On-demand engineered double-network gelatin/silicate composited hydrogels with enhanced wet adhesion and stable release of bioactive ion for promoting wound healing

Abstract

Silicate bioceramics have demonstrated great potential in hydrogel dressings for wound healing due to their special origins of promoting endothelial cell angiogenesis and inhibiting apoptosis of cardiomyocyte. However, there are still some deficiencies, such as insufficient biological activity, instability of silicate ion release, and lower wet adhesion on wounds with tissue exudate, limiting their further clinical applications. Herein, inspired by mussels, a multifunctional double-network hydrogel (FS/PAM-Gel-PDA) wound dressing composited gelatin with silicate ceramic powder with satisfactory wet adhesion, stable release of bioactive ions, hemostasis, and the ability of promoting vascular regeneration was engineered through specifically grafting dopamine to gelatin and introducing ferrous silicate ceramic powder into the hydrogel. The comprehensive experimental results substantiate that the FS/PAM-Gel-PDA has wet-adhesion strength of up to 21.78 kPa, and remains stably adherent to porcine myocardial tissues intuitively after bending, twisting, soaking in water, and stretching. The test results of ion release behavior in vitro show that the oxidation and agglomeration of ferrous silicate ceramic powder can be effectively inhibited by using dopamine to form an antioxidant layer on the surface of ceramic powder, and thus, the stable release of Fe²⁺ and SiO₄⁴⁻ effective ions can be realized. The animal experiment exhibits that FS/PAM-Gel-PDA can achieve rapid hemostasis in the lethal liver defect model. Meanwhile, the FS/PAM-Gel-PDA reveals the remarkable ability to promote wound healing in a full-thickness skin injury model, which can obviously accelerate skin re-epithelialization. To sum up, the FS/PAM-Gel-PDA has excellent wet adhesion and stable release of active ions to accelerate angiogenesis, which shows great potential in promoting wound healing.

Keywords

Hydrogel / Wound dressing / Bioactive ion release / Wet adhesion / Promote wound healing

References

[1] Tottoli EM, Dorati R, Genta I, Chiesa E, Pisani S, Conti B. Skin Wound Healing Process and New Emerging Technologies for Skin Wound Care and Regeneration, Pharmaceutics. 2020;12:2080735.

[2] Luo X, Liu Y, Qin R, Ao F, Wang X, Zhang H, Yang M, Liu X. Tissue-nanoengineered hyperbranched polymer based multifunctional hydrogels as flexible “wounded treatment-health monitoring” bioelectronic implant. Applied Materials Today. 2022;29:101576.

[3] QiL, ZhangC, WangB, YinJ, YanS. Progress in Hydrogels for Skin Wound Repair. Macromol Biosci, 2022, 22: e2100475.

[4] HuS, YangZ, ZhaiQ, LiD, ZhuX, HeQ, LiL, CannonRD, WangH, TangH, JiP, ChenT. An All-in-One “4A Hydrogel”: through First-Aid Hemostatic, Antibacterial, Antioxidant, and Angiogenic to Promoting Infected Wound Healing. Small, 2023, 19: e2207437.

[5] Luo X, Yin C, Ji L, Feng J, Zhang P, Wang X, Ma Y, Liu X. An Antimicrobial Polymer Brush Coating to Fabricate High-Performance, Durable, Self-Sterilization, and Recyclable Face Masks. Chemistry of Materials. 2023;(21):35.

[6] ZengQ, QiX, ShiG, ZhangM, HaickH. Wound Dressing: From Nanomaterials to Diagnostic Dressings and Healing Evaluations. ACS Nano, 2022, 16: 1708-1733.

[7] GhosalK, AgatemorC, ŠpitálskyZ, ThomasS, KnyE. Electrospinning tissue engineering and wound dressing scaffolds from polymer-titanium dioxide nanocomposites. Chem Eng J, 2019, 358: 1262-1278.

[8] XuX, JercaVV, HoogenboomR. Bioinspired double network hydrogels: from covalent double network hydrogels via hybrid double network hydrogels to physical double network hydrogels. Mater Horiz, 2021, 8: 1173-1188.

[9] Cao X, Liu H, Yang X, Tian J, Luo B, Liu M. Halloysite nanotubes@polydopamine reinforced polyacrylamide-gelatin hydrogels with NIR light triggered shape memory and self-healing capability. Composites Science and Technology. 2020;191:108071.

[10] DongH, WangL, DuL, WangX, LiQ, WangX, ZhangJ, NieJ, MaG. Smart Polycationic Hydrogel Dressing for Dynamic Wound Healing. Small, 2022, 18: e2201620.

[11] X. Liu, B. Cui, X. Wang, M. Zheng, Z. Bai, O. Yue, Y. Fei, H. Jiang, Nature-Skin-Derived e-Skin as Versatile “Wound Therapy-Health Monitoring” Bioelectronic Skin-Scaffolds: Skin to Bio-e-Skin, Adv Healthc Mater, (2023) e2202971.

[12] Yuen HY, Bei HP, Zhao X. Underwater and wet adhesion strategies for hydrogels in biomedical applications. Chemical Engineering Journal. 2022;431:133372.

[13] LiH, ChangJ. Stimulation of pro-angiogenesis by calcium silicate bioactive ceramic. Acta Biomater, 2013, 9: 5379-5389.

[14] GongF, YangN, XuJ, YangX, WeiK, HouL, LiuB, ZhaoH, LiuZ, ChengL. Calcium Hydride-Based Dressing to Promote Wound Healing. Adv Healthc Mater, 2023, 12: e2201771.

[15] FanC, XuQ, HaoR, WangC, QueY, ChenY, YangC, ChangJ. Multi-functional wound dressings based on silicate bioactive materials. Biomaterials, 2022, 287: 121652.

[16] Wang X, Ye M, Shen J, Li J, Li Y, Bao Z, Chen H, Wu T, Shen M, Zhong C, Yang X, Gou Z, Zhao S, Xu S. Core-shell-typed selective-area ion doping wollastonite bioceramic fibers enhancing bone regeneration and repair in situ. Applied Materials Today. 2023;32:101849.

[17] HanY, LiY, ZengQ, LiH, PengJ, XuY, ChangJ. Injectable bioactive akermanite/alginate composite hydrogels for in situ skin tissue engineering. J Mater Chem B, 2017, 5: 3315-3326.

[18] Macha IJ, Sufi S. Novel slow drug release bioceramic composite materials for wound dressing applications: potential of natural materials. SN Applied Sciences. 2020;2:1977.

[19] YuQ, SunH, YueZ, YuC, JiangL, DongX, YaoM, ShiM, LiangL, WanY, ZhangH, YaoF, LiJ. Zwitterionic Polysaccharide-Based Hydrogel Dressing as a Stem Cell Carrier to Accelerate Burn Wound Healing. Adv Healthc Mater, 2023, 12: e2202309.

[20] SaghiriMA, AsatourianA, OrangiJ, SorensonCM, SheibaniN. Functional role of inorganic trace elements in angiogenesis-Part II: Cr, Si, Zn, Cu, and S. Crit Rev Oncol Hematol, 2015, 96: 143-155.

[21] Luo X, Wang J, Zhang P, Feng J, Meng X, Li K, Yin C, Wang P, Ji L, Liu Y, Qiao Z. “Rooting” engineering strategy for construction of highly stable, scalable, size-customized oxidized graphene/PA6 ultrafine fiber composite nanofiltration membranes for water purification. Surfaces and Interfaces. 2024;45:103879.

[22] Tanwar A, Date P, Ottoor D. ZnO NPs incorporated gelatin grafted polyacrylamide hydrogel nanocomposite for controlled release of ciprofloxacin. Colloid and Interface Science Communications. 2021;42:100413.

[23] ZhangZ, LiW, LiuY, YangZ, MaL, ZhuangH, WangE, WuC, HuanZ, GuoF, ChangJ. Design of a biofluid-absorbing bioactive sandwich-structured Zn-Si bioceramic composite wound dressing for hair follicle regeneration and skin burn wound healing. Bioact Mater, 2021, 6: 1910-1920

[24] Zong S, Lv H, Liu C, Zhu L, Duan J, Jiang J. Mussel inspired Cu-tannic autocatalytic strategy for rapid self-polymerization of conductive and adhesive hydrogel sensors with extreme environmental tolerance, Chemical Engineering Journal. 2023;465:142831.

[25] Y. Zhang, X. Li, Z. Zhang, H. Li, D. Chen, Y. Jiao, C. Fan, Z. Zeng, J. Chang, Y. Xu, B. Peng, C. Yang, Y. Que, Zn2SiO4 Bioceramic Attenuates Cardiac Remodeling after Myocardial Infarction, Adv Healthc Mater, (2023) e2203365.

[26] ShengL, ZhangZ, ZhangY, WangE, MaB, XuQ, MaL, ZhangM, PeiG, ChangJ. A novel "hot spring"-mimetic hydrogel with excellent angiogenic properties for chronic wound healing. Biomaterials, 2021, 264: 120414.

[27] LvY, CaiF, HeY, LiL, HuangY, YangJ, ZhengY, ShiX. Multi-crosslinked hydrogels with strong wet adhesion, self-healing, antibacterial property, reactive oxygen species scavenging activity, and on-demand removability for seawater-immersed wound healing. Acta Biomater, 2023, 159: 95-110.

[28] HanL, YanL, WangK, FangL, ZhangH, TangY, DingY, WengL, XuJ, WengJ, LiuY, RenF, LuX. Tough, self-healable and tissue-adhesive hydrogel with tunable multifunctionality. NPG Asia Materials, 2017, 9: e372-e372.

[29] Gao Y, Chen J, Han X, Pan Y, Wang P, Wang T, Lu T. A Universal Strategy for Tough Adhesion of Wet Soft Material. Advanced Functional Materials. 2020;30:03207.

[30] Xiang L, Cui W. Biomedical application of photo-crosslinked gelatin hydrogels. Journal of Leather Science and Engineering. 2021;3:43.

[31] Shi S, Wang L, Song C, Yao L, Xiao J. Recent progresses of collagen dressings for chronic skin wound healing. Collagen and Leather. 2023;5:1364.

[32] Deng G, Huang K, Jiang X, Wang K, Song Z, Su Y, Li C, Zhang S, Wang S, Huang Y. Developments for collagen hydrolysates as a multifunctional antioxidant in biomedical domains. Collagen and Leather. 2023;5:1319.

[33] Chen Q, Pei Y, Tang K, Albu-Kaya MG. Structure, extraction, processing, and applications of collagen as an ideal component for biomaterials - a review. Collagen and Leather. 2023;5:1275.

[34] Perez V, Felix M, Romero A, Guerrero A. Influence of the processing variables on the microstructure and properties of gelatin‐based scaffolds by freeze‐drying. Journal of Applied Polymer Science. 2019;136:47671.

[35] MushtaqF, RazaZA, BatoolSR, ZahidM, OnderOC, RafiqueA, NazeerMA. Preparation, properties, and applications of gelatin-based hydrogels (GHs) in the environmental, technological, and biomedical sectors. Int J Biol Macromol, 2022, 218: 601-633.

[36] WuT, CuiC, HuangY, LiuY, FanC, HanX, YangY, XuZ, LiuB, FanG, LiuW. Coadministration of an Adhesive Conductive Hydrogel Patch and an Injectable Hydrogel to Treat Myocardial Infarction. ACS Appl Mater Interfaces, 2020, 12: 2039-2048.

[37] AnH, GuZ, ZhouL, LiuS, LiC, ZhangM, XuY, ZhangP, WenY. Janus mucosal dressing with a tough and adhesive hydrogel based on synergistic effects of gelatin, polydopamine, and nano-clay. Acta Biomater, 2022, 149: 126-138.

[38] HanL, LuX, LiuK, WangK, FangL, WengLT, ZhangH, TangY, RenF, ZhaoC, SunG, LiangR, LiZ. Mussel-Inspired Adhesive and Tough Hydrogel Based on Nanoclay Confined Dopamine Polymerization. ACS Nano, 2017, 11: 2561-2574.

[39] HouY, LiY, LiY, LiD, GuoT, DengX, ZhangH, XieC, LuX. Tuning Water-Resistant Networks in Mussel-Inspired Hydrogels for Robust Wet Tissue and Bioelectronic Adhesion. ACS Nano, 2023, 17: 2745-2760.

[40] LeeSS, KimHD, KimSHL, KimI, KimIG, ChoiJS, JeongJ, KimJH, KwonSK, HwangNS. Self-Healing and Adhesive Artificial Tissue Implant for Voice Recovery. ACS Appl Bio Mater, 2018, 1: 1134-1146.

[41] QiaoZ, MielesM, JiHF. Injectable and moldable hydrogels for use in sensitive and wide range strain sensing applications. Biopolymers, 2020, 111: e23355.

[42] YangK, ZhouX, LiZ, WangZ, LuoY, DengL, HeD. Ultrastretchable, Self-Healable, and Tissue-Adhesive Hydrogel Dressings Involving Nanoscale Tannic Acid/Ferric Ion Complexes for Combating Bacterial Infection and Promoting Wound Healing. ACS Appl Mater Interfaces, 2022, 14: 43010-43025.

[43] MuzzarelliRAA. Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids. Carbohyd Polym, 2009, 77: 1-9.

[44] FanX, WangS, FangY, LiP, ZhouW, WangZ, ChenM, LiuH. Tough polyacrylamide-tannic acid-kaolin adhesive hydrogels for quick hemostatic application. Mater Sci Eng C Mater Biol Appl, 2020, 109: 110649.

[45] AhmedA, NathJ, BaruahK, RatherMA, MandalM, DoluiSK. Development of mussel mimetic gelatin based adhesive hydrogel for wet surfaces with self-healing and reversible properties. Int J Biol Macromol, 2023, 228: 68-77.

[46] ZandiN, DolatyarB, LotfiR, ShallagehY, ShokrgozarMA, TamjidE, AnnabiN, SimchiA. Biomimetic nanoengineered scaffold for enhanced full-thickness cutaneous wound healing. Acta Biomater, 2021, 124: 191-204.

[47] YuanY, ZhangZ, MoF, YangC, JiaoY, WangE, ZhangY, LinP, HuC, FuW, ChangJ, WangL. A biomaterial-based therapy for lower limb ischemia using Sr/Si bioactive hydrogel that inhibits skeletal muscle necrosis and enhances angiogenesis. Bioact Mater, 2023, 26: 264-278

[48] Y. Qiu, J. Tian, S. Kong, Y. Feng, Y. Lu, L. Su, Y. Cai, M. Li, J. Chang, C. Yang, X. Wei, SrCuSi4O10/GelMA Composite Hydrogel-Mediated Vital Pulp Therapy: Integrating Antibacterial Property and Enhanced Pulp Regeneration Activity, Adv Healthc Mater, (2023) e2300546.

[49] Yang Z, Zhao F, Zhang W, Yang Z, Luo M, Liu L, Cao X, Chen D, Chen X. Degradable photothermal bioactive glass composite hydrogel for the sequential treatment of tumor-related bone defects: From anti-tumor to repairing bone defects. Chemical Engineering Journal. 2021;419:129520.

[50] Chen Y, Udduttula A, Xie X, Zhou M, Sheng W, Yu F, Weng J, Wang D, Teng B, Manivasagam G, Zhang JV, Ren P-G, Kang B, Zeng H. A novel photocrosslinked phosphate functionalized Chitosan-Sr5(PO4)2SiO4 composite hydrogels and in vitro biomineralization, osteogenesis, angiogenesis for bone regeneration application. Composites Part B: Engineering. 2021;222:109057.

[51] PokhrelLR, WilliamsF, CookPP, O’RourkeD, MurrayG, AkulaSM. Preclinical efficacy and safety of novel SNAT against SARS-CoV-2 using a hamster model. Drug Deliv Transl Res, 2022, 12: 3007-3016.

[52] Zhang B, He Y, Liu J, Shang J, Chen C, Wang T, Chen M, Li Y, Gong G, Fang J, Zhao Z, Guo J. Advancing collagen-based biomaterials for oral and craniofacial tissue regeneration. Collagen and Leather. 2023;5:120.

[53] Li Y, Xiong J, Hu Y, Miao W, Huang H. Wrapping collagen-based nanoparticle with macrophage membrane for treating multidrug-resistant bacterial infection. Journal of Leather Science and Engineering. 2022;4:1062.

[54] SongF, KongY, ShaoC, ChengY, LuJ, TaoY, DuJ, WangH. Chitosan-based multifunctional flexible hemostatic bio-hydrogel. Acta Biomater, 2021, 136: 170-183.

[55] LuoX, AoF, HuoQ, LiuY, WangX, ZhangH, YangM, MaY, LiuX. Skin-inspired injectable adhesive gelatin/HA biocomposite hydrogel for hemostasis and full-thickness dermal wound healing. Biomater Adv, 2022, 139: 212983.

[56] WangY, XiaoD, QuanL, ChaiH, SuiX, WangB, XuH, MaoZ. Mussel-inspired adhesive gelatin-polyacrylamide hydrogel wound dressing loaded with tetracycline hydrochloride to enhance complete skin regeneration. Soft Matter, 2022, 18: 662-674.

Funding

National Natural Science Foundation of China(22278259 and 22278257)

The Key R&D Program of Shaanxi Province(2022GY-272)

The Scientific Research Program Funded by Shaanxi Provincial Education Department(22JY013)

The Chinese Postdoctoral Science Foundation(2021M692000)

Wenzhou Science and Technology Major Project(ZY2022028)

RIGHTS & PERMISSIONS

The Author(s)