CRIMSON: An open-source software framework for cardiovascular integrated modelling and simulation.

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization.

Controlling cell-cell interactions using surface acoustic waves.

The interactions between pairs of cells and within multicellular assemblies are critical to many biological processes such as intercellular communication, tissue and organ formation, immunological reactions, and cancer metastasis. The ability to precisely control the position of cells relative to one another and within larger cellular assemblies will enable the investigation and characterization of phenomena not currently accessible by conventional in vitro methods. We present a versatile surface acoustic wave technique that is capable of controlling the intercellular distance and spatial arrangement of cells with micrometer level resolution. This technique is, to our knowledge, among the first of its kind to marry high precision and high throughput into a single extremely versatile and wholly biocompatible technology. We demonstrated the capabilities of the system to precisely control intercellular distance, assemble cells with defined geometries, maintain cellular assemblies in suspension, and translate these suspended assemblies to adherent states, all in a contactless, biocompatible manner. As an example of the power of this system, this technology was used to quantitatively investigate the gap junctional intercellular communication in several homotypic and heterotypic populations by visualizing the transfer of fluorescent dye between cells.

On-Chip Production of Size-Controllable Liquid Metal Microdroplets Using Acoustic Waves.

Micro- to nanosized droplets of liquid metals, such as eutectic gallium indium (EGaIn) and Galinstan, have been used for developing a variety of applications in flexible electronics, sensors, catalysts, and drug delivery systems. Currently used methods for producing micro- to nanosized droplets of such liquid metals possess one or several drawbacks, including the lack in ability to control the size of the produced droplets, mass produce droplets, produce smaller droplet sizes, and miniaturize the system. Here, a novel method is introduced using acoustic wave-induced forces for on-chip production of EGaIn liquid-metal microdroplets with controllable size. The size distribution of liquid metal microdroplets is tuned by controlling the interfacial tension of the metal using either electrochemistry or electrocapillarity in the acoustic field. The developed platform is then used for heavy metal ion detection utilizing the produced liquid metal microdroplets as the working electrode. It is also demonstrated that a significant enhancement of the sensing performance is achieved by introducing acoustic streaming during the electrochemical experiments. The demonstrated technique can be used for developing liquid-metal-based systems for a wide range of applications.

Acoustofluidic Rotational Manipulation of Cells and Organisms Using Oscillating Solid Structures.

A polydimethylsiloxane microchannel featuring sidewall sharp-edge structures and bare channels, and a piezoelement transducer is attached to a thin glass slide. When an external acoustic field is applied to the microchannel, the oscillation of the sharp-edge structures and the thin glass slide generate acoustic streaming flows which in turn rotate single cells and C. elegans in-plane and out-of-plane.

Probing Cell Deformability via Acoustically Actuated Bubbles.

An acoustically actuated, bubble-based technique is developed to investigate the deformability of cells suspended in microfluidic devices. A microsized bubble is generated by an optothermal effect near the targeted cells, which are suspended in a microfluidic chamber. Subsequently, acoustic actuation is employed to create localized acoustic streaming. In turn, the streaming flow results in hydrodynamic forces that deform the cells in situ. The deformability of the cells is indicative of their mechanical properties. The method in this study measures mechanical biomarkers from multiple cells in a single experiment, and it can be conveniently integrated with other bioanalysis and drug-screening platforms. Using this technique, the mean deformability of tens of HeLa, HEK, and HUVEC cells is measured to distinguish their mechanical properties. HeLa cells are deformed upon treatment with Cytochalasin. The technique also reveals the deformability of each subpopulation in a mixed, heterogeneous cell sample by the use of both fluorescent markers and mechanical biomarkers. The technique in this study, apart from being relevant to cell biology, will also enable biophysical cellular diagnosis.

Acoustofluidic Fluorescence Activated Cell Sorter.

