Abstract: This review summarizes progress made in research on hydrogel wound dressings in promoting scarless skin healing. Wound healing is a complex biological process that involves four stages: hemostasis, inflammation, proliferation, and remodeling. Scar formation is a common issue during this process, especially pathological scars such as hypertrophic scars and keloids, which severely affect aesthetics and function. In recent years, hydrogel dressings have become a research hotspot for promoting scarless healing due to their unique physicochemical and biological properties. Hydrogels promote wound healing and reduce scar formation through multiple mechanisms, including providing a moist environment, antimicrobial activity, anti-inflammatory effects, promoting tissue regeneration, and regulating the wound microenvironment. This review details the concept and mechanisms of scarless healing and explores the application of hydrogel dressings loaded with anti-scarring drugs, stem cells, and extracellular vesicles (EVs) in scarless wound healing. Additionally, it summarizes progress in research on hydrogel dressings that regulate mechanical signals and innovative multifunctional hydrogel dressings, such as photo-responsive, organic biopolymer, and nanoparticle hydrogels. These hydrogel dressings show great potential for clinical application but still face challenges such as drug delivery efficiency, biocompatibility, and long-term safety. Future research needs to further optimize the composition and functionality of hydrogels and explore their potential applications in clinical settings.

促进皮肤再生：无瘢痕愈合相关水凝胶伤口敷料的研究进展

[1]AbedanzadehM,AbolmaaliSS,HeidariR,et al.,2024.Photo-crosslinked hyaluronic acid hydrogels designed for simultaneous delivery of mesenchymal stem cells and tannic acid: advancing towards scarless wound healing.Int J Biol Macromol,281:136394.

[2]BaiQ,TengL,ZhangXL,et al.,2022.Multifunctional single-component polypeptide hydrogels: the gelation mechanism, superior biocompatibility, high performance hemostasis, and scarless wound healing.Adv Healthc Mater,11(6):2101809.

[3]BainbridgeP,2013.Wound healing and the role of fibroblasts.J Wound Care,22(8):407-408,410-412.

[4]BharadiaSK,BurnettL,GabrielV,2023.Hypertrophic scar.Phys Med Rehabil Clin N Am,34(4):783-798.

[5]BhattacharyaD,TiwariR,BhatiaT,et al.,2019.Accelerated and scarless wound repair by a multicomponent hydrogel through simultaneous activation of multiple pathways.Drug Deliv Transl Res,9(6):1143-1158.

[6]BianJ,BaoLH,GaoXK,et al.,2022.Bacteria-engineered porous sponge for hemostasis and vascularization.J Nanobiotechnol,20:47.

[7]BurringtonJD,1971.Wound healing in the fetal lamb.J Pediatr Surg,6(5):523-528.

[8]ChangLK,XuYL,WuZY,et al.,2023.Hyaluronic acid methacrylate/laponite hydrogel loaded with BMP4 and maintaining its bioactivity for scar-free wound healing.Regen Biomater,10:rbad023.

[9]ChenMY,CaoMQ,XuTY,2024.Progress in the application of artificial intelligence in skin wound assessment and prediction of healing time.Am J Transl Res,16(7):2765-2776.

[10]ChenQ,LiSY,LiK,et al.,2024.A skin stress shielding platform based on body temperature-induced shrinking of hydrogel for promoting scar-less wound healing.Adv Sci,11(41):2306018.

[11]ChenSX,ChengJ,WatchmakerJ,et al.,2022.Review of lasers and energy-based devices for skin rejuvenation and scar treatment with histologic correlations.Dermatol Surg,48(4):441-448.

[12]ChenXH,SongHY,SongK,et al.,2024.Temperature-sensitive hydrogel releasing pectolinarin facilitate scarless wound healing.J Cell Mol Med,28(4):e18130.

[13]ChengXY,LiYQ,LiangY,et al.,2024.Mechanical biomimetic silk nano fiber-magnesium ion complex/hydroxyethylcellulose/glycerol hydrogel dressing with angiogenic capacity for accelerating scarless diabetic wound healing.J Colloid Interface Sci,667:624-639.

