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.

纳米银通过调控巨噬细胞极化以减轻异物反应并促进创面修复

[1]AlsalehNB,MinarchickVC,MendozaRP,et al.,2019.Silver nanoparticle immunomodulatory potential in absence of direct cytotoxicity in RAW 264.7 macrophages and MPRO 2.1 neutrophils.J Immunotoxicol,16(1):63-73.

[2]AndersonJM,JiangSR,2017.Implications of the acute and chronic inflammatory response and the foreign body reaction to the immune response of implanted biomaterials. In: Corradetti B (Ed.),The Immune Response to Implanted Materials and Devices: the Impact of the Immune System on the Success of an Implant.Springer,Cham, p.15-36.

[3]AndersonJM,RodriguezA,ChangDT,2008.Foreign body reaction to biomaterials.Semin Immunol,20(2):86-100.

[4]BenayahuD,PomeraniecL,ShemeshS,et al.,2020.Biocompatibility of a marine collagen-based scaffold in vitro and in vivo.Mar Drugs,18(8):420.

[5]BerganJJ,2005.Chronic venous insufficiency and the therapeutic effects of Daflon 500 mg.Angiology,56(6_suppl):S21-S24.

[6]ChiangYZ,PieroneG,Al-NiaimiF,2017.Dermal fillers: pathophysiology, prevention and treatment of complications.J Eur Acad Dermatol Venereol,31(3):405-413.

[7]ChuCY,LiuL,RungS,et al.,2020.Modulation of foreign body reaction and macrophage phenotypes concerning microenvironment.J Biomed Mater Res Part A,108(1):127-135.

[8]ForbesJM,CooperME,2013.Mechanisms of diabetic complications.Physiol Rev,93(1):137-188.

[9]FurtadoM,ChenL,ChenZH,et al.,2022.Development of fish collagen in tissue regeneration and drug delivery.Eng Regener,3(3):217-231.

[10]GomesA,LeiteF,RibeiroL,2021.Adipocytes and macrophages secretomes coregulate catecholamine-synthesizing enzymes.Int J Med Sci,18(3):582-592.

[11]HeskethM,SahinKB,WestZE,et al.,2017.Macrophage phenotypes regulate scar formation and chronic wound healing.Int J Mol Sci,18(7):1545.

[12]HuangYJ,HungKC,HungHS,et al.,2018.Modulation of macrophage phenotype by biodegradable polyurethane nanoparticles: possible relation between macrophage polarization and immune response of nanoparticles.ACS Appl Mater Interfaces,10(23):19436-19448.

[13]JainN,VogelV,2018.Spatial confinement downsizes the inflammatory response of macrophages.Nat Mater,17(12):1134-1144.

[14]KimH,WangSY,KwakG,et al.,2019.Exosome-guided phenotypic switch of M1 to M2 macrophages for cutaneous wound healing.Adv Sci,6(20):1900513.

[15]LiCD,CuiWG,2021.3D bioprinting of cell-laden constructs for regenerative medicine.Eng Regener,2:195-205.

[16]LiuC,XuXY,CuiWG,et al.,2021.Metal-organic framework (MOF)‍-‍based biomaterials in bone tissue engineering. Eng Regener,2:105-108.

[17]LocatiM,CurtaleG,MantovaniA,2020.Diversity, mechanisms, and significance of macrophage plasticity.Annu Rev Pathol Mech Dis,15:123-147.

[18]MotzK,LinaI,MurphyMK,et al.,2021.M2 macrophages promote collagen expression and synthesis in laryngotracheal stenosis fibroblasts.Laryngoscope,131(2):E346-E353.

[19]OrecchioniM,GhoshehY,PramodAB,et al.,2019.Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages.Front Immunol,10:1084.

[20]O'SheaTM,WollenbergAL,KimJH,et al.,2020.Foreign body responses in mouse central nervous system mimic natural wound responses and alter biomaterial functions.Nat Commun,11:6203.

[21]PaulS,ChhatarS,MishraA,et al.,2019.Natural killer T cell activation increases iNOS⁺CD206^- M1 macrophage and controls the growth of solid tumor.J ImmunoTher Cancer,7(1):208.

[22]SeoSY,LeeGH,LeeSG,et al.,2012.Alginate-based composite sponge containing silver nanoparticles synthesized in situ.Carbohydr Polym,90(1):109-115.

[23]SheikhZ,BrooksPJ,BarzilayO,et al.,2015.Macrophages, foreign body giant cells and their response to implantable biomaterials.Materials,8(9):5671-5701.

[24]ShiCY,WangCY,LiuH,et al.,2020.Selection of appropriate wound dressing for various wounds.Front Bioeng Biotechnol,8:182.

[25]ShiK,QiuX,ZhengW,et al.,2018.MiR-203 regulates keloid fibroblast proliferation, invasion, and extracellular matrix expression by targeting EGR1 and FGF2.Biomed Pharmacother,108:1282-1288.

[26]SnyderRJ,LantisJ,KirsnerRS,et al.,2016.Macrophages: a review of their role in wound healing and their therapeutic use.Wound Repair Regen,24(4):613-629.

[27]TanRZ,LiuJ,ZhangYY,et al.,2019.Curcumin relieved cisplatin-induced kidney inflammation through inhibiting Mincle-maintained M1 macrophage phenotype.Phytomedicine,52:284-294.

[28]VannellaKM,WynnTA,2017.Mechanisms of organ injury and repair by macrophages.Annu Rev Physiol,79:593-617.

[29]Villarreal-LealRA,HealeyGD,CorradettiB,2021.Biomimetic immunomodulation strategies for effective tissue repair and restoration.Adv Drug Deliv Rev,179:113913.

[30]WengTT,WuP,ZhangW,et al.,2020.Regeneration of skin appendages and nerves: current status and further challenges.J Transl Med,18:53.

[31]WicksK,TorbicaT,MaceKA,2014.Myeloid cell dysfunction and the pathogenesis of the diabetic chronic wound.Semin Immunol,26(4):341-353.

[32]WitherelCE,SaoK,BrissonBK,et al.,2021.Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages.Biomaterials,269:120667.

[33]WynnTA,VannellaKM,2016.Macrophages in tissue repair, regeneration, and fibrosis.Immunity,44(3):450-462.

[34]YangYX,ZhaoXD,YuJ,et al.,2021.Bioactive skin-mimicking hydrogel band-aids for diabetic wound healing and infectious skin incision treatment.Bioact Mater,6(11):‍3962-3975.

[35]YouCG,HanCM,WangXG,et al.,2012.The progress of silver nanoparticles in the antibacterial mechanism, clinical application and cytotoxicity.Mol Biol Rep,39(9):9193-9201.

[36]YouCG,LiQ,WangXG,et al.,2017.Silver nanoparticle loaded collagen/chitosan scaffolds promote wound healing via regulating fibroblast migration and macrophage activation.Sci Rep,7:10489.

[37]YunnaC,MengruH,LeiW,et al.,2020.Macrophage M1/M2 polarization.Eur J Pharmacol,877:173090.