Sex matters: the frequently overlooked importance of considering sex in computational models.

Personalised medicine and the development of a virtual human or a digital twin comprises visions of the future of medicine. To realise these innovations, an understanding of the biology and physiology of all people are required if we wish to apply these technologies at a population level. Sex differences in health and biology is one aspect that has frequently been overlooked, with young white males being seen as the "average" human being. This has not been helped by the lack of inclusion of female cells and animals in biomedical research and preclinical studies or the historic exclusion, and still low in proportion, of women in clinical trials. However, there are many known differences in health between the sexes across all scales of biology which can manifest in differences in susceptibility to diseases, symptoms in a given disease, and outcomes to a given treatment. Neglecting these important differences in the development of any health technologies could lead to adverse outcomes for both males and females. Here we highlight just some of the sex differences in the cardio-respiratory systems with the goal of raising awareness that these differences exist. We discuss modelling studies that have considered sex differences and touch on how and when to create sex-specific models. Scientific studies should ensure sex differences are included right from the study planning phase and results reported using sex as a biological variable. Computational models must have sex-specific versions to ensure a movement towards personalised medicine is realised.

An in silico approach to understanding the interaction between cardiovascular and pulmonary lymphatic dysfunction.

The lung is extremely sensitive to interstitial fluid balance, yet the role of pulmonary lymphatics in lung fluid homeostasis and its interaction with cardiovascular pressures is poorly understood. In health, there is a fine balance between fluid extravasated from the pulmonary capillaries into the interstitium and the return of fluid to the circulation via the lymphatic vessels. This balance is maintained by an extremely interdependent system governed by pressures in the fluids (air and blood) and tissue (interstitium), lung motion during breathing, and the permeability of the tissues. Chronic elevation in left atrial pressure (LAP) due to left heart disease increases the capillary blood pressure. The consequent fluid accumulation in the delicate lung tissue increases its weight, decreases its compliance, and impairs gas exchange. This interdependent system is difficult, if not impossible, to study experimentally. Computational modeling provides a unique perspective to analyze fluid movement in the cardiopulmonary vasculature in health and disease. We have developed an initial in silico model of pulmonary lymphatic function using an anatomically structured model to represent ventilation and perfusion and underlying biophysical laws governing fluid transfer at the interstitium. This novel model was tested against increased LAP and noncardiogenic effects (increased permeability). The model returned physiologically reasonable values for all applications, predicting pulmonary edema when LAP reached 25 mmHg and with increased permeability.NEW & NOTEWORTHY This model presents a novel approach to understanding the interaction between cardiac dysfunction and pulmonary lymphatic function, using anatomically structured models and biophysical equations to estimate regional variation in fluid transport from blood to interstitial and lymphatic flux. This fluid transport model brings together advanced models of ventilation, perfusion, and lung mechanics to produce a detailed model of fluid transport in health and various altered pathological conditions.

ECAM: A low-cost vaping device for generating and collecting electronic cigarette condensate for in vitro studies.

The use of electronic cigarettes (ECs) has become widespread despite many unknowns around their long-term health impact. ECs work by vapourising a liquid, known as an e-liquid, typically consisting of propylene glycol, glycerol, flavourings and nicotine. The chemical constituents and resultant impact on cells and tissue are dependent on several factors, including the flavourings used, the vaping topography/use pattern, and the device used. ECAM (Electronic Cigarette Aerosol Machine) is an open source, portable device for creating EC aerosol - for condensate collection and in vitro studies - using a controlled methodology. ECAM was developed as a low cost, automated, and customisable alternative to commercial devices. ECAM consists of a micro diaphragm gas pump to draw air/EC aerosol through the system. The device is automated using an Arduino and solenoid pinch valves are used to alternate between air and EC vapour. Condensate is collected in a vial within a cold-water bath. Each ECAM unit uses a temperature/humidity sensor to measure ambient air conditions and a differential pressure sensor to determine the pressure within the system. ECAM is programmed to adhere to International Standards Organisation 20768:2018. The design files, source code, and build instructions for this device can be found at https://dx.doi.org/10.17605/OSF.IO/3NGU4.

