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The heterogeneity of breast cancer (disease stage and phenotype) makes it challenging to differentiate between each subtype; luminal A, luminal B, HER2, basal-like and claudin-low, on the basis of a single gene or protein. Therefore, a collection of markers is required that can serve as a signature for diagnosing different types of breast cancer. New developments in proteomics have provided the opportunity to look at phenotype-specific breast cancer cell lines and stage-specific liquid biopsies (nipple aspirate fluid [NAF], plasma samples) to identify disease and phenotype specific signature. An 8-plex iTRAQ quantification strategy was employed to compare proteomic profiles of a range of breast cancer and ‘normal-like’ cell lines with primary breast epithelial cells. From this, 2467 proteins were identified on Orbitrap Fusion and Ultraflex II, of which 1430 were common. Matched pairs of NAF samples from four patients with different stages of breast cancer, were analysed by SCX-LC-MS and a total of 1990 unique gene products were identified. More than double the number of proteins previously published data, were detected in NAF, including 300 not detected in plasma. The NAF from the diseased patients have 138 potential phenotype biomarkers that were significantly changed compared to the healthy volunteer (7 for luminal A, 9 for luminal B, 11 for HER2, 14 for basal-like and 52 for claudin-low type). The average coefficient of variation for triplicate analyses by multiple reaction monitoring mass spectrometry (MRM-MS), was 9% in cell lines, 17 % in tissue biopsies, 22% in serum samples and 24% in NAF samples. Overall, the results provide a strong paradigm to develop a clinical assay based on proteomic changes in NAF samples for the early detection of breast cancer supplementary to established mammography programmes.

The CD-ROM disc containing supplementary material is kept in the cardboard box in the Systems Office. / The heterogeneity of breast cancer (disease stage and phenotype) makes it challenging to differentiate between each subtype; luminal A, luminal B, HER2, basal-like and claudin-low, on the basis of a single gene or protein. Therefore, a collection of markers is required that can serve as a signature for diagnosing different types of breast cancer. New developments in proteomics have provided the opportunity to look at phenotype-specific breast cancer cell lines and stage-specific liquid biopsies (nipple aspirate fluid [NAF], plasma samples) to identify disease and phenotype specific signature. An 8-plex iTRAQ quantification strategy was employed to compare proteomic profiles of a range of breast cancer and ‘normal-like’ cell lines with primary breast epithelial cells. From this, 2467 proteins were identified on Orbitrap Fusion and Ultraflex II, of which 1430 were common. Matched pairs of NAF samples from four patients with different stages of breast cancer, were analysed by SCX-LC-MS and a total of 1990 unique gene products were identified. More than double the number of proteins previously published data, were detected in NAF, including 300 not detected in plasma. The NAF from the diseased patients have 138 potential phenotype biomarkers that were significantly changed compared to the healthy volunteer (7 for luminal A, 9 for luminal B, 11 for HER2, 14 for basal-like and 52 for claudin-low type). The average coefficient of variation for triplicate analyses by multiple reaction monitoring mass spectrometry (MRM-MS), was 9% in cell lines, 17 % in tissue biopsies, 22% in serum samples and 24% in NAF samples. Overall, the results provide a strong paradigm to develop a clinical assay based on proteomic changes in NAF samples for the early detection of breast cancer supplementary to established mammography programmes. / The supplementary material submitted with the thesis is not available online.

<p>In this thesis, we unveiled the impact of fluid stratification and viscoelasticity on the transport of microorganisms and microparticles. The thesis is divided into four chapters. Chapters 2 and 3 focus on the transport of the swimming sheet in density and viscosity stratified fluids. Chapter 4 is devoted to analyze the motion of anisotropic particles in density stratified fluids. Chapter 5 focuses on the effect of viscoelasticity on the motion of a suspension of spherical particles.</p>

<p dir="ltr">Subcutaneous injection for self-administration of biotherapeutics, such as monoclonal antibodies (mAbs), is becoming increasingly prominent within the pharmaceutical sector due to its benefits in patient compliance and cost-effectiveness. The success of this drug delivery process depends on the coupled mechanical and transport phenomena within the subcutaneous tissue, both during and after the injection. Yet, the details of these processes are not well-elucidated, sparking a surge in computational efforts to fill this knowledge gap. Remarkably, there are very few computational studies on subcutaneous injection into three-dimensional porous media that account for large tissue deformations, drug transport and absorption, the use medical devices, and human factors. Here, we develop a high-fidelity computational framework to study large-volume subcutaneous injection of mAbs. Our investigation begins with a linear poroelastic model without drug transport, which we employ to study the effect of tissue deformation on injection dynamics. We progressively enhance this model, advancing to a nonlinear porohyperelastic framework that include drug transport and absorption. To capture the anisotropy of subcutaneous tissue, we employ a fibril-reinforced porohyperelastic model. Furthermore, we integrate the multi-layered structure of skin tissue by creating data-driven geometrical models of the tissue layers derived from histological data. Our analysis explores the impact of different handheld autoinjectors on the injection dynamics for various patient-applied forces. We investigate the effect of different pre-injection techniques, such as the pinch and stretch methods, on the drug transport and absorption. Additionally, we evaluate the impact of several physiological variables, including flow rate, injection depth, and body mass index. Our simulations yield crucial insights essential for comprehending and improving subcutaneous drug administration of mAbs. Additionally, they offer a deeper understanding of the human aspect of the injection procedure, thereby paving the way for advancements in the development of patient-centered injection devices and techniques.</p>

