A novel ventilator design for COVID-19 and resource-limited settings

There has existed a severe ventilator deficit in much of the world for many years, due in part to the high cost and complexity of traditional ICU ventilators. This was highlighted and exacerbated by the emergence of the COVID-19 pandemic, during which the increase in ventilator production rapidly over ran the global supply chains for components. In response, we propose a new approach to ventilator design that meets the performance requirements for COVID-19 patients, while using components that minimise interference with the existing ventilator supply chains. The majority of current ventilator designs use proportional valves and flow sensors, which remainin short supply over a year into the pandemic. In the proposed design, the core components are on-off valves. Unlike proportional valves, on-off valves are widely available,but accurate control of ventilation using on-off valves is not straight forward. Our proposed solution combines four on-of 0valves, a two-litre reservoir, an oxygen sensor and two pressure sensors. Benchtop testing of a prototype was performed with a commercially available flow analyser and test lungs. We investigated the accuracy and precision of the prototype using both compressed gas supplies and a portable oxygen concentrator, and demonstrated the long-term durability over 15 days. The precision and accuracy of ventilation parameters were within the ranges specified in international guidelines in all tests.A numerical model of the system was developed and validated against experimental data. The model was used to determine usable ranges of valve flow coefficients to increase supply chain flexibility. This new design provides the performance necessary for the majority of patients that require ventilation. Applications include COVID-19 as well as pneumonia, influenza, and tuberculosis, which remain major causes of mortality in low and middleincome countries.The robustness, energy efficiency, ease of maintenance, price and availability of on-off valves are all advantageous over proportional valves. As a result, the proposed ventilator design will cost significantly less to manufacture and maintain than current market designs and has the potential to increase global ventilator availabilit

Generation of stable advective-diffusive chemokine gradients in a three-dimensional hydrogel

Physiologic chemoattractant gradients are shaped by diffusion, advection, binding to an extracellular matrix, and removal by cells. Previous in vitro tools for studying these gradients and the cellular migratory response have required cells to be constrained to a 2D substrate or embedded in a gel devoid of fluid flow. Cell migration in fluid flow has been quantified in the absence of chemoattractant gradients and shown to be responsive to them, but there is a need for tools to investigate the synergistic, or antagonistic, effects of gradients and flow. We present a microfluidic chip in which we generated precisely controlled gradients of the chemokine CCL19 under advective-diffusive conditions. Using torque-actuated membranes situated between a gel region and the chip outlet, the resistance of fluid channels adjacent to the gel region could be modified, creating a controllable pressure difference across the gel at a resolution inferior to 10 Pa. Constant supply and removal of chemokine on either side of the chip facilitated the formation of stable gradients at Péclet numbers between −10 and +10 in a collagen type I hydrogel. The resulting interstitial flow was steady within 0.05 μm s−1 for at least 8 h and varied by less than 0.05 μm s−1 along the gel region. This method advances the physiologic relevance of the study of the formation and maintenance of molecular gradients and cell migration, which will improve the understanding of in vivo observations

Validation of markerless strain-field optical tracking approach for soft tissue mechanical assessment.

Strain measurement during tissue deformation is crucial to elucidate relationships between mechanical loading and functional changes in biological tissues. When combined with specified loading conditions, assessment of strain fields can be used to craft models that accurately represent the mechanical behavior of soft tissue. Inhomogeneities in strain fields may be indicative of normal or pathological inhomogeneities in mechanical properties. In this study, we present the validation of a modified Demons registration algorithm for non-contact, marker-less strain measurement of tissue undergoing uniaxial loading. We validate the algorithm on a synthetic dataset composed of artificial deformation fields applied to a speckle image, as well as images of aortic sections of varying perceptual quality. Initial results indicate that Demons outperforms recent Optical Flow and Digital Image Correlation methods in terms of accuracy and robustness to low image quality, with similar runtimes. Demons achieves at least 8% lower maximal deviation from ground truth on 50% biaxial and shear strain applied to aortic images. To illustrate utility, we quantified strain fields of multiple human aortic specimens undergoing uniaxial tensile testing, noting the formation of strain concentrations in areas of rupture. The modified Demons algorithm captured a large range of strains (up to 50%) and provided spatially resolved strain fields that could be useful in the assessment of soft tissue pathologies

