-
摘要: 创面愈合是一个被精准调控的复杂过程,包含了炎症、抗炎、再生等多个阶段。由于巨噬细胞具有明显的可塑性,可以在具有差异化的创面愈合过程中发挥重要的调节作用。巨噬细胞若未能适时表达特定功能,将会影响组织的愈合功能并导致组织病理性愈合。因此,了解巨噬细胞在创面愈合的不同阶段发挥的不同功能并进行针对性调控,对促进创伤组织的愈合再生有重要意义。该文根据创面愈合的基本过程,阐述了创面内不同类型巨噬细胞发挥的不同功能及其基本机制,并强调了未来可能应用于临床治疗的巨噬细胞调控策略。Abstract: Wound healing is a complex process under precise regulation, including multiple stages such as inflammation, anti-inflammatory, and regeneration. Macrophages play an important regulatory role in the differentiated process of wound healing due to their obvious plasticity. If macrophages fail to express specific functions in a timely manner, it will affect the healing function of tissues and lead to pathological tissue healing. Therefore, it is of great significance to understand the different functions of different types of macrophages and to regulate them specifically in different stages of wound healing to promote the healing and regeneration of wound tissue. In this paper, we illustrate the different functions of macrophages in the wound and their basic mechanisms, according to the basic process of wound healing, and emphasize the strategies of macrophage regulation that may be applied to clinical treatment in the future.
-
Key words:
- Wound healing /
- E2F1 transcription factor /
- M1 macrophage /
- M2 macrophage
-
(1)采用数字减影血管造影技术定位分析旋股外侧动脉横支,直观了解了横支的出现情况和发出位置、共干情况、走行情况等形态学特点。
以旋股外侧动脉不同分支为蒂的股前外侧皮瓣被广泛应用于四肢软组织损伤的修复 [ 1, 2, 3] 。在旋股外侧动脉各分支中,横支具有解剖学位置较高、供区隐蔽、供皮量大等特点,可为股前外侧皮瓣设计方案提供更多选择 [ 4, 5, 6] 。同时,在旋股外侧动脉的降支与斜支变异或缺如时,可将横支用作股前外侧皮瓣的血管蒂 [ 7, 8] 。然而,目前横支的形态学特点,包括其与旋股外侧动脉其他分支尤其是斜支的相对关系仍需系统性阐明。为明确横支的形态学特征,从而为股前外侧皮瓣设计提供依据,本课题组对四肢软组织损伤患者行股前外侧皮瓣修复术前数字减影血管造影(DSA),对成像资料中旋股外侧动脉横支的形态学特点进行分析并讨论其临床意义。
1. 对象与方法
本回顾性观察性研究符合《赫尔辛基宣言》的基本原则。
1.1 入选标准
纳入标准:采用股前外侧皮瓣修复四肢软组织缺损创面,且术前行下肢DSA定位。排除标准:造影剂充盈不良,血管显影不佳;合并脉管炎、下肢动脉闭塞、动脉瘤等动脉性疾病。
1.2 临床资料
2020年10月—2021年5月,苏州瑞华骨科医院收治62例符合入选标准的四肢软组织损伤患者,其中男40例、女22例,年龄20~72岁(平均50岁),包括机器绞伤者12例、机器压伤者27例、交通伤者23例,均以股前外侧皮瓣修复四肢软组织缺损,术前行下肢DSA检查,均签署特殊检查知情同意书。
1.3 检查方法及相关处理
患者取仰卧位(术中保持体位不变),术前以安尔碘皮肤消毒剂对双侧腹股沟区进行消毒,铺无菌洞巾。于皮瓣供区对侧腹股沟区股动脉浅表搏动点下方2~3 cm处选择穿刺点,常规进行局部浸润麻醉。以髂前上棘内侧水平10 cm为起点,与髂前上棘和髌骨外侧缘的连线平行固定显影标尺。使用改良Seldinger法 [ 9] 置入外径4 F血管穿刺鞘,在直径0.035 mm泥鳅导丝导引下置入外径4 F的Cobra导管或单弯导管,将导管置入股深动脉开口处后,用造影剂注射器(压力2.07 MPa)注入碘克沙醇(流速4 mL/s、总量12 mL)进行首次造影,采集图像,初步观察旋股外侧动脉类型。随后,在泥鳅导丝辅助下推进Cobra导管或单弯导管至旋股外侧动脉处,拔除导丝,行第2次造影(压力1.38 MPa、流速3 mL/s、总量8 mL)并采集图像。拔除导管及血管穿刺鞘,由医师按压穿刺点15 min,密切关注患者出血情况,按压后以无菌纱布覆盖并予弹力胶布固定。返回病房后予沙袋压迫穿刺点4 h、心电监护2 h,按期常规复查肝肾功能。
1.4 观察指标与方法
