ABSTRACT
Hydrogels are cross-linked three-dimensional polymer networks that have tissue-like properties. Dynamic covalent bonds (DCB) can be utilized as hydrogel cross-links to impart injectability, self-healing ability, and stimuli responsiveness to these materials. In our research, we utilized dynamic thiol-Michael bonds as cross-links in poly(ethylene glycol) (PEG)-based hydrogels. Because the equilibrium of the reversible, exothermic thiol-Michael reaction can be modulated by temperature, we investigated the possibility of using thermal and photothermal stimuli to modulate the gel-to-sol transition of these materials with the aim of developing an on-demand pulsatile cargo release system. For this purpose, we incorporated poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles within the hydrogel to facilitate photothermal modulation using near-infrared light. PEDOT nanoparticles of 50 nm in diameter and with strong near-infrared absorption were prepared by oxidative emulsion polymerization. We then used Michael addition of thiol-ene pairs from 4-arm PEG-thiol (PEG-SH) and 4-arm PEG-benzylcyanoacetamide (PEG-BCA) to form dynamically cross-linked hydrogels. PEDOT nanoparticles were entrapped in situ to form Gel/PEDOT composites. Rheology and inverted tube test studies showed that the gel-to-sol transition occurred at 45-50 °C for 5 wt % gels and that this transition could be tailored by varying the wt % of the polymer precursors. The hydrogels were found to be capable of self-healing and being injected with a clinically relevant injection force. Bovine serum albumin-fluorescein isothiocyanate (BSA-FITC), a fluorescently labeled protein, was then loaded into the Gel/PEDOT as a therapeutic mimic. Increased release of BSA-FITC upon direct thermal stimulation and photothermal stimulation with an 808 nm laser was observed. Pulsatile release of BSA-FITC over seven cycles was demonstrated. MTS and live-dead assays demonstrated that Gel/PEDOT was cytocompatible in MDA-MB-231 breast cancer and 3T3 fibroblast cell lines. Further studies demonstrated that the encapsulation and laser-triggered release of the chemotherapeutic agent doxorubicin (DOX) could also be achieved. Altogether, this work advances our understanding of the temperature-dependent behavior of a dynamic covalent hydrogel, Gel/PEDOT, and leverages that understanding for application as a photothermally responsive biomaterial for controlled release.
ABSTRACT
Obesity is accompanied by inflammation in adipose tissue, impaired glucose tolerance, and changes in adipose leukocyte populations. These studies of adipose tissue from humans and mice revealed that increased frequencies of T-bet+ B cells in adipose tissue depend on invariant NKT cells and correlate with weight gain during obesity. Transfer of B cells enriched for T-bet+ cells exacerbates metabolic disorder in obesity, while ablation of Tbx21 specifically in B cells reduces serum IgG2c levels, inflammatory cytokines, and inflammatory macrophages in adipose tissue, ameliorating metabolic symptoms. Furthermore, transfer of serum or purified IgG from HFD mice restores metabolic disease in T-bet+ B cell-deficient mice, confirming T-bet+ B cell-derived IgG as a key mediator of inflammation during obesity. Together, these findings reveal an important pathological role for T-bet+ B cells that should inform future immunotherapy design in type 2 diabetes and other inflammatory conditions.
