Mucus as a Barrier to Drug Delivery – Understanding and Mimicking the Barrier Properties

Boegh, Marie; Nielsen, Hanne Mørck

doi:10.1111/bcpt.12342

Cited by 277 publications

(196 citation statements)

References 49 publications

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“…To overcome this biological barrier caused by some novel inhalation pharmaceuticals, functionalized and nontoxic nanocarriers can be used. Inspired from viruses, nanosized particles with neutrally charged coatings such as polyethylene glycol (PEG) can efficiently penetrate the mucus layer in contrast to charged particles (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

A Model for the Transient Subdiffusive Behavior of Particles in Mucus

Ernst¹,

John

Guenther³

et al. 2017

Biophysical Journal

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In this study we have applied a model to explain the reported subdiffusion of particles in mucus, based on the measured mean squared displacements (MSD). The model considers Brownian diffusion of particles in a confined geometry, made from permeable membranes. The applied model predicts a normal diffusive behavior at very short and long time lags, as observed in several experiments. In between these timescales, we find that the ''subdiffusive'' regime is only a transient effect, MSDft a ; a < 1. The only parameters in the model are the diffusion-coefficients at the limits of very short and long times, and the distance between the permeable membranes L. Our numerical results are in agreement with published experimental data for realistic assumptions of these parameters. Finally, we show that only particles with a diameter less than 40 nm are able to pass through a mucus layer by passive Brownian motion.

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Section: Introductionmentioning

confidence: 99%

A Model for the Transient Subdiffusive Behavior of Particles in Mucus

Ernst¹,

John

Guenther³

et al. 2017

Biophysical Journal

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“…Mucoadhesion is a complex phenomenon that comprises the humectation of the polymer in contact with the mucus, and also specific interactions between mucoadhesive polymers and mucin. Excellent reviews can be found elsewhere (Boegh & Nielsen, 2015;Alexander, 2011;Harding, 2006;Smart, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The exact composition, thickness and structure of mucus are mainly governed by the nature of the tissue that is being protected, and the amount of salts and other minor components. In the case of gastric mucus, it has been studied that in acid media, mucins change their conformation forming a high viscous gel (Boegh & Nielsen, 2015;Hong et al, 2005). This gel becomes an efficient layer that protects the stomach from being ingested by its own gastric acid during digestion.…”

Section: Introductionmentioning

confidence: 99%

Effect of pH on the rheological response of reconstituted gastric mucin

Caicedo¹,

Perilla²

2015

ing.inv.

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The rheological response of reconstituted gastric mucin was studied by time dependent rheological experiments as function of pH. Mucin concentrations of 5 % and 10 % were prepared in buffer dispersions at pH of 1.15, 2.00, 2.55, 4.00 and 7.67. The isoelectric point was identified by z-potential between pH 2.00 to 2.55. Dynamic light scattering showed that as pH reduced, a second population of larger mucin aggregates was formed indicating the presence of new structures. Steady shear rheological measurements reflected the pseudoplastic behavior of mucin dispersions and the effect of concentration on viscosity. Creep-recovery measurements were performed on the regenerated mucus at different levels of pH. By creep, it was possible to determine the values of zero-shear-viscosity of mucin suspensions, with higher precision and in a lower experimental time than steady shear measurements. Additionally, it was found that at pH ∼1.15, the viscosity of the mucus increased to high values, which is an indicative of a gel-like structure. By recovery experiments, it was possible to find that even the very low viscosities the mucin suspensions at pH ∼1.15 possessed a defined elastic character. By the use of a four-element mechanistic viscoelastic model, it was concluded that this elasticity underwent retardation due to the combined effect of viscous and elastic responses.Keywords: Mucin, rheology, z-potential, creep, elasticity. RESUMENSe estudió la respuesta reológica de mucina gástrica reconstituida como función del pH mediante experimentos reológicos dependientes del tiempo. Se usaron concentraciones de mucina del 5 % y 10 % en soluciones buffer a valores de pH de 1.15, 2.00, 2.55, 4.00 y 7.67. Mediante potencial zeta se identifico que el punto isoeléctrico se ubicaba entre pH de 2.00 a 2.55. Los estudios de dispersión de luz dinámica mostraron que a mediada que el pH se reduce, una segunda población de agregados de mucina se forma, indicando el estructuramiento dentro del fluido. Las mediciones reológicas en estado estable, mostraron el comportamiento seudoplástico y el efecto de la concentración en las soluciones de mucina. Se llevaron a cabo determinaciones de fluencia lenta-recuperación sobre las suspensiones de mucina a diferentes valores de pH. Mediante fluencia lenta, se determinaron los valores de viscosidad a cero corte con mayor precisión y menor tiempo experimental que las mediciones de estado estable. Adicionalmente, se encontró que para pH ∼1.15 la viscosidad del mucus incrementó a valores altos, lo cual es una característica de las estructuras tipo gel. Los experimentos de recuperación mostraron que aun a bajas viscosidades las suspensiones de mucina a pH ∼1.15 poseían un carácter elástico definido. Mediante el uso de un modelo viscoelástico de cuatro elementos, se concluyó que esta elasticidad presentaba respuesta retardada debido al efecto combinado de los efectos viscoso y elástico.

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“…The utilization of cell-based model in 2D and the lack of dynamic culture environment could explain this observation. The second shortcoming of the mucus produced by cell-based model is its structure and composition [70]. Some differences between mucus from cell culture and native mucus have been highlighted as the mesh spacing [71] or the mucin expression pattern.…”

Section: New Improved Intestinal Barriersmentioning

confidence: 99%

The role of mucus in cell-based models used to screen mucosal drug delivery

Lechanteur

Neves

Sarmento

2018

Advanced Drug Delivery Reviews

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The increasing interest in developing tools to predict drug absorption through mucosal surfaces is fostering the establishment of epithelial cell-based models. Cell-based in vitro techniques for drug permeability assessment are less laborious, cheaper and address the concerns of using laboratory animals. Simultaneously, in vitro barrier models that thoroughly simulate human epithelia or mucosae may provide useful data to speed up the entrance of new drugs and new drug products into the clinics. Nevertheless, standard cell-based in vitro models that intend to reproduce epithelial surfaces often discard the role of mucus in influencing drug permeation/absorption. Biomimetic models of mucosae in which mucus production has been considered may not be able to fully reproduce the amount and architecture of mucus, resulting in biased characterization of permeability/absorption. In these cases, artificial mucus may be used to supplement cell-based models but still proper identification and quantification are required. In this review, considerations regarding the relevance of mucus in the development of cell-based epithelial and mucosal models mimicking the gastro-intestinal tract, the cervico-vaginal tract and the respiratory tract, and the impact of mucus on the permeability mechanisms are addressed. From simple epithelial monolayers to more complex 3D structures, the impact of the presence of mucus for the extrapolation to the in vivo scenario is critically analyzed. Finally, an overview is provided on several techniques and methods to characterize the mucus layer over cell-based barriers, in order to intimately reproduce human mucosal layer and thereby, improve in vitro/in vivo correlation.

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Mucus as a Barrier to Drug Delivery – Understanding and Mimicking the Barrier Properties

Cited by 277 publications

References 49 publications

A Model for the Transient Subdiffusive Behavior of Particles in Mucus

A Model for the Transient Subdiffusive Behavior of Particles in Mucus

Effect of pH on the rheological response of reconstituted gastric mucin

The role of mucus in cell-based models used to screen mucosal drug delivery

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