David M. Wootton

A Mechanistic Model of Acute Platelet Accumulation in Thrombogenic Stenoses

AbstractThrombosis on an atherosclerotic lesion can cause heart attack or stroke. Thrombosis may be triggered by plaque rupture or erosion, creating a thrombogenic stenosis. To measure and model this situation, collagen-coated stenoses have been exposed to nonanticoagulated blood in a baboon ex vivo shunt. The maximum rate of platelet accumulation, measured using a gamma camera, was highest in the throat region of moderate and severe stenoses, and increased with increasing stenosis severity. A species transport model of platelet accumulation was developed, which included mechanisms of convection, shear-enhanced diffusion, near-wall platelet concentration, and a kinetic model of platelet activation and aggregation. The model accurately reproduced the average spatial pattern and time rate of platelet accumulation in the upstream and throat regions of the stenosis, where shear-enhanced diffusivity increased platelet transport in the stenosis throat. Downstream of the throat where flow is complicated by recirculation, the model computed a transport-limited region with lower than measured platelet accumulation, suggesting that fluid-phase platelet activation may significantly affect both transport and adhesion rates in the poststenotic region. This model may provide an initial quantitative estimate of the likelihood of occlusive thrombus in individual patients due to plaque erosion, artery spasm, incomplete angioplasty, or plaque rupture.

Upper airway structure and body fat composition in obese children with obstructive sleep apnea syndrome.

RATIONALE Mechanisms leading to obstructive sleep apnea syndrome (OSAS) in obese children are not well understood. OBJECTIVES The aim of the study was to determine anatomical risk factors associated with OSAS in obese children as compared with obese control subjects without OSAS. METHODS Magnetic resonance imaging was used to determine the size of upper airway structure, and body fat composition. Paired analysis was used to compare between groups. Mixed effects regression models and conditional multiple logistic regression models were used to determine whether body mass index (BMI) Z-score was an effect modifier of each anatomic characteristic as it relates to OSAS. MEASUREMENTS AND MAIN RESULTS We studied 22 obese subjects with OSAS (12.5 ± 2.8 yr; BMI Z-score, 2.4 ± 0.4) and 22 obese control subjects (12.3 ± 2.9 yr; BMI Z-score, 2.3 ± 0.3). As compared with control subjects, subjects with OSAS had a smaller oropharynx (P < 0.05) and larger adenoid (P < 0.01), tonsils (P < 0.05), and retropharyngeal nodes (P < 0.05). The size of lymphoid tissues correlated with severity of OSAS whereas BMI Z-score did not have a modifier effect on these tissues. Subjects with OSAS demonstrated increased size of parapharyngeal fat pads (P < 0.05) and abdominal visceral fat (P < 0.05). The size of these tissues did not correlate with severity of OSAS and BMI Z-score did not have a modifier effect on these tissues. CONCLUSIONS Upper airway lymphoid hypertrophy is significant in obese children with OSAS. The lack of correlation of lymphoid tissue size with obesity suggests that this hypertrophy is caused by other mechanisms. Although the parapharyngeal fat pads and abdominal visceral fat are larger in obese children with OSAS we could not find a direct association with severity of OSAS or with obesity.

Endothelial-dependent vasodilation is associated with increases in the phosphorylation of a small heat shock protein (HSP20)

PURPOSE Increases in the phosphorylation of a small heat shock protein (HSP20) are associated with cyclic nucleotide-dependent vasorelaxation. The effect of pressure and flow on vessel diameter was studied. We hypothesized that physiologic conditions that induce vasorelaxation would lead to increases in HSP20 phosphorylation. METHODS Flow-dependent changes in vessel diameter, at different intraluminal pressures, were measured with a laser optical micrometer in intact bovine carotid arteries. Experiments were performed in the presence and absence of norepinephrine (10(-5) mol/L). Increases in the phosphorylation of HSP20 were determined with isoelectric focusing immunoblots. RESULTS The increase in vessel diameter was most significant at low intraluminal pressures (20 mm Hg), high flow rates (200 mL/min), and in the presence of the vasoconstrictor norepinephrine (10(-5) mol/L). The addition of methylene blue (a guanylate cyclase inhibitor) completely inhibited flow-induced vasodilation. Under conditions in which maximal flow induced vasodilation occurred, there were significant increases in the phosphorylation of HSP20. CONCLUSION Flow-dependent vasodilation in isolated perfused segments of bovine carotid arteries was maximal when the intraluminal pressures were low and when the vessels were precontracted with norepinephrine. Flow-dependent vasodilation was inhibited by methylene blue and was associated with increases in the phosphorylation of HSP20, suggesting that the vasodilation was mediated by endothelial production of nitric oxide.

