Modeling transit time distributions in microvascular networks.

The time a red blood cell (RBC) spends in the microvasculature is of prime importance for a number of physiological processes. In this work, we present a methodology for computing an approximation of the so-called transit time distribution (TTD), i.e., the probabilistic description of how long a RBC will reside within the network. As a proof of concept, we apply this methodology to three flavors of the mesh networks. We show that each network type supports multiple distinct steady-state configurations and we present tools for analyzing the associated collection of TTDs, ranging from standard measures like mean capillary transit time (MCTT) and capillary transit time heterogeneity (CTTH) to novel metrics.

Model Microvascular Networks Can Have Many Equilibria.

We show that large microvascular networks with realistic topologies, geometries, boundary conditions, and constitutive laws can exhibit many steady-state flow configurations. This is in direct contrast to most previous studies which have assumed, implicitly or explicitly, that a given network can only possess one equilibrium state. While our techniques are general and can be applied to any network, we focus on two distinct network types that model human tissues: perturbed honeycomb networks and random networks generated from Voronoi diagrams. We demonstrate that the disparity between observed and predicted flow directions reported in previous studies might be attributable to the presence of multiple equilibria. We show that the pathway effect, in which hematocrit is steadily increased along a series of diverging junctions, has important implications for equilibrium discovery, and that our estimates of the number of equilibria supported by these networks are conservative. If a more complete description of the plasma skimming effect that captures red blood cell allocation at junctions with high feed hematocrit were to be obtained empirically, then the number of equilibria found by our approach would at worst remain the same and would in all likelihood increase significantly.

Oscillations and Multiple Equilibria in Microvascular Blood Flow.

We investigate the existence of oscillatory dynamics and multiple steady-state flow rates in a network with a simple topology and in vivo microvascular blood flow constitutive laws. Unlike many previous analytic studies, we employ the most biologically relevant models of the physical properties of whole blood. Through a combination of analytic and numeric techniques, we predict in a series of two-parameter bifurcation diagrams a range of dynamical behaviors, including multiple equilibria flow configurations, simple oscillations in volumetric flow rate, and multiple coexistent limit cycles at physically realizable parameters. We show that complexity in network topology is not necessary for complex behaviors to arise and that nonlinear rheology, in particular the plasma skimming effect, is sufficient to support oscillatory dynamics similar to those observed in vivo.

Observations of spontaneous oscillations in simple two-fluid networks.

We investigate the laminar flow of two-fluid mixtures inside a simple network of interconnected tubes. The fluid system is composed of two miscible Newtonian fluids of different viscosity which do not mix and remain as nearly distinct phases. Downstream of a diverging network junction the two fluids do not necessarily split in equal fraction and thus heterogeneity is introduced into network. We find that in the simplest network, a single loop with one inlet and one outlet, under steady inlet conditions, the flow rates and distribution of the two fluids within the network loop can undergo persistent spontaneous oscillations. We develop a simple model which highlights the basic mechanism of the instability and we demonstrate that the model can predict the region of parameter space where oscillations exist. The model predictions are in good agreement with experimental observations.

Stability of a microvessel subject to structural adaptation of diameter and wall thickness.

Vascular adaptation--or structural changes of microvessels in response to physical and metabolic stresses--can influence physiological processes like angiogenesis and hypertension. To better understand the influence of these stresses on adaptation, Pries et al. (1998, 2001a,b, 2005) have developed a computational model for microvascular adaptation. Here, we reformulate this model in a way that is conducive to a dynamical systems analysis. Using th ese analytic methods, we determine the equilibrium geometries of a single vessel under different conditions and classify its type of stability. We demonstrate that our closed-form solution for vessel geometry exhibits the same regions of stability as the numerical predictions of Pries et al. (2005, Remodeling of blood vessels: responses of diameter and wall thickness to hemodynamic and metabolic stimuli. Hypertension, 46, 725-731). Our analytic approach allows us to predict the existence of limit-cycle oscillations and to extend the model to consider a fixed pressure across the vessel in addition to a fixed flow. Under these fixed pressure conditions, we show that the vessel stability is affected and that the multiple equilibria can exist.

Multiple equilibrium states in a micro-vascular network.

We use a simple model of micro-vascular blood flow to explore conditions that give rise to multiple equilibrium states in a three-node micro-vascular network. The model accounts for two primary rheological effects: the Fåhraeus-Lindqvist effect, which describes the apparent viscosity of blood in a vessel, and the plasma skimming effect, which governs the separation of red blood cells at diverging nodes. We show that multiple equilibrium states are possible, and we use our analytical and computational tools to design an experiment for validation.

Bistability in a simple fluid network due to viscosity contrast.

We study the existence of multiple equilibrium states in a simple fluid network using Newtonian fluids and laminar flow. We demonstrate theoretically the presence of hysteresis and bistability, and we confirm these predictions in an experiment using two miscible fluids of different viscosity-sucrose solution and water. Possible applications include blood flow, microfluidics, and other network flows governed by similar principles.

Blood flow in microvascular networks: a study in nonlinear biology.

Plasma skimming and the Fahraeus-Lindqvist effect are well-known phenomena in blood rheology. By combining these peculiarities of blood flow in the microcirculation with simple topological models of microvascular networks, we have uncovered interesting nonlinear behavior regarding blood flow in networks. Nonlinearity manifests itself in the existence of multiple steady states. This is due to the nonlinear dependence of viscosity on blood cell concentration. Nonlinearity also appears in the form of spontaneous oscillations in limit cycles. These limit cycles arise from the fact that the physics of blood flow can be modeled in terms of state dependent delay equations with multiple interacting delay times. In this paper we extend our previous work on blood flow in a simple two node network and begin to explore how topological complexity influences the dynamics of network blood flow. In addition we present initial evidence that the nonlinear phenomena predicted by our model are observed experimentally.

Oscillations in a simple microvascular network.

We have identified the simplest topology that will permit spontaneous oscillations in a model of microvascular blood flow that includes the plasma skimming effect and the Fahraeus-Lindqvist effect and assumes that the flow can be described by a first-order wave equation in blood hematocrit. Our analysis is based on transforming the governing partial differential equations into delay differential equations and analyzing the associated linear stability problem. In doing so we have discovered three dimensionless parameters, which can be used to predict the occurrence of nonlinear oscillations. Two of these parameters are related to the response of the hydraulic resistances in the branches to perturbations. The other parameter is related to the amount of time necessary for the blood to pass through each of the branches. The simple topology used in this study is much simpler than networks found in vivo. However, we believe our analysis will form the basis for understanding more complex networks.