使用TView 6.0.1.2104图像分析软件(上海卫宁健康科技集团股份有限公司)结合显影标尺对造影采集的图像进行测量分析,观测下肢血管大体情况以及旋股外侧动脉横支的出现情况(横支细小或横支缺如均判定为无横支,计算出现率)、源动脉、发出点位置、走行方向与皮穿支穿出点位置,另进行横支形态学特点分类。
2. 结果
2.1 下肢血管大体情况
DSA检查显示,62例患者股动脉、股深动脉及旋股外侧动脉各分支均清晰可辨。
2.2 旋股外侧动脉横支大体情况
在59例患者中观察到旋股外侧动脉横支,其中52例为单横支、7例为双横支,横支出现率为95.2%(59/62)。共观察到66条旋股外侧动脉横支,其中3条发自股深动脉、63条发自旋股外侧动脉。旋股外侧动脉横支发出点多位于髂前上棘与髌骨外侧缘连线近端,距髂前上棘6.5~12.7 cm,平均9.7 cm,见 图1、 2。旋股外侧动脉横支约与身体长轴垂直向外侧发出,在旋股外侧动脉升支与斜支之间走行,沿途发出分支,主干走行至大转子下方。旋股外侧动脉横支皮穿支穿出点距髂前上棘8.0~18.0 cm,平均13.8 cm。
2.3 旋股外侧动脉横支形态学特点分类
旋股外侧动脉横支形态学特点分类中,以与1条旋股外侧动脉其他分支共干发出者最为常见,占50.0%(31/62);其次为自旋股外侧动脉(12例)或股深动脉(3例)单干发出者,占24.2%(15/62);特殊类型者占21.0%(13/62),包括双横支者7例、与多条旋股外侧动脉其他分支共干者6例;横支细小/缺如者仅占4.8%(3/62)。在前述双支共干关系中,以升支与横支共干者最为常见,占77.4%(24/31);横支与斜支共干者(5例)、横支与降支共干者(2例)共占22.6%(7/31)。见 图3。
3. 讨论
经典的股前外侧皮瓣以旋股外侧动脉降支为蒂,在修复较大面积的软组织缺损时,单穿支有时难以满足血供需求;且降支多为肌皮穿支,解剖游离时对供区肌肉损伤较大;当降支发出穿支细小时,不利于血管吻合 [ 10, 11, 12, 13, 14, 15] 。为确保皮瓣血供、减少供区肌肉损伤带来的并发症,高位穿支已成为股前外侧皮瓣血管蒂的重要选择 [ 16] 。由于术中视野的限制,按照传统方式设计股前外侧皮瓣难以解剖到高位穿支,对横支的形态学认识尚有不足。因此,本课题组术前对股前外侧区进行DSA定位寻找合适穿支,通过探讨横支的形态学特点以指导临床应用。
穿支常用影像学定位技术有超声、CT血管造影(CTA)、磁共振血管造影(MRA)和DSA等,后三者均基于造影技术,穿支检出率高 [ 17, 18, 19, 20] 。与MRA、CTA相比,DSA属于有创操作,费用较高 [ 21] 。CTA及MRA可以通过三维技术对目标血管进行多角度观察,但是其准确度受患者身体质量指数、仪器设备要求等因素影响较大 [ 22, 23, 24, 25] 。与CTA和MRA相比,DSA直接置管于目标血管,局部对比剂浓度高,管腔充盈效果好,局部血管对比度、锐利度高 [ 26] 。此外,DSA图像质量稍优于CTA和MRA。本研究中,患者均采用DSA定位股前外侧区血管,各动脉分支清晰可辨。
横支是旋股外侧动脉的主要分支,本研究观察到横支出现率为95.2%。横支多位于升支的下方和斜支的外侧,在与身体水平轴成角约15°的范围内走行,可略向下或向上。横支与其他分支间存在一定的联系 [ 27] ,其常与升支、斜支、降支共干发出(其中与升支共干最为多见),多表现为旋股外侧动脉主干自发出后,向外下走行一段距离后分为上下2支,上支向外上走行,沿途发出横支与升支;下支向外下走行,发出斜支与降支 [ 27, 28] 。本研究显示,旋股外侧动脉横支的发出点距髂前上棘平均距离为9.7 cm,而横支皮穿支穿出点距髂前上棘平均距离为13.8 cm,解剖学位置偏高,提示若以横支为蒂设计皮瓣,具有位置隐蔽、供皮面积较大等优点。
本课题组根据本组患者股前外侧区旋股外侧动脉横支形态学特点,将其分为4类:(1)横支直接由旋股外侧动脉或股深动脉发出,与其他穿支无任何共干关系,即单干发出。(2)横支与1条旋股外侧动脉其他分支由同一源自旋股外侧动脉或股深动脉的短干发出,包括与升支共干、与斜支共干、与降支共干,即共干发出。(3)旋股外侧动脉或股深动脉发出2条横支,或横支与多条旋股外侧动脉其他分支共干,即特殊类型。(4)无横支或横支口径细小,DSA无法探查。以上横支形态学特点分类,可为临床实践提供下述参考:(1)单干发出的横支,血管解剖较为简单,是减轻供区肌肉损伤,增加手术成功率的合适选择。(2)针对共干发出的横支,可联合共干穿支设计多叶皮瓣、嵌合皮瓣、血流桥接皮瓣,为修复合并血管、肌肉等复合组织损伤或大面积软组织缺损提供设计方案。(3)源动脉发出双横支或横支与多条源动脉其他分支共干时,大腿近端血管丰富,横支血管走行较为复杂,需格外谨慎,尽可能采取逆行解剖法,追溯源动脉,避免损伤血管。(4)横支细小/缺如时,不宜选取横支设计股前外侧皮瓣,以避免手术失败。
基于DSA进行血管定位有以下优点:(1)可进行动态的旋股外侧动脉分支成像研究,以更全面地了解血管的形态与分布,有助于制订较具体的手术方案,便于术前模拟设计双叶皮瓣、嵌合皮瓣等 [ 29] 。(2)术前可以准确掌握血管走行分布,明确穿支与源动脉之间关系,避免术中盲目分离,为皮瓣的设计及切取提供依据,减少血管损伤。(3)结合显影标尺,明确穿支血管长度及供血范围,为皮瓣切取范围定位提供参考依据。(4)定位时可使指定穿支管腔充盈,便于术前模拟与受区血管吻合,对于避免吻合口堵塞、降低动脉危象发生概率具有重要意义 [ 30] 。但基于DSA进行血管定位也存在以下不足:(1)以碘克沙醇为造影剂,尽管不良反应较少,但仍有可能引发过敏反应、碘中毒、神经系统并发症 [ 31, 32, 33] 。(2)DSA是一种有创操作,存在X线辐射影响 [ 34] 。(3)DSA造影图像为二维图像,存在空间重叠可能,可造成将深部血管误判为表浅穿支的情况。