Noninvasive estimation of pharyngeal airway resistance and compliance in children based on volume-gated dynamic MRI and computational fluid dynamics

Computational fluid dynamics (CFD) analysis was used to model the effect of collapsing airway geometry on internal pressure and velocity in the pharyngeal airway of three sedated children with obstructive sleep apnea syndrome (OSAS) and three control subjects. Model geometry was reconstructed from volume-gated magnetic resonance images during normal tidal breathing at 10 increments of tidal volume through the respiratory cycle. Each geometry was meshed with an unstructured grid and solved using a low-Reynolds number k-ω turbulence model driven by flow data averaged over 12 consecutive breathing cycles. Combining gated imaging with CFD modeling created a dynamic three-dimensional view of airway anatomy and mechanics, including the evolution of airway collapse and flow resistance and estimates of the local effective compliance. The upper airways of subjects with OSAS were generally much more compliant during tidal breathing. Compliance curves (pressure vs. cross-section area), derived for different locations along the airway, quantified local differences along the pharynx and between OSAS subjects. In one subject, the distal oropharynx was more compliant than the nasopharynx (1.028 vs. 0.450 mm(2)/Pa) and had a lower theoretical limiting flow rate, confirming the distal oropharynx as the flow-limiting segment of the airway in this subject. Another subject had a more compliant nasopharynx (0.053 mm(2)/Pa) during inspiration and apparent stiffening of the distal oropharynx (C = 0.0058 mm(2)/Pa), and the theoretical limiting flow rate indicated the nasopharynx as the flow-limiting segment. This new method may help to differentiate anatomical and functional factors in airway collapse.

Computational fluid dynamics endpoints to characterize obstructive sleep apnea syndrome in children

Computational fluid dynamics (CFD) analysis may quantify the severity of anatomical airway restriction in obstructive sleep apnea syndrome (OSAS) better than anatomical measurements alone. However, optimal CFD model endpoints to characterize or assess OSAS have not been determined. To model upper airway fluid dynamics using CFD and investigate the strength of correlation between various CFD endpoints, anatomical endpoints, and OSAS severity, in obese children with OSAS and controls. CFD models derived from magnetic resonance images were solved at subject-specific peak tidal inspiratory flow; pressure at the choanae was set by nasal resistance. Model endpoints included airway wall minimum pressure (Pmin), flow resistance in the pharynx (Rpharynx), and pressure drop from choanae to a minimum cross section where tonsils and adenoids constrict the pharynx (dPTAmax). Significance of endpoints was analyzed using paired comparisons (t-test or Wilcoxon signed rank test) and Spearman correlation. Fifteen subject pairs were analyzed. Rpharynx and dPTAmax were higher in OSAS than control and most significantly correlated to obstructive apnea-hypopnea index (oAHI), r = 0.48 and r = 0.49, respectively (P < 0.01). Airway minimum cross-sectional correlation to oAHI was weaker (r = -0.39); Pmin was not significantly correlated. CFD model endpoints based on pressure drops in the pharynx were more closely associated with the presence and severity of OSAS than pressures including nasal resistance, or anatomical endpoints. This study supports the usefulness of CFD to characterize anatomical restriction of the pharynx and as an additional tool to evaluate subjects with OSAS.

