While bicuspid aortic valve (BAV) shows different phenotypes associated with aortic aneurysm and valvular dysfunction due to aortic stenosis (AS), hemodynamics in patients with stenotic BAVs remains poorly understood. Here we address a study of the effects of valve phenotypes on aortic hemodynamics in different configurations of AS using an image-based subject-specific left ventricle (LV)-aorta integrated computational model. The model was built up by combining both MRI images and realistic motions of aortic valve, mitral valve, and LV apex as well as its contraction and dilatation of a healthy subject. Physiological boundary conditions were given based on a parameter-adjusted 0-1D cardiovascular model. Symmetrical BAV models with mild and severe stenosis were constructed with the orientation angle varying every 15° from 0° to 165° with regards to mitral valve while within a planar disc and the orientation effects on aortic hemodynamics were systematically investigated. Our results revealed that systolic jets in aorta were dominated by a combination of valve orientation and AS. Furthermore the hemodynamic indices of maximum wall shear stress (WSS), oscillatory shear index (OSI), and axial energy loss also demonstrated a feature of phenotype-and stenosis-dependency, pointing to the importance of taking into account the valve configuration in clinical decision-making on BAV patients.

Keywords

Bicuspid aortic valve, Aortic stenosis, Hemodynamics, Orientation, Phenotype

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Studies on platelet margination have shown that the platelets can effectively marginate at the microvessel wall in a multi-file flow of red blood cells (RBCs), whereas axially migrated RBCs push platelets toward the wall. However, it is unclear whether these results can be extended to capillaries, which potentially cause a single-file line of RBCs, or a so-called bolus flow. Our previous numerical results (Takeishi and Imai, 2017) showed that microparticles with a diameter of 1 μm (1-μm-MPs) were captured by a bolus flow of RBCs, instead of being marginated in capillaries. Herein we perform numerical simulations to clarify whether platelets are captured or escape from the vortex-like flow structures between RBCs. We demonstrate that platelets are also captured in a capillary whose diameter is 25% larger than that of RBCs at a physiologically-relevant hematocrit (Hct ～ 0.2), but the number of captured platelets is smaller than that of 1-μm-MPs. When the capillary diameter is comparable to that of RBCs, however, many platelets flow near the wall due to an unstable bolus flow resulting in a less number of captured platelets. These results suggest that the size effect reduces platelet capture events compared to 1-μm-MPs. We also investigate the effect of Hct and the non-dimensional shear rate (capillary number) on capture events. These findings may help not only to understand platelet adhesion in capillaries but also to develop therapeutic drug carriers.

Keywords

Platelet, Red blood cell, Margination, Capillary, Lattice-Boltzmann method, Finite element method, Computational biomechanics

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Formation of vascular anastomoses is critical for the development of transplantable tissue-engineered grafts, because rapid blood perfusion is required for the maintenance of implanted tissue grafts. However, the process of vascular anastomosis remains unclear due to difficulties in observing vascular anastomosis after transplantation. Although several groups have developed in vitro models of vascular anastomosis, there is a lack of a suitable in vitro anastomosis model that includes perivascular cells. Therefore, we aimed to establish an in vitro vascular anastomosis model containing perivascular cells by a combination of human umbilical vein endothelial cell (HUVEC) monoculture and HUVEC-mesenchymal stem cell (MSC) coculture in a microfluidic device. We found that vascular formation was inhibited when HUVECs were seeded on both sides of gel scaffolds, but HUVECs formed vascular networks when they were seeded on one side only. Next, we tested a series of HUVEC:MSC ratios to induce vascular anastomoses. The results demonstrated that addition of MSCs induced vascular anastomosis. In particular, the number of vascular anastomoses was significantly increased at a HUVEC:MSC ratio of 2:8. The process of vascular anastomosis was further investigated by live-cell imaging of green fluorescent protein-expressing HUVECs, which revealed that vascular anastomoses with continuous lumens were constructed during days 8-10. Computational simulation of VEGF concentrations suggested that local VEGF gradients play important roles in vascular formation while the addition of MSCs was critical for anastomosis. This anastomosis model will provide insights for both the development of tissue-engineered grafts and for the construction of large tissues by assembling multiple tissue-engineered constructs.

Keywords

Vascular anastomosis, In vitro model, Microfluidic device, Human umbilical vein endothelial cell, Mesenchymal stem cell, Chemical gradient

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In this study, we designed and fabricated an AC magnetic field (ACMF) stimulation bio-reactor for a three-dimensional (3D) culture of nerve cells using a collagen gel as a scaffold. Recently, the use of electromagnetic stimulation to enhance nerve axonal extension has attracted significant attention in nerve regeneration. Thus, we designed a novel 3D bio-reactor that can apply ACMF stimulation to nerve cells with a uniform magnetic flux density. We evaluated the morphology of PC12 cells and primary cells derived from the rat cerebral cortex using a multi photon microscope (MPM) and evaluated the effect of ACMF stimulation on axogenesis and nerve axonal extension. First, an ACMF stimulation bio-reactor was designed using a pole-piece structure. We examined the uniformity of the magnetic flux density generated in the 3D culture region of the bio-reactor using the 3D electromagnetic field finite element analyses. Second, we evaluated the effect of ACMF stimulation in enhancing PC12 cells axonal extension. Cells were disseminated into a collagen gel which was poured into a fabricated culture dish. We observed an increase in the axogenesis ratio and axonal extension length of PC12 cells during the later growth stages under ACMF stimulation. Finally, we confirmed that primary cells with enhanced axonal extension became more susceptible to ACMF stimulation as the intercellular distance increased.

Keywords

AC magnetic (ACMF) stimulation, Three-dimensional bio-reactor, Axogenesis, Axonal extension

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Electromyostimulation is a nonpharmacological prevention method for osteoporosis that is safe and feasible for the elderly and people with physical disabilities. Our previous study demonstrated that random pulse train (RdPT) electromyostimulation of rat quadriceps induces an increase in the mechanical properties of the contralateral unstimulated femoral neck. However, the efficacy of this stimulation on other untested bones is still unclear. The objective of this research is to investigate the response of previously unstimulated bones to single-site electromyostimulation. The left quadriceps of rats were stimulated electrically by periodic pulse train (PrPT) or RdPT with 2 mA-magnitude pulses at 552 μs and a 50% duty ratio. The stimulation effect was examined on the diaphysis of long bones and lumbar vertebrae (L2-L5) by quasi-static mechanical tests and microcomputed tomography analysis. RdPT increased the strain energy at the stimulated left femur but did not change the properties of the other long bones. For the lumber vertebrae, on the other hand, both stimulations showed similar results. The stiffness of lumbar vertebra increased in L2, and the stiffness and the maximum load decreased in L4. Additionally, the BMC (bone mineral content), BV (bone volume), and TV (tissue volume) were reduced in L2, but not changed in L4. The other vertebrae were not affected by the stimulations. In conclusion, RdPT influences not only the stimulated femur, but also the lumbar vertebrae site-dependently as well as PrPT. These findings suggest the whole-body scale effect of electromyostimulation, however, which is not positive in all the bones, requiring further investigations for its clinical applications.

Keywords

Electromyostimulation, Random stimulation, Osteoporosis, Mechanical properties, Bone microarchitecture

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[Advance Publication] (Proper information for citation will be announced after formal publication)