An Introductory Module in Medical Image Segmentation for BME Students

To support recent trends toward the use of patient-specific anatomical models from medical imaging data, we present a learning module for use in the undergraduate BME curriculum that introduces image segmentation, the process of partitioning digital images to isolate specific anatomical features. Five commercially available software packages were evaluated based on their perceived learning curve, ease of use, tools for segmentation and rendering, special tools, and cost: ITK-SNAP, 3D Slicer, OsiriX, Mimics, and Amira. After selecting the package best suited for a stand-alone course module on medical image segmentation, instructional materials were developed that included a general introduction to imaging, a tutorial guiding students through a step-by-step process to extract a skull from a provided stack of CT images, and a culminating assignment where students extract a different body part from clinical imaging data. This module was implemented in three different engineering courses, impacting more than 150 students, and student achievement of learning goals was assessed. ITK-SNAP was identified as the best software package for this application because it is free, easiest to learn, and includes a powerful, semi-automated segmentation tool. After completing the developed module based on ITK-SNAP, all students attained sufficient mastery of the image segmentation process to independently apply the technique to extract a new body part from clinical imaging data. This stand-alone module provides a low-cost, flexible way to bring the clinical and industry trends combining medical image segmentation, CAD, and 3D printing into the undergraduate BME curriculum

Computational simulations of the effects of gravity on lymphatic transport

Physical forces, including mechanical stretch, fluid pressure and shear forces alter lymphatic vessel contractions and lymph flow. Gravitational forces can affect these forces, resulting in altered lymphatic transport, but the mechanisms involved have not been studied in detail. Here, we combine a lattice Boltzmann-based fluid dynamics computational model with known lymphatic mechanobiological mechanisms to investigate the movement of fluid through a lymphatic vessel under the effects of gravity that may either oppose or assist flow. Regularly spaced, mechanical bi-leaflet valves in the vessel enforce net positive flow as the vessel walls contract autonomously in response to calcium and nitric oxide (NO) levels regulated by vessel stretch and shear stress levels. We find that large gravitational forces opposing flow can stall the contractions, leading to no net flow, but transient mechanical perturbations can reestablish pumping. In the case of gravity strongly assisting flow, the contractions also cease due to high shear stress and NO production, which dilates the vessel to allow gravity-driven flow. In the intermediate range of oppositional gravity forces, the vessel actively contracts to offset nominal gravity levels or to modestly assist the favorable hydrostatic pressure gradients

The Effects of Gravity and Compression on Interstitial Fluid Transport in the Lower Limb

Edema in the limbs can arise from pathologies such as elevated capillary pressures due to failure of venous valves, elevated capillary permeability from local inflammation, and insufficient fluid clearance by the lymphatic system. The most common treatments include elevation of the limb, compression wraps and manual lymphatic drainage therapy. To better understand these clinical situations, we have developed a comprehensive model of the solid and fluid mechanics of a lower limb that includes the effects of gravity. The local fluid balance in the interstitial space includes a source from the capillaries, a sink due to lymphatic clearance, and movement through the interstitial space due to both gravity and gradients in interstitial fluid pressure (IFP). From dimensional analysis and numerical solutions of the governing equations we have identified several parameter groups that determine the essential length and time scales involved. We find that gravity can have dramatic effects on the fluid balance in the limb with the possibility that a positive feedback loop can develop that facilitates chronic edema. This process involves localized tissue swelling which increases the hydraulic conductivity, thus allowing the movement of interstitial fluid vertically throughout the limb due to gravity and causing further swelling. The presence of a compression wrap can interrupt this feedback loop. We find that only by modeling the complex interplay between the solid and fluid mechanics can we adequately investigate edema development and treatment in a gravity dependent limb

Role of Vascular Normalization in Benefit from Metronomic Chemotherapy

Metronomic dosing of chemotherapy—defined as frequent administration at lower doses—has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor–drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy

Synchronization and Random Triggering of Lymphatic Vessel Contractions

The lymphatic system is responsible for transporting interstitial fluid back to the bloodstream, but unlike the cardiovascular system, lacks a centralized pump-the heart–to drive flow. Instead, each collecting lymphatic vessel can individually contract and dilate producing unidirectional flow enforced by intraluminal check valves. Due to the large number and spatial distribution of such pumps, high-level coordination would be unwieldy. This leads to the question of how each segment of lymphatic vessel responds to local signals that can contribute to the coordination of pumping on a network basis. Beginning with elementary fluid mechanics and known cellular behaviors, we show that two complementary oscillators emerge from i) mechanical stretch with calcium ion transport and ii) fluid shear stress induced nitric oxide production (NO). Using numerical simulation and linear stability analysis we show that the newly identified shear-NO oscillator shares similarities with the well-known Van der Pol oscillator, but has unique characteristics. Depending on the operating conditions, the shear-NO process may i) be inherently stable, ii) oscillate spontaneously in response to random disturbances or iii) synchronize with weak periodic stimuli. When the complementary shear-driven and stretch-driven oscillators interact, either may dominate, producing a rich family of behaviors similar to those observed in vivo

Reply to Davis: Nitric Oxide Regulates Lymphatic Contractions

We appreciate the opportunity to respond to Michael J. Davis’s Letter (1) regarding our paper “Mechanobiological Oscillators Control Lymph Flow” (2). Our model was developed to study phasic contractions and the dynamics of NO and calcium rather than the control of basal tone. Many factors—in addition to NO—affect lymphatic baseline diameter, including inflammatory cytokines and hormones, and the mechanical properties of the surrounding tissue. On the other hand, there are few mechanisms that operate at the short timescales required for the phasic contractions. Our simulations show that NO and Ca2+ are sufficient to drive these phasic contractions and that mechanobiological regulation of their levels provides intrinsic feedback