Lattice Kinetic Monte Carlo Simulations of Platelet Aggregation and Deposition

Platelet aggregation is an essential process in forming a stable clot to prevent blood loss. The response of platelets to a complex signal of pro-clotting agonists determines the stability and size of the resulting clot. An underdeveloped clot represents a bleeding risk, while an overdeveloped clot can cause vessel occlusion, which can lead to heart attack or stroke. A multiscale model was developed to study the integration of platelet signaling within the complex phenomena driven by flow. The model is built upon a lattice kinetic Monte Carlo algorithm (LKMC) to track platelet motion and binding. First, a new method for including flow-driven particle motion in LKMC was derived from a timescale analysis of particle motion. Simple methods for simulating flow-driven motion were found to exhibit concentration dependent velocities violating the assumptions in the model. The nature of the error was analyzed mathematically and resolved by considering the chain length distribution on the lattice. The accuracy of the method was found to scale linearly with the lattice spacing. Second, the LKMC method was extended to study particle aggregation in complex flows. The LKMC results for simple flows were compared directly to a continuum population balance equation (PBE) approach. A contact time model was introduced to capture nonideal collisions in the LKMC model and a connection to the continuum collision efficiency was derived. The particle size distribution for a baffled geometry with regions of standing vortices and squeezing flows was determined using the LKMC method for varying baffle heights. Finally, the LKMC method was incorporated within a multiscale model to simulate platelet aggregation including platelet signaling (neural network model), blood flow (lattice Boltzmann method), and the release of soluble platelet agonists (finite element method). The neural network model for platelet signaling was trained on patient-specific, experimental measurements of intracellular calcium enabling patient-specific predictions of platelet function in flow. The model accurately predicted the order of potency for three antiplatelet therapies, donor-specific aggregate size, and donor-specific response to antiplatelet therapy as compared to microfluidic experiments of platelet aggregation

Detailed population balance modelling of industrial titania synthesis

This thesis presents an efficient and robust detailed population balance framework for simulating aerosol synthesis of structured particles using a stochastic method. This is developed in the context of the industrial titania (TiO2) process to enable extensive numerical characterisation of the pigmentary product. A reactor network model is used to provide a modular treatment of the reactor and account for key features, including multiple reactant injections, and tubular reaction and cooling zones. This approach simplifies the flow field in order to focus computational effort on resolving particle structure using a high-dimensional particle model and its modularity offers flexibility to investigate different configurations. Initial results are presented using a pre-defined temperature profile in the network, and the particulate product is characterised by its property distributions. Numerical performance is studied, highlighting the high computational cost of simulating strong phase-coupling, fast process rates, and broad particle size distributions. A novel hybrid particle model is developed to address these challenges. The hybrid particle model employs a univariate description of small particles and switches to a detailed particle model to resolve morphology of more complicated, aggregate particles. New simulation algorithms are presented to manage interactions between particles of each type. The hybrid model is shown to improve efficiency (resolution versus computational cost) and robustness (sensitivity to numerical parameters), while generating the same solutions and convergence behaviour as earlier models. The reactor model is extended, utilizing the superior numerical performance of the new hybrid particle model to enable inclusion of a system energy balance for more accurate study of a broad range of process conditions, and a more sophisticated particle model to resolve particle geometry. These contributions facilitate the study of particle structure and its sensitivity to reactor design and operational choices, providing insight into how operation affects characteristics of the particles and allowing direct comparison with experimental images of the pigmentary product.This research was supported by the National Research Foundation, Prime Minister's Office, Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) programme, and by Venator

A modeling-based assessment of acousto-optic sensing for monitoring high-intensity focused ultrasound lesion formation

Real-time acousto-optic (AO) sensing - a dual-wave modality that combines ultrasound with diffuse light to probe the optical properties of turbid media - has been demonstrated to non-invasively detect changes in ex vivo tissue optical properties during high-intensity focused ultrasound (HIFU) exposure. The AO signal indicates the onset of lesion formation and predicts resulting lesion volumes. Although proof-of-concept experiments have been successful, many of the underlying parameters and mechanisms affecting thermally induced optical property changes and the AO detectability of HIFU lesion formation are not well understood. In thesis, a numerical simulation was developed to model the AO sensing process and capture the relevant acoustic, thermal, and optical transport processes. The simulation required data that described how optical properties changed with heating. Experiments were carried out where excised chicken breast was exposed to thermal bath heating and changes in the optical absorption and scattering spectra (500 nm - 1100 nm) were measured using a scanning spectrophotometer and an integrating sphere assembly. Results showed that the standard thermal dose model currently used for guiding HIFU treatments needs to be adjusted to describe thermally induced optical property changes. To model the entire AO process, coupled models were used for ultrasound propagation, tissue heating, and diffusive light transport. The angular spectrum method was used to model the acoustic field from the HIFU source. Spatial-temporal temperature elevations induced by the absorption of ultrasound were modeled using a finite-difference time-domain solution to the Pennes bioheat equation. The thermal dose model was then used to determine optical properties based on the temperature history. The diffuse optical field in the tissue was then calculated using a GPU-accelerated Monte Carlo algorithm, which accounted for light-sound interactions and AO signal detection. The simulation was used to determine the optimal design for an AO guided HIFU system by evaluating the robustness of the systems signal to changes in tissue thickness, lesion optical contrast, and lesion location. It was determined that AO sensing is a clinically viable technique for guiding the ablation of large volumes and that real-time sensing may be feasible in the breast and prostate