在DSA定位及参考定位结果进行手术时,需要注意以下几点:(1)行股前外侧区DSA时,常于腹股沟区股动脉浅表处寻找穿刺点,以便穿刺。但是肥胖患者股动脉位置较深,穿刺难度较大,反复穿刺可能造成穿刺点血肿或假性动脉瘤 [ 35] ,需密切关注患者出血情况,出现穿刺部位出血或血肿时,利用1 kg沙袋持续压迫穿刺点4~6 h,可换对侧继续穿刺造影。(2)一旦造影过程中观察到过敏反应,应立即停止造影,积极抢救;对于甲亢患者或有甲亢病史的患者,严禁进行DSA。(3)定位过程中需要患者保持特定体位,避免血管偏移正常位置,术后需复查肝肾功能。(4)术者熟练程度是重要因素,可缩短操作时间,避免反复穿刺,降低辐射影响。(5)DSA图像空间显影能力不佳,皮瓣切取过程中应以术中所见为准。
综上所述,DSA可在一定程度上反映旋股外侧动脉横支形态学特点,结合横支形态学特点,可为以旋股外侧动脉横支为蒂的股前外侧皮瓣设计提供一定思路。然而DSA造影不能显示旋股外侧动脉横支尤其是穿支走行的层次,这仍是目前横支切取过程中的难题,需要临床及解剖的进一步研究。
所有作者均声明不存在利益冲突 -
参考文献
(53) [1] BoniakowskiAE, KimballAS, JacobsBN,et al. Macrophage-mediated inflammation in normal and diabetic wound healing[J].J Immunol,2017,199(1):17-24. DOI: 10.4049/jimmunol.1700223. [2] NobsSP, KopfM. Tissue-resident macrophages: guardians of organ homeostasis[J].Trends Immunol,2021,42(6):495-507. DOI: 10.1016/j.it.2021.04.007. [3] ChakarovS, LimHY, TanL,et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches[J].Science,2019,363(6432):eaau0964.DOI: 10.1126/science.aau0964. [4] YapJ, IreiJ, Lozano-GeronaJ,et al. Macrophages in cardiac remodelling after myocardial infarction[J].Nat Rev Cardiol,2023.DOI: 10.1038/s41569-022-00823-5. [5] WynnTA and VannellaKM. Macrophages in tissue repair, regeneration, and fibrosis[J].Immunity,2016,44(3):450-462. DOI: 10.1016/j.immuni.2016.02.015. [6] FunesSC, RiosM, Escobar-VeraJ,et al. Implications of macrophage polarization in autoimmunity[J].Immunology,2018,154(2):186-195. DOI: 10.1111/imm.12910. [7] ZindelJ, KubesP. DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation[J].Annu Rev Pathol,2020,15:493-518. DOI: 10.1146/annurev-pathmechdis-012419-032847. [8] BakogiannisC, SachseM, StamatelopoulosK,et al. Platelet-derived chemokines in inflammation and atherosclerosis[J].Cytokine,2019,122:154157. DOI: 10.1016/j.cyto.2017.09.013. [9] HassanshahiA, MoradzadM, GhalamkariS,et al. Macrophage-mediated inflammation in skin wound healing[J].Cells,2022,11(19) :2953.DOI: 10.3390/cells11192953. [10] FountainA, InpanathanS, AlvesP,et al. Phagosome maturation in macrophages: eat, digest, adapt, and repeat[J].Adv Biol Regul,2021,82:100832. DOI: 10.1016/j.jbior.2021.100832. [11] GengJ, ShiY, ZhangJ,et al. TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection[J].Nat Commun,2021,12(1):3519. DOI: 10.1038/s41467-021-23683-y. [12] XuX, PiaoHN, AosaiF,et al. Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/ NF-κB and TNF-α/TNFR1/ NF-κB pathways[J].Br J Pharmacol,2020,177(22):5224-5245. DOI: 10.1111/bph.15261. [13] ZumerleS, CalìB, MunariF,et al. Intercellular calcium signaling induced by ATP potentiates macrophage phagocytosis[J].Cell Rep,2019,27(1):1-10.e4. DOI: 10.1016/j.celrep.2019.03.011. [14] ChenW, LiuY, ChenJ,et al. The Notch signaling pathway regulates macrophage polarization in liver diseases[J].Int Immunopharmacol,2021,99:107938. DOI: 10.1016/j.intimp.2021.107938. [15] YunnaC, MengruH, LeiW,et al. Macrophage M1/M2 polarization[J].Eur J Pharmacol,2020,877:173090. DOI: 10.1016/j.ejphar.2020.173090. [16] McCubbreyAL, McManusSA, McClendonJD,et al. Polyamine import and accumulation causes immunomodulation in macrophages engulfing apoptotic cells[J].Cell Rep,2022,38(2):110222. DOI: 10.1016/j.celrep.2021.110222. [17] Greenlee-WackerMC. Clearance of apoptotic neutrophils and resolution of inflammation[J].Immunol Rev,2016,273(1):357-370. DOI: 10.1111/imr.12453. [18] LaskinDL,MalaviyaR, LaskinJD. Role of macrophages in acute lung injury and chronic fibrosis induced by pulmonary toxicants[J].Toxicol Sci,2019,168(2):287-301. DOI: 10.1093/toxsci/kfy309. [19] WuH, ZhengJ, XuS,et al. Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury[J].J Neuroinflammation,2021,18(1):2. DOI: 10.1186/s12974-020-02041-7. [20] ShouvalDS, BiswasA, GoettelJA,et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function[J].Immunity,2014,40(5):706-719. DOI: 10.1016/j.immuni.2014.03.011. [21] ArnoldL, HenryA, PoronF,et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis[J].J Exp Med,2007,204(5):1057-1069. DOI: 10.1084/jem.20070075. [22] BouhlelMA, DerudasB, RigamontiE,et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties[J].Cell Metab,2007,6(2):137-143. DOI: 10.1016/j.cmet.2007.06.010. [23] BaoL, DouG, TianR,et al. Engineered neutrophil apoptotic bodies ameliorate myocardial infarction by promoting macrophage efferocytosis and inflammation resolution[J].Bioact Mater,2022,9:183-197. DOI: 10.1016/j.bioactmat.2021.08.008. [24] HilgendorfI, GerhardtLM, TanTC,et al. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium[J].Circ Res,2014,114(10):1611-1622. DOI: 10.1161/circresaha.114.303204. [25] WangX, CaoQ, YuL,et al. Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity[J].JCI Insight,2016,1(19):e87748. DOI: 10.1172/jci.insight.87748. [26] MullicanSE, GaddisCA, AlenghatT,et al. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation[J].Genes Dev,2011,25(23):2480-2488. DOI: 10.1101/gad.175950.111. [27] CurtaleG,RubinoM, LocatiM. MicroRNAs as molecular switches in macrophage activation[J].Front Immunol,2019,10:799. DOI: 10.3389/fimmu.2019.00799. [28] BernshteinB, CuratoC, IoannouM,et al. IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response[J].Sci Immunol,2019,4(36):eaau6571. DOI: 10.1126/sciimmunol.aau6571. [29] JungM, MaY, IyerRP,et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation[J].Basic Res Cardiol,2017,112(3):33. DOI: 10.1007/s00395-017-0622-5. [30] De NardoD, LabzinLI, KonoH,et al. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3[J].Nat Immunol,2014,15(2):152-160. DOI: 10.1038/ni.2784. [31] WestphalenK, GusarovaGA, IslamMN,et al. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity[J].Nature,2014,506(7489):503-506. DOI: 10.1038/nature12902. [32] JeongH, YoonH, LeeY,et al. SOCS3 attenuates dexamethasone-induced M2 polarization by down-regulation of GILZ via ROS- and p38 MAPK-dependent pathways[J].Immune Netw,2022,22(4):e33. DOI: 10.4110/in.2022.22.e33. [33] KimH, WangSY, KwakG,et al. Exosome-guided phenotypic switch of M1 to M2 macrophages for cutaneous wound healing[J].Adv Sci (Weinh),2019,6(20):1900513. DOI: 10.1002/advs.201900513. [34] WillenborgS, LucasT, van LooG,et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair[J].Blood,2012,120(3):613-625. DOI: 10.1182/blood-2012-01-403386. [35] MantsoungaCS, LeeC, NeversonJ,et al. Macrophage IL-1β promotes arteriogenesis by autocrine STAT3- and NF-κB-mediated transcription of pro-angiogenic VEGF-A[J].Cell Rep,2022,38(5):110309. DOI: 10.1016/j.celrep.2022.110309. [36] GantaVC, ChoiM, FarberCR,et al. Antiangiogenic VEGF(165)b regulates macrophage polarization via S100A8/S100A9 in peripheral artery disease[J].Circulation,2019,139(2):226-242. DOI: 10.1161/circulationaha.118.034165. [37] XiaoH, ZhaoX, LiS,et al. Risk factors for subretinal fibrosis after anti-VEGF treatment of myopic choroidal neovascularisation[J].Br J Ophthalmol,2021,105(1):103-108. DOI: 10.1136/bjophthalmol-2019-315763. [38] PakshirP, HinzB. The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication[J].Matrix Biol,2018,68-69,81-93. DOI: 10.1016/j.matbio.2018.01.019. [39] BorthwickLA, BarronL, HartKM,et al. Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis[J].Mucosal Immunol,2016,9(1):38-55. DOI: 10.1038/mi.2015.34. [40] MengXM, WangS, HuangXR,et al. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis[J].Cell Death Dis,2016,7(12):e2495. DOI: 10.1038/cddis.2016.402. [41] TangPC, ChungJY, XueVW,et al. Smad3 promotes cancer-associated fibroblasts generation via macrophage-myofibroblast transition[J].Adv Sci (Weinh),2022,9(1):e2101235. DOI: 10.1002/advs.202101235. [42] ShookBA, WaskoRR, Rivera-GonzalezGC,et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair[J].Science,2018,362(6417):eaar2971. DOI: 10.1126/science.aar2971. [43] AbeH, TakedaN, IsagawaT,et al. Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M[J].Nat Commun,2019,10(1):2824. DOI: 10.1038/s41467-019-10859-w. [44] StutchfieldBM, AntoineDJ, MackinnonAC,et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure[J].Gastroenterology,2015,149(7):1896-1909.e14. DOI: 10.1053/j.gastro.2015.08.053. [45] WuDC, KolliparaR, CarterMJ,et al. A novel macrophage-activating gel improves healing and skin quality after CO2 laser resurfacing of the chest[J].Dermatol Surg,2022,48(12):1312-1316. DOI: 10.1097/dss.0000000000003622. [46] SchmittH, UlmschneiderJ, BillmeierU,et al. The TLR9 agonist cobitolimod induces IL10-producing wound healing macrophages and regulatory T cells in ulcerative colitis[J].J Crohns Colitis,2020,14(4):508-524. DOI: 10.1093/ecco-jcc/jjz170. [47] 李晓亮, 谢江帆, 叶向阳, 等. 非编码RNA调控糖尿病创面愈合机制的研究进展[J]. 中华烧伤与创面修复杂志, 2023, 39(2): 184-189. DOI: 10.3760/cma.j.cn501225-20221101-00477. [48] ZhouLS, ZhaoGL, LiuQ,et al. Silencing collapsin response mediator protein-2 reprograms macrophage phenotype and improves infarct healing in experimental myocardial infarction model[J].J Inflamm (Lond),2015,12:11. DOI: 10.1186/s12950-015-0053-8. [49] WuX, HeW, MuX,et al. Macrophage polarization in diabetic wound healing[J/OL].Burns Trauma,2022,10:tkac051[2023-01-10].https://pubmed.ncbi.nlm.nih.gov/34089902/.DOI: 10.1093/burnst/tkac051. [50] LiS, YangP, DingX,et al. Puerarin improves diabetic wound healing via regulation of macrophage M2 polarization phenotype[J/OL].Burns Trauma,2022,10:tkac046[2023-01-10]. https://pubmed.ncbi.nlm.nih.gov/36568527/.DOI: 10.1093/burnst/tkac046. [51] HuangYY, LinCW, ChengNC,et al. Effect of a novel macrophage-regulating drug on wound healing in patients with diabetic foot ulcers: a randomized clinical trial[J].JAMA Netw Open,2021,4(9):e2122607. DOI: 10.1001/jamanetworkopen.2021.22607. [52] LopesT, AlmeidaGG, SouzaIA,et al. High-density- immune-complex regulatory macrophages promote recovery of erxperimental colitis in mice[J].Inflammation,2021,44(3):1069-1082. DOI: 10.1007/s10753-020-01403-w. [53] MuR, ZhangZ, HanC,et al. Tumor-associated macrophages-educated reparative macrophages promote diabetic wound healing[J].EMBO Mol Med,2023,15(2):e16671. DOI: 10.15252/emmm.202216671. -