Micro- and macrorheology of mucus Lai, Samuel K.; Wang, Ying-Ying; Wirtz, Denis ...
Advanced drug delivery reviews,
02/2009, Letnik:
61, Številka:
2
Journal Article
Recenzirano
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Mucus is a complex biological material that lubricates and protects the human lungs, gastrointestinal (GI) tract, vagina, eyes, and other moist mucosal surfaces. Mucus serves as a physical barrier ...against foreign particles, including toxins, pathogens, and environmental ultrafine particles, while allowing rapid passage of selected gases, ions, nutrients, and many proteins. Its selective barrier properties are precisely regulated at the biochemical level across vastly different length scales. At the macroscale, mucus behaves as a non-Newtonian gel, distinguished from classical solids and liquids by its response to shear rate and shear stress, while, at the nanoscale, it behaves as a low viscosity fluid. Advances in the rheological characterization of mucus from the macroscopic to nanoscopic levels have contributed critical understanding to mucus physiology, disease pathology, and the development of drug delivery systems designed for use at mucosal surfaces. This article reviews the biochemistry that governs mucus rheology, the macro- and microrheology of human and laboratory animal mucus, rheological techniques applied to mucus, and the importance of an improved understanding of the physical properties of mucus to advancing the field of drug and gene delivery.
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•Methods to examine the interactions between mucus layer and nanocarriers were depicted.•Methods to analyze particle diffusion in mucus were summarized.•The explanations allow a ...better comparison of obtained results.•The discussed pros and cons provide a good starting point in this research field.
The present review provides an overview of methods and techniques for studying interactions of micro- and nanoparticulate drug delivery system with mucus. Nanocarriers trapped by mucus are featuring a change in particle size and zeta potential that can be utilized to predict their mucus permeation behavior. Furthermore, interactions between nanoparticulate drug delivery systems and mucus layer modify the viscoelasticity of mucus which can be detected via rheological studies and quartz crystal microbalance with dissipation monitoring (QCM-D) analysis. Having a closer look at molecular interactions between drug carrier and mucus small-angle neutron scattering (SANS) is an appropriate analysis technique. Moreover, different methods to determine particle diffusion in mucus such as the newly established Transwell diffusion system, rotating silicone tube technique, multiple-particle tracking (MPT) and diffusion NMR are summarized within this review. The explanations and discussed pros and cons of collated methods and techniques should provide a good starting point for all those looking forward to move in this interesting field.
Mucus is a complex hydrogel that acts as a natural barrier to drug delivery at different mucosal surfaces including the respiratory, gastrointestinal, and vaginal tracts. To elucidate the role mucus ...plays in drug delivery, different in vitro, in vivo, and ex vivo mucus models and techniques have been utilized. Drug and drug carrier diffusion can be studied using various techniques in either isolated mucus gels or mucus present on cell cultures and tissues. The species, age, and potential disease state of the animal from which mucus is derived can all impact mucus composition and structure, and therefore impact drug and drug carrier diffusion. This review provides an overview of the techniques used to characterize drug and drug carrier diffusion, and discusses the advantages and disadvantages of the different models available to highlight the information they can afford.
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•Nanotechnology-based strategies to overcome various mucus gel barriers.•Innovative strategies lowering the mucus barrier function by acting in several ways.•Introduce strategies to ...improve the mucus permeation behavior of particles.•Present systems avoiding back-diffusion of particles out of the mucus gel layer.
The present review provides an overview of nanotechnology-based strategies to overcome various mucus gel barriers including the intestinal, nasal, ocular, vaginal, buccal and pulmonary mucus layer without destroying them. It focuses on the one hand on strategies to improve the mucus permeation behavior of particles and on the other hand on systems avoiding the back-diffusion of particles out of the mucus gel layer. Nanocarriers with improved mucus permeation behavior either exhibit a high density of positive and negative charges, bearing mucolytic enzymes such as papain and bromelain on their surface or display a slippery surface due to PEG-ylation. Furthermore, self-nanoemulsifying-drug-delivery-systems (SNEDDS) turned out to exhibit comparatively high mucus permeating properties. Strategies in order to avoid back-diffusion are based on thiolated polymers reacting to a higher extent with cysteine subunits of the mucus at pH 7 in deeper mucus regions than at pH 5 being prevalent in luminal mucus regions of the intestinal and vaginal mucosa. Furthermore, particles changing their zeta potential from negative to positive once they have reached the epithelium seem to be promising carriers. The summarized knowledge should provide a good starting point for further developments in this field.
Mucus is a viscoelastic and adhesive gel that protects the lung airways, gastrointestinal (GI) tract, vagina, eye and other mucosal surfaces. Most foreign particulates, including conventional ...particle-based drug delivery systems, are efficiently trapped in human mucus layers by steric obstruction and/or adhesion. Trapped particles are typically removed from the mucosal tissue within seconds to a few hours depending on anatomical location, thereby strongly limiting the duration of sustained drug delivery locally. A number of debilitating diseases could be treated more effectively and with fewer side effects if drugs and genes could be more efficiently delivered to the underlying mucosal tissues in a controlled manner. This review first describes the tenacious mucus barrier properties that have precluded the efficient penetration of therapeutic particles. It then reviews the design and development of new mucus-penetrating particles that may avoid rapid mucus clearance mechanisms, and thereby provide targeted or sustained drug delivery for localized therapies in mucosal tissues.
