A 3D mechanical model of the gastric esophageal junction: model-based assessment of muscle stretch tension in the gastric smooth muscle with emphasis to reflux disease
Andreas Kuttler (1), Thomas Dimke (1), Ramprasad Ramakrishna (2), Gabriel Helmlinger (2), Anne Ruehl (2), Marie-Laure Rouzade-Dominguez(2), Gervais Tougas (2), Mark Fox (3), Werner Schwizer (3)
(1) Modeling and Simulation, Novartis Pharma AG, Basel, Switzerland, (2) Novartis Institutes of Biomedical Research (Basel, Switzerland and Cambridge, USA), (3) Division of Gastroenterology and Hepatology, University Hospital Zurich
Objectives: Gastroesophageal reflux disease (GERD) is a complex disease that is influenced by a number of biomechanical variables. It occurs following transient relaxation of the lower esophageal sphincter (LES). These relaxations (TLESRs) allow acidic stomach contents to reflux into the esophageal lumen, where exposure of the esophageal lining to the acidic refluxate causes gradual erosive damage. The objective of this modeling exercise was to develop a computer-based model that describes the biomechanical processes involved in the onset of TLESRs. In particular, the model, in combination with experimental measures, can be used to obtain a quantitative measure of the stretch-tension relationship at the stomach wall.
Methods: The 3D mechanical model of the stomach includes an approximation of the orientation of muscle structure and support conditions, both estimated from the literature [1,2]. Starting from an initial geometry [1], features such as stomach filling, the accommodation process, as well as adaptations to environmental conditions (e.g., abdominal pressure, breathing) can be reconstructed from first principles. Quantitative information and relationships, important from a biomechanical perspective, such as Lower Esophageal Sphincter (LES) properties or the stretch-tension state in the smooth muscle may be derived from these conditions.
Results: The model shows a significant influence of material properties (e.g., fiber orientation or smooth muscle tone) and the surrounding organs (e.g., local elasticity) on LES competence and stretch-tension conditions in the stomach wall. With appropriate experimental inputs such as shape and volume information for different stomach fillings and their corresponding intragastric pressure states, a comparison of stretch-tension relationships in subjects with different conditions in clinical research has become feasible. The model has been qualified to represent the actions of agents such as erythromycin and glucagon, which have opposite effects on the compliance of the stomach [3].
Conclusions: In this work, we present a methodology whereby the measurement of a key variable in the pharmacology of a complex disease is enabled through a model-based analysis of experimental results. This variable, the stretch-tension condition and its effect on the LES, is believed to be one critical part of the difference between healthy and disease physiology. There is no direct way to measure this quantity, so an indirect use of a computer model provides a valuable option to clinical research.
References:
[1] Liebermann-Meffert, D.; Allgöwer, M.; Schmid, P.; Blum, A.L.: Muscular Equivalent of Lower Esophageal Sphincter, Gastroenterology vol.76, no.1, 1978
[2] http://visiblehuman.epfl.ch/
[3] Carmagnola, S.; Cantu, P.; Penagini, R.: Mechanoreceptors of Proximal Stomach and Perception of Gastric Distension, American Journal of Gastroenterology, 2005