Injectable thermo-responsive hydrogel composed of xanthan gum and methylcellulose double networks with shear-thinning property

Highlights

• Xanthan gum and methylcellulose forms blend in aqueous solution.

• The blend is a high viscous solution at room temperature.

• The blend immediately forms hydrogel at body temperature after injection.

• The hydrogel is biocompatible and biodegradable in rat body.

• The hydrogel can be used as a long-term drug delivery material.

Abstract

Injectable hydrogel precursor solution was prepared by physical blend of xanthan gum (XG) and methylcellulose (MC) in aqueous solution. Due to the formation of XG network composed of XG double helical strand structure, XG/MC blend was a high viscous solution with good shear-thinning property at room temperature. When the temperature was changed from 23 to 37 °C, thermo-responsive MC network formed, which caused XG/MC blend solution to gelate. The gelation time and storage modulus of the blend can be tuned by XG and/or MC concentrations. Both in vitro and in vivo investigations revealed that the blend solution immediately recovered its high viscosity and rapidly formed hydrogel at body temperature after injection using a syringe. In vivo biocompatibility and biodegradability of the hydrogel were validated by implantation of the hydrogel in rats. In vitro investigation demonstrated that XG/MC blend is a promising injectable hydrogel material for long-term drug delivery.

Introduction

Injectable hydrogels have attracted much attention in biomedical field, such as drug delivery, cell encapsulation and tissue engineering (Li et al., 2012, Lv et al., 2014, Van Vlierberghe et al., 2011) because they can be administrated in a minimally invasive manner and can easily fill arbitrary shaped defects (Yu & Ding, 2008). Shear-thinning injectable hydrogels and high viscosity hydrogel precursor solutions can flow under a shear stress and recover its mechanical properties on removal of the stress, therefore, they can avoid the leakage of the hydrogel precursor solution from injection site (Gutowska et al., 2001, Guvendiren et al., 2012, Lu et al., 2012). Various shear-thinning injectable hydrogel systems have been reported in the literature, such as supramolecular hydrogels, peptide hydrogels and blend hydrogels (Guvendiren et al., 2012, Li and Loh, 2008). Blend hydrogels can combine two or more components with complementary properties together. For instance, Shoichet et al. developed an injectable blend hydrogel system composed of hyaluronic acid (HA) and methylcellulose (MC) for drug and cell deliveries (Caicco et al., 2013, Gupta et al., 2006). HA/MC blends could form hydrogels at room temperature due to the dehydration of MC induced by the carboxylic groups of HA; the hydrogels had a shear-thinning property and a higher modulus post-injection due to the entangled random coil structure of HA and the thermal gelation property of MC, respectively. The blend hydrogels possess the advantages of low cost, easy preparation and improved properties. However, to the best of our knowledge, few blend hydrogels with shear-thinning property have been reported until now. In addition, for widespread biomedical applications of shear-thinning injectable hydrogels, further improvements in mechanical properties, stability, biocompatibility, biodegradability, as well as tunable gelation and self-healing kinetics are required (Guvendiren et al., 2012).

MC is a methyl modified cellulose in the C2, C3 and C6 positions of the anhydroglucose repeat unit (Arvidson et al., 2013), and is widely used in pharmaceutics. When the degree of substitution (DS) of the methyl groups in the repeat unit is between 1.6 and 2.1, MC is water soluble at low temperature, whereas phase separation and gelation occur at elevated temperature (Lott, McAllister, Arvidson, Bates, & Lodge, 2013). The sol-gel transition temperature of MC aqueous solution is about 40–50 °C; the transition temperature lowers when increasing DS and MC concentration as well as adding salting-out salt, such as NaCl, into the solution (Van Vlierberghe et al., 2011, Xu et al., 2004).

Xanthan gum (XG) is a biocompatible and biodegradable anionic polysaccharide produced commercially by bacterial fermentation (Bejenariu, Popa, Dulong, Picton, & Le Cerf, 2009). XG consists of a linear β-(1-4)-d-glucose backbone, which is the same as cellulose. Every alternate glucose reside has a charged trisaccharide side chain consisting of β-d-mannose-(1,4)-β-d-glucuronic acid-(1,2)-α-d-mannose. The internal mannose unit may be acetylated in C-6 position and the terminal mannose may carry pyruvate residues linked in 4- and 6-positions (Bejenariu et al., 2009, Le and Turgeon, 2013). In aqueous solution, XG adopts two different conformations: an ordered and rigid double helical strand structure at low temperature and a disordered and flexible coil structure at high temperature (Roy et al., 2014). The midpoint transition temperature (T_m) is about 40–50 °C depending on ionic strength (Chantaro, Pongsawatmanit & Nishinari, 2013). When the temperature of XG solution is below its T_m, the ordered double helical strand structure forms three-dimensional network, thus XG solution exhibits a weak gel-like behavior and a shear-thinning property under stress (Iijima et al., 2007, Zhang et al., 2015). Dyondi et al. prepared an injectable hydrogel by physical blend of gellan gum and XG as a tissue engineering scaffold for multiple growth factor delivery for bone regeneration (Dyondi, Webster, & Banerjee, 2013).

XG has a good shear-thinning property and MC has a thermal gelation property. Herein, we produced injectable hydrogel precursor solution with high viscosity and excellent shear-thinning property at room temperature by blending XG and MC in pH 7.4 phosphate buffered saline solution (PBS, 10 mM phosphate buffer containing 0.15 M NaCl). The gelation properties of XG/MC blend with various XG and MC concentrations as well as the hydrogel structure were carefully characterized. The gelation mechanism was proposed. The biocompatibility and degradability of XG/MC hydrogel were validated both in vitro and in vivo. Drug loading and in vitro release were investigated. This study demonstrated that XG/MC blend is a promising injectable hydrogel material for drug delivery.