The structural properties of biomaterials play crucial roles in guiding cell behavior and influencing immune responses against the material. We fabricated electrospun membranes with three types of surface topography (random, aligned, and latticed), introduced them to dorsal skin excisional wounds in mice and rats, and evaluated their effects on wound healing and immunomodulatory properties. An overview of different immune cells in the microenvironment with the help of single-cell RNA sequencing revealed diverse cellular heterogeneity in vivo. The time course of immune response was advanced toward an adaptive immunity–dominant stage by the aligned scaffold. In mice without mature T lymphocytes, lack of wound-induced hair neogenesis indicated a regulatory role of T cells on hair follicle regeneration. The microenvironment around scaffolds involved an intricate interplay of immune and cutaneous cells.

The foreign body reaction (FBR) is described as a local chronic inflammation after implantation of biomaterials in which macrophages involved intimately. At the stage of acute inflammation, mast cells release histamine, Interleukin-4 (IL-4) andInterleukin-13 (IL-13), enhancing recruitment, and fusion of macrophages in the following phase. As for chronic intensive inflammation, degradation of biomaterials would be promoted by macrophage-derived foreign body giant cells releasing degradative enzymes, acid and reactive oxygen intermediates. Nevertheless, it could be seen as a breakthrough point for regulating FBR, considering the dominant role of the macrophage in the immune response as exemplified by the decrease of IL-4 and IL-13, stabilizing an appropriate balance between two macrophage phenotypes, selectively suppressing some function of macrophages, and so on. Moreover, the relationship between macrophages polarization and the development of a fibrous capsule, which increase the possibility of implantation failure, will be illustrated later.This review aims at providing readers a comprehensive understanding of FBR and its correlative treatment strategy. K E Y W O R D Sbiomaterials, foreign body reaction, macrophages

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Structural properties of biomaterials play critical roles in guiding cell behaviors and influence the immune response against them. In this study, we fabricated electro-spun membranes with three types of surface topography (Random, Aligned, and Latticed). The aligned membranes showed immunomodulatory ability, and led to faster wound healing, reduced fibrotic response and enhanced regeneration of cutaneous appendages. Based on that, we performed single-cell RNA sequencing analysis on cells of wounded mouse skin in the presence/absence of the Aligned scaffold. We identified 45 cell populations. Keratinocytes, fibroblasts, and immune cells including neutrophils, monocytes, macrophages, dendritic cells, and T cells showed diverse cellular heterogeneity. We found more inner root sheath cells (anagen-related) in the Aligned group, which corresponded to the improved regeneration of hair follicles in the presence of scaffold. The immune microenvironment around the biomaterial involved intricate interplay of immune cells from both innate and adaptive immune system. Immune responses in tissue around scaffold significantly differed from that of saline control. In aligned samples, infiltrated macrophages and neutrophils were reduced, whereas more effector T cells were recruited. The time course of immune response might be advanced towards an adaptive immunity-dominant stage by scaffolds.

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