多功能水凝胶敷料治疗糖尿病致慢性创面的研究进展

曹望北; 高长有

doi:10.3760/cma.j.cn501120-20210715-00249

多功能水凝胶敷料治疗糖尿病致慢性创面的研究进展

doi: 10.3760/cma.j.cn501120-20210715-00249

曹望北,
高长有^,

教育部高分子合成与功能构造重点实验室，浙江大学高分子科学与工程学系，杭州　　310027

基金项目:

国家自然科学基金面上项目 51873188

浙江省自然科学基金 LD21E030001

详细信息

通讯作者:
高长有，Email：cygao@zju.edu.cn

计量
- 文章访问数: 1831
- HTML全文浏览量: 1403
- PDF下载量: 265
- 被引次数: 0
出版历程
- 收稿日期: 2021-07-15

Research advances on multifunctional hydrogel dressings for treatment of diabetic chronic wounds

Cao Wangbei,
Gao Changyou^,

Key Laboratory of Macromolecular Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China

Funds:

General Program of National Natural Science Foundation of China 51873188

Natural Science Foundation of Zhejiang Province of China LD21E030001

More Information

Corresponding author: Gao Changyou, Email: cygao@zju.edu.cn

摘要

摘要:
糖尿病会导致多种并发症如慢性创面（糖尿病足），是导致糖尿病患者死亡的重要原因之一。高血糖、高氧化应激水平、高炎症水平以及易感染等不利因素使糖尿病致慢性创面难以愈合，甚至进一步恶化。水凝胶材料由于具有含水量高、生物相容性好和理化性能可调控等优点，已成为当前创面敷料研究中的热点材料。相较于纱布等传统敷料，水凝胶敷料可为创面提供有利于愈合的湿润环境。通过负载活性物质和改变水凝胶组成及结构，水凝胶敷料可被赋予优异的组织黏附、抗菌、抗氧化以及调控炎症因子表达等功能，因此其在创面敷料应用领域中具有广阔的前景。本文基于糖尿病致慢性创面微环境和水凝胶材料的特点，总结了近年来用于治疗糖尿病致慢性创面的新型多功能水凝胶敷料的研究进展，同时探讨了当前水凝胶敷料的不足并提出展望。
- 糖尿病足 /
- 伤口愈合 /
- 水凝胶 /
- 炎症 /
- 敷料
Abstract:
Diabetes can lead to a variety of complications, such as chronic wound (diabetic foot), which is one of the important causes of death for patients with diabetes. Unfavorable factors such as high blood glucose, high level of oxidative stress and inflammation, and susceptibility to infection lead to difficult healing and even worsening of diabetic chronic wounds. Due to the advantages of high water content, good biocompatibility, and tunable physicochemical properties, the hydrogels have become hot-spot materials in wound dressing research. Compared with the traditional dressings such as gauze, the hydrogel dressings can provide a moist environment that is beneficial for wound healing. By loading of bioactive components and modulation of compositions and structures of hydrogels, the hydrogel dressings can be endowed with excellent tissue adhesion, antibacterial ability, anti-oxidation, and inflammation regulation effect, etc., and thus show great prospects in wound dressing applications. Based on the characteristics of hydrogel materials and microenvironment of diabetic chronic wound, this review summarized the research advances on new multifunctional hydrogel dressings for the treatment of diabetic chronic wounds in recent years, and discussed the drawbacks of current hydrogel dressings with prospects proposed.
- Diabetic foot /
- Wound healing /
- Hydrogel /
- Inflammation /
- Dressing
所有作者均声明不存在利益冲突

慢性感染状态在难愈性创面中经常存在，而导致感染难以清除的主要原因是细菌生物膜，复杂的创面细菌生物膜明显削弱了抗菌药物的效力，使得使用传统抗菌敷料和全身抗菌药治疗这些难愈性创面的临床疗效并不确切。抗菌敷料比抗生素更有优势，因为它们具有更广谱的活性，且抗菌剂仅在局部创面环境中有活性，发生微生物耐药性的可能性显著降低。因此，在没有临床感染扩散迹象的情况下，抗菌敷料应被视为标准护理中创面感染管理的一线方法。解决创面处理中抗生素的过度使用是当务之急，使用适当的抗菌敷料是抗生素管理工作的重要考虑因素。

