Noriaki Matsuki

Can temporal fluctuation in spatial wall shear stress gradient initiate a cerebral aneurysm? A proposed novel hemodynamic index, the gradient oscillatory number (GON).

We propose a new hemodynamic index for the initiation of a cerebral aneurysm, defined by the temporal fluctuations of tension/compression forces acting on endothelial cells. We employed a patient-specific geometry of a human internal carotid artery (ICA) with an aneurysm, and reconstructed the geometry of the ICA before aneurysm formation by artificially removing the aneurysm. We calculated the proposed hemodynamic index and five other hemodynamic indices (wall shear stress (WSS) at peak systole, time-averaged WSS, time-averaged spatial WSS gradient, oscillatory shear index (OSI), and potential aneurysm formation indicator (AFI)) for the geometry before aneurysm formation using a computational fluid dynamics technique. By comparing the distribution of each index at the location of aneurysm formation, we discussed the validity of each. The results showed that only the proposed hemodynamic index had a significant correlation with the location of aneurysm formation. Our findings suggest that the proposed index may be useful as a hemodynamic index for the initiation of cerebral aneurysms.

Red blood cell motions in high-hematocrit blood flowing through a stenosed microchannel

We investigated the behavior of red blood cells (RBCs) in a microchannel with stenosis using a confocal micro-PTV system. Individual trajectories of RBCs in a concentrated suspension of up to 20% hematocrit (Hct) were measured successfully. Results indicated that the trajectories of healthy RBCs became asymmetric before and after the stenosis, while the trajectories of tracer particles in pure water were almost symmetric. The asymmetry was greater in 10% Hct than in 20% Hct. We also investigated the effect of deformability of RBCs on the cell-free layer thickness by hardening RBCs using a glutaraldehyde treatment. The results indicated that deformability is the key factor in the asymmetry of cell-free layer thickness. Therefore, the motions of RBCs are influenced strongly by the Hct, the deformability, and the channel geometry. These results give fundamental knowledge for a better understanding of blood flow in microcirculation and biomedical microdevices.

Fluid particle diffusion through high-hematocrit blood flow within a capillary tube

Fluid particle diffusion through blood flow within a capillary tube is an important phenomenon to understand, especially for studies in mass transport in the microcirculation as well as in solving technical issues involved in mixing in biomedical microdevices. In this paper, the spreading of tracer particles through up to 20% hematocrit blood, flowing in a capillary tube, was studied using a confocal micro-PTV system. We tracked hundreds of particles in high-hematocrit blood and measured the radial dispersion coefficient. Results yielded significant enhancement of the particle diffusion, due to a micron-scale flow-field generated by red blood cell motions. By increasing the flow rate, the particle dispersion increased almost linearly under constant hematocrit levels. The particle dispersion also showed near linear dependency on hematocrit up to 20%. A scaling analysis of the results, on the assumption that the tracer trajectories were unbiased random walks, was shown to capture the main features of the results. The dispersion of tracer particles was about 0.7 times that of RBCs. These findings provide good insight into transport phenomena in the microcirculation and in biomedical microdevices.

Particle-Based Methods for Multiscale Modeling of Blood Flow in the Circulation and in Devices: Challenges and Future Directions

A major computational challenge for a multiscale modeling is the coupling of disparate length and timescales between molecular mechanics and macroscopic transport, spanning the spatial and temporal scales characterizing the complex processes taking place in flow-induced blood clotting. Flow and pressure effects on a cell-like platelet can be well represented by a continuum mechanics model down to the order of the micrometer level. However, the molecular effects of adhesion/aggregation bonds are on the order of nanometer. A successful multiscale model of platelet response to flow stresses in devices and the ensuing clotting responses should be able to characterize the clotting reactions and their interactions with the flow. This paper attempts to describe a few of the computational methods that were developed in recent years and became available to researchers in the field. They differ from traditional approaches that dominate the field by expanding on prevailing continuum-based approaches, or by completely departing from them, yielding an expanding toolkit that may facilitate further elucidation of the underlying mechanisms of blood flow and the cellular response to it. We offer a paradigm shift by adopting a multidisciplinary approach with fluid dynamics simulations coupled to biophysical and biochemical transport.

Asymmetry of blood flow and cancer cell adhesion in a microchannel with symmetric bifurcation and confluence

Bifurcations and confluences are very common geometries in biomedical microdevices. Blood flow at microchannel bifurcations has different characteristics from that at confluences because of the multiphase properties of blood. Using a confocal micro-PIV system, we investigated the behaviour of red blood cells (RBCs) and cancer cells in microchannels with geometrically symmetric bifurcations and confluences. The behaviour of RBCs and cancer cells was strongly asymmetric at bifurcations and confluences whilst the trajectories of tracer particles in pure water were almost symmetric. The cell-free layer disappeared on the inner wall of the bifurcation but increased in size on the inner wall of the confluence. Cancer cells frequently adhered to the inner wall of the bifurcation but rarely to other locations. Because the wall surface coating and the wall shear stress were almost symmetric for the bifurcation and the confluence, the result indicates that not only chemical mediation and wall shear stress but also microscale haemodynamics play important roles in the adhesion of cancer cells to the microchannel walls. These results provide the fundamental basis for a better understanding of blood flow and cell adhesion in biomedical microdevices.

