Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants.

Objective: The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models.

Propagation Characteristics of Fasting Duodeno-Jejunal Contractions in Healthy Controls Measured by Clustered Closely-spaced Manometric Sensors.

Background/aims: High-resolution methods have advanced esophageal and anorectal manometry interpretation but are incompletely established for intestinal manometry. We characterized normal fasting duodeno-jejunal manometry parameters not measurable by standard techniques using clustered closely-spaced recordings.

Methods: Ten fasting recordings were performed in 8 healthy controls using catheters with 3-4 gastrointestinal manometry clusters with 1-2 cm channel spacing.

Formulation predictive dissolution (fPD) testing to advance oral drug product development: An introduction to the US FDA funded '21st Century BA/BE' project.

Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract.

Three-dimensional mechanisms of macro-to-micro-scale transport and absorption enhancement by gut villi motions.

We evaluate the potential for physiological control of intestinal absorption by the generation of "micromixing layers" (MMLs) induced by coordinated motions of mucosal villi coupled with lumen-scale "macro" eddying motions generated by gut motility. To this end, we apply a three-dimensional (3D) multigrid lattice-Boltzmann model of a lid-driven macroscale cavity flow with microscale fingerlike protuberances at the lower surface. Integrated with a previous 2D study of leaflike villi, we generalize to 3D the 2D mechanisms found there to enhance nutrient absorption by controlled villi motility.

Non-steady wind turbine response to daytime atmospheric turbulence.

Relevant to drivetrain bearing fatigue failures, we analyse non-steady wind turbine responses from interactions between energy-dominant daytime atmospheric turbulence eddies and the rotating blades of a GE 1.5 MW wind turbine using a unique dataset from a GE field experiment and computer simulation. Time-resolved local velocity data were collected at the leading and trailing edges of an instrumented blade together with generator power, revolutions per minute, pitch and yaw.

The Esophagiome: concept, status, and future perspectives.

The term "Esophagiome" is meant to imply a holistic, multiscale treatment of esophageal function from cellular and muscle physiology to the mechanical responses that transport and mix fluid contents. The development and application of multiscale mathematical models of esophageal function are central to the Esophagiome concept. These model elements underlie the development of a "virtual esophagus" modeling framework to characterize and analyze function and disease by quantitatively contrasting normal and pathophysiological function.

Analysis of Diffusion-Controlled Dissolution from Polydisperse Collections of Drug Particles with an Assessed Mathematical Model.

We introduce a "hierarchical" modeling strategy designed to be systematically extensible to increase the detail of dissolution predictions from polydisperse collections of drug particles and to be placed on firm mathematical and physical foundations with diffusion-dominated dissolution at its core to predict dissolution and the evolution of particle size distribution. We assess the model with experimental data and demonstrate higher accuracy by treating the polydisperse nature of dissolution. A level in the hierarchy is applied to study elements of diffusion-driven dissolution, in particular the role of particle-size distribution width with varying dose level and the influences of "confinement" on the process of dissolution.

Hydrodynamic Effects on Drug Dissolution and Deaggregation in the Small Intestine-A Study with Felodipine as a Model Drug.

The aim of this study was to understand and predict the influence of hydrodynamic effects in the small intestine on dissolution of primary and aggregated drug particles. Dissolution tests of suspensions with a low-solubility drug, felodipine, were performed in a Couette cell under hydrodynamic test conditions corresponding to the fed small intestine. Dissolution was also performed in the USP II apparatus at two paddle speeds of 25 and 200 rpm and at different surfactant concentrations below critical micelle concentration.

The invalidity of the Laplace law for biological vessels and of estimating elastic modulus from total stress vs. strain: a new practical method.

There are strong medical motivations to measure changes in material properties of tubular organs, in vivo and in vitro. The current approach estimates hoop stress from intraluminal pressure using the Laplace law and identifies 'elastic modulus' as the slope of a curve fitted hoop stress plotted against strain data. We show that this procedure is fundamentally flawed because muscle and other soft tissue are closely incompressible, so that the total stress includes a volume-preserving material-dependent hydrostatic response that invalidates the method.

Comparison and analysis of theoretical models for diffusion-controlled dissolution.

Dissolution models require, at their core, an accurate diffusion model. The accuracy of the model for diffusion-dominated dissolution is particularly important with the trend toward micro- and nanoscale drug particles. Often such models are based on the concept of a "diffusion layer.

The esophagogastric junction.

The following discussion of the esophagogastric junctions includes commentaries on the three component structures of the sphincteric segment between the stomach and the esophagus; the pressure contributions from the three sphincteric components in normal subjects and in gastroesophageal reflux (GERD) patients; the mechanism of action of endoscopic plication to determine the underlying pathophysiology of GERD; and in vitro muscle strip studies of defects within the gastroesophageal sphincteric segment potentially leading to GERD.

A multiscale lattice Boltzmann model of macro- to micro-scale transport, with applications to gut function.

Nutrient absorption in the small intestine cannot occur until molecules are presented to the epithelial cells that line intestinal villi, finger-like protrusions under enteric control. Using a two-dimensional multiscale lattice Boltzmann model of a lid-driven cavity flow with 'villi' at the lower surface, we analyse the hypothesis that muscle-induced oscillatory motions of the villi generate a controlled 'micro-mixing layer' (MML) that couples with the macro-scale flow to enhance absorption. Nutrient molecules are modelled as passive scalar concentrations at high Schmidt number.

Quantitative analysis of peristaltic and segmental motion in vivo in the rat small intestine using dynamic MRI.