In Silico Ventilation Within the Dose-Volume is Predictive of Lung Function Post-radiation Therapy in Patients with Lung Cancer.

Lung cancer is a leading cause of death worldwide. Radiation therapy (RT) is one method to treat this disease. A common side effect of RT for lung cancer is radiation-induced lung damage (RILD) which leads to loss of lung function. RILD often compounds pre-existing smoking-related regional lung function impairment. It is difficult to predict patient outcomes due to large variability in individual response to RT. In this study, the capability of image-based modelling of regional ventilation in lung cancer patients to predict lung function post-RT was investigated. Twenty-five patient-based models were created using CT images to define the airway geometry, size and location of tumour, and distribution of emphysema. Simulated ventilation within the 20 Gy isodose volume showed a statistically significant negative correlation with the change in forced expiratory volume in 1 s 12-months post-RT (p = 0.001, R = - 0.61). Patients with higher simulated ventilation within the 20 Gy isodose volume had a greater loss in lung function post-RT and vice versa. This relationship was only evident with the combined impact of tumour and emphysema, with the location of the emphysema relative to the dose-volume being important. Our results suggest that model-based ventilation measures can be used in the prediction of patient lung function post-RT.

A viscoelastic two-dimensional network model of the lung extracellular matrix.

The extracellular matrix (ECM) comprises a large proportion of the lung parenchymal tissue and is an important contributor to the mechanical properties of the lung. The lung tissue is a biologically active scaffold with a complex ECM matrix structure and composition that provides physical support to the surrounding cells. Nearly all respiratory pathologies result in changes in the structure and composition of the ECM; however, the impact of these alterations on the mechanical properties of the tissue is not well understood. In this study, a novel network model was developed to incorporate the combinatorial effect of lung tissue ECM constituents such as collagen, elastin and proteoglycans (PGs) and used to mimic the experimentally derived length-tension response of the tissue to uniaxial loading. By modelling the effect of collagen elasticity as an exponential function with strain, and in concert with the linear elastic response of elastin, the network model's mechanical response matched experimental stress-strain curves from the literature. In addition, by incorporating spring-dashpot viscoelastic elements, to represent the PGs, the hysteresis response was also simulated. Finally, by selectively reducing volume fractions of the different ECM constituents, we were able to gain insight into their relative mechanical contribution to the larger scale tissue mechanical response.

Hypoxic pulmonary vasoconstriction as a contributor to response in acute pulmonary embolism.

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive response unique to the lung whereby blood flow is diverted away from areas of low alveolar oxygen to improve ventilation-perfusion matching and resultant gas exchange. Some previous experimental studies have suggested that the HPV response to hypoxia is blunted in acute pulmonary embolism (APE), while others have concluded that HPV contributes to elevated pulmonary blood pressures in APE. To understand these contradictory observations, we have used a structure-based computational model of integrated lung function in 10 subjects to study the impact of HPV on pulmonary hemodynamics and gas exchange in the presence of regional arterial occlusion. The integrated model includes an experimentally-derived model for HPV. Its function is validated against measurements of pulmonary vascular resistance in normal subjects at four levels of inspired oxygen. Our results show that the apparently disparate observations of previous studies can be explained within a single model: the model predicts that HPV increases mean pulmonary artery pressure in APE (by 8.2 ± 7.0% in these subjects), and concurrently shows a reduction in response to hypoxia in the subjects who have high levels of occlusion and therefore maximal HPV in normoxia.

Lack of functional information explains the poor performance of 'clot load scores' at predicting outcome in acute pulmonary embolism.

Clot load scores have previously been developed with the goal of improving prognosis in acute pulmonary embolism (PE). These scores provide a simple estimate of pulmonary vascular bed obstruction, however they have not been adopted clinically as they have poor correlation with mortality and right ventricular (RV) dysfunction. This study performed a quantitative analysis of blood flow and gas exchange in 12 patient-specific models of PE, to understand the limitations of current clot load scores and how their prognostic value could be improved. Prediction of hypoxemia in the models when using estimated baseline (non-occluded) minute ventilation and cardiac output correlated closely with clinical metrics for RV dysfunction, whereas the clot load score had only a weak correlation. The model predicts that large central clots have a greater impact on function than smaller distributed clots with the same total clot load, and that the partial occlusion of a vessel only has a significant impact on pulmonary function when the vessel is close to completely occluded. The effect of clot distribution on the redistribution of blood from its normal pattern - and hence the magnitude of the potential effect on gas exchange - is represented in the model but is not included in current clot load scores. Improved scoring systems need to account for the expected normal distribution of blood in the lung, and the impact of clot on redistributing the blood flow.

