracheostomy tube for a patient but for improving existing tracheostomy tube designs., Level of Evidence: NA Laryngoscope, 129:1791-1799, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Women with Turner Syndrome have an increased risk for aortic dissection. Arterial stiffening is a risk factor for aortic dilatation and dissection. Here we investigate if arterial stiffening can be observed in Turner Syndrome patients and is an initial step in the development of aortic dilatation and subsequent dissection., Methods: Fifty-seven women with Turner Syndrome (48 years [29-66]) and thirty-six age- and sex-matched controls (49 years [26-68]) were included. Distensibility, blood pressure, carotid-femoral pulse wave velocity (PWV), the augmentation index (Aix) and central blood pressure were determined using cardiovascular magnetic resonance, a 24-h blood pressure measurement and applanation tonometry. Aortic distensibility was determined at three locations: ascending aorta, transverse aortic arch, and descending aorta., Results: Mean aortic distensibility in the descending aorta was significantly lower in Turner Syndrome compared to healthy controls (P = 0.02), however, this was due to a much lower distensibility among Turner Syndrome with coarctation, while Turner Syndrome without coarctation had similar distensibility as controls. Both the mean heart rate adjusted Aix (31.4% vs. 24.4%; P = 0.02) and central diastolic blood pressure (78.8 mmHg vs. 73.7 mmHg; P = 0.02) were higher in Turner Syndrome compared to controls, and these indices correlated significantly with ambulatory night-time diastolic blood pressure. The presence of aortic coarctation (r = - 0.44, P = 0.005) and a higher central systolic blood pressure (r = - 0.34, P = 0.03), age and presence of diabetes were inversely correlated with aortic distensibility in TS., Conclusion: Aortic wall function in the descending aorta is impaired in Turner Syndrome with lower distensibility among those with coarctation of the aorta, and among all Turner Syndrome higher Aix, and elevated central diastolic blood pressure when compared to sex- and age-matched controls., Trial Registration: The study was registered at ClinicalTrials.gov ( #NCT01678274 ) on September 3, 2012.

Highly compliant tissue supporting the pharynx and low muscle tone enhance the possibility of upper airway occlusion in children with obstructive sleep apnea (OSA). The present study describes subject-specific computational modeling of flow-induced velopharyngeal narrowing in a female child with polycystic ovarian syndrome (PCOS) with OSA and a non-OSA control. Anatomically accurate three-dimensional geometries of the upper airway and soft-palate were reconstructed for both subjects using magnetic resonance (MR) images. A fluid-structure interaction (FSI) shape registration analysis was performed using subject-specific values of flow rate to iteratively compute the biomechanical properties of the soft-palate. The optimized shear modulus for the control was 38 percent higher than the corresponding value for the OSA patient. The proposed computational FSI model was then employed for planning surgical treatment for the apneic subject. A virtual surgery comprising of a combined adenoidectomy, palatoplasty and genioglossus advancement was performed to estimate the resulting post-operative patterns of airflow and tissue displacement. Maximum flow velocity and velopharyngeal resistance decreased by 80 percent and 66 percent respectively following surgery. Post-operative flow-induced forces on the anterior and posterior faces of the soft-palate were equilibrated and the resulting magnitude of tissue displacement was 63 percent lower compared to the pre-operative case. Results from this pilot study indicate that FSI computational modeling can be employed to characterize the mechanical properties of pharyngeal tissue and evaluate the effectiveness of various upper airway surgeries prior to their application., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Innate immunity is characterized by the coordinated activity of multiple leukocytes mobilizing at or near the site of tissue injury. Slow rolling and/or adherent leukocytes have been shown to hydrodynamically recruit free-stream leukocytes to a model of inflamed tissue. In this paper, we numerically investigate the hydrodynamic recruitment of free-stream leukocytes due to the presence of a nearby adherent, deformed leukocyte by using a computational model developed from first principles to simulate these types of interactions. For free-stream cells at least one diameter above the surface and subsequently involved in a glancing (out-of-plane) collision with one or more adherent cell, the simulation indicated that the free-stream cell was driven closer to the surface as a function of increasing glancing distance. Further, with increasing deformation of the adherent cell a similar effect was observed beginning at smaller glancing offsets. The influence of binary interactions on the trajectories of free-stream cells that were less than one