Conventional methods of quantifying segmental and peristaltic motion in animal models are highly invasive; involving, for example, the external isolation of segments of the gastrointestinal (GI) tract either from dead or anesthetized animals. The present study was undertaken to determine the utility of MRI to quantitatively analyze these motions in the jejunum region of anesthetized rats (N = 6) noninvasively. Dynamic images of the GI tract after oral gavage with a Gd contrast agent were acquired at a rate of six frames per second, followed by image segmentation based on a combination of three-dimensional live wire (3D LW) and directional dynamic gradient vector flow snakes (DDGVFS).

Liquid in the gastroesophageal segment promotes reflux, but compliance does not: a mathematical modeling study.

The mechanical force relationships that distinguish normal from chronic reflux at sphincter opening are poorly understood and difficult to measure in vivo. Our aim was to apply physics-based computer simulations to determine mechanical pathogenesis of gastroesophageal reflux. A mathematical model of the gastroesophageal segment (GES) was developed, incorporating the primary anatomical and physiomechanical elements that drive GES opening and reflux.

New observations on the gastroesophageal antireflux barrier.

The use of high-frequency ultrasound transducers combined with manometry in the gastrointestinal (GI) tract has yielded important findings concerning the anatomy, physiology, and pathophysiology of the high-pressure zone of the gastroesophageal junction and the sphincteric muscles within. These transducers have made previously invisible portions of the GI tract accessible to investigation. Three distinct high-pressure zones have been identified and correlated with anatomic structures: the extrinsic sphincter (crural diaphragm) and the two components of the intrinsic sphincter (an upper LES and a lower LES [the gastric sling fiber/clasp fiber complex]).

Function of longitudinal vs circular muscle fibers in esophageal peristalsis, deduced with mathematical modeling.

We summarize from previous works the functions of circular vs. longitudinal muscle in esophageal peristaltic bolus transport using a mix of experimental data, the conservation laws of mechanics and mathematical modeling. Whereas circular muscle tone generates radial closure pressure to create a local peristaltic closure wave, longitudinal muscle tone has two functions, one physiological with mechanical implications, and one purely mechanical.

Pharmacological dissection of the human gastro-oesophageal segment into three sphincteric components.

Quantifications of gastro-oesophageal anatomy in cadavers have led some to identify the lower oesophageal sphincter (LOS) with the anatomical gastric sling-clasp fibres at the oesophago-cardiac junction (OCJ). However, in vivo studies have led others to argue for two overlapping components proximally displaced from the OCJ: an extrinsic crural sphincter of skeletal muscle and an intrinsic physiological sphincter of circular smooth-muscle fibres within the abdominal oesophagus. Our aims were to separate and quantify in vivo the skeletal and smooth muscle sphincteric components pharmacologically and clarify the description of the LOS.

Quantification of distal antral contractile motility in healthy human stomach with magnetic resonance imaging.

Purpose: To quantify healthy postprandial: 1) propagation, periodicity, geometry, and percentage occlusion by distal antral contraction waves (ACWs); and 2) changes in ACW activity in relationship to gastric emptying (GE).

Materials And Methods: Using 1.5-T MR scanner, nine healthy fasted volunteers were examined in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) with 500 microM Gd-DOTA.

A stomach road or "Magenstrasse" for gastric emptying.

Gastric muscle contractions grind and mix solid/liquid meal within the stomach, and move it into the bowels at a controlled rate. Contractions are of two types: slow volume-reducing contractions of the proximal stomach (the fundus), and peristaltic contraction waves in the distal stomach (the antrum). Fundic squeeze maintains gastro-duodenal pressure difference to drive gastric emptying.

Physiology of the esophageal pressure transition zone: separate contraction waves above and below.

Manometrically measured peristaltic pressure amplitude displays a well-defined trough in the upper esophagus. Whereas this manometric "transition zone" (TZ) has been associated with striated-to-smooth muscle fiber transition, the underlying physiology of the TZ and its role in bolus transport are unclear. A computer model study of bolus retention in the TZ showed discoordinated distinct contraction waves above and below.

A novel in vitro and numerical analysis of shear-induced drug release from extended-release tablets in the fed stomach.

Purpose: To design an in vitro apparatus that could simulate the in vivo range of surface shear stresses relevant for the human stomach under fed conditions.

Methods: Computer simulations were combined with in vitro experiments to quantify tablet erosion rate vs. surface shear stress.

Restoration of normal distensive characteristics of the esophagogastric junction after fundoplication.

Objective: To study the mechanical characteristics of the esophagogastric junction (EGJ) of postfundoplication patients and compare them with previously reported data on normal subjects and GERD patients.

Methods: Eight normal subjects, 9 GERD patients, and 8 fundoplication patients were studied with concurrent manometry, fluoroscopy, and stepwise controlled barostat distention of the EGJ. The minimal barostat pressure required to open the EGJ during the interswallow period was determined.

The mechanical basis of impaired esophageal emptying postfundoplication.

Fundoplication (FP) efficacy is a trade-off between protection against reflux and postoperative dysphagia from the surgically altered mechanical balance within the esophagogastric segment. The purpose of the study was to contrast quantitatively the mechanical balance between normal and post-FP esophageal emptying. Physiological data were combined with mathematical models based on the laws of mechanics.

Gastric flow and mixing studied using computer simulation.

The fed human stomach displays regular peristaltic contraction waves that originate in the proximal antrum and propagate to the pylorus. High-resolution concurrent manometry and magnetic resonance imaging (MRI) studies of the stomach suggest a primary function of antral contraction wave (ACW) activity unrelated to gastric emptying. Detailed evaluation is difficult, however, in vivo.