英国 ConvaTec（康维德）公司Daniel G. Metcalf在《Burns & Trauma》发文《Clinical impact of an anti-biofilm Hydrofiber dressing in hard-to-heal wounds previously managed with traditional antimicrobial products and systemic antibiotics》，该研究阐述了新一代抗细菌生物膜水力纤维敷料[AQUACEL Ag⁺ Extra(AQAg⁺ E)]在难愈性创面中的临床疗效。该抗细菌生物膜敷料包含金属螯合剂和表面活性剂组分，是一种含银离子型羧甲基纤维素敷料。金属螯合剂和表面活性剂与银离子有协同作用，破坏细菌生物膜结构，使银离子能够进入并杀死生物膜结构内的微生物。

该研究进行了抗细菌生物膜敷料的临床案例评估，其中临床医师选择恶化或停滞的创面，更换原来的敷料，使用该抗细菌生物膜敷料长达4周时间，并持续监测和评估。同时在使用抗细菌生物膜敷料之前，对传统含银、碘或聚六亚甲基双胍盐酸盐敷料以及全身抗生素治疗的病例数据进行了分层分析。结果显示，65例患者创面经过平均4.2周的抗生物膜敷料治疗后，其中11例(17%)创面愈合，40例(62%)创面好转，9例(14%)创面保持不变，5例(8%)创面恶化。

该研究表明，采用抗细菌生物膜技术合成的含银离子敷料可能是比传统抗菌材料和抗生素更优的选择，该敷料能够破坏细菌生物膜消灭细菌，从而治疗难愈性感染创面，有较好的临床疗效。

王杨平，编译自《Burns Trauma》，2020,8:tkaa004；罗高兴，审校

HTML全文

参考文献(88)

