Critical care, like many healthcare areas, is under a dual assault from significantly increasing demographic and economic pressures. Intensive care unit (ICU) patients are highly variable in response to treatment, and increasingly aging populations mean ICUs are under increasing demand and their cohorts are increasingly ill. Equally, patient expectations are growing, while the economic ability to deliver care to all is declining. Better, more productive care is thus the big challenge. One means to that end is personalised care designed to manage the significant inter- and intra-patient variability that makes the ICU patient difficult. Thus, moving from current “one size fits all” protocolised care to adaptive, model-based “one method fits all” personalised care could deliver the required step change in the quality, and simultaneously the productivity and cost, of care. Computer models of human physiology are a unique tool to personalise care, as they can couple clinical data with mathematical methods to create subject-specific models and virtual patients to design new, personalised and more optimal protocols, as well as to guide care in real-time. They rely on identifying time varying patient-specific parameters in the model that capture inter- and intra-patient variability, the difference between patients and the evolution of patient condition. Properly validated, virtual patients represent the real patients, and can be used in silico to test different protocols or interventions, or in real-time to guide care. Hence, the underlying models and methods create the foundation for next generation care, as well as a tool for safely and rapidly developing personalised treatment protocols over large virtual cohorts using virtual trials. This review examines the models and methods used to create virtual patients. Specifically, it presents the models types and structures used and the data required. It then covers how to validate the resulting virtual patients and trials, and how these virtual trials can help design and optimise clinical trial. Links between these models and higher order, more complex physiome models are also discussed. In each section, it explores the progress reported up to date, especially on core ICU therapies in glycemic, circulatory and mechanical ventilation management, where high cost and frequency of occurrence provide a significant opportunity for model-based methods to have measurable clinical and economic impact. The outcomes are readily generalised to other areas of medical care.

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We propose a detailed CellML model of the human cerebral circulation that runs faster than real time on a desktop computer and is designed for use in clinical settings when the speed of response is important. A lumped parameter mathematical model, which is based on a one-dimensional formulation of the flow of an incompressible fluid in distensible vessels, is constructed using a bond graph formulation to ensure mass conservation and energy conservation. The model includes arterial vessels with geometric and anatomical data based on the ADAN circulation model. The peripheral beds are represented by lumped parameter compartments. We compare the hemodynamics predicted by the bond graph formulation of the cerebral circulation with that given by a classical one-dimensional Navier-Stokes model working on top of the whole-body ADAN model. Outputs from the bond graph model, including the pressure and flow signatures and blood volumes, are compared with physiological data.

Mimicking angiogenetic processes in vascular territories acquires importance in the analysis of the multi-scale circulatory cascade and the coupling between blood flow and cell function. The present work extends, in several aspects, the Constrained Constructive Optimisation (CCO) algorithm to tackle complex automatic vascularisation tasks. The main extensions are based on the integration of adaptive optimisation criteria and multi-staged space-filling strategies which enhance the modelling capabilities of CCO for specific vascular architectures. Moreover, this vascular outgrowth can be performed either from scratch or from an existing network of vessels. Hence, the vascular territory is defined as a partition of vascular, avascular and carriage domains (the last one contains vessels but not terminals) allowing one to model complex vascular domains. In turn, the multi-staged space-filling approach allows one to delineate a sequence of biologically-inspired stages during the vascularisation process by exploiting different constraints, optimisation strategies and domain partitions stage by stage, improving the consistency with the architectural hierarchy observed in anatomical structures. With these features, the aDaptive CCO (DCCO) algorithm proposed here aims at improving the modelled network anatomy. The capabilities of the DCCO algorithm are assessed with a number of anatomically realistic scenarios.

