Redox- and glucose-responsive hydrogels from poly(vinyl alcohol) and 4-mercaptophenylboronic acid
Graphical abstract
Introduction
Hydrogels are soft, wet and elastic materials that are formed from physically or chemically cross-linked networks of hydrophilic polymers upon their swelling in water. Hydrogels have been widely studied as materials for biomedical and pharmaceutical applications. They have already found several commercial applications as contact lenses, wound dressings, drug delivery systems, hygiene products and scaffolds for tissue engineering [1], [2], [3], [4], [5], [6].
Chemically cross-linked hydrogels (or chemical hydrogels) are usually synthesized either by three-dimensional polymerization of hydrophilic monomers (e.g. 2-hydroxyethylmethacrylate and 2-hydroxyethylacrylate) [7] or through cross-linking of ready-made water-soluble polymers using ionizing radiation [8], [9], thermal treatment [10], or reactive low or high molecular weight cross-linkers (e.g. glutaraldehyde) [11]. Chemical hydrogels are usually irreversible, i.e. they cannot be re-dissolved because their cross-linking is achieved via stable covalent bonds [1], [2], [3], [4], [5], [6].
Physically cross-linked hydrogels (physical hydrogels) are formed through non-covalent interactions either in polymers or in low molecular weight organogelators. These may include hydrogen bonding, electrostatic and hydrophobic effects, crystallization, etc. Examples of physical hydrogels include cryogels formed by poly(vinyl alcohol) (PVA) using freeze–thawing technique to induce formation of crystallites that act as physical cross-links [12]; thermally-reversible gels formed by some block-copolymers [13], hydrogels formed by reaction of alginate with calcium ions [14], and gels formed by self-assembly of certain peptide-based hydrogelators [15]. Physical hydrogels are typically reversible, i.e. they could be re-dissolved in response to changes in environmental conditions (e.g. temperature, pH of solution, etc.).
Boronic acid-containing hydrogels have been recently recognized as an important class of intelligent materials due to their unique properties such as glucose-sensitivity, reversibility and self-healing ability [16]. These hydrogels could be formed through interaction between boronic acid – containing molecules and poly(vinyl alcohol) in aqueous solutions. This interaction is covalent in nature but the bonds formed are not very stable and are reversible (dynamic covalent bonds) upon changes in environmental temperature, pH and presence of competitive molecules (e.g. glucose). These materials represent an intermediate class between chemical and physical hydrogels because of their covalent nature of cross-linking but reversibility in their properties. Hydrogels formed in aqueous mixtures of PVA and borate ions were considered as materials promising for pharmaceutical applications [17].
Recently, Yang and co-workers [18] reported the formation of glucose-responsive hydrogels based on dynamic covalent chemistry and inclusion complexation. They have synthesized bifunctional phenylboronic acid (PBA)-terminated cross-linker based on polyethyleneglycol (PBA–PEG–PBA) and formed gels by mixing this material with poly(ethylene oxide)-b-poly(vinyl alcohol) (PEG-b-PVA) and α-cyclodextrin in aqueous solutions. The hydrogel was formed through the interactions of PVA blocks with PBA–PEG–PBA and inclusion complexation between PEO blocks and α-cyclodextrin.
Chemical reactions involving thiol functional groups (–SH) have recently received a lot of interest from material and polymer scientists. Thiol groups have excellent reactivity that allows their use in a variety of reactions leading to new materials, polymers or bioconjugates [19], [20]. One of the unique features of thiol groups is their ability to undergo oxidation under very mild conditions to form disulfide bonds (–S–S–). This oxidation could be mediated by atmospheric oxygen or by the presence of oxidizing agents in solution, e.g. hydrogen peroxide [21], [22].
Here, we report a novel one-pot synthesis of hydrogels in aqueous mixtures of PVA and 4-mercaptophenylboronic acid (MPBA) in the presence of an oxidative environment (atmospheric oxygen or hydrogen peroxide). The oxidative environment facilitated the formation of MPBA dimers via disulfide bringing that act as cross-linker for PVA via dynamic covalent chemistry. The disulfide bridges (–S–S–) in these hydrogels could be easily cleaved in the presence of glutathione, which makes these materials sensitive to redox environment. The bonds formed between –B(OH)2 groups of MPBA and 1,2-diols of PVA could also be cleaved in the presence of d-glucose, making the hydrogels glucose-responsive.
Section snippets
Materials
Two batches of poly(vinyl alcohol) (PVA) were used in this study: 88–97 kDa PVA, 87–89% hydrolyzed (Alpha Aesar) and 205 kDa PVA 86.7–88.7% hydrolyzed (FlukaChemika). 4-mercaptophenylboronic acid (MPBA, purity ⩾ 90%), l-glutathione reduced (purity ⩾ 98%) and hydrogen peroxide (30%) were purchased from Sigma Aldrich, Inc. (UK); d-glucose was received from BDH Analar; sodium hydroxide (analytical grade 97+%) was purchased from Fisher Scientific. All reagents were used as received.
Preparation of solutions
PVA solutions of three
Formation of hydrogels
MPBA is a relatively hydrophobic compound that is soluble in water only at pH > 9, so all experiments used 0.1–1 M NaOH solutions as a medium.
Mixing of aqueous solutions of PVA and MPBA at different concentrations resulted in the formation of hydrogels, which was initially detected visually through the pronounced thickening of the mixture with a subsequent formation of a non-flowing gel. The experiments were performed using rheological measurements and provided a quantitative data on the gelation
Conclusions
Simple mixing of aqueous solutions of poly(vinyl alcohol) with 4-mercaptophenylboronic acid at pH > 9 in an oxidative environment (either presence of hydrogen peroxide or exposure to atmospheric oxygen) results in formation of polymeric hydrogels. These hydrogels are formed due to oxidative dimerization of 4-mercaptophenylboronic acid via disulfide bond formation, and dynamic covalent bond formation between 1,2-diols present in poly(vinyl alcohol) and phenylboronic acid groups. These hydrogels
Acknowledgement
This work was partially supported by the grant from the Ministry of Education and Science of the Republic of Kazakhstan (3471/GF4).
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