Selective isolation of cell subpopulations with defined biological characteristics is crucial for many biological studies and clinical applications. In this work, we present the development of an acoustofluidic fluorescence activated cell sorting (FACS) device that simultaneously performs on-demand, high-throughput, high-resolution cell detection and sorting, integrated onto a single chip. Our acoustofluidic FACS device uses the "microfluidic drifting" technique to precisely focus cells/particles three dimensionally and achieves a flow of single-file particles/cells as they pass through a laser interrogation region. We then utilize short bursts (150 µs) of standing surface acoustic waves (SSAW) triggered by an electronic feedback system to sort fluorescently labeled particles/cells with desired biological properties. We have demonstrated continuous isolation of fluorescently labeled HeLa cells from unlabeled cells at a throughput of ∼1200 events/s with a purity reaching 92.3 ± 3.39%. Furthermore, 99.18% postsort cell viability indicates that our acoustofluidic sorting technique maintains a high integrity of cells. Therefore, our integrated acoustofluidic FACS device is demonstrated to achieve two-way cell sorting with high purity, biocompatibility, and biosafety. We believe that our device has significant potential for use as a low-cost, high-performance, portable, and user-friendly FACS instrument.

An acoustofluidic micromixer via bubble inception and cavitation from microchannel sidewalls.

During the deep reactive ion etching process, the sidewalls of a silicon mold feature rough wavy structures, which can be transferred onto a polydimethylsiloxane (PDMS) microchannel through the soft lithography technique. In this article, we utilized the wavy structures of PDMS microchannel sidewalls to initiate and cavitate bubbles in the presence of acoustic waves. Through bubble cavitation, this acoustofluidic approach demonstrates fast, effective mixing in microfluidics. We characterized its performance by using viscous fluids such as poly(ethylene glycol) (PEG). When two PEG solutions with a resultant viscosity 54.9 times higher than that of water were used, the mixing efficiency was found to be 0.92, indicating excellent, homogeneous mixing. The acoustofluidic micromixer presented here has the advantages of simple fabrication, easy integration, and capability to mix high-viscosity fluids (Reynolds number: ~0.01) in less than 100 ms.

Steerable acoustically powered starfish-inspired microrobot.

Soft polymeric microrobots that can be loaded with nanocargoes and driven via external field stimuli can provide innovative solutions in various fields, including precise microscale assembly, targeted therapeutics, microsurgery, and the capture and degradation of unwanted wastewater fragments. However, in aquatic environments, it remains challenging to operate with microrobotic devices due to the predominant viscous resistances and the robots' limited actuation and sensing capabilities attributed to their miniaturization. The miniature size prevents the incorporation of onboard batteries that can provide sufficient power for propulsion and navigation, necessitating a wireless power supply. Current research examines untethered microrobot manipulation using external magnetic, electric, thermodynamic, or acoustic field-guided technologies: all strategies capable of wireless energy transmission towards sensitive and hard-to-reach locations. Nonetheless, developing a manipulation strategy that harnesses simple-to-induce strong propulsive forces in a stable manner over extended periods of time remains a significant endeavor. This study presents the fabrication and manipulation of a microrobot consisting of a magnetized soft polymeric composite material that enables a combination of stable acoustic propulsion through starfish-inspired artificial cilia and magnetic field-guided navigation. The acousto-magnetic manipulation strategy leverages the unique benefits of each applied field in the viscous-dominated microscale, namely precise magnetic orientation and strong acoustic thrust.

Acoustophoresis around an elastic scatterer in a standing wave field.

Acoustofluidic systems often employ prefabricated acoustic scatterers that perturb the imposed acoustic field to realize the acoustophoresis of immersed microparticles. We present a numerical study to investigate the time-averaged streaming and radiation force fields around a scatterer. Based on the streaming and radiation force field, we obtain the trajectories of the immersed microparticles with varying sizes and identify a critical transition size at which the motion of immersed microparticles in the vicinity of a prefabricated scatterer shifts from being streaming dominated to radiation dominated. We consider a range of acoustic frequencies to reveal that the critical transition size decreases with increasing frequency; this result explains the choice of acoustic frequencies in previously reported experimental studies. We also examine the impact of scatterer material and fluid properties on the streaming and radiation force fields, as well as on the critical transition size. Our results demonstrate that the critical transition size decreases with an increase in acoustic contrast factor: a nondimensional quantity that depends on material properties of the scatterer and the fluid. Our results provide a pathway to realize radiation force based manipulation of small particles by increasing the acoustic contrast factor of the scatterer, lowering the kinematic viscosity of the fluid, and increasing the acoustic frequency.