Inertial migration of cancer cells in blood flow in microchannels

The circulating tumor cell test is used to evaluate the condition of breast cancer patients by counting the number of cancer cells in peripheral blood samples. Although microfluidic systems to detect or separate cells using the inertial migration effect may be applied to this test, the hydrodynamic forces acting on cancer cells in high hematocrit blood flow are incompletely understood. In the present study, we investigated the inertial migration of cancer cells in high hematocrit blood flow in microchannels. The maximum hematocrit used in this study was about 40%. By measuring the cell migration probability, we examined the effects of cell–cell interactions, cell deformability, and variations in cell size on the inertial migration of cancer cells in blood. The results clearly illustrate that cancer cells can migrate towards equilibrium positions up to a hematocrit level of 10%. We also performed simple scaling analysis to explain the differences in migration length between rigid particles and cancer cells as well as the effect of hematocrit on cancer cell migration. These results will be important for the design of microfluidic devices for separating cells from blood.

Low voltage pulses can induce apoptosis

Electroporation is used for gene transfection, drug delivery, and cell fusion. While studies have shown that high voltage electroporation induces apoptosis in vitro, a strong electric field can lower cell survival rates. As there are no published reports which have examined apoptotic properties associate with low voltage electric charges, we demonstrated for the first time that consecutive low voltage pulses with a voltage lower than the membrane breakdown threshold of human cells can increase the membrane potential to the threshold required to induce electroporation. This led to apoptosis through caspase pathways. Moreover, necrotic cell damage was less than that caused by high voltage pulses. Therefore, low voltage electroporation can be a suitable anticancer method.

Blood oxygenation using microbubble suspensions

Microbubbles have been used in a variety of fields and have unique properties, for example shrinking collapse, long lifetime, efficient gas solubility, a negatively charged surface, and the ability to produce free radicals. In medicine, microbubbles have been used mainly as diagnostic aids to scan various organs of the body, and they have recently been investigated for use in drug and gene delivery. However, there have been no reports of blood oxygenation by use of oxygen microbubble fluids without shell reagents. In this study, we demonstrated that nano or microbubbles can achieve oxygen supersaturation of fluids, and may be sufficiently small and safe for infusion into blood vessels. Although Po2 increases in fluids resulting from use of microbubbles were inhibited by polar solvents, normal saline solution (NSS) was little affected. Thus, NSS is suitable for production of oxygen-rich fluid. In addition, oxygen microbubble NSS effectively improved hypoxic conditions in blood. Thus, use of oxygen microbubble (nanobubble) fluids is a potentially effective novel method for oxygenation of hypoxic tissues, for infection control, and for anticancer treatment.

Oxygen supersaturated fluid using fine micro/nanobubbles.

Microbubbles show peculiar properties, such as shrinking collapse, long lifetime, high gas solubility, negative electric charge, and free radical production. Fluids supersaturated with various gases can be easily generated using microbubbles. Oxygen microbubble fluid can be very useful for oxygen delivery to hypoxic tissues. However, there have been no reports of comparative investigations into adding fluids containing oxygen fine micro/nanobubbles (OFM-NBs) to common infusion solutions in daily medical care. In this study, it was demonstrated that OFMNBs can generate oxygen-supersaturated fluids, and they may be sufficiently small to infuse safely into blood vessels. It was found that normal saline solution is preferable for generating an oxygen-rich infusion fluid, which is best administered as a 30-minute intravenous infusion. It was also concluded that dextran solution is suitable for drug delivery substances packing oxygen gas over a 1-hour intravenous infusion. In addition, normal saline solution containing OFMNBs was effective for improving blood oxygenation. Thus, the use of OFMNB-containing fluids is a potentially effective novel method for improving blood oxygenation in cases involving hypoxia, ischemic diseases, infection control, and anticancer chemoradiation therapies.

A realistic simulation of saccular cerebral aneurysm formation: focussing on a novel haemodynamic index, the gradient oscillatory number

Although how cerebral aneurysms initiate and grow is still unclear, haemodynamics is thought to play an important role. In order to better understand the aneurysm formation mechanism, we performed a computational analysis of aneurysm formation for a patient-specific arterial geometry. First, CFD was used to perform a pulsatile blood flow analysis and calculate a novel haemodynamic index, the gradient oscillatory number (GON). Then, using aneurysm growth model in which the proliferation of the wall was hypothesised, we performed an aneurysm formation analysis based on the GON index distribution. The result showed that a saccular cerebral aneurysm could appear based on our hypothesis for a patient-specific arterial geometry. On the other hand, a saccular aneurysm was not observed when assuming only strength degradation of the wall. Our findings have suggested that an arterial biological process, such as the proliferation of the wall, may play a vital role in saccular aneurysm formation.