{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:46:57Z","timestamp":1791888417761,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32471392"],"award-info":[{"award-number":["32471392"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32571555"],"award-info":[{"award-number":["32571555"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470953"],"award-info":[{"award-number":["82470953"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Small"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Precise adhesion of bone fragments and robust bone regeneration are both essential for successful fracture healing, yet existing hydrogel adhesives rarely achieve controllable fixation and sustained osteogenesis simultaneously. Herein, we report a polyphenol\u2010engineered ultrasound\u2010responsive injectable hydrogel for fracture fixation and bone regeneration. The hydrogel is composed of dihydrocaffeic acid\u2010modified chitosan, gelatin methacryloyl, a 2D sonosensitizer (PGO\u2010Fe) constructed from polydopamine\u2010mediated ferroferric oxide\u2010decorated reduced graphene oxide, and polydopamine\u2010modified hydroxyapatite (PHA). The hydrogel initially forms reversible, shape\u2010adaptable adhesion to bone via catechol\u2010mediated noncovalent interactions. Upon high\u2010intensity ultrasound (HUS), PGO\u2010Fe enhances sonodynamic activity through Fe(III)\/Fe(II) redox conversion, triggering secondary covalent crosslinking and enabling a controllable transition from compliant adhesion to rigid fixation. Polyphenolic components confer reactive oxygen species\u2010scavenging capacity and promote macrophage polarization toward the M2 phenotype, creating a favorable regenerative microenvironment. Under low\u2010intensity ultrasound (LUS), the hydrogel activates Piezo1\u2010mediated calcium influx, thereby enhancing osteogenic differentiation. In vivo, this system achieves nearly complete defect bridging and mechanical performance comparable to wire fixation in rat calvarial and rabbit ulna models. This work provides a minimally invasive strategy that integrates controlled fixation, immunomodulation, and mechanically enhanced osteogenesis for complex fracture treatment.<\/jats:p>","DOI":"10.1002\/smll.76230","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:03:06Z","timestamp":1791885786000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ultrasound\u2010Responsive Hydrogels Empowered by Two\u2010Dimensional Sonosensitizers Enable Spatiotemporally Controlled Fracture Fixation and Bone Regeneration"],"prefix":"10.1002","author":[{"given":"Lu","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Advanced Technologies of Materials Ministry of Education Institute of Biomedical Engineering College of Medicine Southwest Jiaotong University  Chengdu China"},{"name":"Department of Stomatology Sichuan Provincial People's Hospital University of Electronic Science and Technology of China  Chengdu China"},{"name":"School of Medicine University of Electronic Science and Technology of China  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Xu","sequence":"additional","affiliation":[{"name":"Rehabilitation Medicine Center and Institute of Rehabilitation Medicine West China Hospital Sichuan University  Chengdu China"},{"name":"Key Laboratory of Rehabilitation Medicine in Sichuan Province West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manman","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Technologies of Materials Ministry of Education Institute of Biomedical Engineering College of Medicine Southwest Jiaotong University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjie","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Technologies of Materials Ministry of Education Institute of Biomedical Engineering College of Medicine Southwest Jiaotong University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3028-4115","authenticated-orcid":false,"given":"Chengxinyue","family":"Ye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7831-0290","authenticated-orcid":false,"given":"Feng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Chest Wall Disease Center West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1829-6116","authenticated-orcid":false,"given":"Yandong","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Stomatology Sichuan Provincial People's Hospital University of Electronic Science and Technology of China  Chengdu China"},{"name":"School of Medicine University of Electronic Science