[1]	中华医学会糖尿病学分会.中国2型糖尿病防治指南(2020年版)[J].中华糖尿病杂志,2021,13(4):315-409.DOI: 10.3760/cma.j.cn115791-20210221-00095.
[2]	中华医学会糖尿病学分会.中国2型糖尿病防治指南(2017年版)[J].中国实用内科杂志,2018,38(4):292-344.DOI: 10.19538/j.nk2018040108.
[3]	ArmstrongDG,BoultonAJM,BusSA.Diabetic foot ulcers and their recurrence[J].N Engl J Med,2017,376(24):2367-2375.DOI: 10.1056/NEJMra1615439.
[4]	HallC,HardinC,CorkinsCJ,et al.Pathophysiologic mechanisms and current treatments for cutaneous sequelae of burn wounds[J].Compr Physiol,2017,8(1):371-405.DOI: 10.1002/cphy.c170016.
[5]	EmingSA,MartinP,Tomic-CanicM.Wound repair and regeneration: mechanisms, signaling, and translation[J].Sci Transl Med,2014,6(265):265sr6.DOI: 10.1126/scitranslmed.3009337.
[6]	KarriVV,KuppusamyG,TalluriSV,et al.Current and emerging therapies in the management of diabetic foot ulcers[J].Curr Med Res Opin,2016,32(3):519-542.DOI: 10.1185/03007995.2015.1128888.
[7]	NegutI,GrumezescuV,GrumezescuAM.Treatment strategies for infected wounds[J].Molecules,2018,23(9):2392.DOI: 10.3390/molecules23092392.
[8]	LipskyBA,BerendtAR,CorniaPB,et al.2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections[J].Clin Infect Dis,2012,54(12):e132-173.DOI: 10.1093/cid/cis346.
[9]	EverettE,MathioudakisN.Update on management of diabetic foot ulcers[J].Ann N Y Acad Sci,2018,1411(1):153-165.DOI: 10.1111/nyas.13569.
[10]	de SmetG,KroeseLF,MenonAG,et al.Oxygen therapies and their effects on wound healing[J].Wound Repair Regen,2017,25(4):591-608.DOI: 10.1111/wrr.12561.
[11]	MurrayRZ,WestZE,CowinAJ,et al.Development and use of biomaterials as wound healing therapies[J/OL].Burns Trauma,2019,7:2[2021-07-15]. https://academic.oup.com/burnstrauma/article/doi/ 10.1186/s41038-018-0139-7/5685924.DOI: 10.1186/s41038-018-0139-7.
[12]	HussainZ,ThuHE,ShuidAN,et al.Recent advances in polymer-based wound dressings for the treatment of diabetic foot ulcer: an overview of state-of-the-art[J].Curr Drug Targets,2018,19(5):527-550.DOI: 10.2174/1389450118666170704132523.
[13]	ShiCY,WangCY,LiuH,et al.Selection of appropriate wound dressing for various wounds[J].Front Bioeng Biotechnol,2020,8:182.DOI: 10.3389/fbioe.2020.00182.
[14]	WellerCD,TeamV,SussmanG.First-line interactive wound dressing update: a comprehensive review of the evidence[J].Front Pharmacol,2020,11:155.DOI: 10.3389/fphar.2020.00155.
[15]	MatooriS,VevesA,MooneyDJ.Advanced bandages for diabetic wound healing[J].Sci Transl Med,2021,13(585):e4839.DOI: 10.1126/scitranslmed.abe4839.
[16]	ZhangYS,KhademhosseiniA.Advances in engineering hydrogels[J]. Science,2017,356(6337):eaaf3627.DOI: 10.1126/science.aaf3627.
[17]	TuYJ,ChenN,LiCP,et al.Advances in injectable self-healing biomedical hydrogels[J].Acta Biomater,2019,90:1-20.DOI: 10.1016/j.actbio.2019.03.057.
[18]	WangHN,XuZJ,ZhaoM,et al.Advances of hydrogel dressings in diabetic wounds[J].Biomater Sci,2021,9(5):1530-1546.DOI: 10.1039/d0bm01747g.
[19]	AhmadS,KhanH,SiddiquiZ,et al.AGEs, RAGEs and s-RAGE; friend or foe for cancer[J].Semin Cancer Biol,2018,49:44-55.DOI: 10.1016/j.semcancer.2017.07.001.
[20]	BrownleeM.Biochemistry and molecular cell biology of diabetic complications[J].Nature,2001,414(6865):813-820.DOI: 10.1038/414813a.
[21]	HudsonBI,LippmanME.Targeting RAGE signaling in inflammatory disease[J].Annu Rev Med,2018,69:349-364.DOI: 10.1146/annurev-med-041316-085215.
