Progress in understanding kidney disease mechanisms and the development of targeted therapeutics have been limited by the lack of functional in vitro models that can closely recapitulate human physiological responses. Organ Chip (or organ-on-a-chip) microfluidic devices provide unique opportunities to overcome some of these challenges given their ability to model the structure and function of tissues and organs in vitro. Previously established organ chip models typically consist of heterogenous cell populations sourced from multiple donors, limiting their applications in patient-specific disease modeling and personalized medicine. In this study, we engineered a personalized glomerulus chip system reconstituted from human induced pluripotent stem (iPS) cell-derived vascular endothelial cells (ECs) and podocytes from a single patient. Our stem cell-derived kidney glomerulus chip successfully mimics the structure and some essential functions of the glomerular filtration barrier. We further modeled glomerular injury in our tissue chips by administering a clinically relevant dose of the chemotherapy drug Adriamycin. The drug disrupts the structural integrity of the endothelium and the podocyte tissue layers, leading to significant albuminuria as observed in patients with glomerulopathies. We anticipate that the personalized glomerulus chip model established in this report could help advance future studies of kidney disease mechanisms and the discovery of personalized therapies. Given the remarkable ability of human iPS cells to differentiate into almost any cell type, this work also provides a blueprint for the establishment of more personalized organ chip and ‘body-on-a-chip’ models in the future.
Neutrophils are rapidly mobilized from the circulation to sites of inflammation. The mechanisms of neutrophil trafficking in the lung are distinct from those in the periphery, in part because the pulmonary capillaries are the primary site of neutrophil emigration rather than postcapillary venules. Since the diameter of a neutrophil is greater than the width of most pulmonary capillary segments, they must deform to transit through this capillary network, even at homeostasis. Resistance to deformation is primarily due to cortical actin that is rapidly assembled when a neutrophil is exposed to a priming or activation stimulus, resulting in neutrophil stiffening and subsequent sequestration within the pulmonary capillary network. In the current study, we use a microfluidic assay to characterize neutrophil transit through model capillary-like channels. Using techniques from single-particle tracking, we analyzed the cumulative distribution of neutrophil transit times and resolve population-based effects. We found that vinculin, an actin-binding adaptor protein, plays an essential role in neutrophil stiffening in response to formyl-Met-Leu-Phe (fMLP). Vinculin-deficient neutrophils lack the development of a population with slow transit through narrow channels that was observed in both wild-type murine bone marrow neutrophils and HoxB8-conditional progenitor-derived neutrophils. Atomic force microscopy studies provide further evidence that vinculin is required for neutrophil stiffening. Consistent with these findings, we observed that neutrophil sequestration in the lungs of mice is attenuated in the absence of vinculin. Together, our studies indicate that vinculin mediates actin-dependent neutrophil stiffening that leads to their sequestration in capillaries.
When fluids flow through straight channels sustained turbulence occurs at high Reynolds numbers (typically $ \textrm{Re}\sim O(1000)$). It is difficult to mix multiple fluids flowing through a straight channel in low Reynolds number laminar regime ($ \textrm{Re}<O(100)$) because in absence of turbulence, mixing between the component fluids occurs primarily via slow molecular diffusion process. This letter reports a simple way to significantly enhance low Reynolds number (in our case $\textrm{Re}\leq10$) passive microfluidic flow mixing in a straight microchannel by introducing asymmetric wetting boundary conditions on the floor of the channel. We show experimentally and numerically that by creating carefully chosen 2D hydrophobic slip patterns on the floor of the channels we can introduce stretching, folding and/or recirculation in the flowing fluid volume, the essential elements to achieve mixing in absence of turbulence. We also show that there are two distinctive pathways to produce homogeneous mixing in microchannels induced by the inhomogeneity of the boundary conditions. It can be achieved either by: 1) introducing stretching, folding and twisting of fluid volumes, i.e., via a horse-shoe type transformation map, or 2) by creating chaotic advection, through manipulation of the hydrophobic boundary patterns on the floor of the channels. We have also shown that by superposing stretching and folding with chaotic advection, mixing can be optimized by significantly reducing mixing length, thereby opening up new design opportunities for simple yet efficient passive microfluidic reactors.
Spectroelectrochemical techniques were used to probe the interaction of adenine with pyridoxine at pH 7.0. Analysis of UV-visible absorption of the adenine-pyridoxine complex at 260 nm using the Lineweaver–Burk double reciprocal plot produced a linear graph indicating a 1 : 1 mode of interaction between the compounds and a binding constant of 29.1. Change in the background current and broadening of adenine and pyridoxine cyclic voltammetry (CV) oxidation peaks at 1.0 V and 0.8 V, respectively, compared to the CV of the individual compounds is indicative of an interaction. The Raman shift of the coupled –C(11)H2-OH bending and in-plane N(7)-H mode at 1235 cm−1 to 1215 cm−1 of pyridoxine and the shift to the lower wavenumber of the adenine –N(10)H2 rocking band from 942 to 906 cm−1 confirm that the adenine exocyclic amino group and its purine nitrogen atom N(7) interacts with pyridoxine O(12) via the formation of hydrogen bonds. Strong enhancement of surface-enhanced Raman spectroscopy (SERS) bands pertaining to adenine and the bathochromic shift of the normal Raman band due to the adenine ring breathing mode observed at 722 cm−1 in the spectrum of adenine, to 732 cm−1 in the SERS spectrum of aqueous adenine-pyridoxine indicates that the complex adsorbs onto the Ag nanoparticle surface with the adenine portion possessing a perpendicular orientation.
Mixing in low Reynolds number flow is difficult because in this laminar regime it occurs mostly via slow molecular diffusion. This letter reports a simple way to significantly enhance low Reynolds number passive microfluidic flow mixing in a straight microchannel by introducing asymmetric wetting boundary conditions on the floor of the channel. We show experimentally and numerically that by creating carefully chosen hydrophobic slip patterns on the floor of the channels we can introduce stretching, folding and/or recirculation in the flowing fluid volume, the essential elements to achieve mixing in absence of turbulence. We also show that there are two distinctive pathways to produce homogeneous mixing in microchannels induced by the inhomogeneity of the boundary conditions. It can be achieved either by: 1) introducing stretching, folding and twisting of fluid volumes, i.e., via a horse-shoe type transformation map, or 2) by creating chaotic advection, through manipulation of the hydrophobic boundary patterns on the floor of the channels. We have also shown that by superposing stretching and folding with chaotic advection, mixing can be optimized by significantly reducing mixing length, thereby opening up new design opportunities for simple yet efficient passive microfluidic reactors.
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