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Abstract:
In situ crosslinked materials are the main interests of both scientific and industrial research. Methylcellulose (MC) aqueous solution is one of the representatives that belongs to this family of thermosensitive materials. At room temperature, MC is a liquid whereupon during temperature increase up to 37 °C, it crosslinks physically and turns into a hydrogel. This feature makes it unique, especially for tissue engineering applications. However, the crosslinking rate of MC alone is relatively slow considering tissue engineering expectations. According to these expectations, the crosslinking should take place slowly enough to allow for complete injection and fill the injury avoiding clogging in the needle, and simultanously, it should be sufficiently fast to prevent it from relocation from the lesion. One of the methods to overcome this problem is MC blending with another substance that increases the crosslinking rate of MC. In these studies, we used agarose (AGR). These studies aim to investigate the effect of different AGR amounts on MC crosslinking kinetics, and thermal, viscoelastic, and biological properties. Differential Scanning Calorimetry (DSC) and dynamic mechanical analysis (DMA) measurements proved that AGR addition accelerates the beginning of MC crosslinking. This phenomenon resulted from AGR's greater affinity to water, which is crucial in this particular crosslinking part. In vitro tests, carried out using the L929 fibroblast line and mesenchymal stem cells (MSCs), confirmed that most of the hydrogel samples were non-cytotoxic in contact with extracts and directly with cells. Not only does this type of thermosensitive hydrogel system provide excellent mechanical and biological cues but also its stimuli-responsive character provides more novel functionalities for designing innovative scaffold/cell delivery systems for tissue engineering applications.

Abstract:
Thermosensitive, physically crosslinked injectable hydrogels are in the area of interests of various scientific fields. One of the representatives of this materials group is an aqueous solution of methylcellulose. At ambient conditions, methylcellulose (MC) is a sol while on heating up to 37 °C, MC undergoes physical crosslinking and transforms into a gel. Injectability at room temperature, and crosslinkability during subsequent heating to physiological temperature raises hopes, especially for tissue engineering applications. This research work aimed at studying crosslinking kinetics, thermal, viscoelastic, and biological properties of MC aqueous solution in a broad range of MC concentrations. It was evidenced by Differential Scanning Calorimetry (DSC) that crosslinking of MC is a reversible two-stage process, manifested by the appearance of two endothermic effects, related to the destruction of water cages around methoxy groups, followed by crosslinking via the formation of hydrophobic interactions between methoxy groups in the polymeric chains. The DSC results also allowed the determination of MC crosslinking kinetics. Complementary measurements of MC crosslinking kinetics performed by dynamic mechanical analysis (DMA) provided information on the final storage modulus, which was important from the perspective of tissue engineering applications. Cytotoxicity tests were performed using mouse fibroblasts and showed that MC at low concentration did not cause cytotoxicity. All these efforts allowed to assess MC hydrogel relevance for tissue engineering applications.

Keywords:
methylcellulose, thermosensitive hydrogel, crosslinking kinetics, DSC, DMA, cellular tests