A numerical model to assess deconditioning of the cardiovascular system in long-term exposure to microgravity. Verification and simulation of Mars mission scenarios

Numerical simulations of the cardiovascular system are particularly important in scenarios where it is difficult to experiment different weightlessness exposure conditions. Technological advances in terms of computational power in the last years, and improvement of algorithms have recently made these techniques more reliable. We report in this paper results from extensive simulations undertaken in a computing facility in our University (UPC BarcelonaTech) aimed at evaluate the risks involved in a long-term exposure to reduced gravity loads for a very extensive range of possible mission scenarios. The simulation allows to introduce different levels of exposure to hypo or hypergravity, and analyze the consequences on relevant figures of cardiovascular deconditioning, such as heart rate, mean stroke volume or vascular resistance. Neurological or thermic stress or aerobic exercise can also be applied in order to better emulate a realistic long-term space mission comprising, for example, Extra Vehicular Activities (EVA) or physical exercise as countermeasures. Gender differences have also been studied, with significant different recommendations given as outcomes of the simulation, for both men and female astronauts. Our model is based on the previous works form Melchier et al. or Heldt et al. who described in analytical terms the process of orthostatic intolerance due to gravity alterations being applied on a human subject. We incorporated these Runge-Kutta equations by using Matlab® and Simulink® software. Results from these models were validated in parabolic flight. We later developed this model to take into account all control system parts involved in the human cardiovascular system, and we finally achieved an electrical-like control model in which we could easily measure the output of the system (vascular resistance, blood volume etc.) as a means to assess the level of cardiovascular deconditioning. Step-by-step changes of gravity and thermal stress were later applied, as well as other real-like mission inputs. Different scenarios of Moon and Mars exploration missions are considered, and their associated risks are quantified. The more relevant results are provided, including the finding that the vascular resistance deconditioning appears to be alike in both microgravity and the reduced gravity at the level of the Moon; which raises concerns for a successful manned Mars mission scenario. This work may contribute to a better understanding of the underlying processes involved for both women in man adaptation to long-term microgravity, and shows the potential of such numerical simulations for designing manned mission scenarios.Peer ReviewedPostprint (published version

A multiscale model for collagen alignment in wound healing

It is thought that collagen alignment plays a significant part in scar tissue formation during dermal wound healing. We present a multiscale model for collagen deposition and alignment during this process. We consider fibroblasts as discrete units moving within an extracellular matrix of collagen and fibrin modelled as continua. Our model includes flux induced alignment of collagen by fibroblasts, and contact guidance of fibroblasts by collagen fibres. We can use the model to predict the effects of certain manipulations, such as varying fibroblast speed, or placing an aligned piece of tissue in the wound. We also simulate experiments which alter the TGF-β concentrations in a healing dermal wound and use the model to offer an explanation of the observed influence of this growth factor on scarring

Cancer modelling: Getting to the heart of the problem

Paradoxically, improvements in healthcare that have enhanced the life expectancy of humans in the Western world have, indirectly, increased the prevalence of certain types of cancer such as prostate and breast. It remains unclear whether this phenomenon should be attributed to the ageing process itself or the cumulative effect of prolonged exposure to harmful environmental stimuli such as ultraviolet light, radiation and carcinogens (Franks and Teich, 1988). Equally, there is also compelling evidence that certain genetic abnormalities can predispose individuals to specific cancers (Ilyas et al., 1999). The variety of factors that have been implicated in the development of solid tumours stems, to a large extent, from the fact that ‘cancer’ is a generic term, often used to characterize a series of disorders that share common features. At this generic level of description, cancer may be viewed as a cellular disease in which controls that usually regulate growth and maintain homeostasis are disrupted. Cancer is typically initiated by genetic mutations that lead to enhanced mitosis of a cell lineage and the formation of an avascular tumour. Since it receives nutrients by diffusion from the surrounding tissue, the size of an avascular tumour is limited to several millimeters in diameter. Further growth relies on the tumour acquiring the ability to stimulate the ingrowth of a new, circulating blood supply from the host vasculature via a process termed angiogenesis (Folkman, 1974). Once vascularised, the tumour has access to a vast nutrient source and rapid growth ensues. Further, tumour fragments that break away from the primary tumour, on entering the vasculature, may be transported to other organs in which they may establish secondary tumours or metastases that further compromise the host. Invasion is another key feature of solid tumours whereby contact with the tissue stimulates the production of enzymes that digest the tissue, liberating space into which the tumour cells migrate. Thus, cancer is a complex, multiscale process. The spatial scales of interest range from the subcellular level, to the cellular and macroscopic (or tissue) levels while the timescales may vary from seconds (or less) for signal transduction pathways to months for tumour doubling times The variety of phenomena involved, the range of spatial and temporal scales over which they act and the complex way in which they are inter-related mean that the development of realistic theoretical models of solid tumour growth is extremely challenging. While there is now a large literature focused on modelling solid tumour growth (for a review, see, for example, Preziosi, 2003), existing models typically focus on a single spatial scale and, as a result, are unable to address the fundamental problem of how phenomena at different scales are coupled or to combine, in a systematic manner, data from the various scales. In this article, a theoretical framework will be presented that is capable of integrating a hierarchy of processes occurring at different scales into a detailed model of solid tumour growth (Alarcon et al., 2004). The model is formulated as a hybrid cellular automaton and contains interlinked elements that describe processes at each spatial scale: progress through the cell cycle and the production of proteins that stimulate angiogenesis are accounted for at the subcellular level; cell-cell interactions are treated at the cellular level; and, at the tissue scale, attention focuses on the vascular network whose structure adapts in response to blood flow and angiogenic factors produced at the subcellular level. Further coupling between the different spatial scales arises from the transport of blood-borne oxygen into the tissue and its uptake at the cellular level. Model simulations will be presented to illustrate the effect that spatial heterogeneity induced by blood flow through the vascular network has on the tumour’s growth dynamics and explain how the model may be used to compare the efficacy of different anti-cancer treatment protocols