<p>The subcutaneous injection has emerged as a common approach for self-administration of biotherapeutics due to the patient comfort and cost-effectiveness. However, the available knowledge about transport and absorption of these agents after subcutaneous injection is limited. Here we aim to find drug distribution in the tissue and lymphatic uptake after subcutaneous (SC) injection. In the first part of the study, a mathematical framework to study the subcutaneous drug delivery from injection to lymphatic uptake is presented. A three-dimensional poroelastic model is exploited to find the biomechanical response of the tissue by taking into account tissue deformation during the injection. The results show that including tissue deformability noticeably changes tissue poromechanical response due to the significant dependence of interstitial pressure on tissue deformation. Moreover, the importance of the amount of lymph fluid at the injection site and injection rate on the drug uptake to lymphatic capillaries is highlighted. Finally, the variability of lymphatic uptake due to uncertainty in parameters, including tissue poromechanical and lymphatic absorption parameters, is evaluated. It is found that interstitial pressure due to injection is the major contributing factor in short-term lymphatic absorption, while the amount of lymph fluid at the site of injection determines the long-term absorption of the drug. Finally, it is shown that the lymphatic uptake results are consistent with experimental data available in the literature.</p><p>In the second part, drug transport and distribution in different tissue layers are studied. A single-layer model of the tissue as a base study was first explored. During injection, the difference between the permeability of the solvent and solute results in a higher drug concentration proportional to the inverse of the permeability ratio. Then the effects of layered tissue properties with primary layers, including epidermis, dermis, subcutaneous, and muscle layers, on tissue biomechanical response to injection and drug transport are studied. The drug distributes mainly in the SQ layer due to its lower elastic moduli. Finally, the effect of secondary tissue elements like the deep fascia layer and the network of septa fibers inside the SQ tissue is investigated. The Voronoi algorithm is exploited to create random geometry of the septa network. It is shown how drug molecules accumulate around these tissue components as observed in experimental SC injection. Next, the effect of injection rate on drug concentration is studied. Higher injection rates slightly increase the drug concentration around septa fibers. Finally, it is demonstrated that the concentration-dependent viscosity increases the concentration of biotherapeutics in the direction of septa fibers.</p><p>In the third part of this thesis, a poro-hyperelastic model of the tissue is exploited to find the biomechanical response of the tissue together with a transport model based on an advection-diffusion equation in large-deformation poro-hyperelastic Media. The process of mAbs transport to the lymphatic system is explored. This process has two major parts. First, the initial phase, where mAbs are dispersed in the tissue as a result of momentum exerted by injection. This stage last for only a few minutes after the injection. Then there is the second stage, which can take tens of hours, and as a result, monoclonal antibodies (mAbs) molecules are transported from the subcutaneous layer towards initial lymphatics in the dermis to enter the lymphatic system. In third chapter, both stages are studied. The process of plume formation, interstitial pressure, and velocity development is explored. Then the effect of the injection device, injection site, and sensitivity of long-term lymphatic uptake due to variability in permeability, diffusivity, viscosity, and binding of mAbs are investigated. Then the results are used to find an equivalent lymphatic uptake coefficient that is widely used in pharmacokinetic (PK) models to study the absorption of mAbs. We show that the injection rate is the least, and the injection site is the most important parameter in the uptake of mAbs. Injection depth and mAbs dose also significantly alter lymphatic absorption. Finally, the computational model is validated against experimental studies available in the literature.</p>