[14]ChildsDR,MurthyAS,2017.Overview of wound healing and management.Surg Clin North Am,97(1):189-207.

[15]DengJ,LiJY,YanLZ,et al.,2024.Accelerated, injectable, self-healing, scarless wound dressings using rGO reinforced dextran/chitosan hydrogels incorporated with PDA-loaded asiaticoside.Int J Biol Macromol,278:134424.

[16]DingJY,ChenMJ,WuLF,et al.,2023.Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges.Mil Med Res,10:36.

[17]FuDL,HuangJF,WuXQ,et al.,2024.Shape-fixing hydrogel promotes scarless healing of wounds under tension.Acta Biomater,183:173-190.

[18]GanDL,SuQY,SuHW,et al.,2021.Burn ointment promotes cutaneous wound healing by modulating the PI3K/AKT/mTOR signaling pathway.Front Pharmacol,12:631102.

[19]GopeA,MukhopadhyayA,MukhopadhyayO,et al.,2022.Regenerative repair of full thickness skin wound assisted by dual crosslinking percolative gel casting maneuvered alginate hydrogel embedded with honey ghee blend resembles standard cutaneous properties.J Tissue Viability,31(4):657-672.

[20]GovindharajM,Al HashimiN,SomanSS,et al.,2024.3D-bioprinted tri-layered cellulose/collagen-based drug-eluting fillers for the treatment of deep tunneling wounds.Bio-Des Manuf,7(6):938-954.

[21]GriffinMF,desJardins-ParkHE,MascharakS,et al.,2020.Understanding the impact of fibroblast heterogeneity on skin fibrosis.Dis Model Mech,13(6):dmm044164.

[22]GuoS,DipietroLA,2010.Factors affecting wound healing.J Dent Res,89(3):219-229.

[23]HanL,LiuZX,LiM,et al.,2025.3D bioprinting of a dermal scaffold for full-thickness skin tissue regeneration.Bio-Des Manuf,8(1):68-84.

[24]HaoAL,DongXY,GouYN,et al.,2025.Engrailed-1 inactivation leads to scarless skin wound healing through extracellular matrix remodeling.Genes Dis,12(3):101484.

[25]HassanWU,GreiserU,WangWX,2014.Role of adipose-derived stem cells in wound healing.Wound Repair Regen,22(3):313-325.

[26]HassanshahiA,MoradzadM,GhalamkariS,et al.,2022.Macrophage-mediated inflammation in skin wound healing.Cells,11(19):295.

[27]HeJH,FangB,ShanSZ,et al.,2021.Mechanical stretch promotes hypertrophic scar formation through mechanically activated cation channel Piezo1.Cell Death Dis,12(3):226.

[28]HuHH,CaoG,WuXQ,et al.,2020.Wnt signaling pathway in aging-related tissue fibrosis and therapies.Ageing Res Rev,60:101063.

[29]HuaYJ,WangK,HuoYY,et al.,2023.Four-dimensional hydrogel dressing adaptable to the urethral microenvironment for scarless urethral reconstruction.Nat Commun,14:7632.

[30]HuangJ,ZhouXB,XiaLL,et al.,2021.Inhibition of hypertrophic scar formation with oral asiaticoside treatment in a rabbit ear scar model.Int Wound J,18(5):598-607.

[31]HuebenerP,SchwabeRF,2013.Regulation of wound healing and organ fibrosis by toll-like receptors.Biochim Biophys Acta-Mol Basis Dis,1832(7):1005-1017.

[32]IndrakumarS,JoshiA,DashTK,et al.,2023.Photopolymerized silk fibroin gel for advanced burn wound care.Int J Biol Macromol,233:123569.

[33]JeonEY,ChoiBH,JungD,et al.,2017.Natural healing-inspired collagen-targeting surgical protein glue for accelerated scarless skin regeneration.Biomaterials,134:154-165.

[34]JereSW,AbrahamseH,HoureldNN,2017.The JAK/STAT signaling pathway and photobiomodulation in chronic wound healing.Cytokine Growth Factor Rev,38:73-79.