A multiscale framework for defining homeostasis in distal vascular trees: applications to the pulmonary circulation.

Pulmonary arteries constitute a low-pressure network of vessels, often characterized as a bifurcating tree with heterogeneous vessel mechanics. Understanding the vascular complexity and establishing homeostasis is important to study diseases such as pulmonary arterial hypertension (PAH). The onset and early progression of PAH can be traced to changes in the morphometry and structure of the distal vasculature. Coupling hemodynamics with vessel wall growth and remodeling (G&R) is crucial for understanding pathology at distal vasculature. Accordingly, the goal of this study is to provide a multiscale modeling framework that embeds the essential features of arterial wall constituents coupled with the hemodynamics within an arterial network characterized by an extension of Murray's law. This framework will be used to establish the homeostatic baseline characteristics of a pulmonary arterial tree, including important parameters such as vessel radius, wall thickness and shear stress. To define the vascular homeostasis and hemodynamics in the tree, we consider two timescales: a cardiac cycle and a longer period of vascular adaptations. An iterative homeostatic optimization, which integrates a metabolic cost function minimization, the stress equilibrium, and hemodynamics, is performed at the slow timescale. In the fast timescale, the pulsatile blood flow dynamics is described by a Womersley's deformable wall analytical solution. Illustrative examples for symmetric and asymmetric trees are presented that provide baseline characteristics for the normal pulmonary arterial vasculature. The results are compared with diverse literature data on morphometry, structure, and mechanics of pulmonary arteries. The developed framework demonstrates a potential for advanced parametric studies and future G&R and hemodynamics modeling of PAH.

Effects of non-Newtonian viscosity on arterial and venous flow and transport.

It is well known that blood exhibits non-Newtonian viscosity, but it is generally modeled as a Newtonian fluid. However, in situations of low shear rate, the validity of the Newtonian assumption is questionable. In this study, we investigated differences between Newtonian and non-Newtonian hemodynamic metrics such as velocity, vorticity, and wall shear stress. In addition, we investigated cardiovascular transport using two different approaches, Eulerian mass transport and Lagrangian particle tracking. Non-Newtonian solutions revealed important differences in both hemodynamic and transport metrics relative to the Newtonian model. Most notably for the hemodynamic metrics, in-plane velocity and vorticity were consistently larger in the Newtonian approximation for both arterial and venous flows. Conversely, wall shear stresses were larger for the non-Newtonian case for both the arterial and venous models. Our results also indicate that for the Lagrangian metrics, the history of accumulated shear was consistently larger for both arterial and venous flows in the Newtonian approximation. Lastly, our results also suggest that the Newtonian model produces larger near wall and luminal mass transport values compared to the non-Newtonian model, likely due to the increased vorticity and recirculation. These findings demonstrate the importance of accounting for non-Newtonian behavior in cardiovascular flows exhibiting significant regions of low shear rate and recirculation.

A robot-assisted acoustofluidic end effector.

Liquid manipulation is the foundation of most laboratory processes. For macroscale liquid handling, both do-it-yourself and commercial robotic systems are available; however, for microscale, reagents are expensive and sample preparation is difficult. Over the last decade, lab-on-a-chip (LOC) systems have come to serve for microscale liquid manipulation; however, lacking automation and multi-functionality. Despite their potential synergies, each has grown separately and no suitable interface yet exists to link macro-level robotics with micro-level LOC or microfluidic devices. Here, we present a robot-assisted acoustofluidic end effector (RAEE) system, comprising a robotic arm and an acoustofluidic end effector, that combines robotics and microfluidic functionalities. We further carried out fluid pumping, particle and zebrafish embryo trapping, and mobile mixing of complex viscous liquids. Finally, we pre-programmed the RAEE to perform automated mixing of viscous liquids in well plates, illustrating its versatility for the automatic execution of chemical processes.

