Collagen, a prominent biopolymer, which is famous for its excellent biological activity, has been used extensively for tissue engineering applications. In this study, a novel solvent system for collagen was developed with an ionic liquid, 1-ethyl-3-methylimidazolium acetate ([EMIM][Ac]), solvent system. A series of sodium salts were introduced into this solvent system to enhance collagen's dissolution procedure. The results show that the solubility of collagen was significantly influenced by the temperature and sodium salts. The solubility reached up to approximately 11% in the [EMIM][Ac]/Na2HPO4 system at 45 degrees C. However, the structure of the regenerated collagen (Col-regenerated) may have been damaged. Hence, we focused on the structural integrity of the collagen regenerated from the [EMIM][Ac] solvent system by the methods of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Fourier transform infrared spectroscopy, ultrasensitive differential scanning calorimetry, atomic force microscopy, X-ray diffraction, and circular dichroism because its signature biological and physicochemical properties were based on its structural integrity. Meanwhile, a possible dissolution mechanism was proposed. The results show that the triple-helical structure of collagen regenerated from the [EMIM][Ac] solvent system below 35 degrees C was retained to a large extent. The biocompatibility of Col-regenerated was first characterized with a fibroblast adhesion and proliferation model. It showed that the Col-regenerated had almost the same good biological activity as nature collagen, and this indicated the potential application of [EMIM][Ac] in tissue engineering. (c) 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 2245-2256, 2013