A rational approach to form disulfide linked mucin hydrogels

Joyner, Katherine; Song, Daniel; Hawkins, Robert F.; Silcott, Richard D.; Duncan, Gregg A.

doi:10.1039/c9sm01715a

Cited by 58 publications

(106 citation statements)

References 38 publications

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“…In this study, we aimed to create a synthetic mucus biomaterial with similar rheological and transport properties to human respiratory mucus. In our previous work, we reported the design of a hydrogel system that employs a thiol-based cross-linking strategy and verified that hydrogel assembly was mediated by hydrogen and disulfide bonding [27]. Using this approach, we prepared hydrogels with 2% (w/v) mucin and 2% (w/v) cross-linking reagent, PEG-4SH, using two types of mucins: porcine gastric mucin (PGM), composed of MUC5AC [35,36], and bovine submaxillary gland mucin (BSM), composed of MUC5B [37,38] (Fig.…”

Section: Engineering Synthetic Mucus Biomaterials With Physicochemicamentioning

confidence: 87%

“…Synthetic mucus hydrogels were prepared using a previously established method [27]. Briefly, porcine gastric mucin (PGM; Sigma-Aldrich) and mucin from bovine submaxillary glands (BSM; Sigma-Aldrich) are mixed with a cross-linking reagent, 4-arm PEG-thiol (PEG-4SH; Laysan Bio Inc.) to mediate crosslinking between mucin biopolymers.…”

Section: Preparation Of Synthetic Mucusmentioning

confidence: 99%

“…Fluorescent carboxylate modified fluorescent polystyrene nanoparticles (PS-COOH; Life Technologies) with a diameter of 100 and 500 nm were coated with a high surface density of polyethylene glycol (PEG) via a carboxyl-amine linkage using 5-kDa methoxy PEG-amine (Creative PEGWorks) as previously reported [21,27]. Particle size and zeta potential was measured in 10 mM NaCl at pH 7 using a NanoBrook Omni (Brookhaven Instruments).…”

Section: Preparation Of Nanoparticles For Particle Tracking Microrheomentioning

confidence: 99%

“…In our work, we report a synthetic mucus biomaterial capable of modeling transport and barrier function of airway mucus. Specifically, we have adapted an approach established in previous work [27] to create mucin-based hydrogels composed of MUC5B and MUC5AC with viscoelastic properties comparable to airway mucus. This model system provides the capability to systematically vary the composition of mucus to capture how these changes impact its physiological function.…”

Section: Introductionmentioning

confidence: 99%

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Modeling airway dysfunction in asthma using synthetic mucus biomaterials

Song

Iverson

Kaler

et al. 2020

Preprint

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As asthma worsens, occlusion of airways with mucus significantly contributes to airflow obstruction and reduced lung function. Recent evidence from clinical studies has shown mucus obtained from adults and children with asthma possesses altered mucin composition. However, how these changes alter the functional properties of the mucus gel is not yet fully understood. To study this, we have engineered a synthetic mucus biomaterial to closely mimic the properties of native mucus in health and disease. We demonstrate this model possesses comparable biophysical and transport properties to native mucus ex vivo collected from human subjects and in vitro isolated from human airway epithelial (HAE) tissue cultures. We found by systematically varying mucin composition that mucus gel viscoelasticity is enhanced when predominantly composed of mucin 5AC (MUC5AC), as is observed in asthma. As a result, asthma-like synthetic mucus gels are more slowly transported on the surface of HAE tissue cultures and at a similar rate to native mucus produced by HAE cultures stimulated with the type 2 cytokine IL-13, known to contribute to airway inflammation and MUC5AC hypersecretion in asthma. We also discovered the barrier function of asthma-like synthetic mucus towards influenza A virus was impaired as evidenced by the increased frequency of infection in MUC5AC-rich hydrogel coated HAE cultures. Together, this work establishes a biomaterial-based approach to understand airway dysfunction in asthma and related muco-obstructive lung diseases.

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Section: Engineering Synthetic Mucus Biomaterials With Physicochemicamentioning

confidence: 87%

Section: Preparation Of Synthetic Mucusmentioning

confidence: 99%

Section: Preparation Of Nanoparticles For Particle Tracking Microrheomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modeling airway dysfunction in asthma using synthetic mucus biomaterials

Song

Iverson

Kaler

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Using a previously established method (28), synthetic mucus hydrogels were prepared using 2% porcine gastric mucin (PGM; Sigma-Aldrich) and varying percentages (1.0%, 1.5%, and 2.0%) of 4-arm polyethylene glycol (PEG; Laysan Bio Inc.) used as a thiosulfate crosslinker. The mucin and the crosslinker were combined in a physiological buffer (154 mM NaCl, 3 mM CaCl2, and 15 mM NaH2PO4 at pH 7.4) and mixed for 2 hours.…”

Section: Synthetic Mucus Hydrogel Preparationmentioning

confidence: 99%

Influenza A virus diffusion through mucus gel networks

Kaler

Iverson

Bader

et al. 2020

Preprint

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In this study, influenza A virus (IAV) and nanoparticle diffusion in human airway mucus was quantified using fluorescent video microscopy and multiple particle tracking. In previous work, it was determined that mucin-associated sialic acid acts as a decoy receptor for IAV hemagglutinin binding, and that virus passage through the mucus gel layer is facilitated through the sialic-acid cleaving enzyme, neuraminidase (NA), also present on the IAV envelope. However, our data suggests the mobility of IAV in mucus is significantly influenced by the mesh structure of the gel, as measured by nanoparticle probes, and NA activity is not required to facilitate virus passage through mucus gels. Using newly developed analyses, the binding affinity of IAV to the 3D mucus meshwork was estimated for individual virions with dissociation constants in the mM range, indicative of weak and reversible IAV-mucus interactions. We also found IAV diffusion significantly increased in mucus when treated with a mucolytic agent to break mucin-mucin disulfide bonds. In addition, IAV diffusion was significantly limited in a synthetic mucus model as crosslink density was systematically increased and network pore size was reduced. The results of this work provide important insights on how the balance of adhesive and physical barrier properties of mucus influence the dissemination of IAV within the lung microenvironment.

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Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

Jiang

Yan

Rickert

et al. 2021

Adv Funct Materials

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Hydrogels made of crosslinked macromolecules used in regenerative medicine technologies can be designed to affect the fate of surrounding cells and tissues in defined ways. Their function typically depends on the type and number of bioactive moieties such as receptor ligands present in the hydrogel. However, the detail in how such moieties are presented to cells can also be instrumental. In this work, how the crosslinking architecture of a hydrogel can affect its bioactivity is explored. It is shown that bovine submaxillary mucins, a highly glycosylated and immune‐modulating protein, exhibit strikingly different bioactivities whether they are crosslinked through their glycans or their protein domains. Both the susceptibility to enzymatic degradation and macrophage response are affected, while rheological properties and barrier to diffusion are mostly unaffected. The results suggest that crosslinking architecture affects the accessibility of the substrate to proteases and the pattern of sialic acid residues exposed to the macrophages. Thus, modulating the accessibility of binding sites through the choice of the crosslinking strategy appears as a useful parameter to tune the bioactivity of hydrogel‐based systems.

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A rational approach to form disulfide linked mucin hydrogels

Abstract: In this work, we demonstrate how crude mucins, incapable of forming gels, may be restored to behave like natural mucus.

Cited by 58 publications

References 38 publications

Modeling airway dysfunction in asthma using synthetic mucus biomaterials

Modeling airway dysfunction in asthma using synthetic mucus biomaterials

Influenza A virus diffusion through mucus gel networks

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

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