RESUMO
Shear-thinning hydrogels represent an important class of injectable soft materials that are often used in a wide range of biomedical applications. Creation of new shear-thinning materials often requires that factors such as viscosity, injection rate/force, and needle gauge be evaluated to achieve efficient delivery, while simultaneously protecting potentially sensitive cargo. Here, a new approach to establishing shear-thinning hydrogels is reported where a host-guest cross-linked network initially remains soluble in deionized water but is kinetically trapped as a viscous hydrogel once exposed to saltwater. The shear-thinning properties of the hydrogel is then "switched on" in response to heating or exposure to visible light. These hydrogels consist of polynorbornene-based bottlebrush copolymers with porphyrin- and oligoviologen-containing side chains that are cross-linked through the reversible formation of ß-cyclodextrin-adamantane inclusion complexes. The resultant viscous hydrogels display broad adhesive properties across polar and nonpolar substrates, mimicking that of natural mucous and thus making it easier to distribute onto a wide range of surfaces. Additional control over the hydrogel's mechanical properties (storage/loss moduli) and performance (adhesion) is achieved post-injection using a low-energy (blue light) photoinduced electron-transfer process. This work envisions these injectable copolymers and multimodal hydrogels can serve as versatile next-generation biomaterials capable of light-based mechanical manipulation post-injection.
RESUMO
The pore-forming S. aureus α-toxin (Hla) contributes to virulence and disease pathogenesis. While high concentrations of toxin induce cell death, neutrophils exhibit relative resistance to lysis, suggesting that the action of Hla may not be solely conferred by lytic susceptibility. Using intravital microscopy, we observed that Hla disrupts neutrophil localization and clustering early in infection. Hla forms a narrow, ion-selective pore, suggesting that Hla may dysregulate calcium or other ions to impair neutrophil function. We found that sub-lytic Hla did not permit calcium influx but caused rapid membrane depolarization. Depolarization decreases the electrogenic driving force for calcium, and concordantly, Hla suppressed calcium signaling in vitro and in vivo and calcium-dependent leukotriene B4 (LTB4) production, a key mediator of neutrophil clustering. Thus, Hla disrupts the early patterning of the neutrophil response to infection, in part through direct impairment of neutrophil calcium signaling. This early mis-localization of neutrophils may contribute to establishment of infection.