and Technology of China  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4438-2760","authenticated-orcid":false,"given":"Weili","family":"Fu","sequence":"additional","affiliation":[{"name":"Sports Medicine Center Department of Orthopedic Surgery\/Orthopedic Research Institute West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6367-430X","authenticated-orcid":false,"given":"Xiong","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Advanced Technologies of Materials Ministry of Education Institute of Biomedical Engineering College of Medicine Southwest Jiaotong University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6916-675X","authenticated-orcid":false,"given":"Chaoming","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Stomatology Sichuan Provincial People's Hospital University of Electronic Science and Technology of China  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1002\/EXP.20210011","article-title":"Biomaterials and Nanomedicine for Bone Regeneration: Progress and Future Prospects","volume":"1","author":"Zhou J.","year":"2021","journal-title":"Exploration"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202408016","article-title":"Photothermal Catalytic Reduction and Bone Tissue Engineering Towards a Three\u2010in\u2010One Therapy Strategy for Osteosarcoma","volume":"36","author":"Lu H.","year":"2024","journal-title":"Advanced Materials"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202202044","article-title":"Osteoimmunity\u2010Regulating Biomimetically Hierarchical Scaffold for Augmented Bone Regeneration","volume":"34","author":"Zhang J.","year":"2022","journal-title":"Advanced Materials"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/jbmr.4821","article-title":"Global Epidemiology of Hip Fractures: Secular Trends in Incidence Rate, Post\u2010Fracture Treatment, and All\u2010Cause Mortality","volume":"38","author":"Sing C. W.","year":"2023","journal-title":"Journal of Bone and Mineral Research"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"6840","DOI":"10.1021\/acsnano.4c11960","article-title":"Micro\/Nanobiomimetic Iron\u2010Based Scaffold Induces Vascularized Bone Regeneration To Repair Large Segmental Bone Defect in Load\u2010Bearing Sites","volume":"19","author":"Yuan B.","year":"2025","journal-title":"ACS Nano"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202206450","article-title":"A Mechanically Reinforced Super Bone Glue Makes a Leap in Hard Tissue Strong Adhesion and Augmented Bone Regeneration","volume":"10","author":"Hu S.","year":"2023","journal-title":"Advanced Science"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202403641","article-title":"Recent Advances in 3D Printing of Smart Scaffolds for Bone Tissue Engineering and Regeneration","volume":"36","author":"Yuan X.","year":"2024","journal-title":"Advanced Materials"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.201907491","article-title":"Bioactive Pore\u2010Forming Bone Adhesives Facilitating Cell Ingrowth for Fracture Healing","volume":"32","author":"Xu L.","year":"2020","journal-title":"Advanced Materials"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202511840","article-title":"A Pseudo\u2010 Mytilus Edulis Foot Protein\u2010Based Hydrogel Adhesive with Osteo\u2010Vascular\u2010Immune Coupling Effects for Osteoporotic Bone\u2010Implant Integration","volume":"38","author":"Wang W.","year":"2026","journal-title":"Advanced Materials"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.advop.2025.12.001","article-title":"Electroactive Hydrogel Bone Adhesives: From Intelligent Design to Biomedical Applications","volume":"2","author":"Zheng Y.","year":"2025","journal-title":"Advanced Orthopaedics"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202501108","article-title":"Dual\u2010Biomimetic Bone Adhesive with Osteoimmunomodulatory Capabilities for Anatomical Reconstruction of Comminuted Fractures","volume":"12","author":"Cheng J.","year":"2025","journal-title":"Advanced Science"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.biomaterials.2024.123059","article-title":"Injectable Bioresponsive Bone Adhesive Hydrogels Inhibit NLRP3 Inflammasome on Demand to Accelerate Diabetic Fracture Healing","volume":"317","author":"Xing X.","year":"2025","journal-title":"Biomaterials"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.bioactmat.2024.09.032","article-title":"Injectable Double\u2010Crosslinked Bone Cement With Enhanced Bone Adhesion And Improved Osteoporotic Pathophysiological