Computational Analysis of Solid Tumor Oxygenation Facilitated by Polymerized Human Hemoglobins
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Date
2017-03
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Abstract
In the U.S., over 60% of patients diagnosed with stage III and IV solid tumors will undergo chemo- and/or radio-therapy during the course of their treatment. A major constraint in chemo-and radio-therapeutic cancer treatment is inadequate oxygenation of solid tumors. Hypoxic conditions in the tumor microenvironment induce quiescence in cancer cells, which reduces the effectiveness of cancer therapies. Consequently, alleviating hypoxia in solid tumors is considered a promising target for improving the efficacy of anti-cancer therapeutics. Polymerized human hemoglobin (PolyhHb) can be transfused to increase solid tumor oxygenation and improve the efficacy of anti-cancer therapeutics. In this study, we analyzed the biophysical properties of synthesized PolyhHbs with low and high oxygen (O2) affinity. Transfusion of PolyhHbs may alter microvascular hemodynamics, which could improve O2 transport into the tumor. We hypothesize that in silico models of the tumor microenvironment may be used to guide the dosage and type of PolyhHb as a function of tumor O2 consumption and O2 tension. yield low and high affinity PolyhHbs respectively, we first polymerized tense (T) and relaxed (R) state PolyhHb via glutaraldehyde as described previously. The diameter, cooperativity, O2 tension at 50% saturation (p50), and rapid offloading kinetics were each analyzed. The resulting biophysical parameters were used to populate a finite element multiphysics arteriole model in COMSOL. Here, blood fluid flow was modeled with the Quemeda constitutive law and the radius of the red blood cell rich core was approximated from experimental data. Starling flow was modeled with Brinkman’s equation for flow through the blood vessel wall and tissue space. The O2 equilibrium for all hemoglobin species was handled with the Hill Equation. In the simulation, we modeled PolyhHb delivery as an exchange transfusion. The inlet partial pressure of dissolved O2 (pO2,in) was varied from normal conditions (90 mm Hg) to hypoxic conditions (1 mm Hg). In addition, diameter of the arteriole, maximum rate of O2 consumption, and thickness of the tissue space were each varied. The fluid velocity profiles, apparent viscosity, wall shear stress, O2 distributions, O2 flux, and model sensitivity were each analyzed. We found that increasing the percent exchange transfusion of PolyhHb may decrease the apparent viscosity of blood in the arteriole. In addition, we found that PolyhHb transfusion decreased the wall shear stress at large diameters (> 20 μm) but increases wall shear stress for small diameters (< 10 μm). Both T- and R-state PolyhHb exchange transfusion may lead to elevated O2 delivery at low pO2,in. In addition, R-state PolyhHb exchange transfusion may be more effective than T-state PolyhHb at similar exchange volumes. The pO2 pressure drop per unit length signifies that while the O2 flux across the vessel wall is similar at high pO2,in, there is significantly more O2 lost at high pO2s but more O2 retained at low pO2s. At low pO2,in the radius of the arteriole had the greatest effect on O2 delivery. At high pO2,in the maximum rate of O2 consumption had the greatest effect on O2 delivery. Interestingly, R-state PolyhHb is much less sensitive to arteriole radius than T-state PolyhHb under hypoxic conditions ( < 10 mm Hg). Decreases in the apparent viscosity resulting from PolyhHb exchange transfusion may result in significant changes in flow distributions throughout the tumor microcirculatory network. The difference in wall shear stress implies that PolyhHb may have a more significant effect on capillary beds. The increased O2 flux and decreased pO2 drop per unit length indicates that both PolyhHbs are suited to deliver O2 under hypoxic conditions. However, the hypoxic volumes estimated here are inconsistent with the literature. This indicates that the assumptions in the Krogh tissue cylinder model may not adequately describe the tumor microenvironment. The system was more sensitive to changes in the tumor microenvironment than to the PolyhHb which indicates that a more descriptive model should be developed to match results from previous studies.
Description
Poster Division: Engineering, Math, and Physical Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Hemoglobin, tumor, hypoxia, hemoglobin based oxygen carrier, Krogh Tissue Cylinder