Development of a micro-scale method to assess the effect of corrosion on the mechanical properties of a biodegradable Fe-316L stent material

The application of biodegradable materials to stent design has the potential to transform coronary artery disease treatment. It is critical that biodegradable stents have sustained strength during degradation and vessel healing to prevent re-occlusion. Proper assessment of the impact of corrosion on the mechanical behaviour of potential biomaterials is important. Investigations within literature frequently implement simplified testing conditions to understand this behaviour and fail to consider size effects associated with strut thickness, or the increase in corrosion due to blood flow, both of which can impact material properties. A protocol was developed that utilizes micro-scale specimens, in conjunction with dynamic degradation, to assess the effect of corrosion on the mechanical properties of a novel Fe-316L material. Dynamic degradation led to increased specimen corrosion, resulting in a greater reduction in strength after 48 h of degradation in comparison to samples statically corroded. It was found that thicker micro-tensile samples (h > 200 μm) had a greater loss of strength in comparison to its thinner counterpart (h < 200 μm), due to increased corrosion of the thicker samples (203 MPa versus 260 MPa after 48 h, p = 0.0017). This investigation emphasizes the necessity of implementing physiologically relevant testing conditions, including dynamic corrosion and stent strut thickness, when evaluating potential biomaterials for biodegradable stent application

An Integrated Pipeline for Combining in vitro Data and Mathematical Models Using a Bayesian Parameter Inference Approach to Characterize Spatio-temporal Chemokine Gradient Formation

All protective and pathogenic immune and inflammatory responses rely heavily on leukocyte migration and localization. Chemokines are secreted chemoattractants that orchestrate the positioning and migration of leukocytes through concentration gradients. The mechanisms underlying chemokine gradient establishment and control include physical as well as biological phenomena. Mathematical models offer the potential to both understand this complexity and suggest interventions to modulate immune function. Constructing models that have powerful predictive capability relies on experimental data to estimate model parameters accurately, but even with a reductionist approach, most experiments include multiple cell types, competing interdependent processes and considerable uncertainty. Therefore, we propose the use of reduced modelling and experimental frameworks in complement, to minimize the number of parameters to be estimated. We present a Bayesian optimization framework that accounts for advection and diffusion of a chemokine surrogate and the chemokine CCL19, transport processes that are known to contribute to the establishment of spatio-temporal chemokine gradients. Three examples are provided that demonstrate the estimation of the governing parameters as well as the underlying uncertainty.This study demonstrates how a synergistic approach between experimental and computational modelling benefits from the Bayesian approach to provide a robust analysis of chemokine transport. It provides a building block for a larger research effort to gain holistic insight and generate novel and testable hypotheses in chemokine biology and leukocyte trafficking

The critical importance of spatial and temporal scales in designing and interpreting immune cell migration assays

Intravital microscopy and other direct-imaging techniques have allowed for a characterisation of leukocyte migration that has revolutionised the field of immunology, resulting in an unprecedented understanding of the mechanisms of immune response and adaptive immunity. However, there is an assumption within the field that modern imaging techniques permit imaging parameters where the resulting cell track accurately captures a cell’s motion. This notion is almost entirely untested, and the relationship between what could be observed at a given scale and the underlying cell behaviour is undefined. Insufficient spatial and temporal resolutions within migration assays can result in misrepresentation of important physiologic processes or cause subtle changes in critical cell behaviour to be missed. In this review, we contextualise how scale can affect the perceived migratory behaviour of cells, summarise the limited approaches to mitigate this effect, and establish the need for a widely implemented framework to account for scale and correct observations of cell motion. We then extend the concept of scale to new approaches that seek to bridge the current “black box” between single-cell behaviour and systemic response