Two-dimensional Tissue Image Reconstruction Based on Magnetic Field Data

This paper introduces new possibilities within two-dimensional reconstruction of internal conductivity distribution. In addition to the electric field inside the given object, the injected current causes a magnetic field which can be measured either outside the object by means of a Hall probe or inside the object through magnetic resonance imaging. The Magnetic Resonance method, together with Electrical impedance tomography (MREIT), is well known as a bio-imaging modality providing cross-sectional conductivity images with a good spatial resolution from the measurements of internal magnetic flux density produced by externally injected currents. A new algorithm for the conductivity reconstruction, which utilizes the internal current information with respect to corresponding boundary conditions and the external magnetic field, was developed. A series of computer simulations has been conducted to assess the performance of the proposed algorithm within the process of estimating electrical conductivity changes in the lungs, heart, and brain tissues captured in two-dimensional piecewise homogeneous chest and head models. The reconstructed conductivity distribution using the proposed method is compared with that using a conventional method based on Electrical Impedance Tomography (EIT). The acquired experience is discussed and the direction of further research is proposed

Nonlinear physics of electrical wave propagation in the heart: a review

The beating of the heart is a synchronized contraction of muscle cells (myocytes) that are triggered by a periodic sequence of electrical waves (action potentials) originating in the sino-atrial node and propagating over the atria and the ventricles. Cardiac arrhythmias like atrial and ventricular fibrillation (AF,VF) or ventricular tachycardia (VT) are caused by disruptions and instabilities of these electrical excitations, that lead to the emergence of rotating waves (VT) and turbulent wave patterns (AF,VF). Numerous simulation and experimental studies during the last 20 years have addressed these topics. In this review we focus on the nonlinear dynamics of wave propagation in the heart with an emphasis on the theory of pulses, spirals and scroll waves and their instabilities in excitable media and their application to cardiac modeling. After an introduction into electrophysiological models for action potential propagation, the modeling and analysis of spatiotemporal alternans, spiral and scroll meandering, spiral breakup and scroll wave instabilities like negative line tension and sproing are reviewed in depth and discussed with emphasis on their impact in cardiac arrhythmias.Peer ReviewedPreprin

HD Physiology Project-Japanese efforts to promote multilevel integrative systems biology and physiome research.

The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research

Aerospace Medicine and Biology: A continuing supplement 180, May 1978

This special bibliography lists 201 reports, articles, and other documents introduced into the NASA scientific and technical information system in April 1978

Competing mechanisms of stress-assisted diffusivity and stretch-activated currents in cardiac electromechanics

We numerically investigate the role of mechanical stress in modifying the conductivity properties of the cardiac tissue and its impact in computational models for cardiac electromechanics. We follow a theoretical framework recently proposed in [Cherubini, Filippi, Gizzi, Ruiz-Baier, JTB 2017], in the context of general reaction-diffusion-mechanics systems using multiphysics continuum mechanics and finite elasticity. In the present study, the adapted models are compared against preliminary experimental data of pig right ventricle fluorescence optical mapping. These data contribute to the characterization of the observed inhomogeneity and anisotropy properties that result from mechanical deformation. Our novel approach simultaneously incorporates two mechanisms for mechano-electric feedback (MEF): stretch-activated currents (SAC) and stress-assisted diffusion (SAD); and we also identify their influence into the nonlinear spatiotemporal dynamics. It is found that i) only specific combinations of the two MEF effects allow proper conduction velocity measurement; ii) expected heterogeneities and anisotropies are obtained via the novel stress-assisted diffusion mechanisms; iii) spiral wave meandering and drifting is highly mediated by the applied mechanical loading. We provide an analysis of the intrinsic structure of the nonlinear coupling using computational tests, conducted using a finite element method. In particular, we compare static and dynamic deformation regimes in the onset of cardiac arrhythmias and address other potential biomedical applications