Facile preparation of poly(N-isopropylacrylamide)-based hydrogels via aqueous Diels–Alder click reaction

Abstract

The study reports a facile method of preparing poly(N-isopropylacrylamide)- based hydrogels by means of the Diels–Alder reaction. First, polymeric dienes were synthesized by free radical copolymerization between N-isopropylacrylamide (NIPA) and furfuryl methacrylate (FM), with 2, 2′-azobisisobutyronitrile (AIBN) as an initiator, and polymeric dienophile was obtained by a coupling reaction of poly(ethylene glycol) (PEG) and N-maleoyl-l-leucine (LMI) under N, N′-dicyclohexylcarbodiimide (DCC). Afterwards, the resultant dienes and dienophiles were dissolved in water and put in a refrigerator remaining a temperature of 9 °C, gelation via Diels–Alder reaction was observed after some time. The samples obtained at different steps were characterized by FTIR, NMR, GPC, SEM, CD, etc. It was found that LCST of copolymers decreases with the increase of FM content in copolymers. And the disassembly time of the hydrogels is closely related to the temperature and the solvents used. The swelling behavior study by gravimetric measurement indicates the hydrogels possess thermosensitivity and exhibit considerable swelling in water. Due to the simplicity of synthesis and no need for initiator or catalyzer and organic solvent, the strategy described here could find a promising application in the preparation of hydrogels.

Introduction

Hydrogels are a class of cross-linked polymers that can swell in water without dissolving [1]. As is well-known, living organs possess fantastic functions in soft and wet gel-like state. Therefore, hydrogels have been the research focus of many material scientists as excellent wet materials which are suitable for making artificial organs for medical treatments [2]. Especially, stimuli responsive or so-called “smart” polymer gels have been studied extensively during the past decades, which are capable to undergo quite strong and abrupt physical or chemical changes in response to small external changes such as pH, temperature, ionic strength, electric and magnetic field, etc. [3]. By far, the most studied temperature-sensitive polymer gel is cross-linked poly(N-isopropylacrylamide) [4], [5]. Due to its special properties, poly(N-isopropylacrylamide) is a good candidate material for many applications, such as in artificial muscles, drug delivery systems, separation membranes, catalysis substrates, actuators, and chemical valves [6]. Poly(N-isopropylacrylamide) gels exhibit a temperature-induced volume phase transition in water upon heating to above its lower critical solution temperature (LCST) at 32 °C, and the LCST can be appropriately adjusted by copolymerizing N-isopropylacrylamide with a more hydrophilic monomer or a more hydrophobic monomer [7], [8], [9], [10], [11]. Below LCST, the poly(N-isopropylacrylamide) hydrogel takes in a lot of water in its network, and thus exhibits a swollen state. But above its LCST, its swollen state collapses and displays an abrupt reduction in volume. And this process of phase transition is thermoreversible [12], [13]. These characteristics make poly(N-isopropylacrylamide) hydrogels a particularly interesting class of “intelligent” materials. Generally, polymer hydrogels can be divided into two main classes: chemically cross-linked hydrogels, and physically cross-linked hydrogels [14]. The hydrogels formed by physical crosslink can perform a reversible gel–sol transition without catalyzer or initiator, but their mechanical strength is lower than that of the hydrogels formed by chemical crosslink and the loss in vivo is unavoidable due to humoral scour. Therefore, much attention has been paid to the hydrogels formed by chemical crosslink. But there are still some drawbacks in the traditional preparation methods of hydrogels. One is that the hydrogels formed by chemical crosslink usually contain catalyzer or initiator, which is difficult to be gotten rid of and debases the biocompatibility of materials. Moreover, traditional hydrogel synthesis relies upon uncontrolled crosslinking methods, such as radical chemistry, which leads to poorly defined materials and increases the difficulty in correlating the network structure with the final physical properties of the gel [15]. Therefore, methods of preparing hydrogels have been constantly explored so as to improve the properties of hydrogels [16], [17]. The Diels–Alder reaction is a chemoselective reaction and water has an extraordinary rate-accelerating effect on the reaction process [18], [19], [20], [21]. On the other hand, Diels–Alder reaction is thermally reversible, whose reaction degree can be controlled by temperature [22], [23], [24], [25], [26], [27], [28]. It is also one representation of “click”-typed reactions [29]. Furthermore, Diels–Alder reaction can be applied to the preparation of chiral polymer [30]. Based on these properties of Diels–Alder reaction, it can be speculated that Diels–Alder reaction is a promising reaction for the preparation of hydrogels. Chujo et al. reported the first example of a thermally reversible hydrogel through the covalent bond, and the hydrogel was prepared by means of intermolecular Diels–Alder reaction between furan-modified poly(N-acetylethylenimine) (PAEI) and maleimide-modified PAEI [31]. Later, they prepared polymer hybrids utilizing the Diels–Alder reaction [26], [32]. Liu et al. reported gel formation through Diels–Alder in N, N-dimethylacetamide from polymers based on maleimide-containing polyamides and a tri-functional furan compound [33]. More recently, we demonstrated a novel gelation process based on the aqueous Diels–Alder reaction of poly(N, N-dimethylacrylamide-co-furfuryl methacrylate) and N-[4-(formyl polyethylene glycol ester) bismaleimide. It was found that water can accelerate Diels–Alder reaction while DMF can accelerate retro-Diels–Alder reaction. Swelling/shrinking kinetics indicates that the as-prepared hydrogels have high swelling ratio and can respond to temperature [34]. But its thermosensitivity is lower, so we replaced N, N-dimethylacrylamide by N-isopropylacrylamide, a most used monomer to prepare thermosensitive hydrogel, to improve its thermosensitivity. In order to enhance the biocompatibility, we use N-maleoyl-l-leucine (LMI) to synthesize polymeric dienophiles, which possess chirality and can be used to prepare chiral hydrogels. As a result, thermosensitive chiral hydrogels were obtained in our laboratory.