<p>This study, motivated by biomedical applications such as drug delivery and adsorption, is aimed at describing magneto- and dielectro-phoretic systems via dimensional analysis to quantitatively assess the relative contribution of hydrodynamics, electromagnetism, and particle dynamics. Magnetophoresis and dielectrophoresis, phenomena of magnetic and dielectric particle transports, respectively, have been used in various applications requiring selective collecting or separating magnetic particles, especially in microfluidic systems.</p> <p>A multiphysics computational model for a magnetophoretic system was developed to assess magnetophoretic characteristics. The magnetically induced mobility of the magnetic particles was simulated for a range of parameters relevant in biomedical applications, including the particle and fluid properties, fluid velocity, and geometries of the particle, flow channel, and magnet. With the help of dimensional analysis, dimensionless numbers were introduced to reduce the number of parameters characterizing the transport of the particles suspended in an electrically non-conducting fluid exposed to an external magnetic field. As a result, 14 relevant variables determining the particle capture were reduced to only 3 dimensionless numbers describing the magnetophoretic system. The results from multiphysics models supported this analysis, suggesting a scaling law. The functional relationship among the dimensionless numbers resulted in prediction curves to assess the particle capture. The performance of the magnetophoretic system predicted with the dimensional analysis was verified in comparison with the available experimental data. In addition, the dimensionless numbers introduced here were compared with established numbers in magnetohydrodynamics (MHD).</p> <p>These theoretical and parametrical analyses of the magnetophoretic system were applied to the novel magnetic filter proposed to capture the drug-loaded small magnetic particles (MPs) from the bloodstream during the Intra-Arterial Chemotherapy (IAC). The IAC is a preferred treatment for unresectable hepatocellular carcinoma (HCC), the primary liver cancer. In the IAC procedure, chemotherapeutic agents, e.g. doxorubicin (Dox), are administered via a catheter placed in an artery supplying the tumor. The effectiveness of the IAC, however, is limited due to the passage of excessive chemotherapy agents to the blood circulation after their effect on the tumor, causing systemic toxicity. To remove the excessive drugs, the endovascular filtration devices have been developed. The proposed magnetic filtration device could be deployed from a catheter placed in the hepatic vein or inferior vena cava (IVC) to remove the excessive Dox from the bloodstream. The Ferumoxytol approved by the FDA is one of the types of the ultrasmall superparamagnetic iron oxide (USPIO) particles. The excessive Dox-coated USPIO can be filtered by a magnetic catheter-based device generating an external magnetic field. The filter utilizing magnetic fields is a promising method for therapeutic applications since an influence of magnetic field reaches comparatively wide ranges and magnetic fields do not affect biological tissues. To optimize the design, efficacy, and performance of the proposed magnetic filtration device, numerical models were developed based on the proposed dimensionless numbers characterizing drug transport and binding. Drug adsorption can be optimized by modifying magnetic field distribution and device configuration. To enhance the filtering up to 70-80 % of the excessive drug, multi-stage filters were developed by optimizing magnet configuration and flow patterns. By decreasing the concentration of toxins in the cardiovascular system, the drug dosage can be increased while reducing side effects, thus improving the effectiveness of the IAC treatment.</p> <p>In addition, new dimensionless numbers for dielectrophoresis analogous to magnetophoresis were introduced for a range of applications. The proposed dimensionless numbers for dielectrophoresis were evaluated for several conditions and compared with the previously established numbers in electrohydrodynamics (EHD). </p> <p>This study provides a promising framework for analyzing and predicting performance of various magneto- and dielectro-phoretic systems for a range of applications, particularly in biomedicine such as –drug filtering, targeted drug delivery, or small particle separation–, thus providing a reliable methodology for predicting particle manipulation. </p>

<p dir="ltr">Fibromuscular Dysplasia (FMD) is a non-inflammatory, non-atherosclerotic blood vessel disorder characterized by a series of narrowed and dilated regions of vasculature. These patients are prescribed blood thinners or anti-platelet therapeutics as treatment to this systemic disease. Current image-based diagnostic methods cannot reliably predict a patient’s risk of stroke in order to properly manage medication. There are also challenges in distinguishing FMD from other diseases that can cause arterial obstructions, like atherosclerosis or vasculitis.</p><p dir="ltr">The ultimate goal of this research is to develop a methodology for evaluating the risk of mechanical platelet activation based on medical imaging. Our hypothesis is that subject-specific assessment of platelet activation due to hemodynamic stress can improve risk stratification of FMD patients. The aims of the projects were therefore to 1) Develop a CFD-based methodology for estimating platelet activation state, and 2) Test this methodology on a small cohort of subjects with FMD, carotid artery stenosis, and healthy controls. A modeling workflow was developed, combining Eulerian and Lagrangian approaches to compute flow fields and evaluate shear stress history of particles advected through the vascular geometries. From this stress history, predictive estimates of mechanical platelet activation can be calculated utilizing a platelet activation state (PAS) metric. We applied this modeling workflow to assess platelet activation in segments of carotid arteries of patients with Fibromuscular Dysplasia, Carotid Artery Stenosis, and healthy controls for comparison against experiments performed at the Cleveland Clinic assessing mechanical platelet activation in patients with each of these conditions. This work supports the development of a patient-specific determination of these same metrics, in order to more precisely assess patient risk of stroke.</p>