Microenvironment for Osteoregeneration In Osteoporosis","volume":"43","author":"Zhao L.","year":"2025","journal-title":"Bioactive Materials"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1038\/s41467-025-58059-z","article-title":"Injectable Bioadhesive and Lubricating Hydrogel with Polyphenol Mediated Single Atom Nanozyme for Rheumatoid Arthritis Therapy","volume":"16","author":"He H.","year":"2025","journal-title":"Nature Communications"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","DOI":"10.1002\/adfm.202415185","article-title":"Calcium\u2010Capturing Hydrogel with Self\u2010Reinforced Multi\u2010Dynamic Networks for Effective Periodontal Bone Regeneration in Three\u2010Dimension","volume":"35","author":"Zhang M.","year":"2025","journal-title":"Advanced Functional Materials"},{"key":"e_1_2_10_17_1","first-page":"207","article-title":"Injectable Self\u2010Healing Hydrogel With Enhanced Mechanical Properties and Antibacterial Activity For Bone Regeneration","volume":"5","author":"Jiang Z.","year":"2024","journal-title":"Smart Materials in Medicine"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","DOI":"10.1002\/adhm.202401687","article-title":"Design and Improvement of Bone Adhesive in response to Clinical Needs","volume":"13","author":"Liu C.","year":"2024","journal-title":"Advanced Healthcare Materials"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.progpolymsci.2018.04.002","article-title":"Recent Advances in the Synthesis of Catechol\u2010Derived (bio)Polymers for Applications in Energy Storage and Environment","volume":"82","author":"Patil N.","year":"2018","journal-title":"Progress in Polymer Science"},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"5679","DOI":"10.1038\/s41467-025-60853-8","article-title":"Injectable Magnesium\u2010Bisphosphonate MOF\u2010Based Bone Adhesive Prevents Excessive Fibrosis for Osteoporotic Fracture Repair","volume":"16","author":"Xiao T.","year":"2025","journal-title":"Nature Communications"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"7156","DOI":"10.1038\/s41467-021-27529-5","article-title":"Hydrogel Tapes for Fault\u2010Tolerant Strong Wet Adhesion","volume":"12","author":"Xue B.","year":"2021","journal-title":"Nature Communications"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/anie.201801063","article-title":"The Chemistry behind Catechol\u2010Based Adhesion","volume":"58","author":"Saiz\u2010Poseu J.","year":"2019","journal-title":"Angewandte Chemie International Edition"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1039\/C9CS00285E","article-title":"Catechol\u2010Functionalized Hydrogels: Biomimetic Design, Adhesion Mechanism, and Biomedical Applications","volume":"49","author":"Zhang W.","year":"2020","journal-title":"Chemical Society Reviews"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202412240","article-title":"An Immunomodulatory Hydrogel Featuring Antibacterial and Reactive Oxygen Species Scavenging Properties for Treating Periodontitis in Diabetes","volume":"37","author":"Ge X.","year":"2025","journal-title":"Advanced Materials"},{"key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"9071","DOI":"10.1038\/s41467-024-53290-6","article-title":"Polyphenol\u2010Mediated Redox\u2010Active Hydrogel with H2S Gaseous\u2010Bioelectric Coupling for Periodontal Bone Healing in Diabetes","volume":"15","author":"Fang X.","year":"2024","journal-title":"Nature Communications"},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","DOI":"10.1002\/adfm.202102465","article-title":"Flexible Osteogenic Glue as an All\u2010In\u2010One Solution to Assist Fracture Fixation and Healing","volume":"31","author":"Tang J.","year":"2021","journal-title":"Advanced Functional Materials"},{"key":"e_1_2_10_27_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.cej.2023.147646","article-title":"On\u2010Demand Detachable Adhesive Hydrogel Based on Dual Dynamic Covalent Cross\u2010linked with NIR\/pH Dual\u2010Responsive Properties for Diabetic Wound Healing","volume":"479","author":"Su K.","year":"2024","journal-title":"Chemical Engineering Journal"},{"key":"e_1_2_10_28_1","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1021\/acs.chemrev.1c00622","article-title":"Ultrasound\u2010Responsive Systems as Components for Smart Materials","volume":"122","author":"Athanassiadis A. G.","year":"2022","journal-title":"Chemical Reviews"},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"8307","DOI":"10.1021\/acs.chemrev.4c00009","article-title":"Ultrasound\u2010Based