Toward the virtual stomach: progress in multiscale modeling of gastric electrophysiology and motility

Du, Peng; O’Grady, Gregory; Gao, Jerry; Sathar, Shameer; Cheng, Leo K.

doi:10.1002/wsbm.1218

Cited by 44 publications

(48 citation statements)

References 80 publications

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“…An alternative strategy involves the use of continuum mathematical modeling techniques that have been used to great effect in elucidating mechanisms of cardiac dysrhythmias, particularly in uncovering the principle of re-entry activities (Paterson 2013). Recently, continuum modeling simulation studies have emerged as a tool to investigate gastric slow wave propagations and dysrhythmia mechanisms (Cheng, Du et al 2013; Du, O'Grady et al 2013). …”

Section: Introductionmentioning

confidence: 99%

A theoretical study of the initiation, maintenance and termination of gastric slow wave re-entry

Paskaranandavadivel

O’Grady

et al. 2014

Math Med Biol

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Gastric slow wave dysrhythmias are associated with motility disorders. Periods of tachygastria associated with slow wave re-entry were recently recognized as one important dysrhythmia mechanism, but factors promoting and sustaining gastric reentry are currently unknown. This study reports two experimental forms of gastric re-entry and presents a series of multi-scale models that define criteria for slow wave re-entry initiation, maintenance, and termination. High-resolution electrical mapping was conducted in porcine and canine models and two spatiotemporal patterns of re-entrant activities were captured: single-loop rotor and double-loop figure-of-eight. Two separate multi-scale mathematical models were developed to reproduce the velocity and entrainment frequency of these experimental recordings. A single-pulse stimulus was used to invoke a rotor re-entry in the porcine model and a figure-of-eight re-entry in the canine model. In both cases, the simulated re-entrant activities were found to be perpetuated by tachygastria that was accompanied by a reduction in the propagation velocity in the re-entrant pathways. The simulated re-entrant activities were terminated by a single-pulse stimulus targeted at the tip of re-entrant wave, after which normal antegrade propagation was restored by the underlying intrinsic frequency gradient. Main findings: (i) the stability of re-entry is regulated by stimulus timing, intrinsic frequency gradient and conductivity; (ii) tachygastria due to re-entry increases the frequency gradient while showing decreased propagation velocity; (iii) re-entry may be effectively terminated by a targeted stimulus at the core, allowing the intrinsic slow wave conduction system to re-establish itself.

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Section: Introductionmentioning

confidence: 99%

A theoretical study of the initiation, maintenance and termination of gastric slow wave re-entry

Paskaranandavadivel

O’Grady

et al. 2014

Math Med Biol

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“…More exhaustive simulations with extended-bidomain formulations have also been performed, but anisotropic conduction was not incorporated in the simulation [19]. This study resolves all of these issues and therefore represents a significant advance in physiologically accurate gastric modeling, with diverse potential applications in integrated electrophysiology, investigating pathophysiology, and therapeutic assessments for electroceuticals and drug design [39]. …”

Section: Discussionmentioning

confidence: 99%

A Multiscale Tridomain Model for Simulating Bioelectric Gastric Pacing

Sathar

Trew

O’Grady

et al. 2015

IEEE Trans. Biomed. Eng.

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Goal Gastric motility disorders have been associated with abnormal slow wave electrical activity (‘gastric dysrhythmias’). Gastric pacing is a potential therapy for gastric dysrhythmias, however, new pacing protocols are required that can effectively modulate motility patterns, while being power efficient. This study presents a novel comprehensive 3D multi-scale modeling framework of the human stomach, including anisotropic conduction, capable of evaluating pacing strategies. Methods A high resolution anatomically realistic mesh was generated from CT images taken from a human stomach. Principal conduction axes were calculated and embedded within this model based on a modified Laplace-Dirichlet rule based algorithm. A continuum based tridomain formulation was implemented and evaluated for performance, and used to model the slow wave propagation, which takes into account the two main cell types present in gastric musculature. Model parameters were found by matching predicted normal slow-wave activity to experimental observation and data. These simulation parameters were applied while modeling an external pacing event to entrain slow wave patterns. Results The proposed formulation was found to be 2 times more efficient than a previous formulation for a normal slow wave simulation. Convergence analysis showed that a mesh resolution of ≈ 0.4 –0.5mm is required for an accurate solution process. Conclusion The effect of different pacing frequencies on entrainment demonstrated that the pacing protocols are limited by the frequency of the native propagation and the refractory period of the cellular activity. Significance The model is expected to become an important tool in studying pacing protocols for both efficiency and effectiveness.

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“…Biophysically based mathematical models related to electrophysiology have been developed on a cellular level (e.g., interstitial cell of Cajal models, GI smooth muscle models), tissue level, and whole organ level (Du et al 2013). In addition, another field of active modeling is related to electrophysiological, electromechanical coupling, and fluid dynamics methods to predict the dynamic effects of luminal contents on GI motility, luminal content mixing, and propulsion using computational fluid dynamic (CFD) techniques (Ferrua and Singh 2010).…”

Section: In Silico Organ Modelingmentioning

confidence: 99%

Gastrointestinal Safety Pharmacology in Drug Discovery and Development

Al‐Saffar

Costa²,

Delaunois³

et al. 2015

Principles of Safety Pharmacology

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Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.

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Toward the virtual stomach: progress in multiscale modeling of gastric electrophysiology and motility

Cited by 44 publications

References 80 publications

A theoretical study of the initiation, maintenance and termination of gastric slow wave re-entry

A theoretical study of the initiation, maintenance and termination of gastric slow wave re-entry

A Multiscale Tridomain Model for Simulating Bioelectric Gastric Pacing

Gastrointestinal Safety Pharmacology in Drug Discovery and Development

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