[22]	YaoD,BrownleeM.Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands[J].Diabetes,2010,59(1):249-255.DOI: 10.2337/db09-0801.
[23]	DavisFM,KimballA,BoniakowskiA,et al.Dysfunctional wound healing in diabetic foot ulcers: new crossroads[J].Curr Diab Rep,2018,18(1):2.DOI: 10.1007/s11892-018-0970-z.
[24]	TellecheaA,LealEC,KafanasA,et al.Mast cells regulate wound healing in diabetes[J].Diabetes,2016,65(7):2006-2019.DOI: 10.2337/db15-0340.
[25]	WilgusTA,RoyS,McDanielJC.Neutrophils and wound repair: positive actions and negative reactions[J].Adv Wound Care (New Rochelle),2013,2(7):379-388.DOI: 10.1089/wound.2012.0383.
[26]	KrzyszczykP,SchlossR,PalmerA,et al.The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes[J].Front Physiol,2018,9:419.DOI: 10.3389/fphys.2018.00419.
[27]	HeskethM,SahinKB,WestZE,et al.Macrophage phenotypes regulate scar formation and chronic wound healing[J].Int J Mol Sci,2017,18(7):1545.DOI: 10.3390/ijms18071545.
[28]	MoseleyR,StewartJE,StephensP,et al.Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases?[J].Br J Dermatol,2004,150(3):401-413.DOI: 10.1111/j.1365-2133.2004.05845.x.
[29]	DunnillC,PattonT,BrennanJ,et al.Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process[J].Int Wound J,2017,14(1):89-96.DOI: 10.1111/iwj.12557.
[30]	BaltzisD,EleftheriadouI,VevesA.Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights[J].Adv Ther,2014,31(8):817-836.DOI: 10.1007/s12325-014-0140-x.
[31]	FadiniGP,AlbieroM,MenegazzoL,et al.The redox enzyme p66Shc contributes to diabetes and ischemia-induced delay in cutaneous wound healing[J].Diabetes,2010,59(9):2306-2314.DOI: 10.2337/db09-1727.
[32]	KimJH,YangB,TedescoA,et al.High levels of oxidative stress and skin microbiome are critical for initiation and development of chronic wounds in diabetic mice[J].Sci Rep,2019,9(1):19318.DOI: 10.1038/s41598-019-55644-3.
[33]	SchremlS,SzeimiesRM,PrantlL,et al.Oxygen in acute and chronic wound healing[J].Br J Dermatol,2010,163(2):257-268.DOI: 10.1111/j.1365-2133.2010.09804.x.
[34]	Cabral-PachecoGA,Garza-VelozI,Castruita-De La RosaC,et al.The roles of matrix metalloproteinases and their inhibitors in human diseases[J].Int J Mol Sci,2020,21(24):9739.DOI: 10.3390/ijms21249739.
[35]	MastBA,SchultzGS.Interactions of cytokines, growth factors, and proteases in acute and chronic wounds[J].Wound Repair Regen,1996,4(4):411-420.DOI: 10.1046/j.1524-475X.1996.40404.x.
[36]	AcostaJB,del BarcoDG,VeraDC,et al.The pro-inflammatory environment in recalcitrant diabetic foot wounds[J].Int Wound J,2008,5(4):530-539.DOI: 10.1111/j.1742-481X.2008.00457.x.
[37]	PitoccoD,SpanuT,Di LeoM,et al.Diabetic foot infections: a comprehensive overview[J].Eur Rev Med Pharmacol Sci,2019,23(2 Suppl):S26-37.DOI: 10.26355/eurrev_201904_17471.
[38]	FalangaV. Wound healing and its impairment in the diabetic foot[J]. Lancet,2005,366(9498):1736-1743. DOI: 10.1016/S0140-6736(05)67700-8.
[39]	LimJZ,NgNS,ThomasC.Prevention and treatment of diabetic foot ulcers[J].J R Soc Med,2017,110(3):104-109.DOI: 10.1177/0141076816688346.
[40]	WuYK,ChengNC,ChengCM.Biofilms in chronic wounds: pathogenesis and diagnosis[J].Trends Biotechnol,2019,37(5):505-517.DOI: 10.1016/j.tibtech.2018.10.011.
[41]	ThurlowLR,HankeML,FritzT,et al.Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo[J].J Immunol,2011,186(11):6585-6596.DOI: 10.4049/jimmunol.1002794.