Ultrasound-activated ciliary bands for microrobotic systems inspired by starfish.

Cilia are short, hair-like appendages ubiquitous in various biological systems, which have evolved to manipulate and gather food in liquids at regimes where viscosity dominates inertia. Inspired by these natural systems, synthetic cilia have been developed and utilized in microfluidics and microrobotics to achieve functionalities such as propulsion, liquid pumping and mixing, and particle manipulation. Here, we demonstrate ultrasound-activated synthetic ciliary bands that mimic the natural arrangements of ciliary bands on the surface of starfish larva. Our system leverages nonlinear acoustics at microscales to drive bulk fluid motion via acoustically actuated small-amplitude oscillations of synthetic cilia. By arranging the planar ciliary bands angled towards (+) or away (-) from each other, we achieve bulk fluid motion akin to a flow source or sink. We further combine these flow characteristics with a physical principle to circumvent the scallop theorem and realize acoustic-based propulsion at microscales. Finally, inspired by the feeding mechanism of a starfish larva, we demonstrate an analogous microparticle trap by arranging + and - ciliary bands adjacent to each other.

Imaging surveillance after open aortic repair: a feasibility study of three-dimensional growth mapping.

OBJECTIVES: Confident growth assessment during imaging follow-up is often limited by substantial variability of diameter measurements and the fact that growth does not always occur at standard measurement locations. There is a need for imaging-based techniques to more accurately assess growth. In this study, we investigated the feasibility of a three-dimensional aortic growth assessment technique to quantify aortic growth in patients following open aortic repair. METHODS: Three-dimensional aortic growth was measured using vascular deformation mapping (VDM), a technique which quantifies the localized rate of volumetric growth at the aortic wall, expressed in units of Jacobian (J) per year. We included 16 patients and analysed 6 aortic segments per patient (96 total segments). Growth was assessed by 3 metrics: clinically reported diameters, Jacobian determinant and targeted diameter re-measurements. RESULTS: VDM was able to clearly depict the presence or absence of localized aortic growth and allows for an assessment of the distribution of growth and its relation to anatomic landmarks (e.g. anastomoses, branch arteries). Targeted diameter change showed a stronger and significant correlation with J (r = 0.20, P = 0.047) compared to clinical diameter change (r = 0.15, P = 0.141). Among 20/96 (21%) segments with growth identified by VDM, growth was confirmed by clinical measurements in 7 and targeted re-measurements in 11. Agreement of growth assessments between VDM and diameter measurements was slightly higher for targeted re-measurements (kappa = 0.38) compared to clinical measurements (kappa = 0.25). CONCLUSIONS: Aortic growth is often uncertain and underappreciated when assessed via standard diameter measurements. Three-dimensional growth assessment with VDM offers a more comprehensive assessment of growth, allows for targeted diameter measurements and could be an additional tool to determine which post-surgical patients at high and low risk for future complications.

A nonlinear rotation-free shell formulation with prestressing for vascular biomechanics.

We implement a nonlinear rotation-free shell formulation capable of handling large deformations for applications in vascular biomechanics. The formulation employs a previously reported shell element that calculates both the membrane and bending behavior via displacement degrees of freedom for a triangular element. The thickness stretch is statically condensed to enforce vessel wall incompressibility via a plane stress condition. Consequently, the formulation allows incorporation of appropriate 3D constitutive material models. We also incorporate external tissue support conditions to model the effect of surrounding tissue. We present theoretical and variational details of the formulation and verify our implementation against axisymmetric results and literature data. We also adapt a previously reported prestress methodology to identify the unloaded configuration corresponding to the medically imaged in vivo vessel geometry. We verify the prestress methodology in an idealized bifurcation model and demonstrate the significance of including prestress. Lastly, we demonstrate the robustness of our formulation via its application to mouse-specific models of arterial mechanics using an experimentally informed four-fiber constitutive model.

Wafer-Scale Fabrication of Micro- to Nanoscale Bubble Swimmers and Their Fast Autonomous Propulsion by Ultrasound.