Multi-scale computational models of the airways to unravel the pathophysiological mechanisms in asthma and chronic obstructive pulmonary disease (AirPROM).

THE RESPIRATORY SYSTEM COMPRISES SEVERAL SCALES OF BIOLOGICAL COMPLEXITY: the genes, cells and tissues that work in concert to generate resultant function. Malfunctions of the structure or function of components at any spatial scale can result in diseases, to the detriment of gas exchange, right heart function and patient quality of life. Vast amounts of data emerge from studies across each of the biological scales; however, the question remains: how can we integrate and interpret these data in a meaningful way? Respiratory disease presents a huge health and economic burden, with the diseases asthma and chronic obstructive pulmonary disease (COPD) affecting over 500 million people worldwide. Current therapies are inadequate owing to our incomplete understanding of the disease pathophysiology and our lack of recognition of the enormous disease heterogeneity: we need to characterize this heterogeneity on a patient-specific basis to advance healthcare. In an effort to achieve this goal, the AirPROM consortium (Airway disease Predicting Outcomes through patient-specific computational Modelling) brings together a multi-disciplinary team and a wealth of clinical data. Together we are developing an integrated multi-scale model of the airways in order to unravel the complex pathophysiological mechanisms occurring in the diseases asthma and COPD.

Assessing potential errors of MRI-based measurements of pulmonary blood flow using a detailed network flow model.

MRI images of pulmonary blood flow using arterial spin labeling (ASL) measure the delivery of magnetically tagged blood to an image plane during one systolic ejection period. However, the method potentially suffers from two problems, each of which may depend on the imaging plane location: 1) the inversion plane is thicker than the imaging plane, resulting in a gap that blood must cross to be detected in the image; and 2) ASL includes signal contributions from tagged blood in conduit vessels (arterial and venous). By using an in silico model of the pulmonary circulation we found the gap reduced the ASL signal to 64-74% of that in the absence of a gap in the sagittal plane and 53-84% in the coronal. The contribution of the conduit vessels varied markedly as a function of image plane ranging from ∼90% of the overall signal in image planes that encompass the central hilar vessels to <20% in peripheral image planes. A threshold cutoff removing voxels with intensities >35% of maximum reduced the conduit vessel contribution to the total ASL signal to ∼20% on average; however, planes with large contributions from conduit vessels underestimate acinar flow due to a high proportion of in-plane flow, making ASL measurements of perfusion impractical. In other image planes, perfusion dominated the resulting ASL images with good agreement between ASL and acinar flow. Similarly, heterogeneity of the ASL signal as measured by relative dispersion is a reliable measure of heterogeneity of the acinar flow distribution in the same image planes.

Blood flow redistribution and ventilation-perfusion mismatch during embolic pulmonary arterial occlusion.

Acute pulmonary embolism causes redistribution of blood in the lung, which impairs ventilation/perfusion matching and gas exchange and can elevate pulmonary arterial pressure (PAP) by increasing pulmonary vascular resistance (PVR). An anatomically-based multi-scale model of the human pulmonary circulation was used to simulate pre- and post-occlusion flow, to study blood flow redistribution in the presence of an embolus, and to evaluate whether reduction in perfused vascular bed is sufficient to increase PAP to hypertensive levels, or whether other vasoconstrictive mechanisms are necessary. A model of oxygen transfer from air to blood was included to assess the impact of vascular occlusion on oxygen exchange. Emboli of 5, 7, and 10 mm radius were introduced to occlude increasing proportions of the vasculature. Blood flow redistribution was calculated after arterial occlusion, giving predictions of PAP, PVR, flow redistribution, and micro-circulatory flow dynamics. Because of the large flow reserve capacity (via both capillary recruitment and distension), approximately 55% of the vasculature was occluded before PAP reached clinically significant levels indicative of hypertension. In contrast, model predictions showed that even relatively low levels of occlusion could cause localized oxygen deficit. Flow preferentially redistributed to gravitationally non-dependent regions regardless of occlusion location, due to the greater potential for capillary recruitment in this region. Red blood cell transit times decreased below the minimum time for oxygen saturation (<0.25 s) and capillary pressures became high enough to initiate cell damage (which may result in edema) only after ~80% of the lung was occluded.

