Abstract
Foreign body reactions induced by macrophages often cause delay or failure of wound healing in the application of tissue engineering scaffolds. This study explores the application of nanosilver (NAg) to reduce foreign body reactions during scaffold transplantation. An NAg hybrid collagen-chitosan scaffold (NAg-CCS) was prepared using the freeze-drying method. The NAg-CCS was implanted on the back of rats to evaluate the effects on foreign body reactions. Skin tissue samples were collected for histological and immunological evaluation at variable intervals. Miniature pigs were used to assess the effects of NAg on skin wound healing. The wounds were photographed, and tissue samples were collected for molecular biological analysis at different time points post-transplantation. NAg-CCS has a porous structure and the results showed that it could release NAg constantly for two weeks. The NAg-CCS group rarely developed a foreign body reaction, while the blank-CCS group showed granulomas or necrosis in the subcutaneous grafting experiment. Both matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were reduced significantly in the NAg-CCS group. The NAg-CCS group had higher interleukin (IL)-10 and lower IL-6 than the blank CCS group. In the wound healing study, M1 macrophage activation and inflammatory-related proteins (inducible nitric oxide synthase (iNOS), IL-6, and interferon-γ (IFN-γ)) were inhibited by NAg. In contrast, M2 macrophage activation and proinflammatory proteins (arginase-1, major histocompatibility complex-II (MHC-II), and found in inflammatory zone-1 (FIZZ-1)) were promoted, and this was responsible for suppressing the foreign body responses and accelerating wound healing. In conclusion, dermal scaffolds containing NAg suppressed the foreign body reaction by regulating macrophages and the expression of inflammatory cytokines, thereby promoting wound healing.
摘要
在组织工程支架的应用中, 巨噬细胞引起的异物反应常导致伤口愈合延迟或失败. 本研究探讨了纳米银(NAg)在支架移植过程中减少异物反应的作用. 首先采用冷冻干燥法制备了包覆NAg的胶原-壳聚糖支架(NAg-CCS). 将Nag-CCS植入大鼠背部以评估对异物反应的影响, 并在不同的时间间隔收集皮肤组织样本用于组织学和免疫学评估. 小型猪创面愈合模型被用来评估NAg对皮肤伤口愈合的影响. 在不同时间点对创面进行拍照, 并收集组织样本用于移植后不同时间点的分子生物学分析. 结果表明, NAg-CCS具有多孔结构, 可以持续释放NAg超过2周. NAg-CCS组很少发生异物反应, 而空白CCS组在皮下移植实验中出现明显的肉芽肿或坏死. NAg-CCS组的基质金属蛋白酶-1(MMP-1)和组织金属蛋白酶抑制剂-1(TIMP-1)均显着降低. Nag-CCS组比空白CCS组具有更高的白细胞介素(IL)-10和更低的IL-6. 在创面愈合实验中, NAg显著抑制了M1巨噬细胞的活化和炎症相关蛋白(一氧化氮合成酶(iNOS)、 IL-6和干扰素-γ(IFN-γ))的表达, 而促进了M2巨噬细胞的活化和抗炎相关蛋白(精氨酸酶-1、 主要组织相容性复合体-II(MHC-II)和抵抗素样分子-1(FIZZ-1))的表达, 这些改变均有助于抑制创面的异物反应并加速创面的愈合. 总之, 含有NAg的真皮支架通过调节巨噬细胞极化和炎性细胞因子的表达来抑制异物反应, 从而促进皮肤创面的修复.
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Acknowledgments
This work was supported by the Zhejiang Province Key Research and Development Program (No. 2019C03083), the Zhejiang Provincial Basic Public Welfare Research Program (No. LGF19H150008), and the National Natural Science Foundation of China (Nos. 81601681 and 81871558).
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Conceptualization and methodology: Chuangang YOU and Zhikang ZHU; Formal analysis: Shuangshuang WANG, Xingang WANG, and Chuangang YOU; Funding acquisition: Huawei SHAO, Zhikang ZHU, Chuangang YOU, and Chunmao HAN; Supervision: Chunmao HAN and Huawei SHAO; Writing–original draft: Chuangang YOU and Zhikang ZHU; Writing–review and editing: Chunmao HAN and Huawei SHAO. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Chuangang YOU, Zhikang ZHU, Shuangshuang WANG, Xingang WANG, Chunmao HAN, and Huawei SHAO disclose that there is no financial and personal relationship with other people or organizations that might raise any questions of bias in our work.
Experiments were approved and supervised by the Animal Care and Ethical Committee of the Second Affiliated Hospital of Zhejiang University (No. 2020-720).
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You, C., Zhu, Z., Wang, S. et al. Nanosilver alleviates foreign body reaction and facilitates wound repair by regulating macrophage polarization. J. Zhejiang Univ. Sci. B 24, 510–523 (2023). https://doi.org/10.1631/jzus.B2200447
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DOI: https://doi.org/10.1631/jzus.B2200447