Fuel-free, biocompatible swimmers with dimensions smaller than one micrometer have the potential to revolutionize the way we study and manipulate microscopic systems. Sub-micrometer, metallic Janus particles can be propelled rapidly and autonomously by acoustically induced fluid streaming, but their operation at acoustic pressure nodes limits their utility. In contrast, bubble-based microswimmers have an "on board" resonant cavity that enables them to operate far from the source of acoustic power. So far, they have been fabricated by direct writing techniques that limit both their minimum dimensions and the number that can be produced. Consequently, the size scaling of the properties of bubble swimmers has not been explored experimentally. Additionally, 3D autonomous motion has not yet been demonstrated for this type of swimmer. We describe here a method for fabricating bubble swimmers in large numbers (>109) with sizes ranging from 5 µm to 500 nm without direct writing or photolithographic tools. These swimmers follow a previously proposed scaling theory and reveal useful phenomena that enable their propulsion in different modes in the same experiment: with magnetic steering, autonomously in 3D, and in frequency-specific autonomous modes. These interesting behaviors are relevant to possible applications of autonomously moving micro- and nanorobots.

Correction: An acoustofluidic device for efficient mixing over a wide range of flow rates.

Correction for 'An acoustofluidic device for efficient mixing over a wide range of flow rates' by Hunter Bachman et al., Lab Chip, 2020, 20, 1238-1248, DOI: .

Numerical considerations for advection-diffusion problems in cardiovascular hemodynamics.

Numerical simulations of cardiovascular mass transport pose significant challenges due to the wide range of Péclet numbers and backflow at Neumann boundaries. In this paper we present and discuss several numerical tools to address these challenges in the context of a stabilized finite element computational framework. To overcome numerical instabilities when backflow occurs at Neumann boundaries, we propose an approach based on the prescription of the total flux. In addition, we introduce a "consistent flux" outflow boundary condition and demonstrate its superior performance over the traditional zero diffusive flux boundary condition. Lastly, we discuss discontinuity capturing (DC) stabilization techniques to address the well-known oscillatory behavior of the solution near the concentration front in advection-dominated flows. We present numerical examples in both idealized and patient-specific geometries to demonstrate the efficacy of the proposed procedures. The three contributions discussed in this paper successfully address commonly found challenges when simulating mass transport processes in cardiovascular flows.

An acoustofluidic device for efficient mixing over a wide range of flow rates.

Whether reagents and samples need to be combined to achieve a desired reaction, or precise concentrations of solutions need to be mixed and delivered downstream, thorough mixing remains a critical step in many microfluidics-based biological and chemical assays and analyses. To achieve complete mixing of fluids in microfluidic devices, researchers have utilized novel channel designs or active intervention to facilitate mass transport and exchange of fluids. However, many of these solutions have a major limitation: their design inherently limits their operational throughput; that is, different designs work at specific flow rates, whether that be low or high ranges, but have difficulties outside of their tailored design regimes. In this work, we present an acoustofluidic mixer that is capable of achieving efficient, thorough mixing across a broad range of flow rates (20-2000 µL min-1) using a single device. Our mixer combines active acoustofluidic mixing, which is responsible for mixing fluids at lower flow rates, with passive hydrodynamic mixing, which accounts for mixing fluids at higher flow rates. The mechanism, functionality, and performance of our acoustofluidic device are both numerically and experimentally validated. Additionally, the real-world potential of our device is demonstrated by synthesizing polymeric nanoparticles with comparable sizes over a two-order-of-magnitude wide range of flow rates. This device can be valuable in many biochemical, biological, and biomedical applications. For example, using our platform, one may synthesize nanoparticles/nanomaterials at lower flow rates to first identify optimal synthesis conditions without having to waste significant amounts of reagents, and then increase the flow rate to perform high-throughput synthesis using the optimal conditions, all using the same single device and maintaining performance.

Correction: Three-dimensional numerical simulation and experimental investigation of boundary-driven streaming in surface acoustic wave microfluidics.

Correction for 'Three-dimensional numerical simulation and experimental investigation of boundary-driven streaming in surface acoustic wave microfluidics' by Chuyi Chen et al., Lab Chip, 2018, 18, 3645-3654, DOI: .