diameter above the surface was also examined. For fixed glancing distance, increased adherent cell deformation led to enhanced recruiting effectiveness which was quantified by determining the time needed for the free-stream cell to enter the reactive zone; that is, a membrane separation distance such that receptor-ligand binding was possible. This effectiveness was only moderately influenced by variations in shear rate and cell buoyancy. Finally, for large glancing offset the domain of influence of the adherent cell diminished and the trajectory of the free-stream cell was unaffected by the adherent cell, with regard to hydrodynamic recruitment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pharyngeal narrowing in obstructive sleep apnea (OSA) results from flow-induced displacement of soft tissue. The objective of this study is to evaluate the effect of airflow parameters and material model on soft tissue displacement for planning surgical treatment in pediatric patients with OSA and Down syndrome (DS). Anatomically accurate, three-dimensional geometries of the pharynx and supporting tissue were reconstructed for one pediatric OSA patient with DS using magnetic resonance images. Six millimeters of adenoid tissue was virtually removed based on recommendations from the surgeon, to replicate the actual adenoidectomy. Computational simulations of flow-induced obstruction of the pharynx during inspiration were performed using patient-specific values of tissue elasticity for pre and post-operative airways. Sensitivity of tissue displacement to selection of turbulence model, variation in inspiratory airflow, nasal airway resistance and choice of non-linear material model was evaluated. The displacement was less sensitive to selection of turbulence model (10% difference) and more sensitive to airflow rate (20% difference) and nasal resistance (30% difference). The sensitivity analysis indicated that selection of Neo-Hookean, Yeoh, Mooney-Rivlin or Gent models would result in identical tissue displacements (less than 1% difference) for the same flow conditions. Change in pharyngeal airway resistance between the rigid and collapsible models was nearly twice for the pre-operative case as compared to the post-operative scenario. The tissue strain at the site of obstruction in the velopharyngeal airway was lowered by approximately 84% following surgery. Inclusion of tissue elasticity resulted in better agreement with the actual surgical outcome compared to a rigid wall assumption, thereby emphasizing the importance of pharyngeal compliance for guiding treatment in pediatric OSA patients., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Severity of thoracic aortic disease in Turner syndrome (TS) patients is currently described through measures of aorta size and geometry at discrete locations. The objective of this study is to develop an improved measurement tool that quantifies changes in size and geometry over time, continuously along the length of the thoracic aorta., Methods: Cardiovascular magnetic resonance (CMR) scans for 15 TS patients [41 ± 9 years (mean age ± standard deviation (SD))] were acquired over a 10-year period and compared with ten healthy gender and age-matched controls. Three-dimensional aortic geometries were reconstructed, smoothed and clipped, which was followed by identification of centerlines and planes normal to the centerlines. Geometric variables, including maximum diameter and cross-sectional area, were evaluated continuously along the thoracic aorta. Distance maps were computed for TS and compared to the corresponding maps for controls, to highlight any asymmetry and dimensional differences between diseased and normal aortae. Furthermore, a registration scheme was proposed to estimate localized changes in aorta geometry between visits. The estimated maximum diameter from the continuous method was then compared with corresponding manual measurements at 7 discrete locations for each visit and for changes between visits., Results: Manual measures at the seven positions and the corresponding continuous measurements of maximum diameter for all visits considered, correlated highly (R-value = 0.77, P < 0.01). There was good agreement between manual and continuous measurement methods for visit-to-visit changes in maximum diameter. The continuous method was less sensitive to inter-user variability [0.2 ± 2.3 mm (mean difference in diameters ± SD)] and choice of smoothing software [0.3 ± 1.3 mm]. Aortic diameters were larger in TS than controls in the ascending [TS: 13.4 ± 2.1 mm (mean distance ± SD), Controls: 12.6 ± 1 mm] and descending [TS: 10.2 ± 1.3 mm (mean distance ± SD), Controls: 9.5 ± 0.9 mm] thoracic aorta as observed from the distance maps., Conclusions: An automated methodology is presented that enables rapid and precise three-dimensional measurement of thoracic aortic geometry, which can serve as an improved tool to define disease severity and monitor disease progression., Trial Registration: ClinicalTrials.gov Identifier - NCT01678274 . Registered - 08.30.2012.