Computational models of many aspects of the mammalian cardiovascular circulation have been developed. Indeed, along with orthopaedics, this area of physiology is one that has attracted much interest from engineers, presumably because the equations governing blood flow in the vascular system are well understood and can be solved with well-established numerical techniques. Unfortunately, there have been only a few attempts to create a comprehensive public domain resource for cardiovascular researchers. In this paper we propose a roadmap for developing an open source cardiovascular circulation model. The model should be registered to the musculo-skeletal system. The computational infrastructure for the cardiovascular model should provide for near real-time computation of blood flow and pressure in all parts of the body. The model should deal with vascular beds in all tissues, and the computational infrastructure for the model should provide links into CellML models of cell function and tissue function. In this work we review the literature associated with 1D blood flow modelling in the cardiovascular system, discuss model encoding standards, software and a model repository. We then describe the coordinate systems used to define the vascular geometry, derive the equations and discuss the implementation of these coupled equations in the open source computational software OpenCMISS. Finally, some preliminary results are presented and plans outlined for the next steps in the development of the model, the computational software and the graphical user interface for accessing the model.

Liver structures of a healthy subject are digitised and segmented from computed tomography (CT) images, and hepatic perfusion is modelled in the hepatic artery and portal vein of the healthy subject with structured tree‐based outflow boundary conditions. This self‐similar structured tree is widely used in the literature, eg, blood flow simulation in larger systemic arteries and cerebral circulation, and is used in this study to model the effect of the smaller hepatic arteries and arterioles, as well as the smaller hepatic portal veins and portal venules. Physiologically reasonable results are obtained. Since the structured tree terminates at the size of the microvasculature system in liver lobules, the structured tree boundary condition will enable the proposed organ‐level model of hepatic arterial flow to be easily connected to tissue‐level models of liver lobules. Blood flow in the hepatic vein is also modelled in this subject with three‐element Windkessel model as outflow boundary conditions. The benefit of integrating the perfusion in all hepatic vascular vessels is that it helps us analyse some complicated clinical phenomenon more efficiently, eg, one possible application is to obtain the portal pressure gradient (PPG) to help examine the reliability of hepatic venous pressure gradient (HVPG) as an indirect measure of portal pressure. Moreover, since four to six generations of hepatic vessels, which are sufficient for liver classification analysis, were employed in the model, this study is setting the computational foundation of a potentially handy surgical tool.

We introduce, and provide examples of, the application of the bond graph formalism to explicitly represent biophysical processes between and within modular biological compartments in ApiNATOMY. In particular, we focus on modelling scenarios from acid-base physiology to link distinct process modalities as bond graphs over an ApiNATOMY circuit of multiscale compartments. The embedding of bond graphs onto ApiNATOMY compartments provides a semantically and mathematically explicit basis for the coherent representation, integration and visualisation of multiscale physiology processes together with the compartmental topology of those biological structures that convey these processes.

OpenCMISS is an open-source modeling environment aimed, in particular, at the solution of bioengineering problems. OpenCMISS consists of two main parts: a computational library (OpenCMISS-Iron) and a field manipulation and visualization library (OpenCMISS-Zinc). OpenCMISS is designed for the solution of coupled multi-scale, multi-physics problems in a general-purpose parallel environment. CellML is an XML format designed to encode biophysically based systems of ordinary differential equations and both linear and non-linear algebraic equations. A primary design goal of CellML is to allow mathematical models to be encoded in a modular and reusable format to aid reproducibility and interoperability of modeling studies. In OpenCMISS, we make use of CellML models to enable users to configure various aspects of their multi-scale physiological models. This avoids the need for users to be familiar with the OpenCMISS internal code in order to perform customized computational experiments. Examples of this are: cellular electrophysiology models embedded in tissue electrical propagation models; material constitutive relationships for mechanical growth and deformation simulations; time-varying boundary conditions for various problem domains; and fluid constitutive relationships and lumped-parameter models. In this paper, we provide implementation details describing how CellML models are integrated into multi-scale physiological models in OpenCMISS. The external interface OpenCMISS presents to users is also described, including specific examples exemplifying the extensibility and usability these tools provide the physiological modeling and simulation community. We conclude with some thoughts on future extension of OpenCMISS to make use of other community developed information standards, such as FieldML, SED-ML, and BioSignalML. Plans for the integration of accelerator code (graphical processing unit and field programmable gate array) generated from CellML models is also discussed.