Sensing Inhalation Injury-Associated Changes in Airway Wall Compliance by Anatomic Optical Coherence Elastography.

Quantitative methods for assessing the severity of inhalation (burn) injury are needed to aid in treatment decisions. We hypothesize that it is possible to assess the severity of injuries on the basis of differences in the compliance of the airway wall. Here, we demonstrate the use of a custom-built, endoscopic, anatomic optical coherence elastography (aOCE) system to measure airway wall compliance. The method was first validated using airway phantoms, then performed on ex vivo porcine tracheas under varying degrees of inhalation (steam) injury. A negative correlation between aOCE-derived compliance and severity of steam injuries is found, and spatially-resolved compliance maps reveal regional heterogeneity in airway properties.

Localized compliance measurement of the airway wall using anatomic optical coherence elastography.

We describe an elastographic method to circumferentially-resolve airway wall compliance using endoscopic, anatomic optical coherence tomography (aOCT) combined with an intraluminal pressure catheter. The method was first demonstrated on notched silicone phantoms of known elastic modulus under respiratory ventilation, where localized compliance measurements were validated against those predicted by finite element modeling. Then, ex vivo porcine tracheas were scanned, and the pattern of compliance was found to be consistent with histological identification of the locations of (stiff) cartilage and (soft) muscle. This quantitative method may aid in diagnosis and monitoring of collapsible airway wall tissues in obstructive respiratory disorders.

An Interactive, Patient-Specific Virtual Surgical Planning System for Upper Airway Obstruction Treatments.

Upper airway obstructions leading todifficulty breathing are significant problems that often require surgery to improve patient quality of life. However, these surgeries often have poor outcomes with little symptom improvement. This paper outlines the design of an interactive, patient-specific virtual surgical planning system that uses patient CT scans to generate three-dimensional representations of the airways and incorporates computational fluid dynamics (CFD) as a part of the surgical planning process. Individualized virtual surgeries can be performed by editing these models, which are then analyzed using CFD to compare pre- and post- surgery flow characteristics to assess patient symptom improvement. The prototype system shows significant promise by being intuitive, interactive, with a potential fast flow solver that provides near real-time feedback to the clinician.

An experimentally-calibrated damage mechanics model for stone fracture in shock wave lithotripsy.

A damage model suggested by the Tuler-Butcher concept of dynamic accumulation of microscopic defects is obtained from experimental data on microcrack formation in synthetic kidney stones. Experimental data on appearance of microcracks is extracted from micro-computed tomography images of BegoStone simulants obtained after subjecting the stone to successive pulses produced by an electromagnetic shock-wave lithotripter source. Image processing of the data is used to infer statistical distributions of crack length and width in representative transversal cross-sections of a cylindrical stone. A high-resolution finite volume computational model, capable of accurately modeling internal reflections due to local changes in material properties produced by material damage is used to simulate the accumulation of damage due to successive shocks. Comparison of statistical distributions of microcrack formation in computation and experiment allows calibration of the damage model. The model is subsequently used to compute fracture of a different aspect-ratio cylindrical stone predicting concurrent formation of two main fracture areas as observed experimentally.

Data-driven reduced-order model of microtubule mechanics.

A beam element is constructed for microtubules based upon data reduction of the results from atomistic simulation of the carbon backbone chain of αß-tubulin dimers. The database of mechanical responses to various types of loads from atomistic simulation is reduced to dominant modes. The dominant modes are subsequently used to construct the stiffness matrix of a beam element that captures the anisotropic behavior and deformation mode coupling that arises from a microtubule's spiral structure. In contrast to standard Euler-Bernoulli or Timoshenko beam elements, the link between forces and node displacements results not from hypothesized deformation behavior, but directly from the data obtained by molecular scale simulation. Differences between the resulting microtubule data-driven beam model (MTDDBM) and standard beam elements are presented, with a focus on coupling of bending, stretch, shear deformations. The MTDDBM is just as economical to use as a standard beam element, and allows accurate reconstruction of the mechanical behavior of structures within a cell as exemplified in a simple model of a component element of the mitotic spindle.

Swept-Source Anatomic Optical Coherence Elastography of Porcine Trachea.