Micro\u2010\/Nanosystems for Biomedical Applications","volume":"124","author":"Huang H.","year":"2024","journal-title":"Chemical Reviews"},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","first-page":"4422","DOI":"10.1021\/acsnano.4c13357","article-title":"Low\u2010Intensity Pulsed Ultrasound Responsive Scaffold Promotes Intramembranous and Endochondral Ossification via Ultrasonic, Thermal, and Electrical Stimulation","volume":"19","author":"Jia W.","year":"2025","journal-title":"ACS Nano"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","DOI":"10.1002\/adhm.202404024","article-title":"Ultrasound\u2010Driven Innervated Bone Regeneration in Additively Manufactured Degradable Metallic Scaffolds","volume":"14","author":"Song W.","year":"2025","journal-title":"Advanced Healthcare Materials"},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41413-021-00168-8","article-title":"Roles of Mechanosensitive Channel Piezo1\/2 Proteins in Skeleton and Other Tissues","volume":"9","author":"Qin L.","year":"2021","journal-title":"Bone Research"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","DOI":"10.3389\/fbioe.2024.1347406","article-title":"Low\u2010Intensity Pulsed Ultrasound Promotes the Osteogenesis of Mechanical Force\u2010Treated Periodontal Ligament Cells via Piezo1","volume":"12","author":"Zheng F.","year":"2024","journal-title":"Frontiers in Bioengineering and Biotechnology"},{"key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/s44222-025-00273-x","article-title":"Vibration\u2010Based Cell Engineering","volume":"3","author":"Johnson\u2010Love O.","year":"2025","journal-title":"Nature Reviews Bioengineering"},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.cej.2025.170537","article-title":"Injectable Nanocomposite Hydrogel with Antibacterial\/Osteogenic Dual Functions for Synergistic Repair of Infectious Bone defects in Hyperlipidemia Microenvironment","volume":"526","author":"Wang Y.","year":"2025","journal-title":"Chemical Engineering Journal"},{"key":"e_1_2_10_36_1","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1186\/s12951-022-01587-3","article-title":"Low\u2010Intensity Pulsed Ultrasound\/Nanomechanical Force Generators Enhance Osteogenesis of BMSCs Through Microfilaments and TRPM7","volume":"20","author":"Yao H.","year":"2022","journal-title":"Journal of Nanobiotechnology"},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.biomaterials.2025.123084","article-title":"LIPUS Activated Piezoelectric pPLLA\/SrSiO3 Composite Scaffold Promotes Osteochondral Regeneration Through P2RX1 Mediated Ca2+ Signaling Pathway","volume":"317","author":"Liu C.","year":"2025","journal-title":"Biomaterials"},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41413-020-00124-y","article-title":"Piezo1 Channel Activation in Response to Mechanobiological Acoustic Radiation Force in Osteoblastic Cells","volume":"9","author":"Zhang G.","year":"2021","journal-title":"Bone Research"},{"key":"e_1_2_10_39_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.bioactmat.2022.03.021","article-title":"Polydopamine\u2010Mediated Graphene Oxide and Nanohydroxyapatite\u2010Incorporated Conductive Scaffold With an Immunomodulatory Ability Accelerates Periodontal Bone Regeneration in Diabetes","volume":"18","author":"Li Y.","year":"2022","journal-title":"Bioactive Materials"},{"key":"e_1_2_10_40_1","doi-asserted-by":"crossref","DOI":"10.1002\/adfm.201907678","article-title":"Graphene Oxide\u2010Templated Conductive and Redox\u2010Active Nanosheets Incorporated Hydrogels for Adhesive Bioelectronics","volume":"30","author":"Gan D.","year":"2020","journal-title":"Advanced Functional Materials"}],"container-title":["Small"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.76230","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/smll.76230","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.76230","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:03:11Z","timestamp":1791885791000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/smll.76230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,13]]},"references-count":39,"alternative-id":["10.1002\/smll.76230"],"URL":"https:\/\/doi.org\/10.1002\/smll.76230","archive":["Portico"],"relation":{},"ISSN":["1613-6810","1613-6829"],"issn-type":[{"value":"1613-6810","type":"print"},{"value":"1613-6829","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,13]]},"assertion":[{"value":"2026-05-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e76230"}}