Frontal polymerization synthesis of temperature-sensitive hydrogels.

The study of hydrogels and their response to external environment is of special interest because of their potential as drug delivery systems,1,2 actuators,3 and separation devices.4,5 Temperature-sensitive hydrogels undergo a reversible swellingdeswelling transition with a small change of temperature near the phase transition point.6 A frequently studied thermosensitive hydrogel is based on solution free-radical cross-linking copolymerization of the monomer N-isopropylacrylamide and the crosslinker N-N-methylenebisacrylamide. The availability of preparation techniques allowing the synthesis of hydrogels with structural uniformity is limited by the exothermicity of the polymerization reaction which induces phase separation of linear poly(N-isopropylacrylamide) chains, PNIPAM, at 32 °C.7 Therefore, to generate uniform hydrogels, small-sized samples are usually produced at low monomer and initiator concentration and at low synthesis temperature that circumvent spatial inhomogeneties and microaggregation. Under these reaction conditions, the rates of polymerization and gelation are low, requiring longer time to synthesize hydrogels. We present here the first frontal polymerization synthesis of isopropylacrylamide (NIPAM) hydrogels at high monomer and initiator concentration. It has been found that, in addition to a more rapid synthesis of hydrogels, a substantial increase in the homogeneity of the microstructure of the hydrogel with respect to the solution polymerization is obtained. Moreover, large hydrogel samples with similar equilibrium swelling ratio can be readily produced without the effect of microaggregation and phase separation. Frontal polymerization involves the conversion of monomer to polymer in a localized reaction zone which propagates due to the interplay of thermal conduction and temperature-dependent reaction rates.8,9 First introduced as a way to synthesize poly(methyl methacrylate) at high pressure,10 the method was later extended by Pojman and co-workers to include numerous polymers11,12 and cross-linked networks13 produced at ambient pressure. Thermochromic composite materials, polymer blends, and simultaneous interpenetrating polymer networks have been synthesized by frontal polymerization.14-16 In these examples, the rapid reaction rate, observed in propagating fronts, circumvents phase separation that is common in batch studies. Consequently, the resulting materials are more uniform than ones synthesized in a batch reactor. At times, frontal polymerization may not be sufficient to arrest phase separation because the synthesis of polyacrylamide cross-linked with bisacrylamide leads to opaque gels, suggesting that phase separation does occur.13 Because the temperature of traveling fronts reaches close to the boiling point of water, DMSO was used as the solvent for producing isopropylacrylamide hydrogels. The gel system was typically studied for solutions containing NIPAM (2 g/mL), persulfate (0.008 g/mL), and bisacrylamide (0.02 g/mL). The monomer, NIPAM, the cross-linking agent, and the initiator were dissolved in a known amount of degassed DMSO. The homogeneous solution was purged with nitrogen for 10 minutes and transferred to a 10 cm long test tube (ID 13 mm). Initiation of the front was achieved by using a soldering iron as the heat source. Figure 1 shows a representative time series of frontal polymerization of NIPAM hydrogel. The initial temperature perturbation dissociates the initiator, persulfate, into radicals that combine with monomer units resulting in a polymer network after subsequent cross-linking. The heat of the polymerization reaction disperses into the unreacted region by thermal conduction, and a propagation front ensues. A slight difference in refractive index between the synthesized hydrogel and the gelling solution allows us to optically monitor the progression of the front and to determine its velocity from distance versus time plots. Under the conditions specified in Figure 1, the propagating front traveled through the system at a constant velocity of 8.3 mm/min. For the given dimensions, the entire hydrogel sample was synthesized within 10 min. Furthermore, we found that the speed of the front depends strongly on the initial concentration of persulfate, which can be used to further shorten the synthesis time. For example, a 2-fold increase in persulfate (0.032 to 0.064 m) corresponds to an increase in propagation velocity from 8.3 to 12.6 mm/min. The concentration of bisacrylamide, however, has little effect on the front velocity. To compare the macroscopic as well as microscopic properties of hydrogels obtained from frontal and conventional synthesis, reference gels with the same nominal composition were synthesized in a batch reactor at 60 °C. Both preparation schemes (1) Okano, T. AdV. Polym. Sci. 1993, 110, 180-195. (2) Dong, L. C.; Hoffman, A. S. J. Controlled Release 1986, 4, 223-226. (3) De Rossi, D.; Kajiwara, K.; Osada, Y.; Yamauchi, A., Eds. Polymer Gels Fundamental and Biomedical Applications; Plenum Press: New York, 1991. (4) Freitas, R. F. S.; Cussler, E. F. Chem. Eng. Sci. 1987, 42, 97-106. (5) Park, C.; Orozco-Avila, C. Biotechnol. Prog. 1992, 8, 521-524. (6) Hirotsu, S.; Hirokawa, Y.; Tanaka, T. J. Chem. Phys. 1984, 18, 63796382. (7) Gehrke, S. K. AdV. Polym. Sci. 1993, 110, 83-144. (8) Pojman, J. A.; Willis, J.; Fortenberry, D. I.; Ilyashenko, V.; Khan, A. J. Polym. Sci. Part A: Polym. Chem. 1995, 33, 643-652. (9) Pojman, J. A.; Ilyashenko, V. M.; Khan, A. M. J. Chem. Soc., Faraday Trans. 1996, 92, 2825-2837. (10) Chechilo, N. M.; Enikolopyan, N. S. Dokl. Akad. Nauk SSSR 1974, 214, 174-176. (11) Pojman, J. A. J. Am. Chem. Soc. 1991, 113, 6284-6286. (12) Pojman, J. A.; Nagy, I. P.; Salter, C. J. Am. Chem. Soc. 1993, 115, 11044-11045. (13) Pojman, J. A.; Curtis, G.; Ilyashenko, V. M. J. Am. Chem. Soc. 1996, 118, 3783-3784. (14) Nagy, I. P.; Sike, L.; Pojman, J. A. J. Am. Chem. Soc. 1995, 117, 3611-3612. (15) Pojman, J. A.; Elcan, W.; Khan, A. M.; Mathias, L. J. Polym. Sci., Part A: Polym. Chem. 1997, 35, 227-230. (16) Tredici, A.; Pecchini, R.; Sliepcevich, A.; Morbidelli, M. J. Appl. Polym. Sci. 1998, 70, 2695-2702. Figure 1. Sequence of image-processed video-frames illustrating the constant-speed propagation of the polymerization front. Initial conditions: 5 g of isopropylacrylamide, 0.02 g of ammonium persulfate, and 0.05 g of bisacrylamide in 2.5 mL of DMSO. 7933 J. Am. Chem. Soc. 2001, 123, 7933-7934