Quantitative endoscopic imaging is at the vanguard of novel techniques in the assessment upper airway obstruction. Anatomic optical coherence tomography (aOCT) has the potential to provide the geometry of the airway lumen with high-resolution and in 4 dimensions. By coupling aOCT with measurements of pressure, optical coherence elastography (OCE) can be performed to characterize airway wall stiffness. This can aid in identifying regions of dynamic collapse as well as informing computational fluid dynamics modeling to aid in surgical decision-making. Toward this end, here we report on an anatomic optical coherence tomography (aOCT) system powered by a wavelength-swept laser source. The system employs a fiber-optic catheter with outer diameter of 0.82 mm deployed via the bore of a commercial, flexible bronchoscope. Helical scans are performed to measure the airway geometry and to quantify the cross-sectional-area (CSA) of the airway. We report on a preliminary validation of aOCT for elastography, in which aOCT-derived CSA was obtained as a function of pressure to estimate airway wall compliance. Experiments performed on a Latex rubber tube resulted in a compliance measurement of 0.68±0.02 mm2/cmH2O, with R2=0.98 over the pressure range from 10 to 40 cmH2O. Next, ex vivo porcine trachea was studied, resulting in a measured compliance from 1.06±0.12 to 3.34±0.44 mm2/cmH2O, (R2>0.81). The linearity of the data confirms the elastic nature of the airway. The compliance values are within the same order-of-magnitude as previous measurements of human upper airways, suggesting that this system is capable of assessing airway wall compliance in future human studies.

Effects of Stone Size on the Comminution Process and Efficiency in Shock Wave Lithotripsy.

The effects of stone size on the process and comminution efficiency of shock wave lithotripsy (SWL) were investigated in experiments, numerical simulations and scale analysis. Cylindrical BegoStone phantoms with approximately equal height and diameter of either 4, 7 or 10 mm, in a total aggregated mass of about 1.5 g, were treated in an electromagnetic shock wave lithotripter field. The resultant stone comminution was found to correlate closely with the average peak pressure, P+(avg), incident on the stones. The P+(avg) threshold necessary to initiate stone fragmentation in water increased from 7.9 to 8.8 to 12.7 MPa, respectively, as stone size decreased from 10 to 7 to 4 mm. Similar changes in the P+(avg) threshold were observed for the 7- and 10-mm stones treated in 1,3-butanediol, in which cavitation is suppressed, suggesting that the observed size dependency is due to changes in stress distribution within stones of different size. Moreover, the slope of the correlation curve between stone comminution and ln(P¯+(avg)) in water increased with decreasing stone size, whereas the opposite trend was observed in 1,3-butanediol. The progression of stone comminution in SWL exhibited size-dependence: the 7- and 10-mm stones fragmented into progressively smaller pieces, whereas a significant portion (>30%) of the 4-mm stones reached a stalemate within the size range of 2.8 ∼ 4 mm, even after 1000 shocks. Analytical scaling considerations suggest size-dependent fragmentation behavior, a hypothesis further supported by numerical model calculations that reveal changing patterns of constructive and destructive wave interference and, thus, variations in the maximum tensile stress or stress integral produced in cylindrical and spherical stone of different sizes.

The Virtual Pediatric Airways Workbench.

The Virtual Pediatric Airways Workbench (VPAW) is a patient-centered surgical planning software system targeted to pediatric patients with airway obstruction. VPAW provides an intuitive surgical planning interface for clinicians and supports quantitative analysis regarding prospective surgeries to aid clinicians deciding on potential surgical intervention. VPAW enables a full surgical planning pipeline, including importing DICOM images, segmenting the airway, interactive 3D editing of airway geometries to express potential surgical treatment planning options, and creating input files for offline geometric analysis and computational fluid dynamics simulations for evaluation of surgical outcomes. In this paper, we describe the VPAW system and its use in one case study with a clinician to successfully describe an intended surgery outcome.

Quantitative assessment of the upper airway in infants and children with subglottic stenosis.

OBJECTIVES/HYPOTHESIS: Determine whether quantitative geometric measures and a computational fluid dynamic (CFD) model derived from medical imaging of children with subglottic stenosis (SGS) can be effective diagnostic and treatment planning tools. STUDY DESIGN: Retrospective chart and imaging review in a tertiary care hospital. METHODS: Computed tomography scans (n = 17) of children with SGS were analyzed by geometric and CFD methods. Polysomnograms (n = 15) were also analyzed. Radiographic data were age/weight flow normalized and were compared to an atlas created from radiographically normal airways. Five geometric, seven CFD, and five polysomnography measures were analyzed. Statistical analysis utilized a two-sample t test with Bonferroni correction and area under the curve analysis. RESULTS: Two geometric indices (the ratio of the subglottic to midtracheal airway, the percent relative reduction of the subglottic airway) and one CFD measure (the percent relative reduction of the hydraulic diameter of the subglottic airway) were significant for determining which children with SGS received surgical intervention. Optimal cutoffs for these values were determined. Polysomnography, the respiratory effort-related arousals index, was significant only prior to Bonferroni correction for determining which children received surgical intervention. CONCLUSIONS: Geometric and CFD variables were sensitive at determining which patients with SGS received surgical intervention. Discrete quantitative assessment of the pediatric airway was performed, yielding preliminary data regarding possible objective thresholds for surgical versus nonsurgical treatment of disease. This study is limited by its small, retrospective, single-institution nature. Further studies to validate these findings and possibly optimize treatment threshold recommendations are warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1225-1231, 2016.