Fish mucus layers are the main surface of exchange between fish and the environment, and they possess important biological and ecological functions. Fish mucus research is increasing rapidly, along ...with the development of high-throughput techniques, which allow the simultaneous study of numerous genes and molecules, enabling a deeper understanding of the fish mucus composition and its functions. Fish mucus plays a major role against fish infections, and research has mostly focused on the study of fish mucus bioactive molecules (e.g., antimicrobial peptides and immune-related molecules) and associated microbiota due to their potential in aquaculture and human medicine. However, external fish mucus surfaces also play important roles in social relationships between conspecifics (fish shoaling, spawning synchronisation, suitable habitat finding, or alarm signals) and in interspecific interactions such as prey-predator relationships, parasite–host interactions, and symbiosis. This article reviews the biological and ecological roles of external (gills and skin) fish mucus, discussing its importance in fish protection against pathogens and in intra and interspecific interactions. We also discuss the advances that “omics” sciences are bringing into the fish mucus research and their importance in studying the fish mucus composition and functions.
The viscoelastic mucus secretions coating exposed organs such as the lung airways and the female reproductive tract can trap and quickly eliminate not only foreign pathogens and ultrafine particles ...but also particle-based drug delivery systems, thus limiting sustained and targeted drug delivery at mucosal surfaces. To improve particle distribution across the mucosa and enhance delivery to the underlying epithelium, many investigators have sought to develop nanoparticles capable of readily traversing mucus. The first synthetic nanoparticles shown capable of rapidly penetrating physiological mucus secretions utilized a dense coating of polyethylene glycol (PEG) covalently grafted onto the surface of preformed polymeric nanoparticles. In the decade since, PEG has become the gold standard in engineering mucus-penetrating drug carriers for sustained and targeted drug delivery to the lungs, gastrointestinal tract, eyes, and female reproductive tract. This review summarizes the history of the development of various PEG-based mucus-penetrating particles, and highlights the key physicochemical properties of PEG coatings and PEGylation strategies to achieve muco-inert PEG coatings on nanoparticle drug carriers for improved drug and gene delivery at mucosal surfaces.
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Barrier properties of mucus Cone, Richard A.
Advanced drug delivery reviews,
02/2009, Letnik:
61, Številka:
2
Journal Article
Recenzirano
Mucus is tenacious. It sticks to most particles, preventing their penetration to the epithelial surface. Multiple low-affinity hydrophobic interactions play a major role in these adhesive ...interactions. Mucus gel is also shear-thinning, making it an excellent lubricant that ensures an unstirred layer of mucus remains adherent to the epithelial surface. Thus nanoparticles (NP) must diffuse readily through the unstirred adherent layer if they are to contact epithelial cells efficiently. This article reviews some of the physiological and biochemical properties that form the mucus barrier. Capsid viruses can diffuse through mucus as rapidly as through water and thereby penetrate to the epithelium even though they have to diffuse ‘upstream’ through mucus that is being continuously secreted. These viruses are smaller than the mucus mesh spacing, and have surfaces that do not stick to mucus. They form a useful model for developing NP for mucosal drug delivery.
Mucus separates gut-luminal microbes from the tissue. It is unclear how pathogens like Salmonella Typhimurium (S.Tm) can overcome this obstacle. Using live microscopy, we monitored S.Tm interactions ...with native murine gut explants and studied how mucus affects the infection. A dense inner mucus layer covers the distal colon tissue, limiting direct tissue access. S.Tm performs near-surface swimming on this mucus layer, which allows probing for colon mucus heterogeneities, but can also entrap the bacterium in the dense inner colon mucus layer. In the cecum, dense mucus fills only the bottom of the intestinal crypts, leaving the epithelium between crypts unshielded and prone to access by motile and non-motile bacteria alike. This explains why the cecum is highly infection permissive and represents the primary site of S.Tm enterocolitis in the streptomycin mouse model. Our findings highlight the importance of mucus in intestinal defense and homeostasis.
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•Live imaging of Salmonella near-surface swimming on mouse colon inner mucus layer•Colon inner mucus layer traversal requires mucus breaches and flagellar propulsion•The mouse cecum lacks a continuous mucus layer, leaving epithelium tips uncovered•Exposed cecum epithelium tips are a hotspot for Salmonella infection
Using live microscopy, Furter et al. describe how the enteropathogen Salmonella Typhimurium crosses the protective intestinal mucus layer of its murine host. Flagella-driven motility, the mucus architecture, and its distribution determine where the pathogen preferentially infects the gut epithelium.
Colon has been shown to have a two-layered mucus system where the inner layer is devoid of bacteria. However, a complete overview of the mouse gastrointestinal mucus system is lacking. We now ...characterize mucus release, thickness, growth over time, adhesive properties, and penetrability to fluorescent beads from stomach to distal colon. Colon displayed spontaneous mucus release and all regions released mucus in response to carbachol and PGE2, except the distal colon and domes of Peyer's patches. Stomach and colon had an inner mucus layer that was adherent to the epithelium. In contrast, the small intestine and Peyer's patches had a single mucus layer that was easily aspirated. The inner mucus layer of the distal colon was not penetrable to beads the size of bacteria and the inner layer of the proximal colon was only partly penetrable. In contrast, the inner mucus layer of stomach was fully penetrable, as was the small intestinal mucus. This suggests a functional organization of the intestinal mucus system, where the small intestine has loose and penetrable mucus that may allow easy penetration of nutrients, in contrast to the stomach, where the mucus provides physical protection, and the colon, where the mucus separates bacteria from the epithelium. This knowledge of the mucus system and its organization improves our understanding of the gastrointestinal tract physiology.
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