[42]	PidwillGR,GibsonJF,ColeJ,et al.The role of macrophages in Staphylococcus aureus infection[J].Front Immunol,2021,11:620339.DOI: 10.3389/fimmu.2020.620339.
[43]	JayakumarA,JoseVK,LeeJM.Hydrogels for medical and environmental applications[J].Small Methods,2020,4(3):1900735.DOI: 10.1002/smtd.201900735.
[44]	Maaz ArifM,KhanSM,GullN,et al.Polymer-based biomaterials for chronic wound management: promises and challenges[J].Int J Pharm,2021,598:120270.DOI: 10.1016/j.ijpharm.2021.120270.
[45]	ZhangX,ShuW,YuQ,et al.Functional biomaterials for treatment of chronic wound[J].Front Bioeng Biotechnol,2020,8:516.DOI: 10.3389/fbioe.2020.00516.
[46]	WalkerBW,LaraRP,MogadamE,et al.Rational design of microfabricated electroconductive hydrogels for biomedical applications[J].Prog Polym Sci,2019,92:135-157.DOI: 10.1016/j.progpolymsci.2019.02.007.
[47]	LiS,DongS,XuW,et al.Antibacterial hydrogels[J].Adv Sci (Weinh),2018,5(5):1700527.DOI: 10.1002/advs.201700527.
[48]	WangT,ZhengY,ShiY,et al.pH-responsive calcium alginate hydrogel laden with protamine nanoparticles and hyaluronan oligosaccharide promotes diabetic wound healing by enhancing angiogenesis and antibacterial activity[J].Drug Deliv Transl Res,2019,9(1):227-239.DOI: 10.1007/s13346-018-00609-8.
[49]	MasoodN,AhmedR,TariqM,et al.Silver nanoparticle impregnated chitosan-PEG hydrogel enhances wound healing in diabetes induced rabbits[J].Int J Pharm,2019,559:23-36.DOI: 10.1016/j.ijpharm.2019.01.019.
[50]	GuptaA,BriffaSM,SwinglerS,et al.Synthesis of silver nanoparticles using curcumin-cyclodextrins loaded into bacterial cellulose-based hydrogels for wound dressing applications[J].Biomacromolecules,2020,21(5):1802-1811.DOI: 10.1021/acs.biomac.9b01724.
[51]	NešovićK,Mišković StankovićV.A comprehensive review of the polymer-based hydrogels with electrochemically synthesized silver nanoparticles for wound dressing applications[J].Polym Eng Sci,2020,60(7):1393-1419.DOI: 10.1002/pen.25410.
[52]	KoehlerJ,BrandlFP,GoepferichAM.Hydrogel wound dressings for bioactive treatment of acute and chronic wounds[J].Eur Polym J,2018,100:1-11.DOI: 10.1016/j.eurpolymj.2017.12.046.
[53]	ZhaoY,LiZ,SongS,et al.Skin-inspired antibacterial conductive hydrogels for epidermal sensors and diabetic foot wound dressings[J].Adv Funct Mater,2019,29(31):1901474.DOI: 10.1002/adfm.201901474.
[54]	WangM,WangC,ChenM,et al.Efficient angiogenesis-based diabetic wound healing/skin reconstruction through bioactive antibacterial adhesive ultraviolet shielding nanodressing with exosome release[J].ACS Nano,2019,13(9):10279-10293.DOI: 10.1021/acsnano.9b03656.
[55]	TuZ,ChenM,WangM,et al.Engineering bioactive M2 macrophage-polarized anti-inflammatory, antioxidant, and antibacterial scaffolds for rapid angiogenesis and diabetic wound repair[J].Adv Funct Mater,2021,31(30):2100924.DOI: 10.1002/adfm.202100924.
[56]	WangJ,ChenXY,ZhaoY,et al.pH-switchable antimicrobial nanofiber networks of hydrogel eradicate biofilm and rescue stalled healing in chronic wounds[J].ACS Nano,2019,13(10):11686-11697.DOI: 10.1021/acsnano.9b05608.
[57]	MasoodN,AhmedR,TariqM,et al.Silver nanoparticle impregnated chitosan-PEG hydrogel enhances wound healing in diabetes induced rabbits[J].Int J Pharm,2019,559:23-36.DOI: 10.1016/j.ijpharm.2019.01.019.
[58]	ZhongY,SeidiF,LiC,et al.Antimicrobial/biocompatible hydrogels dual-reinforced by cellulose as ultrastretchable and rapid self-healing wound dressing[J].Biomacromolecules,2021,22(4):1654-1663.DOI: 10.1021/acs.biomac.1c00086.
