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The Particle in the Spider's Web: Transport Through Biological Hydrogels

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The Particle in the Spider's Web: Transport Through Biological Hydrogels Nanoscale View Article Online FEATURE ARTICLE View Journal | View Issue The particle in the spider’s web: transport through biological hydrogels Cite this: Nanoscale, 2017, 9, 8080 Jacob Witten a,b and Katharina Ribbeck*a Biological hydrogels such as mucus, extracellular matrix, biofilms, and the nuclear pore have diverse func- tions and compositions, but all act as selectively permeable barriers to the diffusion of particles. Each barrier has a crosslinked polymeric mesh that blocks penetration of large particles such as pathogens, nanotherapeutics, or macromolecules. These polymeric meshes also employ interactive filtering, in which affinity between solutes and the gel matrix controls permeability. Interactive filtering affects the transport Received 18th December 2016, of particles of all sizes including peptides, antibiotics, and nanoparticles and in many cases this filtering Accepted 12th May 2017 can be described in terms of the effects of charge and hydrophobicity. The concepts described in this DOI: 10.1039/c6nr09736g review can guide strategies to exploit or overcome gel barriers, particularly for applications in diagnostics, rsc.li/nanoscale pharmacology, biomaterials, and drug delivery. 1. Introduction: hydrogels are example, both archaea1 and bacteria can form biofilms, or microbial aggregates surrounded by secreted extracellular poly- ubiquitous selective barriers in biology meric substances (EPS) that act as a protective barrier and Biological hydrogels, which are composed of hydrated polymer create microenvironments within which microbes thrive and 2,3 networks, are found throughout every domain of life. For adapt to harsh conditions. In eukaryotes, hydrogels have evolved to fulfill an astonishingly diverse set of functions. For example, the nuclear pore is a barrier formed from crosslinked aDepartment of Biological Engineering, Massachusetts Institute of Technology, intrinsically disordered proteins called nucleoporins, which Cambridge, MA 02139, USA. E-mail: [email protected]; Tel: +1 (617) 715-4575 b control the passage of macromolecules between the nucleus Computational and Systems Biology Initiative, Massachusetts Institute of 4,5 Published on 16 May 2017. Downloaded by MIT Library 10/07/2017 16:04:33. and the cytoplasm. One of the largest hydrogels in the body Technology, Cambridge, MA 02139, USA Jacob Witten received his BA in Katharina Ribbeck is Eugene Bell Mathematics and Biophysics Career Development Professor of from Amherst College in 2014, Tissue Engineering in the where he researched compu- Department of Biological tational methods for hydrogen Engineering at the Massachusetts exchange mass spectrometry. In Institute of Technology. She 2015, he joined Professor received her Ph.D. in Biology at Katharina Ribbeck’s group in the the University of Heidelberg in department of Biological Germany. Her lab studies the Engineering at Massachusetts basic mechanisms by which bio- Institute of Technology as a doc- logical hydrogels barriers toral student. His current exclude, or allow passage of Jacob Witten research combines compu- Katharina Ribbeck different molecules and patho- tational and experimental tech- gens, and the mechanisms patho- niques to study molecular transport in mucus, focusing on appli- gens have evolved to penetrate mucus barriers. Her goal is to cations to drug delivery for treating diseases such as cystic develop the foundation for a theoretical framework that captures fibrosis. general principles governing selectivity biological hydrogels, and for the reconstitution of synthetic gels that mimic the basic selective properties of biological gels. 8080 | Nanoscale,2017,9,8080–8095 This journal is © The Royal Society of Chemistry 2017 View Article Online Nanoscale Feature article ponents. However, biofilm EPS commonly contains extracellu- lar DNA and various types of polysaccharides.2 One well- studied biofilm is that formed by Pseudomonas aeruginosa,an opportunistic pathogen that can cause biofilm-associated infection in wounds27 or in the lungs of patients with cystic fibrosis (CF).28 Interestingly, even this single species pro- duces anionic (alginate), cationic (Pel),29 and neutral (Psl)30 polysaccharides in differing amounts depending on context and bacterial strain.31 Fibrous structural proteins such as collagens, elastin, fibro- nectin, and laminins, together provide much of the structural integrity of ECM. ECM also contains high levels of polyanionic glycosaminoglycans (GAGs) and proteoglycans (proteins with densely grafted GAGs) that give ECM a high net negative charge density. Structural components of ECM are covalently crosslinked to varying degrees, regulating matrix