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Role and regulation of macrophages in biomaterial-mediated fibrosis formation
Deng Moyuan, Peng Kun
2023, 27 (25):
4085-4092.
doi: 10.12307/2023.541
BACKGROUND: The foreign body reaction induced by implanted biomaterials leads to the formation of surface fibrosis (also known as implant fibrosis), that is, biomaterials are wrapped by fibrous tissue, making them lose their functionality and producing serious clinical complications, which is a major problem in the field of tissue regeneration and repair. The key cells involved in implant fibrosis are macrophages. However, the effects and mechanism of macrophages on the process of implant fibrosis and the strategy of inhibiting fibrosis remain unclear.
OBJECTIVE: To review the effects of macrophage polarization and differentiation events on material fibrosis, including fibrogenic signal pathways, and strategies to inhibit biomaterial fibrosis based on specific regulation of macrophages.
METHODS: The relevant articles up to 2022 were searched on PubMed, Wiley, EBSCOhost, ScienceDirect, and Elsevier databases using English search terms “macrophages, biological materials, fibrosis, foreign body reaction, myofibroblasts, inflammation, regulation, surface topology, mechanical properties, chemical signals”, and 60 articles were finally included for the further analysis.
RESULTS AND CONCLUSION: (1) Both M1 and M2 macrophages may participate in the formation of biomaterial fibrosis. Maybe strategies that regulate macrophage polarity alone cannot inhibit the formation of fibrosis in biomaterials. (2) As a key cellular event in the regulation of macrophage-mediated biomaterial fibrosis, the differentiation of macrophages into myofibroblasts can induce the expression of marker α-smooth muscle actin, indicating that this process has a direct effect on fibrosis. (3) In terms of the signaling pathway of macrophages promoting fibrosis, the analysis suggests that there may be differences in the signaling pathway of macrophages with different phenotypes. (4) Two main pathways are involved in the regulation of macrophage-induced inflammation using the physical properties of biomaterials. First, based on the biomaterial surface topology, the construction of patterning surface less than 100 nm or the enhancement of surface roughness of biomaterial is expected to reduce macrophage fusion and expression of inflammatory factors, reducing fibrosis caused by macrophages. Second, researchers prefer to design and prepare biomaterials with smaller modulus of elasticity to reduce the stress transfer induced by the implant to the injured tissue, reduce macrophage-induced inflammation, and improve the fibrosis during tissue repair. (5) Regarding the use of chemical signals to regulate the expression of macrophage-induced inflammation, regulatory strategies can be implemented mainly in macrophage-derived inflammatory factors, as well as chemical signals for macrophage recruitment, fusion, and differentiation; therefore, effective use of inhibitors and antioxidants can achieve reverse regulation of transforming growth factor β1, reactive oxygen species, nuclear transcription factor κB, and miRNA-21 through the above pathways, thus delaying fibrosis induced by macrophages.
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