After implantation of a biomaterial, both the host immune system and properties of the material determine the local immune response. In a scaffold-induced immune micro-environment, immune cells like macrophages present functional heterogeneity and plasticity. With the advancement of technology, emerging techniques such as single-cell RNA sequencing (scRNA-seq) enable high-resolution characterization of immune cell populations. In-depth understanding of the interaction between scaffolds and the host immune system helps to provide clues for the design of biomaterials to optimize regeneration and promote a pro-regenerative local immune micro-environment. In this review, we discuss the procedures of foreign body reaction in brief, present recent advances in elucidating mechanisms of foreign body response, and discuss the application of scRNA-seq in probing the scaffold immune micro-environment. With regard to biomaterial design, we summarize the influences that physical and chemical properties of biomaterials have on cell behaviors in the micro-environment and provide some reference to designing immunomodulatory biomaterials.