stiffness.11 In human mucus, the main gel-forming components consist of a family of large, intrinsically disordered secreted glycoproteins called mucins. The main secreted mucins are MUC2, MUC5B, and MUC5AC, although other secreted mucins can be present in smaller amounts as well.7 Mucins have alter- nating regions of small, globular hydrophobic domains and highly glycosylated, primarily anionic (due to sialic acid and 7,32,33 Fig. 1 Scanning electron microscopy of biological hydrogels. (a) sulfation) unstructured regions. Other components of Cervical mucus samples from pregnant patients at low or high risk for mucus include lipids, soluble proteins and peptides, and preterm birth. Scale bar: 200 nm. Reprinted with permission from nucleic acids.32 Mucus composition can vary depending on 196 Critchfield et al. (2013). Copyright (2013) PLOS. Published under CC disease state, and in this review we highlight CF, a genetic BY license. https://creativecommons.org/licenses/by/4.0/legalcode. (b) μ disease in which improper ion balance results in pathologi- Reconstituted basal lamina ECM gels. Scale bar: 25 m. Reprinted with 34 permission from Arends et al. (2015).197 Copyright (2015) PLOS. cally thick, dehydrated mucus. The presence of necrotic Published under CC BY license. https://creativecommons.org/licenses/ neutrophils in CF airways results in high levels of free DNA by/4.0/legalcode. and actin filaments in lung mucus,35 increasing the mucus’ viscoelasticity32 and playing important roles in binding to cations. More detailed reviews can be found on composition of is the mucus gel (Fig. 1a) that lines all wet epithelia and pro- biofilms,2,36 of the ECM,11,24,37 and of mucus.6,7,32,38,39 Published on 16 May 2017. Downloaded by MIT Library 10/07/2017 16:04:33. tects the underlying cells against toxins, pollutants, and invad- While biological hydrogels are distinct in terms of their – ing pathogens.6 10 Another example of a hydrogel-based locations and molecular compositions, they share certain barrier is the extracellular matrix (ECM) surrounding cells common principles that govern selective filtration. The goal of within tissues. ECM provides mechanical stability but also this review is to address the general principles that apply to forms a selective barrier that regulates transport of signaling the permeability of many types of biological hydrogels. – molecules secreted by the cells (Fig. 1b).11 16 Broadly speaking, the transport of a solute through a gel is The permeability of biological hydrogels poses a challenge controlled by the solute’s size, its interactions with the com- for biomedical development. For example, biofilms are ponents of the gel, or a combination of the two (Fig. 2).40 Size, involved in the majority of infections in developed countries; or steric, filtering is a universal feature of biological gels, they form on medical implants and wounds, cause middle-ear which have a polymeric mesh size that constrains the infections and gingivitis, and more.17 One driver of antibiotic diffusion of large particles (Fig. 2a). Pure steric filtering is an resistance in biofilms is binding of antibiotics to EPS, which important component of hydrogel selectivity, but it is also sequesters them and/or reduces their penetration into the crude because it only selects based on one parameter. Filtering biofilm. In humans, the ECM is an obstacle to drug delivery, based on chemical interactions between solutes and gel com- as its mesh prevents large nanoparticles from penetrating ponents is also a common feature of biological gels. – deep into tissue or tumors.18 24 Mucus similarly controls the Depending on their chemistry, the gel components interact permeability of nanoparticles,25,26 but can also limit diffusion with solutes across gradients of chemical properties including of small molecules such as antibiotics. charge and hydrophobicity, thereby differentially affecting Biological hydrogels are complex molecular assemblies diffusion.40 A lack of interactions enables unhindered with context-dependent properties. For biofilm EPS, the struc- diffusion (Fig. 2b), while certain weak and diffuse solute–gel ture of the matrix varies widely across species, strains, and interactions can facilitate penetration of the solute into the gel environments, complicating the characterization of EPS com- without slowing transport (Fig. 2c). Binding to hydrogels, on This journal is © The Royal Society of Chemistry 2017 Nanoscale,2017,9,8080–8095 | 8081 View Article Online Feature article Nanoscale Fig. 2 Effects of steric hindrance and chemical interactions on gel penetration. (a) Particles above the mesh size are unable to penetrate the gel, even if they do not interact with the gel. (b) Small inert particles penetrate gels. (c) Under some conditions (see Section 3.4 for details), weak inter- actions with gel polymers can enhance partitioning into
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