Computational fluid dynamics endpoints for assessment of adenotonsillectomy outcome in obese children with obstructive sleep apnea syndrome

BACKGROUND Improvements in obstructive sleep apnea syndrome (OSAS) severity may be associated with improved pharyngeal fluid mechanics following adenotonsillectomy (AT). The study objective is to use image-based computational fluid dynamics (CFD) to model changes in pharyngeal pressures after AT, in obese children with OSAS and adenotonsillar hypertrophy. METHODS Three-dimensional models of the upper airway from nares to trachea, before and after AT, were derived from magnetic resonance images obtained during wakefulness, in a cohort of 10 obese children with OSAS. Velocity, pressure, and turbulence fields during peak tidal inspiratory flow were computed using commercial software. CFD endpoints were correlated with polysomnography endpoints before and after AT using Spearman׳s rank correlation (rs). RESULTS Apnea hypopnea index (AHI) decreases after AT was strongly correlated with reduction in maximum pressure drop (dPTAmax) in the region where tonsils and adenoid constrict the pharynx (rs=0.78, P=0.011), and with decrease of the ratio of dPTAmax to flow rate (rs=0.82, P=0.006). Correlations of AHI decrease to anatomy, negative pressure in the overlap region (including nasal flow resistance), or pressure drop through the entire pharynx, were not significant. In a subgroup of subjects with more than 10% improvement in AHI, correlations between flow variables and AHI decrease were stronger than in all subjects. CONCLUSIONS The correlation between change in dPTAmax and improved AHI suggests that dPTAmax may be a useful index for internal airway loading due to anatomical narrowing, and may be better correlated with AHI than direct airway anatomic measurements.

Electrowetting-based multi-microfluidics array printing of high resolution tissue construct with embedded cells and growth factors

To overcome limitations of current tissue fabrication methods, explore new biocompatible materials, and develop new biomimetic manufacturing process for soft tissue, we are developing a new technology, electrowetting-based microfluidics array printing, which will be used in a solid freeform fabrication (SFF) system to meet the challenges of high resolution manufacture of hydrogel scaffolds with dimension scale less than 10 µm, cell placement, growth factor delivery, and vascularization for soft tissue engineering. Preliminary work has been done on the biomaterials research, electrowetting printing, biomimetic modeling, scaffold fabrication, and system integration and control. This research is the first application of electrowetting on dielectric to tissue engineering and dispensing hydrogels.

Biomimetic design and fabrication of porous chitosan–gelatin liver scaffolds with hierarchical channel network

The presence of a hierarchical channel network in tissue engineering scaffold is essential to construct metabolically demanding liver tissue with thick and complex structures. In this research, chitosan–gelatin (C/G) scaffolds with fine three-dimensional channels were fabricated using indirect solid freeform fabrication and freeze-drying techniques. Fabrication processes were studied to create predesigned hierarchical channel network inside C/G scaffolds and achieve desired porous structure. Static in-vitro cell culture test showed that HepG2 cells attached on both micro-pores and micro-channels in C/G scaffolds successfully. HepG2 proliferated at much higher rates on C/G scaffolds with channel network, compared with those without channels. This approach demonstrated a promising way to engineer liver scaffolds with hierarchical channel network, and may lead to the development of thick and complex liver tissue equivalent in the future.

Developmental aspects of the upper airway: report from an NHLBI Workshop, March 5-6, 2009.

The upper airway serves three important functions: respiration, swallowing, and speech. During development it undergoes significant structural and functional changes that affect its size, shape, and mechanical properties. Abnormalities of the upper airway require prompt attention, because these often alter ventilatory patterns and gas exchange, particularly during sleep when upper airway motor tone and ventilatory drive are diminished. Recognizing the relationship of early life events to lung health and disease, the National Heart, Lung, and Blood Institute (NHLBI), with cofunding from the Office of Rare Diseases (ORD), convened a workshop of extramural experts, from many disciplines. The objective of the workshop was: (1) to review the state of science in pediatric upper airway disorders; (2) to make recommendations to the Institute to fill knowledge gaps; (3) to prioritize new research directions; and (4) to capitalize on scientific opportunities. This report provides recommendations that could facilitate translation of basic research findings into practice to better diagnose, treat, and prevent airway compromise in children.

Rhino‐sinus involvement in children with obstructive sleep apnea syndrome

Obstructive sleep apnea syndrome (OSAS) is commonly associated with adenotonsillar hypertrophy. We hypothesized that respiratory perturbations extend to other regions of the upper respiratory tract in such children, particularly to rhino‐sinus regions.