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1. Roles of mucus adhesion and cohesion in cough clearance

   https://doi.org/10.1073/pnas.1811787115  

   Button, Brian; Goodell, Henry P.; Atieh, Eyad; Chen, Yu-Cheng; Williams, Robert; Shenoy, Siddharth; Lackey, Elijah; Shenkute, Nathan T.; Cai, Li-Heng; Dennis, Robert G.; et al (November 2018, Proceedings of the National Academy of Sciences)

   Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies. 

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2. Empirical and Theoretical Analysis of Particle Diffusion in Mucus

   https://doi.org/10.3389/fphy.2021.594306  

   Cobarrubia, Antonio; Tall, Jarod; Crispin-Smith, Austin; Luque, Antoni (November 2021, Frontiers in Physics)

   Mucus is a complex fluid that coats multiple organs in animals. Various physicochemical properties can alter the diffusion of microscopic particles in mucus, impacting drug delivery, virus infection, and disease development. The simultaneous effect of these physicochemical properties in particle diffusion, however, remains elusive. Here, we analyzed 106 published experiments to identify the most dominant factors controlling particle diffusion in mucus. The effective diffusion—defined using a one-second sampling time window across experiments—spanned seven orders of magnitude, from 10 –5 to 10 2  μm 2 /s. Univariate and multivariate statistical analyses identified the anomalous exponent (the logarithmic slope of the mean-squared displacement) as the strongest predictor of effective diffusion, revealing an exponential relationship that explained 89 % of the variance. A theoretical scaling analysis revealed that a stronger correlation of the anomalous exponent over the generalized diffusion constant occurs for sampling times two orders of magnitude larger than the characteristic molecular (or local) displacement time. This result predicts that at these timescales, the molecular properties controlling the anomalous exponent, like particle–mucus unbinding times or the particle to mesh size ratio, would be the most relevant physicochemical factors involved in passive microrheology of particles in mucus. Our findings contrast with the fact that only one-third of the studies measured the anomalous exponent, and most experiments did not report the associated molecular properties predicted to dominate the motion of particles in mucus. The theoretical foundation of our work can be extrapolated to other systems, providing a guide to identify dominant molecular mechanisms regulating the mobility of particles in mucus and other polymeric fluids. 

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3. Ultrasonic characterization and beyond: How to select a hydrogel for tissue engineering

   https://doi.org/10.1121/10.0018760  

   Anderson, Megan S.; Bulusu, Kartik V.; Plesniak, Michael W.; Zhang, Lijie Grace; Sarkar, Kausik (March 2023, The Journal of the Acoustical Society of America)

   Hydrogels have emerged as a crucial class of materials within the field of tissue engineering. There is growing interest in matching the mechanical properties of hydrogel scaffolds to tissues in the human body and optimizing these properties for cell growth and differentiation. Gelatin methacrylate (GelMA) is a well-accepted, biocompatible hydrogel with tunable mechanical properties. However, the effects of various formulation parameters on its mechanical properties are not well understood. In this study, an array of GelMA scaffold fabrication parameters is evaluated by varying GelMA concentration and ultraviolet light exposure time. Our overarching goal is to characterize the mechanical properties through ultrasound and rheological measurements, providing a framework for GelMA scaffold selection. Pulse-echo ultrasound techniques were used to non-invasively determine the sound speed and attenuation of the scaffolds, revealing significant dependence on GelMA concentration. Steady shear rate and strain- and frequency-controlled oscillatory shear tests using a rotational rheometer (Model: DHR-2, TA Instruments) revealed a range in the levels of shear-thinning as well as viscoelasticity and showed moduli-dependence on both GelMA concentration and light exposure time. Together, this acoustic and rheological characterization can be used to inform the selection of GelMA scaffolds in tissue engineering applications. 

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4. Spontaneous symmetry breaking propulsion of chemically coated magnetic microparticles

   https://doi.org/10.1038/s41598-022-21725-z  

   Rogowski, Louis William; Kim, Min Jun (October 2022, Scientific Reports)

   Abstract Chemically coated micro/nanoparticles are often used in medicine to enhance drug delivery and increase drug up-take into specific areas of the body. Using a recently discovered spontaneous symmetry breaking propulsion mechanism, we demonstrate that chemically coated microparticles can swim through mucus solution under precise navigation and that certain functionalizations can dynamically change propulsion behavior. For this investigation biotin, Bitotin-PEG3-amine, and biotin chitosan were chemically functionalized onto the surfaces of magnetic microparticles using an avidin–biotin complex. These chemicals were chosen because they are used prolifically in drug delivery applications, with PEG and chitosan having well known mucoadhesive effects. Coated microparticles were then suspended in mucus synthesized from porcine stomach mucins and propelled using rotating magnetic fields. The relationship between different chemical coatings, microparticle velocity, and controllability were thoroughly explored and discussed. Results indicate that the biotinylated surface coatings altered the propulsion behavior of microparticles, with performance differences interlinked to both magnetic field properties and localized mucus properties. Precisely controlled drug carrying microparticles are envisioned to help supplant traditional drug delivery methods and enhance existing medical techniques utilizing micro/nanoparticles. 

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5. Constitutive relationship and governing physical properties for magnetophoresis

   https://doi.org/10.1073/pnas.2018568117  

   Ayansiji, Ayankola O.; Dighe, Anish V.; Linninger, Andreas A.; Singh, Meenesh R. (November 2020, Proceedings of the National Academy of Sciences)

   Magnetophoresis is an important physical process with application to drug delivery, biomedical imaging, separation, and mixing. Other than empirically, little is known about how the magnetic field and magnetic properties of a solution affect the flux of magnetic particles. A comprehensive explanation of these effects on the transport of magnetic particles has not been developed yet. Here we formulate a consistent, constitutive equation for the magnetophoretic flux of magnetic nanoparticles suspended in a medium exposed to a stationary magnetic field. The constitutive relationship accounts for contributions from magnetic diffusion, magnetic convection, residual magnetization, and electromagnetic drift. We discovered that the key physical properties governing the magnetophoresis are magnetic diffusion coefficient, magnetic velocity, and activity coefficient, which depend on relative magnetic energy and the molar magnetic susceptibility of particles. The constitutive equation also reveals previously unknown ballistic and diffusive limits for magnetophoresis wherein the paramagnetic particles either aggregate near the magnet or diffusive away from the magnet, respectively. In the diffusive limit, the particle concentration is linearly proportional to the relative magnetic energy of the suspension of paramagnetic particles. The region of the localization of paramagnetic particles near the magnet decreases with increasing the strength of the magnet. The dynamic accumulation of nanoparticles, measured as the thickness of the nanoparticle aggregate, near the magnet compares well with the theoretical prediction. The effect of convective mixing on the rate of magnetophoresis is also discussed for the magnetic targeting applications. 

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