Abstract:This work proposes a model of particle agglomeration in elastic valves replicating the geometry and the fluid dynamics of a venous valve. The fluid dynamics is simulated with Smooth Particle Hydrodynamics, the elastic leaflets of the valve with the Lattice Spring Model, while agglomeration is modelled with a 4-2 Lennard-Jones potential. All the models are combined together within a single Discrete Multiphysics framework. The results show that particle agglomeration occurs near the leaflets, supporting the hypo… Show more
“…Fluid inside the colon: SPH particles (liquid) Membrane: LSM particles (solid) "drain tank" "DCMDT" Further details on the DT and the simulation parameters are given in Section 2.2.2. For a general overview on the DMP theory and how it can be applied to a variety of applications such as biological flows and/or fluid-structure interactions [3,5,[21][22][23][24][25][26][27], solidification and dissolution [28][29][30], machine learning [31,32], and composite materials [33], the reader can refer to the available literature (e.g., DMP: [17,18], SPH: [34], LSM: [35][36][37]). For technical details and how it is applied to the large intestine, the reader is referred to Refs.…”
The performance of solid oral dosage forms targeting the colon is typically evaluated using standardised pharmacopeial dissolution apparatuses. However, these fail to replicate colonic hydrodynamics. This study develops a digital twin of the Dynamic Colon Model; a physiologically representative in vitro model of the human proximal colon. Magnetic resonance imaging of the Dynamic Colon Model verified that the digital twin robustly replicated flow patterns under different physiological conditions (media viscosity, volume, and peristaltic wave speed). During local contractile activity, antegrade flows of 0.06–0.78 cm s−1 and backflows of −2.16–−0.21 cm s−1 were measured. Mean wall shear rates were strongly time and viscosity dependent although peaks were measured between 3.05–10.12 s−1 and 5.11–20.34 s−1 in the Dynamic Colon Model and its digital twin respectively, comparable to previous estimates of the USPII with paddle speeds of 25 and 50 rpm. It is recommended that viscosity and shear rates are considered when designing future dissolution test methodologies for colon-targeted formulations. In the USPII, paddle speeds >50 rpm may not recreate physiologically relevant shear rates. These findings demonstrate how the combination of biorelevant in vitro and in silico models can provide new insights for dissolution testing beyond established pharmacopeial methods.
“…Fluid inside the colon: SPH particles (liquid) Membrane: LSM particles (solid) "drain tank" "DCMDT" Further details on the DT and the simulation parameters are given in Section 2.2.2. For a general overview on the DMP theory and how it can be applied to a variety of applications such as biological flows and/or fluid-structure interactions [3,5,[21][22][23][24][25][26][27], solidification and dissolution [28][29][30], machine learning [31,32], and composite materials [33], the reader can refer to the available literature (e.g., DMP: [17,18], SPH: [34], LSM: [35][36][37]). For technical details and how it is applied to the large intestine, the reader is referred to Refs.…”
The performance of solid oral dosage forms targeting the colon is typically evaluated using standardised pharmacopeial dissolution apparatuses. However, these fail to replicate colonic hydrodynamics. This study develops a digital twin of the Dynamic Colon Model; a physiologically representative in vitro model of the human proximal colon. Magnetic resonance imaging of the Dynamic Colon Model verified that the digital twin robustly replicated flow patterns under different physiological conditions (media viscosity, volume, and peristaltic wave speed). During local contractile activity, antegrade flows of 0.06–0.78 cm s−1 and backflows of −2.16–−0.21 cm s−1 were measured. Mean wall shear rates were strongly time and viscosity dependent although peaks were measured between 3.05–10.12 s−1 and 5.11–20.34 s−1 in the Dynamic Colon Model and its digital twin respectively, comparable to previous estimates of the USPII with paddle speeds of 25 and 50 rpm. It is recommended that viscosity and shear rates are considered when designing future dissolution test methodologies for colon-targeted formulations. In the USPII, paddle speeds >50 rpm may not recreate physiologically relevant shear rates. These findings demonstrate how the combination of biorelevant in vitro and in silico models can provide new insights for dissolution testing beyond established pharmacopeial methods.
“…In a recently published elegant study ( 28 ), authors demonstrated the initial formation of fibrin gel, followed by accumulation and activation of procoagulant platelets and thrombus growth in a microfluidics device, which combines biological (blood, tissue factor) and hemodynamic factors (valve leaflets steadily fixed at different angles) inducing thrombosis in a vein. We have recently reported a new microfluidics model with mobile valves and a pulsatile flow pattern typical for veins ( 29 ) and was validated by our in silico model ( 30 ). In the present study, we have developed a method to grow human endothelial cells on the entire surface of the channel including valve leaflets (Cellular Elastic Vein Valve model, CEVV chip).…”
Deep vein thrombosis is a life-threatening disease that takes millions of people's lives worldwide. Given both technical and ethical issues of using animals in research, it is necessary to develop an appropriate in vitro model that would recapitulate the conditions of venous thrombus development. We present here a novel microfluidics vein-on-a-chip with moving valve leaflets to mimic the hydrodynamics in a vein, and Human Umbilical Vein Endothelial Cell (HUVEC) monolayer. A pulsatile flow pattern, typical for veins, was used in the experiments. Unstimulated human platelets, reconstituted with the whole blood, accumulated at the luminal side of the leaflet tips proportionally to the leaflet flexibility. Platelet activation by thrombin induced robust platelet accrual at the leaflet tips. Inhibition of glycoprotein (GP) IIb-IIIa did not decrease but, paradoxically, slightly increased platelet accumulation. In contrast, blockade of the interaction between platelet GPIbα and A1 domain of von Willebrand factor completely abolished platelet deposition. Stimulation of the endothelium with histamine, a known secretagogue of Weibel-Palade bodies, promoted platelet accrual at the basal side of the leaflets, where human thrombi are usually observed. Thus, platelet deposition depends on the leaflet flexibility, and accumulation of activated platelets at the valve leaflets is mediated by GPIbα-VWF interaction.
“…This study uses a simulation technique called Discrete Multiphysics (DMP) (Alexiadis, 2015(Alexiadis, , 2014. DMP is a mesh-free technique that uses computational particles instead of computational grids and has been successfully used to model human organs: Ariane et al (2017aAriane et al ( , 2018aAriane et al ( , 2018bAriane et al ( , 2017b, Baksamawi et al (2021), Mohammed et al (2020Mohammed et al ( , 2021, Alexiadis (2015bAlexiadis ( , 2015aAlexiadis ( , 2019, Alexiadis et al (2017), and Schütt et al (2021, 2022. It couples particle-based methods such as Smoothed Particle Hydrodynamics (SPH), Lattice Spring Model (LSM), and Discrete Element Method (DEM) and Peridynamics (Sanfilipo et al, 2021).…”
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