A consistent hierarchy of generalized kinetic equation approximations to the master equation applied to surface catalysis.

We develop a hierarchy of approximations to the master equation for systems that exhibit translational invariance and finite-range spatial correlation. Each approximation within the hierarchy is a set of ordinary differential equations that considers spatial correlations of varying lattice distance; the assumption is that the full system will have finite spatial correlations and thus the behavior of the models within the hierarchy will approach that of the full system. We provide evidence of this convergence in the context of one- and two-dimensional numerical examples. Lower levels within the hierarchy that consider shorter spatial correlations are shown to be up to three orders of magnitude faster than traditional kinetic Monte Carlo methods (KMC) for one-dimensional systems, while predicting similar system dynamics and steady states as KMC methods. We then test the hierarchy on a two-dimensional model for the oxidation of CO on RuO2(110), showing that low-order truncations of the hierarchy efficiently capture the essential system dynamics. By considering sequences of models in the hierarchy that account for longer spatial correlations, successive model predictions may be used to establish empirical approximation of error estimates. The hierarchy may be thought of as a class of generalized phenomenological kinetic models since each element of the hierarchy approximates the master equation and the lowest level in the hierarchy is identical to a simple existing phenomenological kinetic models.

Improving the lens design and performance of a contemporary electromagnetic shock wave lithotripter.

The efficiency of shock wave lithotripsy (SWL), a noninvasive first-line therapy for millions of nephrolithiasis patients, has not improved substantially in the past two decades, especially in regard to stone clearance. Here, we report a new acoustic lens design for a contemporary electromagnetic (EM) shock wave lithotripter, based on recently acquired knowledge of the key lithotripter field characteristics that correlate with efficient and safe SWL. The new lens design addresses concomitantly three fundamental drawbacks in EM lithotripters, namely, narrow focal width, nonidealized pulse profile, and significant misalignment in acoustic focus and cavitation activities with the target stone at high output settings. Key design features and performance of the new lens were evaluated using model calculations and experimental measurements against the original lens under comparable acoustic pulse energy (E+) of 40 mJ. The -6-dB focal width of the new lens was enhanced from 7.4 to 11 mm at this energy level, and peak pressure (41 MPa) and maximum cavitation activity were both realigned to be within 5 mm of the lithotripter focus. Stone comminution produced by the new lens was either statistically improved or similar to that of the original lens under various in vitro test conditions and was significantly improved in vivo in a swine model (89% vs. 54%, P = 0.01), and tissue injury was minimal using a clinical treatment protocol. The general principle and associated techniques described in this work can be applied to design improvement of all EM lithotripters.

Experimentally validated multiphysics computational model of focusing and shock wave formation in an electromagnetic lithotripter.

A multiphysics computational model of the focusing of an acoustic pulse and subsequent shock wave formation that occurs during extracorporeal shock wave lithotripsy is presented. In the electromagnetic lithotripter modeled in this work the focusing is achieved via a polystyrene acoustic lens. The transition of the acoustic pulse through the solid lens is modeled by the linear elasticity equations and the subsequent shock wave formation in water is modeled by the Euler equations with a Tait equation of state. Both sets of equations are solved simultaneously in subsets of a single computational domain within the BEARCLAW framework which uses a finite-volume Riemann solver approach. This model is first validated against experimental measurements with a standard (or original) lens design. The model is then used to successfully predict the effects of a lens modification in the form of an annular ring cut. A second model which includes a kidney stone simulant in the domain is also presented. Within the stone the linear elasticity equations incorporate a simple damage model.

Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment.

The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale.

Spatial Stress and Strain Distributions of Viscoelastic Layers in Oscillatory Shear.