[59]	ThapaRK,DiepDB,TønnesenHH.Topical antimicrobial peptide formulations for wound healing: current developments and future prospects[J].Acta Biomater,2020,103:52-67.DOI: 10.1016/j.actbio.2019.12.025.
[60]	FjellCD,HissJA,HancockRE,et al.Designing antimicrobial peptides: form follows function[J].Nat Rev Drug Discov,2011,11(1):37-51.DOI: 10.1038/nrd3591.
[61]	DimaS,LeeYY,WatanabeI,et al.Antibacterial effect of the natural polymer ε-polylysine against oral pathogens associated with periodontitis and caries[J].Polymers (Basel),2020,12(6):1218.DOI: 10.3390/polym12061218.
[62]	LiP,ZhouC,RayatpishehS,et al.Cationic peptidopolysaccharides show excellent broad-spectrum antimicrobial activities and high selectivity[J].Adv Mater,2012,24(30):4130-4137.DOI: 10.1002/adma.201104186.
[63]	WangC,WangM,XuT,et al.Engineering bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration[J].Theranostics,2019,9(1):65-76.DOI: 10.7150/thno.29766.
[64]	LiuH,LiZ,ZhaoY,et al.Novel diabetic foot wound dressing based on multifunctional hydrogels with extensive temperature- tolerant, durable, adhesive, and intrinsic antibacterial properties[J].ACS Appl Mater Interfaces,2021,13(23):26770-26781.DOI: 10.1021/acsami.1c05514.
[65]	ZhaoY,DuX,JiangL,et al.Glucose oxidase-loaded antimicrobial peptide hydrogels: potential dressings for diabetic wound[J].J Nanosci Nanotechnol,2020,20(4):2087-2094.DOI: 10.1166/jnn.2020.17189.
[66]	ZhaoH,HuangJ,LiY,et al.ROS-scavenging hydrogel to promote healing of bacteria infected diabetic wounds[J].Biomaterials,2020,258:120286.DOI: 10.1016/j.biomaterials.2020.120286.
[67]	WangJ,YeY,YuJ,et al.Core-shell microneedle gel for self- regulated insulin delivery[J].ACS Nano,2018,12(3):2466-2473.DOI: 10.1021/acsnano.7b08152.
[68]	WangC,WangJ,ZhangX,et al.In situ formed reactive oxygen species-responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy[J].Sci Transl Med,2018,10(429):eaan3682. DOI: 10.1126/scitranslmed.aan3682.
[69]	BankotiK,RameshbabuAP,DattaS,et al.Carbon nanodot decorated acellular dermal matrix hydrogel augments chronic wound closure[J].J Mater Chem B,2020,8(40):9277-9294.DOI: 10.1039/d0tb01574a.
[70]	ZhaoX,LiangY,HuangY,et al.Physical double-network hydrogel adhesives with rapid shape adaptability, fast self- healing, antioxidant and NIR/pH stimulus-responsiveness for multidrug-resistant bacterial infection and removable wound dressing[J].Adv Funct Mater,2020,30(17):1910748.DOI: 10.1002/adfm.201910748.
[71]	ZhaoX,PeiD,YangY,et al.Green tea derivative driven smart hydrogels with desired functions for chronic diabetic wound treatment[J].Adv Funct Mater,2021,31(18):2009442.DOI: 10.1002/adfm.202009442.
[72]	ZhaoW,ZhangX,ZhangR,et al.Self-assembled herbal medicine encapsulated by an oxidation-sensitive supramolecular hydrogel for chronic wound treatment[J].ACS Appl Mater Interfaces,2020,12(51):56898-56907.DOI: 10.1021/acsami.0c19492.
[73]	WuH,LiF,ShaoW,et al.Promoting angiogenesis in oxidative diabetic wound microenvironment using a nanozyme-reinforced self-protecting hydrogel[J].ACS Cent Sci,2019,5(3):477-485.DOI: 10.1021/acscentsci.8b00850.
[74]	KrishnaswamyVR,MintzD,SagiI.Matrix metalloproteinases: the sculptors of chronic cutaneous wounds[J].Biochim Biophys Acta Mol Cell Res,2017,1864(11 Pt B):2220-2227.DOI: 10.1016/j.bbamcr.2017.08.003.