[35]JinL,GuoXQ,GaoD,et al.,2022.An NIR photothermal-responsive hybrid hydrogel for enhanced wound healing.Bioact Mater,16:162-172.

[36]KadotaT,FujitaY,ArayaJ,et al.,2021.Human bronchial epithelial cell-derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF-β-WNT crosstalk.J Extracell Vesicles,10(10):e12124.

[37]KanchanawongP,CalderwoodDA,2023.Organization, dynamics and mechanoregulation of integrin-mediated cell‒ECM adhesions.Nat Rev Mol Cell Biol,24(2):142-161.

[38]KarppinenSM,HeljasvaaraR,GullbergD,et al.,2019.Toward understanding scarless skin wound healing and pathological scarring.F1000Res,8:F1000.

[39]KavanaghF,RozenW,SethI,et al.,2024.Exploring the efficacy of negative pressure wound therapy in the management of mycobacterium ulcerans wounds: a comprehensive literature review.Plast Aesthet Res,11:43.

[40]KeykhaeeM,RahimifardM,NajafiA,et al.,2023.Alginate/gum arabic-based biomimetic hydrogel enriched with immobilized nerve growth factor and carnosine improves diabetic wound regeneration.Carbohydr Polym,321:121179.

[41]KluweJ,MencinA,SchwabeRF,2009.Toll-like receptors, wound healing, and carcinogenesis.J Mol Med,87(2):125-138.

[42]KnoedlerS,BroichhausenS,GuoRJ,et al.,2023.Fibroblasts ‒ the cellular choreographers of wound healing.Front Immunol,14:1233800.

[43]LeeHJ,JangYJ,2018.Recent understandings of biology, prophylaxis and treatment strategies for hypertrophic scars and keloids.Int J Mol Sci,19(3):711.

[44]LeeSH,AnS,RyuYC,et al.,2023.Adhesive hydrogel patch-mediated combination drug therapy induces regenerative wound healing through reconstruction of regenerative microenvironment.Adv Healthc Mater,12(18):2203094.

[45]LeiLJ,WangXG,ZhuYL,et al.,2022.Antimicrobial hydrogel microspheres for protein capture and wound healing.Mater Des,215:110478.

[46]LiAQ,MaB,HuaSY,et al.,2024.Chitosan-based injectable hydrogel with multifunction for wound healing: a critical review.Carbohydr Polym,333:121952.

[47]LiJ,ChenJ,KirsnerR,2007.Pathophysiology of acute wound healing.Clin Dermatol,25(1):9-18.

[48]LiMZ,WangP,LiJT,et al.,2023.NRP1 transduces mechanical stress inhibition via LATS1/YAP in hypertrophic scars.Cell Death Discov,9:341.

[49]LiX,WangX,ShenT,et al.,2024.Advances in photodynamic therapy of pathologic scar.Photodiagnosis Photodyn Ther,46:104040.

[50]LiZ,LiYN,LiuCR,et al.,2024.Research progress of the mechanisms and applications of ginsenosides in promoting bone formation.Phytomedicine,129:155604.

[51]LiangYP,HeJH,GuoBL,2021.Functional hydrogels as wound dressing to enhance wound healing.ACS Nano,15(8):12687-12722.

[52]LiuLT,DingZZ,YangY,et al.,2021.Asiaticoside-laden silk nanofiber hydrogels to regulate inflammation and angiogenesis for scarless skin regeneration.Biomater Sci,9(15):5227-5236.

[53]LouJQ,XiangZY,ZhuXY,et al.,2025.Evaluating the therapeutic efficacy and safety of alginate-based dressings in burn wound and donor site wound management associated with burn surgery: a systematic review and meta-analysis of contemporary randomized controlled trials.BMC Surg,25:215.

[54]MargadantC,SonnenbergA,2010.Integrin-TGF-β crosstalk in fibrosis, cancer and wound healing.EMBO Rep,11(2):97-105.

