Rheological Aspect of Cell-Free Layer Formation in Micro-blood Flow: Experimental and Numerical Study

Ph.DDOCTOR OF PHILOSOPH

Effect of Cell-Free Layer Variation on Arteriolar Wall Shear Stress

Relationship between a cell-free layer and wall shear stress (WSS) in small arterioles has been of interest in microcirculatory research. However, influence of temporal variation in the cell-free layer width on the WSS in vivo has not been fully elucidated. In this study, we tested the hypothesis that the layer variation would increase the WSS, and this effect would be enhanced by red blood cell aggregation. The cell-free layer width in arterioles (29.5–67.1 μm ID) in rat cremaster muscles were obtained with a high-speed video camera, and the layer width data were introduced into WSS estimation. Dextran 500 was administrated to elevate the aggregation level of red blood cells to those seen in normal human blood. The variation of the layer was quantified by the variability (coefficient of variation), and its effect on WSS was studied under normal and reduced flow conditions. We found that the dextran-induced red blood cell aggregation significantly elevated the variability (p < 0.01) at low pseudoshear rates of 9.2 ± 0.6 s−1. The WSS estimated without taking account of the variability showed underestimation of its value than that of with consideration of the variability under all flow conditions, and this effect became more pronounced with increasing the variability. The variation of the cell-free layer should, therefore, be considered in the determination of the WSS particularly in the presence of red blood cell aggregation under reduced flow condition

Near-Wall Migration Dynamics of Erythrocytes in Vivo: Effects of Cell Deformability and Arteriolar Bifurcation

Red blood cell (RBC) deformability has a significant impact on microcirculation by affecting cell dynamics. Despite previous studies that have demonstrated the margination of rigid cells and particles in vitro, little information is available on the in vivo margination of deformability-impaired RBCs under physiological flow and hematocrit conditions. Thus, in this study, we examined how the deformability-dependent, RBC migration alters the cell distribution under physiological conditions, particularly in arteriolar network flows. The hardened RBCs (hRBCs) were found to preferentially flow near the vessel walls of small arterioles (diameter = 47.1–93.3 μm). The majority of the hRBCs (63%) were marginated within the range of 0.7R-0.9R (R: radial position normalized by vessel radius), indicating that the hRBCs preferentially accumulated near the vessel walls. The laterally marginated hRBCs maintained their lateral positions near the walls while traversing downstream with attenuated radial dispersion. In addition, the immediate displacement of RBCs while traversing a bifurcation also contributes to the near-wall accumulation of hRBCs. The notable difference in the inward migration between the marginated nRBCs and hRBCs after bifurcations further supports the potential role of bifurcations in the accumulation of hRBCs near the walls

Engineering in Medicine to Address the Challenge of Cancer Drug Resistance: From Micro-and Nanotechnologies to Computational and Mathematical Modeling

Drug resistance has profoundly limited the success of cancer treatment, driving relapse, metastasis, and mortality. Nearly all anticancer drugs and even novel immunotherapies, which recalibrate the immune system for tumor recognition and destruction, have succumbed to resistance development. Engineers have emerged across mechanical, physical, chemical, mathematical, and biological disciplines to address the challenge of drug resistance using a combination of interdisciplinary tools and skill sets. This review explores the developing, complex, and under-recognized role of engineering in medicine to address the multitude of challenges in cancer drug resistance. Looking through the "lens"of intrinsic, extrinsic, and drug-induced resistance (also referred to as "tolerance"), we will discuss three specific areas where active innovation is driving novel treatment paradigms: (1) nanotechnology, which has revolutionized drug delivery in desmoplastic tissues, harnessing physiochemical characteristics to destroy tumors through photothermal therapy and rationally designed nanostructures to circumvent cancer immunotherapy failures, (2) bioengineered tumor models, which have benefitted from microfluidics and mechanical engineering, creating a paradigm shift in physiologically relevant environments to predict clinical refractoriness and enabling platforms for screening drug combinations to thwart resistance at the individual patient level, and (3) computational and mathematical modeling, which blends in silico simulations with molecular and evolutionary principles to map mutational patterns and model interactions between cells that promote resistance. On the basis that engineering in medicine has resulted in discoveries in resistance biology and successfully translated to clinical strategies that improve outcomes, we suggest the proliferation of multidisciplinary science that embraces engineering. </p

Effect of erythrocyte aggregation at pathological levels on NO/O2 transport in small arterioles

Clinical Hemorheology and Microcirculation592163-17

Biomimetic Precapillary Flow Patterns for Enhancing Blood Plasma Separation: A Preliminary Study

In this study, a biomimetic microfluidic plasma separation device is discussed. The design of the device drew inspiration from in vivo observations of enhanced cell-free layer (CFL) formation downstream of vascular bifurcations. The working principle for the plasma separation was based on the plasma skimming effect in an arteriolar bifurcation, which is modulated by CFL formation. The enhancement of the CFL width was achieved by a local hematocrit reduction near the collection channel by creating an uneven hematocrit distribution at the bifurcation of the channel. The device demonstrated a high purity of separation (~99.9%) at physiological levels of hematocrit (~40%)

Schematic diagram of intravital microscopic laser speckle contrast imaging system (LSCI).

<p>Schematic diagram of intravital microscopic laser speckle contrast imaging system (LSCI).</p

Effect of arterial pressure reduction and dextran infusion on functional vascular density (FVD).

<p><b>A:</b> Typical examples of speckle contrast images at 30 and 100 mmHg before and after dextran infusion. <b>B:</b> FVD corresponding to the MAP reduction before and after dextran infusion. Scale bar = 500 μm. (* <i>P</i> < 0.5, ** <i>P</i> < 0.005; significant decrease due to the dextran infusion.)</p