3D native tissue-derived scaffolding materials are made in various formats, including but not limited to hydrogel, sponge, fibers, microspheres, and films, all of which function to better preserve natural extracellular matrix molecules and to recapitulate the natural tissue environment, thereby effectively guiding tissue regeneration. Tissue-derived scaffolds are prepared by incorporating a homogenized tissue-derived suspension into a polymeric solution of synthetic, natural, or hybrid polymers. Such tissue-derived scaffolds and scaffolding materials have a variety of utilities, including: the creation of 3D tissue models such as skin, bone, liver, pancreas, lung, and so on; facilitation of studies on cell-matrix interactions; and the fabrication of implantable scaffolding materials for guided tissue formation in vivo. The tissue-derived scaffolds and scaffolding materials also provide the opportunity to correlate the functions of extracellular matrix with tissue regeneration and cancer metastasis, for example.