One of the standard experimental probes of a viscoelastic material is to measure the response of a layer trapped between parallel surfaces, imposing either periodic stress or strain at one boundary and measuring the other. The relative phase between stress and strain yields solid-like and liquid-like properties, called the storage and loss moduli, respectively, which are then captured over a range of imposed frequencies. Rarely are the full spatial distributions of shear and normal stresses considered, primarily because they cannot be measured except at boundaries and the information was not deemed of particular interest in theoretical studies. Likewise, strain distributions throughout the layer were traditionally ignored except in a classical protocol of Ferry, Adler and Sawyer, based on snapshots of standing shear waves. Recent investigations of thin lung mucus layers exposed to oscillatory stress (breathing) and strain (coordinated cilia), however, suggest that the wide range of healthy conditions and environmental or disease assaults lead to conditions that are quite disparate from the "surface loading" and "gap loading" conditions that characterize classical rheometers. In this article, we extend our previous linear and nonlinear models of boundary stresses in controlled oscillatory strain to the entire layer. To illustrate non-intuitive heterogeneous responses, we characterize experimental conditions and material parameter ranges where the maximum stresses migrate into the channel interior.

A numerical model of cellular blebbing: a volume-conserving, fluid-structure interaction model of the entire cell.

In animal cells, blebs are smooth, quasi-hemispherical protrusions of the plasma membrane that form when a section of the membrane detaches from the underlying actin cytoskeleton and is inflated by flowing cytosol. The mechanics behind this common cellular activity are not yet clear. As a first step in the development of a full computational framework, we present a numerical model of overall cell behavior based upon the interaction between a background Newtonian-fluid cytosol and elastic structures modeling the membrane and filaments. The detailed micromechanics of the cytoskeletal network are the subject of future work. Here, the myosin-driven contraction of the actin network is modeled through stressed elastic filaments. Quantitative models of cytoskeletal micromechanics and biochemistry require accurate estimates of local stress and flow conditions. The main contribution of this paper is the development of a computationally efficient fluid-structure interaction model based on operator splitting, to furnish this data. Cytosol volume conservation (as supported by experimental evidence) is enforced through an intermediate energy minimization step. Realistic bleb formation and retraction is observed from this model, offering an alternative formulation to positing complex continuum behavior of the cytoplasm (e.g. poroelastic model of Charras et al., 2008).

Extensions of the Ferry shear wave model for active linear and nonlinear microrheology.

The classical oscillatory shear wave model of Ferry et al. [J. Polym. Sci. 2:593-611, (1947)] is extended for active linear and nonlinear microrheology. In the Ferry protocol, oscillation and attenuation lengths of the shear wave measured from strobe photographs determine storage and loss moduli at each frequency of plate oscillation. The microliter volumes typical in biology require modifications of experimental method and theory. Microbead tracking replaces strobe photographs. Reflection from the top boundary yields counterpropagating modes which are modeled here for linear and nonlinear viscoelastic constitutive laws. Furthermore, bulk imposed strain is easily controlled, and we explore the onset of normal stress generation and shear thinning using nonlinear viscoelastic models. For this paper, we present the theory, exact linear and nonlinear solutions where possible, and simulation tools more generally. We then illustrate errors in inverse characterization by application of the Ferry formulas, due to both suppression of wave reflection and nonlinearity, even if there were no experimental error. This shear wave method presents an active and nonlinear analog of the two-point microrheology of Crocker et al. [Phys. Rev. Lett. 85: 888 - 891 (2000)]. Nonlocal (spatially extended) deformations and stresses are propagated through a small volume sample, on wavelengths long relative to bead size. The setup is ideal for exploration of nonlinear threshold behavior.

Metachronal wave formation in a model of pulmonary cilia.

A three-dimensional simulation of the formation of metachronal waves in rows of pulmonary cilia is presented. The cilia move in a two-layer fluid model. The fluid layer adjacent to the cilia bases is purely viscous while the tips of the cilia move through a viscoelastic fluid. An overlapping fixed-moving grid formulation is employed to capture the effect of the cilia on the surrounding fluid. In contrast with immersed boundary methods, this technique allows a natural enforcement of boundary conditions without the need for smoothing of singular force distributions. The fluid domains are discretized using a finite volume method. The 9 + 2 internal microtubule structure of an individual cilium is modeled using large-deflection, curved, finite-element beams. The microtubule skeleton is cross-linked to itself and to the cilium membrane through spring elements which model nexin links. The cilium membrane itself is considered to be elastic and subject to fluid stresses computed from the moving grid formulation as well as internal forces transmitted from the microtubule skeleton. A cilium is set into motion by the action of dynein molecules exerting forces between adjacent microtubules. Realistic models of the forces exerted by dynein molecules are extracted from measurements of observed cilia shapes.