Volume 37 Issue 11
Nov.  2021
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Article Contents
Cao WB,Gao CY.Research advances on multifunctional hydrogel dressings for treatment of diabetic chronic wounds[J].Chin J Burns,2021,37(11):1090-1098.DOI: 10.3760/cma.j.cn501120-20210715-00249.
Citation: Cao WB,Gao CY.Research advances on multifunctional hydrogel dressings for treatment of diabetic chronic wounds[J].Chin J Burns,2021,37(11):1090-1098.DOI: 10.3760/cma.j.cn501120-20210715-00249.

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

doi: 10.3760/cma.j.cn501120-20210715-00249
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
  • Received Date: 2021-07-15
  • 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.

     

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  • [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.
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