MULTISCALE COMPUTATIONAL MODELING OF VASCULAR-INTERSTITIAL TRANSPORT IN THE BRAIN AND SUBCUTANEOUS TISSUE

<pre>The transport of fluids and solutes across vascular and interstitial spaces is fundamental to physiological functionality, disease progression, and therapeutic delivery. Disruption of this transport causes disease like lymphedema and Alzheimer's disease, while therapeutic delivery often relies on effective vascular-interstitial transport. This dissertaion develops multiscale and multiphysics models to study vascular-interstitial fluid and solute transport in three representative systems: lymphatic uptake, subcutaneous delivery of monoclonal antibodies, and interstitial transport in the brain. The first study focuses on the hydrodynamics of lymphatic uptake, where poroelastic tissue and initial lymphatics are explicitly coupled. The model quantifies how interstitial pressure, downstream pressure oscillations, and tissue deformation govern fluid entry into the lymphatic system. The results indicate that lymphatic uptake increases with the amplitude of the oscillating downstream pressure when the amplitude exceeds a threshold. Additionally, deformation of the surrounding tissue alters the interstitial pressure and the cross-sectional area of initial lymphatics, leading to variations in lymphatic uptake. The model suggests that uptake reaches its maximum when the tissue has positive volumetric strain while being compressed. Intersection angles and positions of initial lymphatics show minor impacts, while the uptake per unit length decreases with the total length of initial lymphatics. The second study investigates the transport of monoclonal antibodies through skin tissue and initial lymphatics, which impacts the pharmacokinetics of monoclonal antibodies. The model integrates a macroscale representation of the entire skin tissue with a mesoscale model that focuses on the papillary dermis layer. Our results indicate that it takes hours for the drugs to disperse from the injection site to the papillary dermis before entering the initial lymphatics. Additionally, we observe an inhomogeneous drug distribution in the interstitial space of the papillary dermis, with higher drug concentrations near initial lymphatics and lower concentrations near blood capillaries. To validate our model, we compared our numerical simulation results with experimental data, finding a good alignment. Our parametric studies on the drug molecule properties and injection parameters suggest that a higher diffusion coefficient increases the transport and uptake rate while binding slows down these processes. Furthermore, shallower injection depths lead to faster lymphatic uptake, whereas a larger injection plume size expands the drug plume closer to the initial lymphatics, leading to an earlier peak of lymphatic uptake rate. The third study explores the convective transport mechanism through brain tissue, which has implications for both brain waste clearance and drug delivery. We propose a multiphysics model that incorporates the poroelastic nature of brain tissue, capturing the dynamic interactions between periarterial and perivenous spaces. Our results demonstrate that net glymphatic flow sweeps from periarterial space across parenchyma and is modulated by the periarterial-perivenous interactions, leading to higher pressure in periarterial space that drives unidirectional bulk transport from periarterial space to perivenous space. We also show that brain tissue stiffness presents a non-monotonic effect on both the glymphatic transport and its efficiency, with their respective peaks occurring at different stiffness values. Notably, the glymphatic convection rate peaks at physiologically relevant levels of brain stiffness. Furthermore, phase-delayed venous vasomotion is found to enhance glymphatic flow. Collectively, these studies establish mechanistic frameworks for vascular-interstitial transport that bridges tissue mechanics, vascular dynamics, and solute movement across scales. The findings deepen our understanding of physiological transport mechanisms and provide quantitative insights for improving therapeutic delivery and interpretability of disease-related transport dysfunctions.</pre><p></p>