Biomedical subjects

Nicolas Smith

Publications and source records attributed to Nicolas Smith.

5 recordsLinked to original sources

PubMed2006

Hodgkin-Huxley type ion channel characterization: an improved method of voltage clamp experiment parameter estimation.

The Hodgkin-Huxley formalism for quantitative characterization of ionic channels is widely used in cellular electrophysiological models. Model parameters for these individual channels are determined from voltage clamp experiments and usually involve the assumption that inactivation process occurs on a time scale which is infinitely slow compared to the activation process. This work shows that such an assumption may lead to appreciable errors under certain physiological conditions and proposes a new numerical approach to interpret voltage clamp experiment results. In simulated experimental protocols the new method was shown to exhibit superior accuracy compared to the traditional least squares fitting methods. With noiseless input data the error in gating variables and time constants was less than 1%, whereas the traditional methods generated upwards of 10% error and predicted incorrect gating kinetics. A sensitivity analysis showed that the new method could tolerate up to approximately 15% perturbation in the input data without unstably amplifying error in the solution. This method could also assist in designing more efficient experimental protocols, since all channel parameters (gating variables, time constants and maximum conductance) could be determined from a single voltage step.

Animals↗

PubMed2005

New developments in a strongly coupled cardiac electromechanical model.

AIM: The aim of this study is to develop a coupled three-dimensional computational model of cardiac electromechanics to investigate fibre length transients and the role of electrical heterogeneity in determining left ventricular function. METHODS: A mathematical model of cellular electromechanics was embedded in a simple geometric model of the cardiac left ventricle. Electrical and mechanical boundary conditions were applied based on Purkinje fibre activation times and ventricular volumes through the heart cycle. The mono-domain reaction diffusion equations and finite deformation elasticity equations were solved simultaneously through the full pump cycle. Simulations were run to assess the importance of cellular electrical heterogeneity on myocardial mechanics. RESULTS: Following electrical activation, mechanical contraction moves out through the wall to the circumferentially oriented mid-wall fibres, producing a progressively longitudinal and twisting deformation. This is followed by a more spherical deformation as the inclined epicardial fibres are activated. Mid-way between base and apex peak tensions and fibre shortening of 40 kPa and 5%, respectively, are generated at the endocardial surface with values of 18 kPa and 12% at the epicardial surface. Embedding an electrically homogeneous cell model for the same simulations produced equivalent values of 36.5 kPa, 4% at the endocardium and 14 kPa, 13.5% at the epicardium. CONCLUSION: The substantial redistribution of fibre lengths during the early pre-ejection phase of systole may play a significant role in preparing the mid-wall fibres to contract. The inclusion of transmural heterogeneity of action potential duration has a marked effect on reducing sarcomere length transmural dispersion during repolarization.

Computer Simulation↗

PubMed2005

Integration from proteins to organs: the IUPS Physiome Project.

The IUPS Physiome Project is an internationally collaborative open source project intended to provide a public domain framework for computational physiology, including the development of modeling standards, computational tools and web-accessible databases of models of structure and function at all spatial scales and across all organ systems. Here, we illustrate the application of this multi-scale modeling approach to three organ systems: the heart, the lungs and the musculo-skeletal system, and in each case we show how the organ level models incorporate tissue and cell-level physiology. Although the computational physiology framework presented here does not yet incorporate models of ageing processes, the model-based approach is certainly capable of describing ageing and disease-related processes both via parameter changes within the models of normal physiological processes and via models of additional processes added to the framework.

Animals↗

PubMed2004

Computational physiology and the Physiome Project.

Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization--from proteins to cells, tissues, organs and organ systems--these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline.

Biophysical Phenomena↗

PubMed2004

Giving form to the function of the heart: embedding cellular models in an anatomical framework.

A computational framework is presented for integrating the electrical, mechanical, and biochemical functions of the heart. The construction of efficient finite element representations of canine and porcine ventricular geometry and microstructure is outlined. Computational techniques are applied to solve large deformation soft tissue mechanics by using orthotropic constitutive laws for myocardial tissue and models of active tension generation embedded at the Gauss points in the finite element mesh. The reaction-diffusion equations governing electrical current flow in the heart are solved on a grid of deforming material points that access systems of ordinary differential equations representing the cellular processes underlying the cardiac action potential. Navier-Stokes equations are solved to predict coronary blood flow in a system of branching blood vessels embedded in the deforming myocardium.

Animals↗