[55]MascharakS,Desjardins-ParkHE,DavittMF,et al.,2021.PreventingEngrailed-1 activation in fibroblasts yields wound regeneration without scarring.Science,372(6540):eaba2374.

[56]MatsuzakiK,UptonD,2013.Wound treatment and pain management: a stressful time.Int Wound J,10(6):638-644.

[57]MussbacherM,DerlerM,BasílioJ,et al.,2023.NF-κB in monocytes and macrophages ‒ an inflammatory master regulator in multitalented immune cells.Front Immunol,14:1134661.

[58]NaasaniLIS,PrettoL,ZanatelliC,et al.,2023.Bioscaffold developed with decellularized human amniotic membrane seeded with mesenchymal stromal cells: assessment of efficacy and safety profiles in a second-degree burn preclinical model.Biofabrication,15:015012.

[59]NegutI,GrumezescuV,GrumezescuAM,2018.Treatment strategies for infected wounds.Molecules,23(9):2392.

[60]NguyenAV,SoulikaAM,2019.The dynamics of the skin’s immune system.Int J Mol Sci,20(8):1811.

[61]NowakNC,MenichellaDM,MillerR,et al.,2021.Cutaneous innervation in impaired diabetic wound healing.Transl Res,236:87-108.

[62]OgawaR,DohiT,TosaM,et al.,2021.The latest strategy for keloid and hypertrophic scar prevention and treatment: the nippon medical school (NMS) protocol.J Nippon Med Sch,88(1):2-9.

[63]OuMY,TanPC,XieY,et al.,2022.Dedifferentiated Schwann cell-derived TGF-β3 is essential for the neural system to promote wound healing.Theranostics,12(12):5470-5487.

[64]PeñaOA,MartinP,2024.Cellular and molecular mechanisms of skin wound healing.Nat Rev Mol Cell Biol,25(8):599-616.

[65]PignetAL,HeckerA,VoljcT,et al.,2024.The use of acellular fish skin grafts in burns and complex trauma wounds: a systematic review of clinical data.Plast Aesthet Res,11:40.

[66]PratsinisH,MavrogonatouE,KletsasD,2019.Scarless wound healing: from development to senescence.Adv Drug Deliv Rev,146:325-343.

[67]QinBQ,WuSZ,DongHX,et al.,2023.Accelerated healing of infected diabetic wounds by a dual-layered adhesive film cored with microsphere-loaded hydrogel composite dressing.ACS Appl Mater Interfaces,15(28):33207-33222.

[68]RabelloFB,SouzaCD,Farina JúniorJA,2014.Update on hypertrophic scar treatment.Clinics,69(8):565-573.

[69]RahimiF,AhmadkhaniN,GoodarziA,et al.,2023.Gelatin-based hydrogel functionalized with taurine moieties for in vivo skin tissue regeneration.Bio-Des Manuf,6(3):284-297.

[70]SchusterR,YounesiF,EzzoM,et al.,2023.The role of myofibroblasts in physiological and pathological tissue repair.Cold Spring Harb Perspect Biol,15(1):a041231.

[71]ShanJY,CheJY,SongCH,et al.,2023.Emerging antibacterial nanozymes for wound healing.Smart Med,2(3):e20220025.

[72]SharifiE,SadatiSA,YousefiaslS,et al.,2022.Cell loaded hydrogel containing Ag-doped bioactive glass-ceramic nanoparticles as skin substitute: antibacterial properties, immune response, and scarless cutaneous wound regeneration.Bioeng Transl Med,7(3):e10386.

[73]ShenYF,XuGZ,HuangHX,et al.,2021.Sequential release of small extracellular vesicles from bilayered thiolated alginate/polyethylene glycol diacrylate hydrogels for scarless wound healing.ACS Nano,15(4):6352-6368.

[74]ShiM,GaoYF,LeeL,et al.,2022.Adaptive gelatin microspheres enhanced stem cell delivery and integration with diabetic wounds to activate skin tissue regeneration.Front Bioeng Biotechnol,10:813805.

