The particle in the spider's web: transport through biological hydrogels

Abstract

Biological hydrogels such as mucus, extracellular matrix, biofilms, and the nuclear pore have diverse functions 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 of particles of all sizes including peptides, antibiotics, and nanoparticles and in many cases this filtering can be described in terms of the effects of charge and hydrophobicity. The concepts described in this review can guide strategies to exploit or overcome gel barriers, particularly for applications in diagnostics, pharmacology, biomaterials, and drug delivery.

Figure 1

Scanning electron microscopy of biological hydrogels. a) Cervical mucus samples from pregnant patients at low or high risk for preterm birth. Scale bar: 200nm. Reprinted with permission from Critchfield et al. (2013). Copyright (2013) PLOS. b) Reconstituted basal lamina ECM gels. Scale bar: 25μm. Reprinted with permission from Arends et al. (2015). Copyright (2015) PLOS.

Figure 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 interactions with gel polymers can enhance partitioning into the gel and subsequent penetration. The schematic assumes that the bath is fixed at a constant solute concentration. d) Binding to the gel causes enrichment of solute at the interface but slowed gel penetration.

Figure 3

Steric effects on diffusion in gels (a-c) and mechanisms to modulate steric hindrance (d-e). Thin lines represent thermal motion of the particle. a) Particles smaller than the mesh size diffuse freely in interstitial fluid. b) Particles on the order of the mesh size have significant steric hindrance but eventually penetrate gels. c) Large particles are trapped. d) Particles that cleave gel polymers may diffuse more quickly. Notched green circles attached to particle are lytic enzymes; green segments of gel polymer are substrates for the enzymes. e) Particles may reversibly disrupt gel crosslinks (blue-blue contacts), allowing enhanced diffusion without irreversibly degrading the gel.

Figure 4

Distinction between “binding” and “partitioning.” a) Penetration of Cy5-labeled (fluorescent) tobramycin and ciprofloxacin into P. aeruginosa biofilms. Plots represent quantified timecourses of penetration, with representative images shown above plots. Cy5-tobramycin penetrates the gel less extensively than Cy5-ciprofloxacin. Adapted with permission from Tseng et al. (2013). Copyright (2013) Society for Applied Microbiology and John Wiley and Sons Ltd. b) Penetration of Avidin and a neutral Avidin variant (NeutrAvidin), both fluorescently labeled with fluorescein isocyanate (shown in green), into bovine articular cartilage. Positively charged Avidin penetrates more than NeutrAvidin. Reprinted with permission from Bajpayee et al. (2014). Copyright (2014) Elsevier. c, d) Schematic of difference between a and b in terms of nanoscale free energy landscape. c) Cy5-tobramycin binds specific targets and must escape binding energy wells to continue diffusing, meaning that electrostatic potential is not constant on the nanoscale. d) Avidin diffuses in nearly uniformly charged cartilage; thus, binding energy wells are minimal and a Donnan treatment of electrostatics is appropriate.

Figure 5

Nanoscale heterogeneity of solutes and effect on gel diffusion. a) Surfaces of (i) human rhinovirus (PDB: 2rm2) and (ii) human albumin (PDB: 2bxi), with positive charges in blue and negative charges in red. Reprinted with permission from Cone (2009), (Copyright (2009) Elsevier). Rhinovirus and albumin are densely coated with opposing charges. b) Two fluorescently labeled peptides with the same net charge but different spatial arrangement. The “block” peptide at left interacts weakly with mucin while the “alternating” peptide at right does not; schematic shows potential mechanism for this difference. c) Effect of immobilized charges on nearby hydrophobic interactions, probed by measuring the adhesion of a hydrophobically functionalized gold (Au) atomic force microscopy tip adhesion to surface monolayers. Amine (NH₃⁺) groups strengthen hydrophobic interactions between these hydrophobic surfaces, while guanidinium (Gdm⁺) groups weaken or eliminate them. Adapted by permission from Macmillan Publisher Ltc: Nature (Ma et al., 2015). Copyright (2015).

Figure 6

Mechanisms of polyvalent trapping in gels. a) Non-specific interactions (hydrophobic, electrostatic, etc) with gel can trap a particle, even if individual interactions are weak. b) Binding to decoy receptors (such as sialic acid) that are present on gel polymers can trap a particle. c) Gel-binding antibody bound to an otherwise inert particle mediates trapping.