<p>Subcutaneous administration has become a common approach for drug delivery of biotherapeutics, such as monoclonal antibodies, which is achieved mainly by absorption through the lymphatic system. This dissertation focuses on the computational modeling of the fluid flow and solute transport in the skin tissue and the quantitative investigation of lymphatic uptake. First, the various mechanisms governing drug transport and lymphatic uptake of biotherapeutics through subcutaneous injection are investigated quantitatively through high-fidelity numerical simulations, including lymphatic drainage, blood perfusion, binding, and metabolism. The tissue is modeled as a homogeneous porous medium using both a single-layered domain and a multi-layered domain, which includes the epidermis, dermis, hypodermis (subcutaneous tissue), and muscle layers. A systematic parameter study is conducted to understand the roles of different properties of the tissue in terms of permeability, porosity, and vascular permeability. The role of binding and metabolism on drug absorption is studied by varying the binding parameters for different macromolecules after coupling the transport equation with a pharmacokinetic equation. The interstitial pressure plays an essential role in regulating the absorption of unbound drug proteins during the injection, while the binding and metabolism of drug molecules reduce the total free drugs. </p> <p>  </p> <p>The lymphatic vessel network is essential to achieve the functions of the lymphatic system. Thus, the drug transport and lymphatic uptake through a three-dimensional hybrid discrete-continuum vessel network in the skin tissue are investigated through high-fidelity numerical simulations. The explicit heterogeneous vessel network is embedded into the continuum model to investigate the role of explicit heterogeneous vessel network in drug transport and absorption. The solute transport across the vessel wall is investigated under various transport conditions. The diffusion of the drug solutes through the explicit vessel wall affects the drug absorption after the injection, while the convection under large interstitial pressure dominates the drug absorption during the injection. The effect of diffusion cannot be captured by the previously developed continuum model. Furthermore, the effects of injection volume and depth on the lymphatic uptake are investigated in a multi-layered domain. The injection volume significantly affects lymphatic uptake through the heterogeneous vessel network, while the injection depth has little influence. At last, the binding and metabolism of drug molecules are studied to bridge the simulation to the experimentally measured drug clearance. </p> <p><br></p> <p>Convective transport of drug solutes in biological tissues is regulated by the interstitial fluid pressure, which plays a crucial role in drug absorption into the lymphatic system through the subcutaneous (SC) injection.  An approximate continuum poroelasticity model is developed to simulate the pressure evolution in the soft porous tissue during an SC injection. This poroelastic model mimics the deformation of the tissue by introducing the time variation of the interstitial fluid pressure. The advantage of this method lies in its computational time efficiency and simplicity, and it can accurately model the relaxation of pressure. The interstitial fluid pressure obtained using the proposed model is validated against both the analytical and the numerical solution of the poroelastic tissue model. The decreasing elasticity elongates the relaxation time of pressure, and the sensitivity of pressure relaxation to elasticity decreases with the hydraulic permeability, while the increasing porosity and permeability due to deformation alleviate the high pressure. </p> <p><br></p> <p>At last, an improved Kedem-Katchalsky model is developed to study solute transport across the lymphatic vessel network, including convection and diffusion in the multi-layered poroelastic tissue with a hybrid discrete-continuum vessel network embedded inside. The effect of different drug solutes with different Stokes radii and different structures of the lymphatic vessel network, such as fractal trees and Voronoi structure, on the lymphatic uptake is investigated. The drug solute with a small size has a larger partition coefficient and diffusivity across the openings of the lymphatic vessel wall, which favors drug absorption. The Voronoi structure is found to be more efficient in lymphatic uptake. </p> <p><br></p> <p>The systematic and quantitative investigation of subcutaneous absorption based on high-fidelity numerical simulations can provide guidance on the optimization of drug delivery systems and is valuable for the translation of bioavailability from the pre-clinical species to humans. We provide a novel approach to studying the diffusion and convection of drug molecules into the lymphatic system by developing the hybrid discrete-continuum vessel network. The study of the solute transport across the discrete lymphatic vessel walls further improves our understanding of lymphatic uptake. The novel and time-efficient computational model for solute transport across the lymphatic vasculature connects the microscopic properties of the lymphatic vessel membrane to macroscopic drug absorption. The comprehensive hybrid vessel network model developed here can be further used to improve our understanding of the diseases caused by the disturbed lymphatic system, such as lymphedema, and provide insights into the treatment of diseases caused by the malfunction of lymphatics.</p>