Janus Adhesive Dressing with Macro/Micro Dual Design Enabling Sequential Microenvironment Regulation for Scarless Wound Healing

Abstract

Continuous wound healing micro-environment regulation and timely angiogenesis modulation are crucial for preventing excessive collagen accumulation and promoting scarless wound healing. Herein, a bilayer silk fibroin (SF)-based Janus adhesive dressing (SCE) was developed, featuring a lower layer of Ca²⁺/Zn²⁺-modified silk fibroin (SCZ) and an upper layer of silk fibroin core–shell electrospun fibers with epigallocatechin gallate (EGCG) encapsulated in the core (SE). The Ca²⁺/Zn²⁺ modification induced decrystallization of the SF, thereby conferring strong tissue adhesion to the lower SCZ layer and providing rapid hemostasis and initial anti-inflammatory effects upon wound contact. The macro (double layers) and micro (core–shell) dual design enabled EGCG to be slowly released during the early healing stage, exerting both antioxidant and synergistic anti-inflammatory effects in conjunction with Zn²⁺. With complete absorption of the lower layer and degradation of the shell of the upper layer, substantial amounts of EGCG were continuously released to inhibit angiogenesis during the later healing stages. In vivo studies employing both rat full-thickness skin wound models and rabbit ear scar models further confirmed the potential of SCE to promote scarless wound healing by combining early-stage hemostatic, antimicrobial, antioxidant, and anti-inflammatory properties with late-stage angiogenesis braking to reduce vascular density and blood supply, thereby allowing extracellular matrix remodeling and preventing collagen overproduction and deposition.

Graphical Abstract

Keywords

Janus adhesive / Silk fibroin / EGCG / Antiangiogenesis / Scarless wound healing

References

[1] Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature, 2020, 587: 555

[2] Moretti L, Stalfort J, Barker TH, Abebayehu D. The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation. J Biol Chem, 2022, 298 101530

[3] Keane TJ, Horejs CM, Stevens MM. Scarring vs. functional healing: matrix-based strategies to regulate tissue repair. Adv Drug Deliv Rev, 2018, 129: 407

[4] Finnerty CC, Jeschke MG, Branski LK, Barret JP, Dziewulski P, Herndon DN. Hypertrophic scarring: the greatest unmet challenge after burn injury. Lancet, 2016, 388: 1427

[5] Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev, 2019, 99: 665

[6] Zhang J, Zheng Y, Lee J, Hua J, Li S, Panchamukhi A, Yue J, Gou X, Xia Z, Zhu L, Wu X. A pulsatile release platform based on photo-induced imine-crosslinking hydrogel promotes scarless wound healing. Nat Commun, 2021, 12: 1670

[7] Deng F, Yang R, Yang Y, Li X, Hou J, Liu Y, Lu J, Huangfu S, Meng Y, Wu S, Zhang L. Visible light accelerates skin wound healing and alleviates scar formation in mice by adjusting STAT3 signaling. Commun Biol, 2024, 7: 1266

[8] Wu M, Zhao Y, Tao M, Fu M, Wang Y, Liu Q, Lu Z, Guo J. Malate-based biodegradable scaffolds activate cellular energetic metabolism for accelerated wound healing. ACS Appl Mater Interfaces, 2023, 15: 50836

[9] Jeschke MG, Wood FM, Middelkoop E, Bayat A, Teot L, Ogawa R, Gauglitz GG. Scars. Nat Rev Dis Primers, 2023, 9: 64

[10] Mbituyimana B, Bukatuka CF, Qi F, Ma G, Shi Z, Yang G. Microneedle-mediated drug delivery for scar prevention and treatment. Drug Discov Today, 2023, 28 103801

[11] Jonidi Shariatzadeh F, Currie S, Logsetty S, Spiwak R, Liu S. Enhancing wound healing and minimizing scarring: a comprehensive review of nanofiber technology in wound dressings. Prog Mater Sci, 2025, 147 101350

[12] Cao X, Wu X, Zhang Y, Qian X, Sun W, Zhao Y. Emerging biomedical technologies for scarless wound healing. Bioact Mater, 2024, 42: 449

[13] Coentro JQ, Pugliese E, Hanley G, Raghunath M, Zeugolis DI. Current and upcoming therapies to modulate skin scarring and fibrosis. Adv Drug Deliv Rev, 2019, 146: 37