Pulmonary embolism: predicting disease severity.

Pulmonary embolism (PE) is the most common cause of acute pulmonary hypertension, yet it is commonly undiagnosed, with risk of death if not recognized promptly and managed accordingly. Patients typically present with hypoxemia and hypomania, although the presentation varies greatly, being confounded by co-morbidities such as pre-existing cardio-respiratory disease. Previous studies have demonstrated variable patient outcomes in spite of similar extent and distribution of pulmonary vascular occlusion, but the path physiological determinants of outcome remain unclear. Computational models enable exact control over many of the compounding factors leading to functional outcomes and therefore provide a useful tool to understand and assess these mechanisms. We review the current state of pulmonary blood flow models. We present a pilot study within 10 patients presenting with acute PE, where patient-derived vascular occlusions are imposed onto an existing model of the pulmonary circulation enabling predictions of resultant haemodynamic after embolus occlusion. Results show that mechanical obstruction alone is not sufficient to cause pulmonary arterial hypertension, even when up to 65 per cent of lung tissue is occluded. Blood flow is found to preferentially redistribute to the gravitationally non-dependent regions. The presence of an additional downstream occlusion is found to significantly increase pressures.

The interdependent contributions of gravitational and structural features to perfusion distribution in a multiscale model of the pulmonary circulation.

Recent experimental and imaging studies suggest that the influence of gravity on the measured distribution of blood flow in the lung is largely through deformation of the parenchymal tissue. To study the contribution of hydrostatic effects to regional perfusion in the presence of tissue deformation, we have developed an anatomically structured computational model of the pulmonary circulation (arteries, capillaries, veins), coupled to a continuum model of tissue deformation, and including scale-appropriate fluid dynamics for blood flow in each vessel type. The model demonstrates that both structural and the multiple effects of gravity on the pulmonary circulation make a distinct contribution to the distribution of blood. It shows that postural differences in perfusion gradients can be explained by the combined effect of tissue deformation and extra-acinar blood vessel resistance to flow in the dependent tissue. However, gravitational perfusion gradients persist when the effect of tissue deformation is eliminated, highlighting the importance of the hydrostatic effects of gravity on blood distribution in the pulmonary circulation. Coupling of large- and small-scale models reveals variation in microcirculatory driving pressures within isogravitational planes due to extra-acinar vessel resistance. Variation in driving pressures is due to heterogeneous large-vessel resistance as a consequence of geometric asymmetry in the vascular trees and is amplified by the complex balance of pressures, distension, and flow at the microcirculatory level.

The impact of micro-embolism size on haemodynamic changes in the pulmonary micro-circulation.

Embolus occlusion of pulmonary arteries can result in elevated pulmonary blood pressures, often resulting in pulmonary hypertension (PH). Experimental observations have shown that small emboli (diameter <170 µm) can have a disproportionate effect on pulmonary vascular resistance (PVR) compared with larger emboli for the same tissue occlusion. We present an anatomically based theoretical model of perfusion in the acinar blood vessels designed to investigate changes in PVR following occlusion of arteries <500 µm in diameter. The model predicts that emboli lodged near proximal capillary beds have a greater effect on PVR--regardless of their size--than emboli occluding 200 µm diameter arterioles, with PH occurring for 10% less tissue occlusion. Capillary blood pressures are predicted to exceed 24 mmHg (levels initiating capillary wall damage) in regions of the capillary bed at approximately the onset of PH. This study focuses on the effect of mechanical obstruction alone; however, we present simple models of vasoconstriction illustrating an increased impact on PVR.

Contribution of serial and parallel microperfusion to spatial variability in pulmonary inter- and intra-acinar blood flow.

