Fast-Forming Dissolvable Redox-Responsive Hydrogels: Exploiting the Orthogonality of Thiol-Maleimide and Thiol-Disulfide Exchange Chemistry

Abstract

Fast-forming yet easily dissolvable hydrogels (HGs) have potential applications in wound healing, burn incidences, and delivery of therapeutic agents. Herein, a combination of a thiol-maleimide conjugation and thiol-disulfide exchange reaction is employed to fabricate fast-forming HGs which rapidly dissolve upon exposure to dithiothreitol (DTT), a nontoxic thiol-containing hydrophilic molecule. In particular, maleimide disulfide-terminated telechelic linear poly(ethylene glycol) (PEG) polymer and PEG-based tetrathiol macromonomers are employed as gel precursors, which upon mixing yield HGs within a minute. The selectivity of the thiol-maleimide conjugation in the presence of a disulfide linkage was established through ¹H NMR spectroscopy and Ellman's test. Rapid degradation of HGs in the presence of thiol-containing solution was evident from the reduction in storage modulus. HGs encapsulated with fluorescent dye-labeled dextran polymers and bovine serum albumin were fabricated, and their cargo release was investigated under passive and active conditions upon exposure to DTT. One can envision that the rapid gelation and fast on-demand dissolution under relatively benign conditions would make these polymeric materials attractive for a range of biomedical applications.

Scheme 1. Schematic Illustration of Fabrication and Protein Encapsulation and Release from Fast-Forming Dissolvable HGs

Figure 1

Synthesis of the maleimide disulfide-terminated telechelic PEG polymer.

Figure 2

(A) ¹H and (B) ¹³C NMR spectra of maleimide disulfide-terminated PEG polymer.

Figure 3

Comparison of (A) ¹H and (B) ¹³C NMR spectra of the PEG bismaleimide polymer and thiol-conjugated bismaleimide polymers.

Figure 4

(A) Photographic image of a wet HG sample, (B) SEM image of a dry HG sample (scale bar: 100 μm), (C) frequency sweep test, and (D) water uptake swelling profile.

Figure 5

(A) Degradation behavior of the disulfide-containing HG in PBS and DTT (200 mM) solutions and (B) rheological analysis of the degradation of the HG in DTT solutions (10 and 100 mM).

Figure 6

Release profiles of 150 and 20 kDa FITC-dextran (F-Dextran) from HGs in DTT and PBS solutions.

Figure 7

Release profile of FITC–BSA protein from HGs immersed in reducing and nonreducing environments.

Figure 8

(A) Cell viability of L929 fibroblasts upon treatment with varying amount of HGs and with the degradation product of the HG (HG-d). Fluorescence microscopy images of the live/dead cell viability assay upon treatment with the (B) HG and (C) with the degradation product of hydrogel (scale bar in images: 50 μm).