[14] An R, Shi C, Tang Y, Cui Z, Li Y, Chen Z, Xiao M, Xu L. Chitosan/rutin multifunctional hydrogel with tunable adhesion, anti-inflammatory and antibacterial properties for skin wound healing. Carbohydr Polym, 2024, 343 122492

[15] Liu T. Recent advances in reactive oxygen species scavenging nanomaterials for wound healing. Exploration, 2024, 4: 20230066

[16] Yi Y, Yang Z, Zhou C, Yang Y, Wu Y, Zhang Q. Quercetin-encapsulated GelMa hydrogel microneedle reduces oxidative stress and facilitates wound healing. Nano TransMed, 2024, 3 100030

[17] Liu L, Ding Z, Yang Y, Zhang Z, Lu Q, Kaplan DL. Asiaticoside-laden silk nanofiber hydrogels to regulate inflammation and angiogenesis for scarless skin regeneration. Biomater Sci, 2021, 9: 5227

[18] Hong Y, Wang M, Hu D, Wang Y, Ji S, Xiang J, Zhang H, Chen H, Li Y, Xiong M, Pi W, Wang Q, Yang X, Li Y, Shui C, Wang X, Fu X, Sun X. NIR-responsive multifunctional artificial skin for regenerative wound healing. Adv Funct Mater, 2024, 34 2405876

[19] Rybak D, Du J, Nakielski P, Rinoldi C, Kosik-Kozioł A, Zakrzewska A, Wu H, Li J, Li X, Yu Y, Ding B, Pierini F. Nir-light activable 3D printed platform nanoarchitectured with electrospun plasmonic filaments for on demand treatment of infected wounds. Adv Healthc Mater, 2025, 14 2404274

[20] Qi X, Li Y, Xiang Y, Chen Y, Shi Y, Ge X, Zeng B, Shen J. Hyperthermia-enhanced immunoregulation hydrogel for oxygenation and ROS neutralization in diabetic foot ulcers. Cell Biomater, 2025, 1 100020

[21] Zhang Y, Wang S, Yang Y, Zhao S, You J, Wang J, Cai J, Wang H, Wang J, Zhang W, Yu J, Han C, Zhang Y, Gu Z. Scarless wound healing programmed by core-shell microneedles. Nat Commun, 2023, 14: 3431

[22] Yang Y, Suo D, Xu T, Zhao S, Xu X, Bei HP, Wong KK, Li Q, Zheng Z, Li B, Zhao X. Sprayable biomimetic double mask with rapid autophasing and hierarchical programming for scarless wound healing. Sci Adv, 2024, 10 eado9479

[23] Liu X, Sun Y, Wang J, Kang Y, Wang Z, Cao W, Ye J, Gao C. A tough, antibacterial and antioxidant hydrogel dressing accelerates wound healing and suppresses hypertrophic scar formation in infected wounds. Bioact Mater, 2024, 34: 269

[24] Xu N, Yuan Y, Ding L, Li J, Jia J, Li Z, He D, Yu Y. Multifunctional chitosan/gelatin@tannic acid cryogels decorated with in situ reduced silver nanoparticles for wound healing. Burns Trauma, 2022, 10 tkac019

[25] Guo Y, Huang J, Fang Y, Huang H, Wu J. 1D, 2D, and 3D scaffolds promoting angiogenesis for enhanced wound healing. Chem Eng J, 2022, 437 134690

[26] Wang X, Li R, Zhao H. Enhancing angiogenesis: Innovative drug delivery systems to facilitate diabetic wound healing. Biomed Pharmacother, 2024, 170 116035

[27] Olgasi C, Assanelli S, Cucci A, Follenzi A. Hemostasis and endothelial functionality: the double face of coagulation factors. Haematologica, 2024, 109: 2041

[28] Yu Y, Dai K, Gao Z, Tang W, Shen T, Yuan Y, Wang J, Liu C. Sulfated polysaccharide directs therapeutic angiogenesis via endogenous tgftg secretion of macrophages. Sci Adv, 2021, 7 eabd8217

[29] Yang P, Lu Y, Gou W, Qin Y, Zhang X, Li J, Zhang Q, Zhang X, He D, Wang Y, Xue D, Liu M, Chen Y, Zhou J, Zhang X, Lv J, Tan J, Luo G, Zhang Q. Andrias davidianus derived glycosaminoglycans direct diabetic wound repair by reprogramming reparative macrophage glucolipid metabolism. Adv Mater, 2025, 37 2417801

[30] Liu H, Qin S, Zhang H, Chen Z, Zhao Y, Liu J, Deng Y, Liu M, Chen W, Wang Z, Wang L. Silk Sericin-based ROS-responsive oxygen generating microneedle platform promotes angiogenesis and decreases inflammation for scarless diabetic wound healing. Adv Funct Mater, 2025, 35: 2404461

[31] Fu M, Zhao Y, Wang Y, Li Y, Wu M, Liu Q, Hou Z, Lu Z, Wu K, Guo J. On-demand removable self-healing and pH-responsive europium-releasing adhesive dressing enables inflammatory microenvironment modulation and angiogenesis for diabetic wound healing. Small, 2023, 19 e2205489

[32] Shao Z, Yin T, Jiang J, He Y, Xiang T, Zhou S. Wound microenvironment self-adaptive hydrogel with efficient angiogenesis for promoting diabetic wound healing. Bioact Mater, 2023, 20: 561

[33] Fu Y-J, Shi Y-F, Wang L-Y, Zhao Y-F, Wang R-K, Li K, Zhang S-T, Zha X-J, Wang W, Zhao X, Yang W. All-natural immunomodulatory bioadhesive hydrogel promotes angiogenesis and diabetic wound healing by regulating macrophage heterogeneity. Adv Sci, 2023, 10 2206771

[34] Shen Y, Xu G, Huang H, Wang K, Wang H, Lang M, Gao H, Zhao S. Sequential release of small extracellular vesicles from bilayered thiolated alginate/polyethylene glycol diacrylate hydrogels for scarless wound healing. ACS Nano, 2021, 15: 6352

[35] Wu K, Fu M, Zhao Y, Gerhard E, Li Y, Yang J, Guo J. Anti-oxidant anti-inflammatory and antibacterial tannin-crosslinked citrate-based mussel-inspired bioadhesives facilitate scarless wound healing. Bioact Mater, 2023, 20: 93

[36] Yuan B, Upton Z, Leavesley D, Fan C, Wang X-Q. Vascular and collagen target: a rational approach to hypertrophic scar management. Adv Wound care, 2021, 12: 38

[37] Boucher JM, Clark RP, Chong DC, Citrin KM, Wylie LA, Bautch VL. Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis. Nat Commun, 2017, 8: 15699

[38] Korntner S, Lehner C, Gehwolf R, Wagner A, Grütz M, Kunkel N, Tempfer H, Traweger A. Limiting angiogenesis to modulate scar formation. Adv Drug Deliv Rev, 2019, 146: 170

[39] Wu Y, Zhang Q, Ann DK, Akhondzadeh A, Duong HS, Messadi DV, Le AD. Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts. Am J Physiol Cell Physiol, 2004, 286: C905

[40] Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med, 2007, 4 e234

[41] Gira AK, Brown LF, Washington CV, Cohen C, Arbiser JL. Keloids demonstrate high-level epidermal expression of vascular endothelial growth factor. J Am Acad Dermatol, 2004, 50: 850

[42] Han C, Barakat M, DiPietro LA. Angiogenesis in wound repair: too much of a good thing?. Cold Spring Harb Perspect Biol, 2022, 14 a041225

[43] Tran HA, Hoang TT, Maraldo A, Do TN, Kaplan DL, Lim KS, Rnjak-Kovacina J. Emerging silk fibroin materials and their applications: new functionality arising from innovations in silk crosslinking. Mater Today, 2023, 65: 244

[44] Reizabal A, Costa CM, Pérez-Álvarez L, Vilas-Vilela JL, Lanceros-Méndez S. Silk fibroin as sustainable advanced material: material properties and characteristics, processing, and applications. Adv Funct Mater, 2023, 33 2210764

[45] Forouzideh N, Nadri S, Fattahi A, Abdolahinia ED, Habibizadeh M, Rostamizadeh K, Baradaran-Rafii A, Bakhshandeh H. Epigallocatechin gallate loaded electrospun silk fibroin scaffold with anti-angiogenic properties for corneal tissue engineering. J Imaging Sci Technol, 2020, 56101498

[46] Tsakiroglou P, VandenAkker NE, Del Bo C, Riso P, Klimis-Zacas D. Role of berry anthocyanins and phenolic acids on cell migration and angiogenesis: an updated overview. Nutrients, 2019, 11: 1075

[47] Alizadeh S, Samadikuchaksaraei A, Jafari D, Orive G, Dolatshahi-Pirouz A, Pezeshki-Modaress M, Gholipourmalekabadi M. Enhancing diabetic wound healing through improved angiogenesis: the role of emulsion-based core-shell micro/nanofibrous scaffold with sustained CuO nanoparticle delivery. Small, 2024, 20 e2309164

[48] Bi S, Lin H, Zhu K, Zhu Z, Zhang W, Yang X, Chen S, Zhao J, Liu M, Pan P, Liang G. Chitosan-salvianolic acid B coating on the surface of nickel-titanium alloy inhibits proliferation of smooth muscle cells and promote endothelialization. Front Bioeng Biotechnol, 2023, 11: 1300336

[49] Amini Moghaddam M, Di Martino A, Šopík T, Fei H, Císař J, Pummerová M, Sedlařík V. Polylactide/Polyvinylalcohol-based porous bioscaffold loaded with gentamicin for wound dressing applications. Polymers, 2021, 13 921

[50] Seo J-W, Kim H, Kim K, Choi SQ, Lee HJ. Calcium-modified silk as a biocompatible and strong adhesive for epidermal electronics. Adv Funct Mater, 2018, 28: 1800802

[51] Liu Z, Tang W, Liu J, Han Y, Yan Q, Dong Y, Liu X, Yang D, Ma G, Cao H. A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound. Bioact Mater, 2023, 20: 610

[52] Subramaniam T, Fauzi MB, Lokanathan Y, Law JX. The role of calcium in wound healing. Int J Mol Sci, 2021, 22 6486

[53] Lei Q, He D, Ding L, Kong F, He P, Huang J, Guo J, Brinker CJ, Luo G, Zhu W, Yu Y. Microneedle patches integrated with biomineralized melanin nanoparticles for simultaneous skin tumor photothermal therapy and wound healing. Adv Funct Mater, 2022, 32 2113269

[54] Xu N, Gao Y, Li Z, Chen Y, Liu M, Jia J, Zeng R, Luo G, Li J, Yu Y. Immunoregulatory hydrogel decorated with tannic acid/ferric ion accelerates diabetic wound healing via regulating macrophage polarization. Chem Eng J, 2023, 466 143173

[55] Qian Y, Ding J, Zhao R, Song Y, Yoo J, Moon H, Koo S, Kim JS, Shen J. Intrinsic immunomodulatory hydrogels for chronic inflammation. Chem Soc Rev, 2025, 54: 33

[56] Tonnesen MG, Feng X, Clark RAF. Angiogenesis in wound healing. J Invest Dermatol Symp Proc, 2000, 5: 40

[57] Tao B, Lin C, Guo A, Yu Y, Qin X, Li K, Tian H, Yi W, Lei D, Chen L. Fabrication of copper ions-substituted hydroxyapatite/polydopamine nanocomposites with high antibacterial and angiogenesis effects for promoting infected wound healing. Ind Eng Chem, 2021, 104: 345

[58] Bhol NK, Bhanjadeo MM, Singh AK, Dash UC, Ojha RR, Majhi S, Duttaroy AK, Jena AB. The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed Pharmacother, 2024, 178 117177

[59] Yaseen MM, Abuharfeil NM, Darmani H, Daoud A. Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine. Open Biol, 2020, 10 200111

[60] Shi A, Li J, Qiu X, Sabbah M, Boroumand S, Huang TC, Zhao C, Terzic A, Behfar A, Moran SL. TGF-β loaded exosome enhances ischemic wound healing in vitro and in vivo. Theranostics, 2021, 11: 6616

[61] Li Q, Song H, Li S, Hu P, Zhang C, Zhang J, Feng Z, Kong D, Wang W, Huang P. Macrophage metabolism reprogramming EGCG-Cu coordination capsules delivered in polyzwitterionic hydrogel for burn wound healing and regeneration. Bioact Mater, 2023, 29: 251

[62] Gu Y, You Y, Yang Y, Liu X, Yang L, Li Y, Zhang C, Yang H, Sha Z, Ma Y, Pang Y, Liu Y. Multifunctional EGCG@ZIF-8 nanoplatform with photodynamic therapy/chemodynamic therapy antibacterial properties promotes infected wound healing. ACS Appl Mater Interfaces, 2024, 16: 50238

[63] Kciuk M, Alam M, Ali N, Rashid S, Głowacka P, Sundaraj R, Celik I, Yahya EB, Dubey A, Zerroug E, Kontek R. Epigallocatechin-3-gallate therapeutic potential in cancer: mechanism of action and clinical implications. Molecules, 2023, 28: 5246

[64] Rashidi B, Malekzadeh M, Goodarzi M, Masoudifar A, Mirzaei H. Green tea and its anti-angiogenesis effects. Biomed Pharmacother, 2017, 89: 949

[65] Rodriguez SK, Guo W, Liu L, Band MA, Paulson EK, Meydani M. Green tea catechin, epigallocatechin-3-gallate, inhibits vascular endothelial growth factor angiogenic signaling by disrupting the formation of a receptor complex. Int J Cancer, 2006, 118: 1635

[66] Wang L, Liu WQ, Broussy S, Han B, Fang H. Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis. Front Pharmacol, 2023, 14 1307860

[67] Harris-Tryon TA, Grice EA. Microbiota and maintenance of skin barrier function. Science, 2022, 376: 940

[68] Chen YE, Fischbach MA, Belkaid Y. Skin microbiota-host interactions. Nature, 2018, 553: 427

[69] Almoughrabie S, Cau L, Cavagnero K, O'Neill AM, Li F, Roso-Mares A, Mainzer C, Closs B, Kolar MJ, Williams KJ, Bensinger SJ, Gallo RL. Commensal Cutibacterium acnes induce epidermal lipid synthesis important for skin barrier function. Sci Adv, 2023, 9 eadg6262

[70] Hou K, Wu ZX, Chen XY, Wang JQ, Zhang D, Xiao C, Zhu D, Koya JB, Wei L, Li J, Chen ZS. Microbiota in health and diseases. Signal Transduct Target Ther, 2022, 7 135

[71] Fyhrquist N, Muirhead G, Prast-Nielsen S, Jeanmougin M, Olah P, Skoog T, Jules-Clement G, Feld M, Barrientos-Somarribas M, Sinkko H, van den Bogaard EH, Zeeuwen P, Rikken G, Schalkwijk J, Niehues H, Däubener W, Eller SK, Alexander H, Pennino D, Suomela S, Tessas I, Lybeck E, Baran AM, Darban H, Gangwar RS, Gerstel U, Jahn K, Karisola P, Yan L, Hansmann B, Katayama S, Meller S, Bylesjö M, Hupé P, Levi-Schaffer F, Greco D, Ranki A, Schröder JM, Barker J, Kere J, Tsoka S, Lauerma A, Soumelis V, Nestle FO, Homey B, Andersson B, Alenius H. Microbe-host interplay in atopic dermatitis and psoriasis. Nat Commun, 2019, 10: 4703

[72] Zhang Q, Shi L, He H, Liu X, Huang Y, Xu D, Yao M, Zhang N, Guo Y, Lu Y, Li H, Zhou J, Tan J, Xing M, Luo G. Down-regulating scar formation by microneedles directly via a mechanical communication pathway. ACS Nano, 2022, 16: 10163

[73] Liu L, Yu H, Long Y, You Z, Ogawa R, Du Y, Huang C. Asporin inhibits collagen matrix-mediated intercellular mechanocommunications between fibroblasts during keloid progression. FASEB J, 2021, 35 e21705

[74] Sedaghat ES, Gold MH. Skin care for scars: where we have been and what's new. Dermatological Reviews, 2023, 4: 278

[75] Hoeksema H, De Vos M, Verbelen J, Pirayesh A, Monstrey S. Scar management by means of occlusion and hydration: a comparative study of silicones versus a hydrating gel-cream. Burns, 2013, 39: 1437

[76] Nguyen N, Dulai AS, Adnan S, Khan Z-e-h, Sivamani RK. Narrative review of the use of hydrocolloids in dermatology: applications and benefits. J Clin Med, 2025, 14 1345

Funding

the Natural Science Foundation of China(82272453)

the Guangdong Basic and Applied Basic Research Foundation(2024A1515012664)

the Shenzhen Medical Research Special Fund(A2402019)

RIGHTS & PERMISSIONS

Donghua University, Shanghai, China