Elsevier

Biomaterials

Volume 25, Issue 15, July 2004, Pages 3005-3012
Biomaterials

A rapid temperature-responsive sol–gel reversible poly(N-isopropylacrylamide)-g-methylcellulose copolymer hydrogel

https://doi.org/10.1016/j.biomaterials.2003.09.077Get rights and content

Abstract

Poly(N-isopropylacrylamide) (PNIPAAm) was grafted to methylcellulose (MC) with various feeding ratios using ammonium persulfate and N,N,N′,N′-tetramethyl ethylene diamine as an initiator. FTIR results confirm the formation of PNIPAAm-g-MC copolymers. The temperature responsiveness of copolymer gels was investigated by turbidimetry, dynamic contact angle (DCA), differential scanning calorimetry and dynamic mechanical analysis (DMA). The results indicate that PNIPAAm-g-MC hydrogels are strongly temperature responsive. At lower contents of MC, the lower critical solution temperature (LCST) is decreased, whereas further increasing MC contents raises the LCSTs. It is observed that the phase transition of the hydrogels occurs reversibly within 1 min, and near body temperature, a rigid gel can be generated in a certain range of MC content. What is more, the incorporation of MC prevents the syneresis of copolymer hydrogel. DMA measurement reveals that the storage moduli (E′) of the gels increase upon increasing MC contents, and moreover the values of E′ go up markedly above LCST. The copolymer hydrogels hold a promise as a blood vessel barrier by tuning gelation temperature, gelation time and mechanical strength.

Introduction

In the past decade, temperature-induced sol–gel reversible hydrogels have gained increasing attention of many investigators for scientific interest and for practical biomedical or pharmaceutical applications since the administration is convenient, and no organic solvents or toxic cross-linkers are involved during gelation [1]. Such a thermogelation may provide a convenient means for injectable drug delivery, particularly for biomacromolecules labile to be denatured. The in situ gelation is also beneficial for cell encapsulation in an extracellular matrix and for providing a scaffold for tissue regeneration [2]. Additionally, the sol–gel transition can be exploited as anatomical barriers.

Among the temperature-responsive hydrogels reported to date, poly(N-isopropylacrylamide) (PNIPAAm) homopolymer and its copolymers have been most intensively investigated [3], [4], [5], [6]. Okano’s group [7] developed a temperature-sensitive PNIPAAm-based vector for gene transfection. Above the lower critical transition temperature (LCST), PNIPAAm aggregated and formed a tight complex with DNA, which was favorable for protection of DNA from DNase degradation. Below LCST, PNIPAAm networks are hydrated, and consequently the complex became loosely packed, facilitating the gene transcription. Moreover, the transfection efficiency could be raised by copolymerizing hydrophobic monomers, 2-(dimethylamino)ethyl methacrylate and butylmethacrylate. It was reported that the chondrocytes encapsulated in a thermoreversible NIPAAM/acrylic acid copolymer gel demonstrated better phenotype expression [1]. Yoshioka et al. [8] investigated the thermogelation behavior of isopropylacrylamide-co-gelatin copolymers. The aqueous solution of isopropylacrylamide–gelatin conjugates turned into an elastic hydrogel upon heating above 34°C or cooling below 10°C. The hydrogel could turn back into a solution when an opposite temperature cycle was conducted. Stile et al. [9] synthesized an injectable PNIPAAm hydrogel loosely cross-linked with methylenebis(acrylamide). The hydrogels showed a great potential as a scaffold for tissue engineering. But the safety of the cross-linker remained uncertain for a long-term implantation. It was recently reported that poly(N-isopropylacrylamide-co-vinyl laurate) microgel dispersions demonstrated some unusual behaviors such as irreversible aggregation or macrogels in electrolyte solution when temperature is elevated [10]. It should be pointed out that the aforementioned research work did not touch upon the response time, which is rather important for in situ encapsulation of cells and anatomical barriers, particularly for the blood vessel barrier. It is imaginable that at slower gelation rate, the injected polymer solution would be carried away by blood stream, and consequently blocking the normal vessels. More recently, block and star copolymers of poly(ethylene glycol) and PNIPAAm with varying architectures have been synthesized. The copolymers formed somewhat viscoelastic gels within 1 min upon heating when the concentration of aqueous solution was >20%. And the resulting gels displayed no syneresis which frequently occurred for PNIPAAm [11].

Methylcellulose (MC) is also known to exhibit a typical reversible gelation in water on heating (gelation temperature 60–80°C) and then revert to the solution on cooling [12]. The thermoreversible gelation is the results of the cooperation of the hydrophobic interaction among methyl substituents with the intermolecular hydrogen bonds among hydroxyl groups [13], [14]. Compared to PNIPAAm, the MC hydrogel shows no syneresis.

Motivated by the need for hydrogels as anatomical barriers, in the present work we developed copolymers of polyisopropylacrylamide with MC for the first time. The aim is to combine two thermally sensitive hydrogels together to create a rapid responding sol–gel reversible hydrogel without syneresis. This article includes: (1) the gelation temperature and response rate were determined; (2) the surface transition behavior was examined; (3) the thermogelation behavior was elucidated by differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA); and (4) gelation was visually inspected.

Section snippets

Materials

N-isopropylacrylamide (NIPAAm, purchased from Aldrich Chemical Co.) was purified by recrystallization in hexane and dried in vacuo at 25°C. MC (DS is 1.6, Dow Chemical Co.) was purified by dissolution in distilled water, dialysis for 5 days using Cellu SepH1 membrane (MWCO=12,000) against water. The solution was then freeze-dried. The initiator ammonium persulfate (APS) and the activator N,N,N′,N′-tetramethyl ethylene diamine (TEMED) (Fluka Co.) were used as received. All reagents used were of

Characterization of copolymers by FTIR

Fig. 1 shows the FTIR spectra of PNIPAAm, MC and PNIPAAm-g-MC copolymers. As shown in Fig. 1(a), an absorbance band at 1647 cm−1 is assigned to the carbonylamide and N–H stretching of PNIPAAm; while the sharp peaks at 1387, 1367 cm−1 correspond to the characteristic absorbance of isopropyl in PNIPAAm [15]. From Fig. 1(g), it can be seen that two bands located around 1117 and 1070 cm−1 are attributed to the stretching of ether bonds in MC. An intense band at 3455 cm−1 is the stretching vibration of

Conclusions

Fast reversibly temperature-responsive copolymers based on poly(N-isopropylacrylamide)-g-methylcellulose (PNIPAAm-g-MC) can be prepared by adjusting compositions. The incorporation of MC affects the lower critical solution temperature (LCST). At lower contents of MC, LCSTs are decreased, whereas further increasing MC contents raises the LCSTs, which is presumably due to the formation and dissociation of ordered water caused by MC. The storage moduli (E′) of copolymers are dependent on

Acknowledgements

The authors are indebted to the financial supports from the High Tech Research and Development (863) Programme of China (Grant No. 2002AA326100).

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