Modeling Airway Dysfunction in Asthma Using Synthetic Mucus Biomaterials

Song, Daniel; Iverson, Ethan; Kaler, Logan; Bader, Shahed; Scull, Margaret A.; Duncan, Gregg A.

doi:10.1021/acsbiomaterials.0c01728

Cited by 31 publications

(37 citation statements)

References 56 publications

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“… 3 We note that in our study we use bovine submaxillary mucins (BSM) as a commercially available and economical reagent, though the same chemistry can be readily applied to other mucins. BSM is commonly used as a source of the secretory mucin MUC5B, 17 but it exhibits high degrees of O-glycosylation and a comparable molecular weight to MUC1 and MUC4. 3 Our platform is also adaptable to combinations of several mucins by exposure to a mixture during the mucin incubation step.…”

Section: Discussionmentioning

confidence: 99%

Tear Film Stability as a Function of Tunable Mucin Concentration Attached to Supported Lipid Bilayers

2022

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In this work, we describe the development of a tunable, acellular in vitro model of the mucin layer of the human tear film. First, supported lipid bilayers (SLBs) comprised of the phospholipid DOPC (1,2-dioleoyl- sn -glycero-3-phosphocholine) and biotinyl cap PE (1,2-dioleoyl- sn -glycero-3-phosphoethanolamine-N-(cap biotinyl)) are created on the surface of a glass dome with radius of curvature comparable to the human eye. Next, biotinylated bovine submaxillary mucins (BSM) are tethered onto the SLB using streptavidin protein. The mucin presentation can be tuned by altering the concentration of biotinylated BSM, which we confirm using fluorescence microscopy. Due to the optically smooth surface that results, this model is compatible with interferometry for monitoring film thickness. Below a certain level of mucin coverage, we observe short model tear film breakup times, mimicking a deficiency in membrane-associated mucins. In contrast, the breakup time is significantly delayed for SLBs with high mucin coverage. Because no differences in mobility or wettability were observed, we hypothesize that higher mucin coverage provides a thicker hydrated layer that can protect against external disturbances to thin film stability. This advance paves the way for a more physiological, interferometry-based in vitro model for investigating tear film breakup.

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Section: Discussionmentioning

confidence: 99%

Tear Film Stability as a Function of Tunable Mucin Concentration Attached to Supported Lipid Bilayers

2022

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“…To minimize the dynamic and static error in our measurements, a lag time of 1 s was used as a representative value for comparison between conditions. The pore size ( ξ ) can be estimated as , where MSD is the measured MSD at τ = 1s and a is the NP radius (Song et al, 2021). The same methods were used in the analysis of influenza A virus diffusion in human mucus in our previously published work (Kaler et al, 2022).…”

Section: Methodsmentioning

confidence: 99%

Machine Learning–Informed Predictions of Nanoparticle Mobility and Fate in the Mucus Barrier

Kaler

Joyner

Duncan

2022

Preprint

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Diffusion and transport of nanomaterials through mucus, is of critical importance to many basic and applied areas of research such as drug delivery and infectious disease. However, it is often challenging to interpret the dynamics of nanoparticles within the mucus gel due to its inherently heterogeneous microstructure and biochemistry. In this study, we measured the diffusion of densely PEGylated nanoparticles (NP) in human airway mucus ex vivo using multiple particle tracking and utilized machine learning to classify NP movement as either traditional Brownian motion (BM) or one of two different models of anomalous diffusion, fractional Brownian motion (FBM) and continuous time random walk (CTRW). Specifically, we employed a physics-based neural network model to predict the modes of diffusion experienced by individual NP in human airway mucus. We observed rapidly diffusing NP primarily exhibit BM whereas CTRW and FBM exhibited lower diffusion rates. Given the use of muco-inert nanoparticles, the observed transition from diffusive (BM) to sub-diffusive (CTRW/FBM) motion is likely a result of patient-to-patient variation in mucus network pore size. Using mathematic models that account for the mode of NP diffusion, we predicted the percentage of nanoparticles that would cross the mucus barrier over time in human airway mucus with varied total solids concentration. We also applied this approach to explore the transport modes and predicted fate of influenza A virus within human mucus. These results provide new tools to evaluate the extent of synthetic and viral nanoparticle penetration through mucus in the lung and other tissues.

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“…The characteristic lengths of the mucus models were identified to aid in the development of treatment for CF that can penetrate through the thick mucus layer. A 2021 report also employed VPT to aid in the design of synthetic mucus with microrheological properties comparable to native healthy and asthma mucus ( Song et al, 2021 ). As infection by influenza A virus was introduced to the asthma-like synthetic mucus rich in MUC5AC, the increase in the diffusion rate in the mucus medium indicated impairment of its barrier function.…”

Section: Microrheological Approaches To Evaluate Mechanical Propertie...mentioning

confidence: 99%

Passive and Active Microrheology for Biomedical Systems

Mao

Nielsen

Ali

2022

Front. Bioeng. Biotechnol.

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Microrheology encompasses a range of methods to measure the mechanical properties of soft materials. By characterizing the motion of embedded microscopic particles, microrheology extends the probing length scale and frequency range of conventional bulk rheology. Microrheology can be characterized into either passive or active methods based on the driving force exerted on probe particles. Tracer particles are driven by thermal energy in passive methods, applying minimal deformation to the assessed medium. In active techniques, particles are manipulated by an external force, most commonly produced through optical and magnetic fields. Small-scale rheology holds significant advantages over conventional bulk rheology, such as eliminating the need for large sample sizes, the ability to probe fragile materials non-destructively, and a wider probing frequency range. More importantly, some microrheological techniques can obtain spatiotemporal information of local microenvironments and accurately describe the heterogeneity of structurally complex fluids. Recently, there has been significant growth in using these minimally invasive techniques to investigate a wide range of biomedical systems both in vitro and in vivo. Here, we review the latest applications and advancements of microrheology in mammalian cells, tissues, and biofluids and discuss the current challenges and potential future advances on the horizon.

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Modeling Airway Dysfunction in Asthma Using Synthetic Mucus Biomaterials

Cited by 31 publications

References 56 publications

Tear Film Stability as a Function of Tunable Mucin Concentration Attached to Supported Lipid Bilayers

Tear Film Stability as a Function of Tunable Mucin Concentration Attached to Supported Lipid Bilayers

Machine Learning–Informed Predictions of Nanoparticle Mobility and Fate in the Mucus Barrier

Passive and Active Microrheology for Biomedical Systems

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