[75]ShpichkaA,ButnaruD,BezrukovEA,et al.,2019.Skin tissue regeneration for burn injury.Stem Cell Res Ther,10:94.

[76]SongYT,HuQX,LiuSH,et al.,2024.Electrospinning drug-loaded polycaprolactone/polycaprolactone-gelatin multi-functional bilayer nanofibers composite scaffold for postoperative wound healing of cutaneous squamous cell carcinoma.Biomed Technol,8:65-80.

[77]SorgH,TilkornDJ,HagerS,et al.,2017.Skin wound healing: an update on the current knowledge and concepts.Eur Surg Res,58(1-2):81-94.

[78]TalbottHE,MascharakS,GriffinM,et al.,2022.Wound healing, fibroblast heterogeneity, and fibrosis.Cell Stem Cell,29(8):1161-1180.

[79]VågesjöE,ÖhnstedtE,MortierA,et al.,2018.Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria.Proc Natl Acad Sci USA,115(8):1895-1900.

[80]VelnarT,BaileyT,SmrkoljV,2009.The wound healing process: an overview of the cellular and molecular mechanisms.J Int Med Res,37(5):1528-1542.

[81]VerdolinoDV,ThomasonHA,FotticchiaA,et al.,2021.Wound dressings: curbing inflammation in chronic wound healing.Emerg Top Life Sci,5(4):523-537.

[82]WangXJ,BandaJ,QiH,et al.,2022.Scarless wound healing: current insights from the perspectives of TGF-β, KGF-1, and KGF-2.Cytokine Growth Factor Rev,66:26-37.

[83]WangYJ,HeG,TangH,et al.,2019.Aspirin inhibits inflammation and scar formation in the injury tendon healing through regulating JNK/STAT-3 signalling pathway.Cell Prolif,52(4):e12650.

[84]WangZC,ZhaoWY,CaoYY,et al.,2020.The roles of inflammation in keloid and hypertrophic scars.Front Immunol,11:603187.

[85]WengWQ,WangL,FanL,et al.,2024.Ordered micro-nano structured biomaterials for wound healing.Biomed Technol,8:104-114.

[86]XieJL,QiSH,LiTZ,et al.,2009.Effect of asiaticoside on hypertrophic scar in the rabbit ear model.J Cutan Pathol,36(2):234-239.

[87]XingDD,DuYR,DaiK,et al.,2024.Polysaccharide-based injectable hydrogel loaded with quercetin promotes scarless healing of burn wounds by reducing inflammation.Biomacromolecules,25(11):7529-7542.

[88]XingDL,XiaGQ,TangXD,et al.,2024.A multifunctional nanocomposite hydrogel delivery system based on dual-loaded liposomes for scarless wound healing.Adv Healthc Mater,13(28):2401619.

[89]XiongMC,YangXL,ShiZW,et al.,2024.Programmable artificial skins accomplish antiscar healing with multiple appendage regeneration.Adv Mater,36(50):2407322.

[90]XuTT,YangR,MaXB,et al.,2019.Bionic poly(γ-glutamic acid) electrospun fibrous scaffolds for preventing hypertrophic scars.Adv Healthc Mater,8(13):1900123.

[91]XuXY,WangYW,HanCH,et al.,2024.Poison turned panacea: arsenic trioxide loaded hydrogel for inhibiting scar formation in wound healing.ACS Biomater Sci Eng,10(10):6533-6544.

[92]YangBW,LinYM,HuangYB,et al.,2023.Extracellular vesicles modulate key signalling pathways in refractory wound healing.Burns Trauma,11:tkad039.

[93]YangCH,ZhangZK,GanL,et al.,2023.Application of biomedical microspheres in wound healing.Int J Mol Sci,24(8):7319.

[94]YangGW,LiuLT,XiaoLY,et al.,2024.Accelerated scarless wound healing by dynamical regulation of angiogenesis and inflammation with immobilized asiaticoside and magnesium ions in silk nanofiber hydrogels.J Mater Chem B,12(45):11670-11684.