Study Objectives: To describe a dynamic three-dimensional (3D) computed tomography (CT) technique for the upper airway and compare the required radiation dose to that used for common clinical studies of a similar anatomical area, such as for subjects undergoing routine clinical facial CT., Methods: Dynamic upper-airway CT was performed on eight subjects with persistent obstructive sleep apnea, four of whom were undergoing magnetic resonance imaging and an additional four subjects who had a contraindication to magnetic resonance imaging. This Health Insurance Portability and Accountability Act-compliant study was approved by our institutional review board, and informed consent was obtained. The control subjects (n = 41) for comparison of radiation dose were obtained from a retrospective review of the clinical picture-archiving computer system to identify 10 age-matched patients per age-based control group undergoing facial CT., Results: Dynamic 3D CT can be performed with an effective radiation dose of less than 0.38 mSv, a dose that is less than or comparable to that used for clinical facial CT. The resulting data- set is a uniquely complete, dynamic 3D volume of the upper airway through a full respiratory cycle that can be processed for clinical and modeling analyses., Conclusions: A dynamic 3D CT technique of the upper airway is described that can be performed with a clinically reasonable radiation dose and sets a benchmark for future use., (© 2017 American Academy of Sleep Medicine)

Particle suspensions are common to biological fluid flows; for example, flow of red- and white-blood cells, and platelets. In medical technology, current and proposed methods for drug delivery use membrane-bounded liquid capsules for transport via the microcirculation. In this paper, we consider a 3D linear elastic particle inserted into a Newtonian fluid and investigate the time-dependent deformation using a numerical simulation. Specifically, a boundary element technique is used to investigate the motion and deformation of initially spherical or spheroidal particles in bounded linear shear flow. The resulting deformed shapes reveal a steady-state profile that exhibits a 'tank-treading' motion for initially spherical particles. Wall effects on particle trajectory are seen to include a modified Jeffrey׳s orbit for spheroidal inclusions with a period that varies inversely with the strength of the shear flow. Alternately, spheroidal inclusions may exhibit either a 'tumbling' or 'trembling' motion depending on the initial particle aspect ratio and the capillary number (i.e., ratio of fluid shear to elastic restoring force). We find for a capillary number of 0.1, a tumbling mode transitions to a trembling mode at an aspect ratio of 0.87 (approx.), while for a capillary number of 0.2, this transition takes place at a lower aspect ratio. These oscillatory modes are consistent with experimental observations involving similarly shaped vesicles and thus serves to validate the use of a simple elastic constitutive model to perform relevant physiological flow calculations., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Elasticity of the soft tissues surrounding the upper airway lumen is one of the important factors contributing to upper airway disorders such as snoring and obstructive sleep apnea. The objective of this study is to calculate patient specific elasticity of the pharynx from magnetic resonance (MR) images using a 'tube law', i.e., the relationship between airway cross-sectional area and transmural pressure difference. MR imaging was performed under anesthesia in children with Down syndrome (DS) and obstructive sleep apnea (OSA). An airway segmentation algorithm was employed to evaluate changes in airway cross-sectional area dilated by continuous positive airway pressure (CPAP). A pressure-area relation was used to make localized estimates of airway wall stiffness for each patient. Optimized values of patient specific Young's modulus for tissue in the velopharynx and oropharynx, were estimated from finite element simulations of airway collapse. Patient specific deformation of the airway wall under CPAP was found to exhibit either a non-linear 'hardening' or 'softening' behavior. The localized airway and tissue elasticity were found to increase with increasing severity of OSA. Elasticity based patient phenotyping can potentially assist clinicians in decision making on CPAP and airway or tissue elasticity can supplement well-known clinical measures of OSA severity.