This study presents a theoretical model of combined series and parallel perfusion in the human pulmonary acinus that maintains computational simplicity while capturing some important features of acinar structure. The model provides a transition between existing models of perfusion in the large pulmonary blood vessels and the pulmonary microcirculation. Arterioles and venules are represented as distinct elastic vessels that follow the branching structure of the acinar airways. These vessels are assumed to be joined at each generation by capillary sheets that cover the alveoli present at that generation, forming a "ladderlike" structure. Compared with a model structure in which capillary beds connect only the most distal blood vessels in the acinus, the model with combined serial and parallel perfusion provides greater capacity for increased blood flow in the lung via capillary recruitment when the blood pressure is elevated. Stratification of acinar perfusion emerges in the model, with red blood cell transit time significantly larger in the distal portion of the acinus compared with the proximal portion. This proximal-to-distal pattern of perfusion may act in concert with diffusional screening to optimize the potential for gas exchange.

Species-specific pulmonary arterial asymmetry determines species differences in regional pulmonary perfusion.

The functional significance of differences in pulmonary vascular branching and diameter asymmetry between the human and quadruped lung has not previously been addressed. To evaluate the contribution of branching asymmetry to observable species differences in blood flow gradients, computed distributions of blood flow were compared in structure-based models of the human and ovine pulmonary arteries. The models were derived using a combination of computed tomography and a volume-filling algorithm. Pressure, flow, and deformed vessel diameter were calculated in both species models using equations representing conservation of mass and momentum, and a pressure-diameter relationship. The major difference between the human and ovine results was the presence of a large region of "zone 4" flow and higher mean flows in the central region of the ovine lung compared to that in the human. Heterogeneity in tissue perfusion and the contribution of gravity were similar in both species models; however, the gravitationally directed gradients of perfusion in the human and ovine models were different and each consistent with human and quadruped measurements, respectively. The results suggest that measured species differences in pulmonary perfusion gradients are largely determined by differences in branching asymmetry.

Towards a virtual lung: multi-scale, multi-physics modelling of the pulmonary system.

The essential function of the lung, gas exchange, is dependent on adequate matching of ventilation and perfusion, where air and blood are delivered through complex branching systems exposed to regionally varying transpulmonary and transmural pressures. Structure and function in the lung are intimately related, yet computational models in pulmonary physiology usually simplify or neglect structure. The geometries of the airway and vascular systems and their interaction with parenchymal tissue have an important bearing on regional distributions of air and blood, and therefore on whole lung gas exchange, but this has not yet been addressed by modelling studies. Models for gas exchange have typically incorporated considerable detail at the level of chemical reactions, with little thought for the influence of structure. To date, relatively little attention has been paid to modelling at the cellular or subcellular level in the lung, or to linking information from the protein structure/interaction and cellular levels to the operation of the whole lung. We review previous work in developing anatomically based models of the lung, airways, parenchyma and pulmonary vasculature, and some functional studies in which these models have been used. Models for gas exchange at several spatial scales are briefly reviewed, and the challenges and benefits from modelling cellular function in the lung are discussed.

Evaluation of the effect of postural and gravitational variations on the distribution of pulmonary blood flow via an image-based computational model.

We have developed an image-based computational model of blood flow within the human pulmonary circulation in order to investigate the distribution of flow under various conditions of posture and gravity. Geometric models of the lobar surfaces and largest arterial and venous vessels were derived from multi-detector row X-ray computed tomography. The remaining blood vessels were generated using a volume-filling branching algorithm. Equations representing conservation of mass and momentum are solved within the vascular geometry to calculate pressure, radius, and velocity distributions. Flow solutions are obtained within the model in the upright, inverted, prone, and supine postures and in the upright posture with and without gravity. Additional equations representing large deformation mechanics are used to calculate the change in lung geometry and pressure distributions within the lung in the various postures - creating a coupled, co-dependent model of mechanics and flow. The embedded vascular meshes deform in accordance with the lung geometry. Results illustrate a persistent flow gradient from the top to the bottom of the lung even in the absence of gravity and in all postures, indicating that vascular branching structure is largely responsible for the distribution of flow.