[95]YangJT,WuDW,LiJP,et al.,2024.An injectable composite hydrogel of verteporfin-bonded carboxymethyl chitosan and oxidized sodium alginate facilitates scarless full-thickness skin regeneration.Macromol Biosci,24(2):2300165.

[96]YangS,JiangH,QianM,et al.,2022.MSC-derived sEV-loaded hyaluronan hydrogel promotes scarless skin healing by immunomodulation in a large skin wound model.Biomed Mater,17(3):034104.

[97]YangYH,SuoD,XuTP,et al.,2024.Sprayable biomimetic double mask with rapid autophasing and hierarchical programming for scarless wound healing.Sci Adv,10(33):eado9479.

[98]YangYL,ZhangJN,WuSW,et al.,2024.Exosome/antimicrobial peptide laden hydrogel wound dressings promote scarless wound healing through miR-21-5p-mediated multiple functions.Biomaterials,308:122558.

[99]YinJY,ZhangSM,YangC,et al.,2022.Mechanotransduction in skin wound healing and scar formation: potential therapeutic targets for controlling hypertrophic scarring.Front Immunol,13:1028410.

[100]YingXZ,YuCC,YangWT,et al.,2024.The transformation of multifunctional bio-patch to hydrogel on skin wounds for efficient scarless wound healing.Mater Today Bio,24:100901.

[101]YounesiFS,MillerAE,BarkerTH,et al.,2024.Fibroblast and myofibroblast activation in normal tissue repair and fibrosis.Nat Rev Mol Cell Biol,25(8):617-638.

[102]YuQY,SunH,YueZW,et al.,2023.Zwitterionic polysaccharide-based hydrogel dressing as a stem cell carrier to accelerate burn wound healing.Adv Healthc Mater,12(7):2202309.

[103]YuanNN,ShaoK,HuangS,et al.,2023.Chitosan, alginate, hyaluronic acid and other novel multifunctional hydrogel dressings for wound healing: a review.Int J Biol Macromol,240:124321.

[104]YueK,Trujillo-de SantiagoG,AlvarezMM,et al.,2015.Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels.Biomaterials,73:254-271.

[105]ZhangAD,LiuY,QinD,et al.,2020.Research status of self-healing hydrogel for wound management: a review.Int J Biol Macromol,164:2108-2123.

[106]ZhangDY,OuyangQQ,HuZ,et al.,2021.Catechol functionalized chitosan/active peptide microsphere hydrogel for skin wound healing.Int J Biol Macromol,173:591-606.

[107]ZhangJ,ZhengYJ,LeeJ,et al.,2021.A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing.Nat Commun,12:1670.

[108]ZhangQ,ShiL,HeH,et al.,2022.Down-regulating scar formation by microneedles directlyvia a mechanical communication pathway.ACS Nano,16(7):10163-10178.

[109]ZhangT,WangXF,WangZC,et al.,2020.Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation.Biomed Pharmacother,129:110287.

[110]ZhangYH,KangJ,ChenX,et al.,2023.Ag nanocomposite hydrogels with immune and regenerative microenvironment regulation promote scarless healing of infected wounds.J Nanobiotechnol,21:435.

[111]ZhaoRL,LiangH,ClarkeE,et al.,2016.Inflammation in chronic wounds.Int J Mol Sci,17(12):2085.

[112]ZhaoY,LiMX,MaoJY,et al.,2024.Immunomodulation of wound healing leading to efferocytosis.Smart Med,3(1):e20230036.

[113]ZhaoYF,LiuJ,SunLX,et al.,2025.Zinc-doped curcumin carbon dots promote infected wound healing with photodynamic via the VEGF signaling pathway.J Nanobiotechnol,23:424.

[114]ZhengX,DingZZ,ChengWN,et al.,2020.Microskin-inspired injectable MSC-laden hydrogels for scarless wound healing with hair follicles.Adv Healthc Mater,9(10):2000041.

[115]ZouML,LiuSY,SunZL,et al.,2021.Insights into the role of adipose-derived stem cells: wound healing and clinical regenerative potential.J Cell Physiol,236(4):2290-2297.