With mechanical thrombectomy emerging as the new standard of care for stroke treatment, clot analogues provide an extremely useful tool in the testing and design of these treatment devices. The aim ...of this study is to characterise the mechanical behavior of thrombus analogues as a function of composition. Platelet-contracted clot analogues were prepared from blood mixtures of various hematocrits. Mechanical testing was performed whereby clots were subjected to unconfined compression between two rigid plates. Two loading protocols were imposed: cyclic compression for 10 cycles at a constant strain-rate magnitude; stress-relaxation at a constant applied compressive strain. A hyper-viscoelastic constitutive law was identified and calibrated based on the experimental mechanical test data. Scanning electron microscopy (SEM) investigated the clot microstructure at various time-points. Clot analogue composition was found to strongly affect the observed mechanical behavior. The SEM found that the microstructure of the clot analogues was affected by the storage solution and age of the clot. The proposed hyper-viscoelastic constitutive model was found to successfully capture the material test data. The results presented in this study are of key importance to the evaluation and future development mechanical thrombectomy devices and procedures.
Access to robust and information-rich human cardiac tissue models would accelerate drug-based strategies for treating heart disease. Despite significant effort, the generation of high-fidelity ...adult-like human cardiac tissue analogs remains challenging. We used computational modeling of tissue contraction and assembly mechanics in conjunction with microfabricated constraints to guide the design of aligned and functional 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues that we term cardiac microwires (CMWs). Miniaturization of the platform circumvented the need for tissue vascularization and enabled higher-throughput image-based analysis of CMW drug responsiveness. CMW tissue properties could be tuned using electromechanical stimuli and cell composition. Specifically, controlling self-assembly of 3D tissues in aligned collagen, and pacing with point stimulation electrodes, were found to promote cardiac maturation-associated gene expression and in vivo-like electrical signal propagation. Furthermore, screening a range of hPSC-derived cardiac cell ratios identified that 75% NKX2 Homeobox 5 (NKX2-5)+ cardiomyocytes and 25% Cluster of Differentiation 90 OR (CD90)+ nonmyocytes optimized tissue remodeling dynamics and yielded enhanced structural and functional properties. Finally, we demonstrate the utility of the optimized platform in a tachycardic model of arrhythmogenesis, an aspect of cardiac electrophysiology not previously recapitulated in 3D in vitro hPSC-derived cardiac microtissue models. The design criteria identified with our CMW platform should accelerate the development of predictive in vitro assays of human heart tissue function.
Mechanical thrombectomy can be significantly affected by the mechanical properties of the occluding thrombus. In this study, we provide the first characterisation of the volumetric behaviour of blood ...clots. We propose a new hyperelastic model for the volumetric and isochoric deformation of clot. We demonstrate that the proposed model provides significant improvements over established models in terms of accurate prediction of nonlinear stress–strain and volumetric behaviours of clots with low and high red blood cell compositions. We perform a rigorous investigation of the factors that govern clot occlusion of a tapered vessel. The motivation for such an analysis is twofold: (i) the role of clot composition on the in vivo occlusion location is an open clinical question that has significant implications for thrombectomy procedures; (ii) in vitro measurement of occlusion location in an engineered tapered tube can be used as a quick and simple methodology to assess the mechanical properties/compositions of clots. Simulations demonstrate that both isochoric and volumetric behaviours of clots are key determinants of clot lodgement location, in addition to clot-vessel friction. The proposed formulation is shown to provide accurate predictions of in vitro measurement of clot occlusion location in a silicone tapered vessel, in addition to accurately predicting the deformed shape of the clot.
