Collagen and multifunctional epoxides, which are respectively the common constituents of natural and polymer interfaces, were combined to fabricate integrative biointerfaces with device/tissue heterogeneous affinity. Further, the traditional 2D and advanced 2.5D conformational designs were achieved on collagen-based biointerfaces. The 2D conformational biointerfaces were formed by the self-entanglement of collagen molecules based on extensive hydrogen bonds among molecules, and the lamellar structures of 2D conformational biointerfaces could act as barriers to protect both biointerfaces and substrates from enzymes and corrosion. The unique stacking structures of 2.5D conformational biointerfaces were formed by cross-linking microaggregates that were established and connected by epoxy cross-linking bonds and provided the extra 0.5D degree of freedom on structure design and functional specialization through artificially manipulating the constituents and density of microaggregates. Besides, the intersecting channels among microaggregates gave 2.5D biointerfaces diffusion behaviors, which further brought good wettability and biodegradability. The integrative biointerfaces behaved well on cell viability and enhanced the cell adhesion strength in vitro, which could be attributed to the collaborations of collagen and epoxy groups. The subcutaneous implant model in rats was utilized to investigate soft tissue response, and the results demonstrated that the tissues around implantation areas healed well and without calcification or infection. The coating of integrative biointerfaces alleviated the fibrosis around implantation areas, and the inflammatory responses and foreign body reactions were improved.