[75]	StefanovI,Pérez-RafaelS,HoyoJ,et al.Multifunctional enzymatically generated hydrogels for chronic wound application[J].Biomacromolecules,2017,18(5):1544-1555.DOI: 10.1021/acs.biomac.7b00111.
[76]	HuberD,GrzelakA,BaumannM,et al.Anti-inflammatory and anti-oxidant properties of laccase-synthesized phenolic-O-carboxymethyl chitosan hydrogels[J].N Biotechnol,2018,40(Pt B):236-244.DOI: 10.1016/j.nbt.2017.09.004.
[77]	LanB,ZhangL,YangL,et al.Sustained delivery of MMP-9 siRNA via thermosensitive hydrogel accelerates diabetic wound healing[J].J Nanobiotechnology,2021,19(1):130.DOI: 10.1186/s12951-021-00869-6.
[78]	MizunoD,Konoha-MizunoK,MoriM,et al.Protective activity of carnosine and anserine against zinc-induced neurotoxicity: a possible treatment for vascular dementia[J].Metallomics,2015,7(8):1233-1239.DOI: 10.1039/c5mt00049a.
[79]	SonamuthuJ,CaiY,LiuH,et al.MMP-9 responsive dipeptide-tempted natural protein hydrogel-based wound dressings for accelerated healing action of infected diabetic wound[J].Int J Biol Macromol,2020,153:1058-1069.DOI: 10.1016/j.ijbiomac.2019.10.236.
[80]	LamJK,ChowMY,ZhangY,et al.siRNA versus miRNA as therapeutics for gene silencing[J].Mol Ther Nucleic Acids,2015,4(9):e252.DOI: 10.1038/mtna.2015.23.
[81]	SalehB,DhaliwalHK,Portillo-LaraR,et al.Local immunomodulation using an adhesive hydrogel loaded with miRNA-laden nanoparticles promotes wound healing[J].Small,2019,15(36):e1902232.DOI: 10.1002/smll.201902232.
[82]	TellecheaA,BaiS,DangwalS,et al.Topical application of a mast cell stabilizer improves impaired diabetic wound healing[J].J Invest Dermatol,2020,140(4):901-911.e11.DOI: 10.1016/j.jid.2019.08.449.
[83]	FengZ,SuQ,ZhangC,et al.Bioinspired nanofibrous glycopeptide hydrogel dressing for accelerating wound healing: a cytokine- free, M2-type macrophage polarization approach[J].Adv Funct Mater,2020,30(52):2006454.DOI: 10.1002/adfm.202006454.
[84]	PengY,HeD,GeX,et al.Construction of heparin-based hydrogel incorporated with Cu5.4O ultrasmall nanozymes for wound healing and inflammation inhibition[J].Bioact Mater,2021,6(10):3109-3124.DOI: 10.1016/j.bioactmat.2021.02.006.
[85]	LiuT,XiaoB,XiangF,et al.Ultrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases[J].Nat Commun,2020,11(1):2788.DOI: 10.1038/s41467-020-16544-7.
[86]	LohmannN,SchirmerL,AtallahP,et al.Glycosaminoglycan- based hydrogels capture inflammatory chemokines and rescue defective wound healing in mice[J].Sci Transl Med,2017,9(386):eaai9044.DOI: 10.1126/scitranslmed.aai9044.
[87]	XuX,GuS,HuangX,et al.The role of macrophages in the formation of hypertrophic scars and keloids[J/OL].Burns Trauma,2020,8:tkaa006[2021-07-15].https://academic.oup.com/burnstrauma/article/doi/ 10.1093/burnst/tkaa006/5801085?searchresult=1.DOI: 10.1093/burnst/tkaa006.
[88]	MosserDM,EdwardsJP.Exploring the full spectrum of macrophage activation[J].Nat Rev Immunol,2008,8(12):958-969.DOI: 10.1038/nri2448.

表1 当前临床所使用的创面敷料简介

种类	组成	特点	适应证
凡士林油纱	纤维素和凡士林	廉价、干燥、需多次换药，易造成二次伤害	广泛使用，但在复杂创面治疗时需配合其他操作或药物
水凝胶敷料	三维亲水聚合物网络	渗出液吸收性强、优异的保湿性能（有利于清理坏死组织）、透明材质（可直接观察创面）、可负载活性分子、方便去除及换药	干燥至中等量渗出液的非感染创面
水胶体敷料	水凝胶与合成橡胶以及黏性聚合物复合而成	渗出液吸收性强、优异的保湿性能（有利于清理坏死组织）、皮肤黏合性良好，可用于关节处	中等量渗出液的非感染创面
藻酸盐类敷料	褐藻内提取的多糖	渗出液吸收性优异（吸收后成水凝胶态）、止血	中等量至大量渗出液的感染或非感染创面
海绵（泡沫）敷料	硅胶或聚氨酯	半透过性（可阻隔细菌）、保温保湿	中等量至大量渗出液的非感染创面
薄膜敷料	胶黏剂和多孔透明聚氨酯薄膜	透气性好、隔绝水和细菌	渗出液较少的表面浅层非感染创面、上皮化创面