Compliance of soft tissue and muscle supporting the upper airway are two of several factors contributing to pharyngeal airway collapse. We present a novel, minimally invasive method of estimating regional variations in pharyngeal elasticity. Magnetic resonance images for pediatric sleep apnea patients with Down syndrome [9.5 ± 4.3 years (mean age ± standard deviation)] were analyzed to segment airways corresponding to baseline (no mask pressure) and two positive pressures. A three dimensional map was created to evaluate axial and circumferential variation in radial displacements of the airway, dilated by the positive pressures. The displacements were then normalized with respect to the appropriate transmural pressure and radius of an equivalent circle to obtain a measure of airway compliance. The resulting elasticity maps indicated the least and most compliant regions of the pharynx. Airway stiffness of the most compliant region [403 ± 204 (mean ± standard deviation) Pa] decreased with severity of obstructive sleep apnea. The non-linear response of the airway wall to continuous positive airway pressure was patient specific and varied between anatomical locations. We identified two distinct elasticity phenotypes. Patient phenotyping based on airway elasticity can potentially assist clinical practitioners in decision making on the treatments needed to improve airway patency.

Leukocyte trafficking in the microvasculature during inflammatory response is known to involve multiple adhesion molecules and is referred to as the leukocyte adhesion cascade (LAC). Surface-bound selectins and their respective ligands are primarily responsible for tethering and rolling of leukocytes over inflamed endothelium. Numerical modeling of this response is challenging due to the nature of cell-cell interactions in Stokes flow (i.e., large domain of influence for each cell over its neighbors). Here, we discuss a novel simulation capable of modeling several steps of the LAC. The new model includes relevant contact and lubrication forces and extends a physics-based model for single particle rolling interactions developed by Hammer and Apte (1992), for multiparticle interactions by King and Hammer (2001a), and for deformable particles by Gee and King (2006). We initially demonstrate the model for cell-cell collisions occurring near a planar substrate, and for cell-substrate adhesive interactions. The adhesion studies provide a new perspective of the contribution of Hertzian contact mechanics toward variations in contact area at the cell-substrate interface. The results confirm that interfacial contact area will increase as a result of the contact formulation and that this mechanism may enhance cell rolling interactions for cells driven toward endothelium by cell-cell collisions. As a result of cell compliance, rolling velocity may decrease significantly, compared to non-compliant cells., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC). This novel serine protease causes the degradation of hepatic LDL receptors by an unknown mechanism. In humans, gain-of-function mutations in the PCSK9 gene cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDLC and decreased cardiovascular risk. Relatively little is known about PCSK9 in human serum., Methods: We used recombinant human PCSK9 protein and 2 different anti-PCSK9 monoclonal antibodies to build a sandwich ELISA. We measured PCSK9 and lipids in 55 human serum samples and correlated the results. We used the anti-PCSK9 antibodies to assay lipoprotein particle fractions separated by sequential flotation ultracentrifugation., Results: Serum concentrations of PCSK9 ranged from 11 to 115 microg/L and were directly correlated with serum concentrations of LDLC (r = 0.45, P = 0.001) and total cholesterol (r = 0.50, P = 0.0003), but not with triglycerides (r = 0.15, P = 0.28) or HDL cholesterol concentrations (r = 0.13, P = 0.36). PCSK9 was not detectable in any lipoprotein particle fraction, including LDL., Conclusions: PCSK9 is present in human serum, likely not associated with specific lipoprotein particles. The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations.