A Polyphenol–Metal Network of Propyl Gallate Gallium/Hafnium Oxide on Polyimide Fibers for Facilitating Ligament–Bone Healing

Abstract

The development of an artificial ligament for promoting ligament–bone healing in anterior cruciate ligament (ACL) reconstruction still faces enormous challenges. Herein, a polyphenol–metal network (PMN) composed of propyl gallate (PG)-gallium (Ga) and -hafnium oxide (HfO₂) is deposited on polyimide fiber (PIF) woven fabric (PGPH) for artificial ligament application. Compared with PIF, the surface properties (e.g., hydrophilicity) of PMN of PGPH significantly improve. The in vitro cell experiments confirm that PGPH remarkably facilitates proliferation and osteoblastic differentiation due to the synergistic effects of enhanced surface properties and the sustained release of Hf ions. Moreover, PGPH inhibits M1 macrophage polarization, thereby reducing the production of pro-inflammatory cytokines while improving anti-inflammatory cytokines secretion by favoring M2 macrophage polarization, displaying anti-inflammatory effects due to the slow release of PG. Compared with PIF, PGPH exhibits adequate antibacterial activity in vitro and effectively prevents bacterial infection in vivo because of the sustained release of Ga ions, which damages the bacterial membrane and leads to the leakage of cell components (such as proteins). The in vivo experiments reveal that PGPH obviously inhibits fibrous encapsulation formation while promoting bone regeneration for ligament–bone healing. In short, PGPH creates a favorable microenvironment for enhancing M2 macrophage polarization and osteoblastic differentiation, which facilitates ligament–bone healing, thereby exhibiting enormous promise for ACL restoration.

Graphical Abstract

References

[1] WangJL, WuYH, LiHF, LiuY, BaiXL, ChauWH, ZhengYF, QinL. Magnesium alloy based interference screw developed for ACL reconstruction attenuates peri-tunnel bone loss in rabbits. Biomaterials, 2018, 157: 86

[2] WangLY, WanF, XuYF, XieSL, ZhaoTC, ZhangF, YangH, ZhuJJ, GaoJM, ShiX, WangC, LuLW, YangYF, YuXY, ChenSY, SunXM, DingJD, ChenPN, DingC, XuF, YuHB, PengHS. Hierarchical helical carbon nanotube fibre as a bone-integrating anterior cruciate ligament replacement. Nat Nanotechnol, 2023, 18: 1085

[3] DongQL, CaiJY, WangHP, ChenSY, LiuYZ, YaoJR, ShaoZZ, ChenX. Artificial ligament made from silk protein/Laponite hybrid fibers. Acta Biomater, 2020, 106: 102

[4] WangLY, JiangHY, WanF, SunHJ, YangYQ, LiWJ, QianZY, SunXM, ChenPN, ChenSY, PengHS. High-performance artificial ligament made from helical polyester fibers wrapped with aligned carbon nanotube sheets. Adv Healthc Mater, 2023, 12: 2301610

[5] XieXJ, XuJJ, LinJ, JiangJ, HuangYF, LuJ, KangYH, HuYG, CaiJY, WangFJ, ZhuTH, ZhaoJZ, WangL. A regeneration process-matching scaffold with appropriate dynamic mechanical properties and spatial adaptability for ligament reconstruction. Bioact Mater, 2022, 13: 82

[6] CaiJY, ZhangQQ, ChenJB, JiangJ, MoXM, HeCL, ZhaoJZ. Electrodeposition of calcium phosphate onto polyethylene terephthalate artificial ligament enhances graft-bone integration after anterior cruciate ligament reconstruction. Bioact Mater, 2021, 6: 783

[7] LiCX, JiaRL, YangYK, LiaoGF. A hierarchical helical carbon nanotube fiber artificial ligament. Adv Fiber Mater, 2023, 5: 1549

[8] ChenTW, WuXP, ZhangP, WuW, DaiHL, ChenSY. Strontium-doped hydroxyapatite coating improves osteo/Angiogenesis for ameliorative graft-bone integration via the macrophage-derived cytokines-mediated integrin signal pathway. ACS Appl Mater Interfaces, 2024, 16: 15687

[9] LiYM, ChenC, JiangJ, LiuSY, ZhangZR, XiaoL, LianRX, SunLL, LuoW, OngMTY, LeeWYW, ChenYS, YuanY, ZhaoJZ, LiuCS, LiYL. Bioactive film-guided soft-hard interface design technology for multi-tissue integrative regeneration. Adv Sci, 2022, 9: 2105945

[10] AsadullahS, WuH, MeiSQ, WangDQ, PanYK, WangDL, ZhaoJ, WeiJ. Preparation, characterization, in vitro bioactivity and rBMSCs responses to tantalum pentoxide/polyimide biocomposites for dental and orthopedic implants. Compos Part B-Eng, 2019, 177: 107433

[11] LiQ, LiaoGF, TianJ, XuZS. Preparation of novel fluorinated copolyimide/amine-functionalized sepia eumelanin nanocomposites with enhanced mechanical, thermal, and UV-shielding properties. Macromol Mater Eng, 2017, 303: 1700407

[12] LiQ, LiaoGF, ZhangSL, PangL, TongH, ZhaoWZ, XuZS. Effect of adjustable molecular chain structure and pure silica zeolite nanoparticles on thermal, mechanical, dielectric, UV-shielding and hydrophobic properties of fluorinated copolyimide composites. Appl Surf Sci, 2018, 427: 437

[13] LiQ, LiJ, LiaoGF, XuZS. The preparation of heparin-like hyperbranched polyimides and their antithrombogenic, antibacterial applications. J Mater Sci-Mater M, 2018, 29: 126

[14] ZhouSX, DongJ, LiXT, ZhaoX, ZhangQH. Continuous surface metallization of polyimide fibers for textile-substrate electromagnetic shielding applications. Adv Fiber Mater, 2023, 5: 1892

[15] YinWD, QinMM, YuHT, SunJX, FengW. Hyperelastic graphene aerogels reinforced by in-suit welding polyimide nano fiber with leaf skeleton structure and adjustable thermal conductivity for morphology and temperature sensing. Adv Fiber Mater, 2023, 5: 1037

[16] LiYM, GuoXM, DongSK, ZhuTH, ChenYS, ZhaoS, XieGM, JiangJ, HeHY, LiuCS, ZhaoJZ. A triple-coated ligament graft to facilitate ligament–bone healing by inhibiting fibrogenesis and promoting osteogenesis. Acta Biomater, 2020, 115: 160

[17] FengP, HeRZ, GuYL, YangF, PanH, ShuaiCJ. Construction of antibacterial bone implants and their application in bone regeneration. Mater Horiz, 2024, 11: 590

[18] WangZJ, HuWK, WangW, XiaoY, ChenY, WangXH. Antibacterial electrospun nanofibrous materials for wound healing. Adv Fiber Mater, 2023, 5: 107

[19] SkrodzkiD, MolinaroM, BrownR, MoitraP, PanD. Synthesis and bioapplication of emerging nanomaterials of hafnium. ACS Nano, 2024, 18: 1289

[20] CaoYH, DingSS, HuYP, ZengLJ, ZhouJR, LinL, ZhangX, MaQH, CaiRL, ZhangY, DuanGJ, BianXW, TianG. An immunocompetent hafnium oxide-based STING nanoagonist for cancer radio-immunotherapy. ACS Nano, 2024, 18: 4189

[21] WangXY, DaiWL, GaoCY, ZhangLW, WanZ, ZhangTY, WangY, TangYJ, YuYJ, YangXP, CaiQ. Spatiotemporal modulated scaffold for endogenous bone regeneration via harnessing sequentially released guiding signals. ACS Appl Mater Interfaces, 2023, 15: 58873

[22] GaoCY, DaiWL, WangXY, ZhangLW, WangY, HuangYQ, YuanZY, ZhangX, YuYJ, YangXP, CaiQ. Magnesium gradient-based hierarchical scaffold for dual-lineage regeneration of osteochondral defect. Adv Funct Mater, 2023, 33: 2304829

[23] ZhangLX, YuYJ, FengKC, ChuangYC, ZuoXH, ZhouYC, ChangCC, SimonM, RafailovichM. Templated dentin formation by dental pulp stem cells on banded collagen bundles nucleated on electrospun poly (4-vinyl pyridine) fibers in vitro. Acta Biomater, 2018, 76: 80

[24] PengXX, ZhangH, ZhangRJ, LiZH, YangZS, ZhangJ, GaoS, ZhangJL. Gallium triggers ferroptosis through a synergistic mechanism. Angew Chem Edit, 2023, 62: e202307838

[25] HuangK, WangJB, ZhangQH, YuanK, YangYQ, LiFP, SunXJ, ChangHS, LiangYK, ZhaoJ, TangTT, YangSB. Sub 150 nm nanoscale gallium based metal-organic frameworks armored antibiotics as super penetrating bombs for eradicating persistent bacteria. Adv Funct mater, 2022, 32: 2204906

[26] KurtulduF, MutluN, BoccacciniAR, GalusekD. Gallium containing bioactive materials: a review of anticancer, antibacterial, and osteogenic properties. Bioact Mater, 2022, 17: 125

[27] GuoYX, SunQ, WuFG, DaiYL, ChenXY. Polyphenol-containing nanoparticles: synthesis, properties, and therapeutic delivery. Adv Mater, 2021, 33: 2007356

[28] FengYY, LiP, WeiJ. Engineering functional mesoporous materials from plant polyphenol based coordination polymers. Coordin Chem Rev, 2022, 468: 214649

[29] ZhouJJ, LinZX, JuY, RahimMA, RichardsonJJ, CarusoF. Polyphenol-mediated assembly for particle engineering. Acc Chem Res, 2020, 53: 1269

[30] HuangPK, WuF, ShenB, ZhengH, RenQ, LuoHB, ZhengWG. Biomimetic porous polypropylene foams with special wettability properties. Compos Part B-Eng, 2020, 190: 107927

[31] TanYY, ZhouB, YeXY, CaiJX, ZhouJH. Dual-phase nanoplasmonic sensing platform for monitoring blood protein adsorption and its coagulation in vitro. Sensor Actuat B-Chem, 2022, 368: 132240

[32] DaiWY, ShuR, YangF, LiB, JohnsonHM, YuS, YangH, ChanYK, YangWZ, BaiD, DengY. Engineered bio-Heterojunction confers extra- and intracellular bacterial ferroptosis and hunger-triggered cell protection for diabetic wound repair. Adv Mater, 2024, 36: 2305277

[33] JungJW, KimGY, LeeNW, RyuWH. Low-temperature synthesis of tetragonal phase of hafnium oxide using polymer-blended nanofiber precursor. Appl Surf Sci, 2020, 533: 147496

[34] BillingF, WalterB, FinkS, ArefaineE, PickarskiL, MaierS, KretzR, JakobiM, FeuererN, Schneiderhan-MarraN, BurkhardtC, TemplinM, ZeckA, KrastevR, HartmannH, ShippC. Altered proinflammatory responses to polyelectrolyte multilayer coatings are associated with differences in protein adsorption and wettability. ACS Appl Mater Interfaces, 2022, 13: 55534

[35] YangY, XiaoY. Biomaterials regulating bone hematoma for osteogenesis. Adv Healthc Mater, 2020, 9: 2000726

[36] WangGY, LvZH, WangT, HuTT, BianYX, YangY, LiangRZ, TanCL, WengXS. Surface functionalization of hydroxyapatite scaffolds with MgAlEu-LDH nanosheets for high-performance bone regeneration. Adv Sci, 2022, 10: 2204234

[37] HuangYQ, DuZY, LiK, JingW, WeiPF, ZhaoB, YuYJ, CaiQ, YangXP. ROS-scavenging electroactive polyphosphazene-based core-shell nanofibers for bone regeneration. Adv Fiber Mater, 2022, 4: 894

[38] YangYS, SuSH, LiuSC, LiuWL, YangQF, TianLJ, TanZL, FanL, YuB, WangJ, HuYJ. Triple-functional bone adhesive with enhanced internal fixation, bacteriostasis and osteoinductive properties for open fracture repair. Bioact Mater, 2023, 25: 273

[39] QiX, LiuY, YinXL, ZhaoRL, ZhangW, CaoJQ, WangW, JiaWT. Surface-based modified 3D-printed BG/GO scaffolds promote bone defect repair through bone immunomodulation. Compos Part B-Eng, 2023, 257: 110673

[40] ChenYMF, LuoZY, MengWK, LiuK, ChenQQ, CaiYR, DingZC, HuangC, ZhouZK, JiangM, ZhouLQ. Decoding the “fingerprint” of implant materials: insights into the foreign body reaction. Small, 2024

[41] FuLW, FengQ, ChenYJ, FuJZ, ZhouXJ, HeCL. Nanofibers for the immunoregulation in biomedical applications. Adv Fiber Mater, 2022, 4: 1334

[42] WangZJ, YouWJ, WangW, TianWQ, ChenFJ, XiaoY, ChenY, WangXH. Dihydromyricetin-incorporated multilayer nanofibers accelerate chronic wound healing by remodeling the harsh wound microenvironment. Adv Fiber Mater, 2022, 4: 1556

[43] HuangX, HeD, PanZ, LuoG, DengJ. Reactive-oxygen-species-scavenging nanomaterials for resolving inflammation. Mater Today Bio, 2021, 11: 100124

[44] ArciolaCR, CampocciaD, MontanaroL. Implant infections: adhesion, biofilm formation and immune evasion. Nat Rev Microbiol, 2018, 16: 397

[45] WuY, ZhangYH, ZhangR, ChenSY. Preparation and properties of antibacterial polydopamine and nano-hydroxyapatite modified polyethylene terephthalate artificial ligament. Front Bioeng Biotechnol, 2021, 9: 630745

[46] WangF, WangMY, HeQS, WangXH, SunP, JiYJ, NiuYF, LiFQ, WeiJ. Black tantalic oxide submicro-particles coating on PEEK fibers woven into fabrics as artificial ligaments with photothermal antibacterial effect and osteogenic activity for promoting ligament–bone healing. J Mater Sci Technol, 2023, 133: 195

[47] XueY, ZhangL, ZhouJH, ChenJ, MaYW, HanY. Low-dose Cu ions assisted by mild thermal stimulus inducing bacterial cuproptosis-like death for antibiosis and biointegration. Adv Funct Mater, 2023, 34: 2308197

[48] XueY, ZhangL, LiuFW, DaiF, KongL, MaDY, HanY. Alkaline, “nanoswords” coordinate ferroptosis-like bacterial death for antibiosis and osseointegration. ACS Nano, 2023, 17: 2711

[49] BalabiyevA, PodolnikovaNP, KilbourneJA, BaluchDP, LowryD, ZareA, RosR, FlickMJ, UgarovaTP. Fibrin polymer on the surface of biomaterial implants drives the foreign body reaction. Biomaterials, 2021, 277: 121087

[50] ChenN, JinWH, GaoH, HongJC, SunLY, YaoJR, ChenX, ChenJ, ChenSY, ShaoZZ. Sequential intervention of anti-inflammatory and osteogenesis with silk fibroin coated polyethylene terephthalate artificial ligaments for anterior cruciate ligament reconstruction. J Mater Chem B, 2023, 11: 8281

[51] WangF, XieE, WangXH, SunP, JiYJ, NiuYF, WangDL, LiFQ, WeiJ. Polyetheretherketone fibers woven fabrics coated nanostructured silicon nitride and load EGCG as artificial ligaments for promoting ligament–bone integration. Appl Mater Today, 2022, 27: 101409

[52] LiaoGF, ZhangL, LiCX, LiuSY, FangBZ, YangHM. Emerging carbon-supported single-atom catalysts for biomedical applications. Matter-US, 2022, 5: 3341

[53] LiangS, LiuYF, ZhuHQ, LiaoGF, ZhuWZ, ZhangL. Emerging nitric oxide gas-assisted cancer photothermal treatment. Exploration, 2024

[54] LiaoGF, HeF, LiQ, ZhongL, ZhaoRZ, CheHN, GaoHY, FangBZ. Emerging graphitic carbon nitride-based materials for biomedical applications. Prog Mater Sci, 2020, 112: 100666

[55] AltmanGH, HoranRL, LuHH, MoreauJ, MartinI, RichmondJC, KaplanDL. Silk matrix for tissue engineered anterior cruciate ligaments. Biomaterials, 2002, 23: 4131

[56] WangF, SunP, XieE, JiYJ, NiuYF, LiFQ, WeiJ. Phytic acid/magnesium ion complex coating on PEEK fiber woven fabric as an artificial ligament with anti-fibrogenesis and osteogenesis for ligament–bone healing. Biomater Adv, 2022, 140: 213079

[57] BezM, KremenTJ, TawackoliW, AvalosP, SheynD, ShapiroG, GiaconiJC, Ben DavidS, SnedekerJG, GazitZ, FerraraKW, GazitD, PelledG. Ultrasound-mediated gene delivery enhances tendon allograft integration in mini-pig ligament reconstruction. Mol Ther, 2018, 26: 1746

[58] YuXH, MengsteabPY, NarayananG, NairLS, LaurencinCT. Enhancing the surface properties of a bioengineered anterior cruciate ligament matrix for use with point-of-care stem cell therapy. Engineering, 2021, 7: 153

Funding

National Natural Science Foundation of China(32171340)

Health and Family Planning Commission of Sichuan Province(20224Y0393)

Science and Technology Development Fund of Shanghai Pudong New Area(PKJ2023-Y09)

Young Medical Talents Training Program of Pudong Health Committee of Shanghai(PWRq 2021-08)

Outstanding Clinical Discipline Project of Shanghai Pudong(PWYgy2021-04)