Numerous experimental studies have established that cells can sense the stiffness of underlying substrates and have quantified the effect of substrate stiffness on stress fibre formation, focal ...adhesion area, cell traction, and cell shape. In order to capture such behaviour, the current study couples a mixed mode thermodynamic and mechanical framework that predicts focal adhesion formation and growth with a material model that predicts stress fibre formation, contractility, and dissociation in a fully 3D implementation. Simulations reveal that SF contractility plays a critical role in the substrate-dependent response of cells. Compliant substrates do not provide sufficient tension for stress fibre persistence, causing dissociation of stress fibres and lower focal adhesion formation. In contrast, cells on stiffer substrates are predicted to contain large amounts of dominant stress fibres. Different levels of cellular contractility representative of different cell phenotypes are found to alter the range of substrate stiffness that cause the most significant changes in stress fibre and focal adhesion formation. Furthermore, stress fibre and focal adhesion formation evolve as a cell spreads on a substrate and leading to the formation of bands of fibres leading from the cell periphery over the nucleus. Inhibiting the formation of FAs during cell spreading is found to limit stress fibre formation. The predictions of this mutually dependent material-interface framework are strongly supported by experimental observations of cells adhered to elastic substrates and offer insight into the inter-dependent biomechanical processes regulating stress fibre and focal adhesion formation.
Treatment of acute ischemic stroke has been recently improved with the introduction of endovascular mechanical thrombectomy, a minimally invasive procedure able to remove a clot using aspiration ...devices and/or stent-retrievers. Despite the promising and encouraging results, improvements to the procedure and to the stent design are the focus of the recent efforts. Computational studies can pave the road to these improvements, providing their ability to describe and accurately reproduce a real procedure. A patient with ischemic stroke due to intracranial large vessel occlusion was selected and after the creation of the cerebral vasculature from computed tomography images and a histologic analysis to determine the clot composition, the entire thrombectomy procedure was virtually replicated. As in the real situation, the computational replica showed that two attempts were necessary to remove the clot, as a result of the position of the stent retriever with respect to the clot. Furthermore, the results indicated that clot fragmentation did not occur as the deformations were mainly in a compressive state without the possibility for clot cracks to propagate. The accurate representation of the procedure can be used as an important step for operative optimization planning and future improvements of stent designs.
Numerous in-vitro studies have established that cells react to their physical environment and to applied mechanical loading. However, the mechanisms underlying such phenomena are poorly understood. ...Previous modelling of cell compression considered the cell as a passive homogenous material, requiring an artificial increase in the stiffness of spread cells to replicate experimentally measured forces. In this study, we implement a fully 3D active constitutive formulation that predicts the distribution, remodelling, and contractile behaviour of the cytoskeleton. Simulations reveal that polarised and axisymmetric spread cells contain stress fibres which form dominant bundles that are stretched during compression. These dominant fibres exert tension; causing an increase in computed compression forces compared to round cells. In contrast, fewer stress fibres are computed for round cells and a lower resistance to compression is predicted. The effect of different levels of cellular contractility associated with different cell phenotypes is also investigated. Highly contractile cells form more dominant circumferential stress fibres and hence provide greater resistance to compression. Computed predictions correlate strongly with published experimentally observed trends of compression resistance as a function of cellular contractility and offer an insight into the link between cell geometry, stress fibre distribution and contractility, and cell deformability. Importantly, it is possible to capture the behaviour of both round and spread cells using a given, unchanged set of material parameters for each cell type. Finally, it is demonstrated that stress distributions in the cell cytoplasm and nucleus computed using the active formulation differ significantly from those computed using passive material models.
Display omitted
► 3D finite element implementation of active stress fibre constitutive formulation. ► Stress fibre growth, remodelling and contractility predicted for round and spread cells. ► Dominant fibres are predicted parallel to the long axis of polarised spread cells. ► Simulated compression of contractile cells agrees with experimental data. ► Stress fibres in spread cells increase compression resistance.
