Collagen molecules are widely used in the field of tissue engineering, especially as cell culture hydrogels. However, the cellular effects on collagen fiber formation inside collagen gels have not been reported. Here, we evaluated the effect of cells on collagen triple helix fiber formation at a molecular level in collagen hydrogels or on cell surfaces. Swelling ratios of collagen gels decreased with increasing cell numbers, most likely because of interactions between cell surface integrin molecules and collagen fibers. Circular dichroism and ultraviolet-visible spectroscopic analyses revealed aggregations of cells and collagen molecules because of their strong interaction. X-ray diffraction analyses suggested that cells did not affect the weak molecular orientation of collagen fibers inside collagen gels because the collagen gels usually do not have as dense molecular packing as natural collagen fibers in tendons. Scanning electron microscopy showed aggregations of submicrometer-sized spherical collagen structures mainly around cells inside collagen gels. The results suggest that interactions between cell surfaces and collagen molecules induce the formation of spherical constructs rather than microfiber formation, which in turn indicates that interactions between cells and collagen molecules induce the adsorption of collagen molecules onto cell surfaces and lead to the formation of spherical constructs in hydrogels.
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