Abstract Micropipette aspiration (MA) has been used extensively in biomechanical investigations of un-adhered cells suspended in media. In the current study, a custom MA system is developed to ...aspirate substrate adhered spread cells. Additionally, the system facilitates immuno-fluorescent staining of aspirated cells to investigate stress fibre redistribution and nucleus deformation during MA. In response to an applied pressure, significantly lower aspiration length is observed for untreated contractile cells compared to cells in which actin polymerisation is chemically inhibited, demonstrating the important contribution of stress fibres in the biomechanical behaviour of spread cells. Additional experiments are performed in which untreated contractile cells are subjected to a range of applied pressures. Computational finite element simulations reveal that a viscoelastic material model for the cell cytoplasm is incapable of accurately predicting the observed aspiration length over the range of applied pressures. It is demonstrated that an active computational framework that incorporates stress fibre remodelling and contractility must be used in order to accurately simulate MA of untreated spread cells. Additionally, the stress fibre distribution observed in immuno-fluorescent experimental images of aspirated cells is accurately predicted using the active stress fibre modelling framework. Finally, a detailed experimental-computational investigation of the nucleus mechanical behaviour demonstrates that the nucleus is highly deformable in cyto , reaching strain levels in excess of 100% during MA. The characterisation of stress fibres and nucleus biomechanics in spread cells presented in the current study can potentially be used to guide tissue engineering strategies to control cell behaviour and gene expression.
An acute ischaemic stroke appears when a blood clot blocks the blood flow in a cerebral artery. Intra-arterial thrombectomy, a mini-invasive procedure based on stent technology, is a mechanical ...available treatment to extract the clot and restore the blood circulation. After stent deployment, the clot, trapped in the stent struts, is pulled along with the stent towards a receiving catheter. Recent clinical trials have confirmed the effectiveness and safety of mechanical thrombectomy. However, the procedure requires further investigation. The aim of this study is the development of a numerical finite-element-based model of the thrombectomy procedure.
thrombectomy tests are performed in different vessel geometries and one simulation for each test is carried out to verify the accuracy and reliability of the proposed numerical model. The results of the simulations confirm the efficacy of the model to replicate all the experimental setups. Clot stress and strain fields from the numerical analysis, which vary depending on the geometric features of the vessel, could be used to evaluate the possible fragmentation of the clot during the procedure. The proposed
/
comparison aims at assessing the applicability of the numerical model and at providing validation evidence for the specific
thrombectomy outcomes prediction.
As a first line option in the treatment of acute ischemic stroke (AIS), direct aspiration is a fast and effective technique with promising outcomes. In silico models are widely used for design and ...preclinical assessment of new developed devices and therapeutic methods. Accurate modelling of the mechanical behaviour of blood clot is a key factor in the design and simulation of aspiration devices. In this study we develop a new constitutive model which incorporates the unrecoverable plastic deformation of clots. The model is developed based on the deformation-induced microstructural changes in fibrin network, including the formation and dissociation of the cross-links between fibrin fibres. The model is calibrated using previously reported experimentally measured permanent clot deformation following uniaxial stretching. The calibrated plasticity model is then used to simulate aspiration thrombectomy. Results reveal that inclusion of permanent plastic deformation results in ∼ 15 % increase in clot aspiration length at an applied aspiration pressure of 100 mmHg. The constitutive law developed in this study provides a basis for improved design and evaluation of novel aspiration catheters leading to increased first-pass revascularization rate.
The current study presents the development and implementation of a bespoke experimental technique to generate and characterise mode II crack initiation and propagation in arterial tissue. The current ...study begins with a demonstration that lap-shear testing of arterial tissue results in mixed mode fracture, rather than mode II. We perform a detailed computational design of a bespoke experimental method (which we refer to as a shear fracture ring test (SFRT)) to robustly and repeatably generate mode II crack initiation and propagation in arteries. This method is based on generating a localised region of high shear adjacent to a cylindrical loading bar. Placement of a radial notch in this region of high shear stress is predicted to result in a kinking of the crack during a mode II initiation and propagation of the crack over a long distance in the circumferential (c)-direction along the circumferential-axial (c-a) plane. Fabrication and experimental implementation of the SFRT on excised ovine aorta specimens confirms that the bespoke test method results in pure mode II initiation and propagation. We demonstrate that the mode II fracture strength along the c-a plane is eight times higher than the corresponding mode I strength determined from a standard peel test. We also calibrate the mode II fracture energy based on our measurement of crack propagation rates. The mechanisms of fracture uncovered in the current study, along with our quantification of mode II fracture properties have significant implications for current understanding of the biomechanical conditions underlying aortic dissection.
Display omitted
PDF
