4D printed hydrogel scaffolds with shape morphing by near-infrared to promote bone regeneration through immune and vascular coupling

4D printed hydrogel scaffolds with shape morphing by near-infrared to promote bone regeneration through immune and vascular coupling | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 4D printed hydrogel scaffolds with shape morphing by near-infrared to promote bone regeneration through immune and vascular coupling Chuqiao Wei, Jingjie Zhai, Yidi Zhang, Yuemeng Zhu, Yuzhu Han, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8124694/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 19 You are reading this latest preprint version Abstract The regeneration of critical-size irregular bone defects, especially those with irregular shapes, remains clinically challenging due to inadequate shape-conformability, immune dysregulation, poor vascularization and the unsatisfied osteogenic bioactivity. Self-fitting tissue scaffolds that can be implanted by minimally invasive procedures are a promising solution. Herein, we present a 4D-printed hydrogel scaffold (PASN) composed of polydopamine (PDA), alginate (Alg), and strontium ions (Sr²⁺), that is 3D-printed and NIR-induced shape-morphing to match defect and orchestrate both immunomodulation and osteogenesis. By eliminating reactive oxygen species and driving M2 macrophage polarization through PDA, PASN improves immune regulation through the PI3K signaling pathway as well as stimulates osteogenesis and angiogenesis through release of Sr²⁺. The deformation angle of the scaffold is adjusted by the laser power, irradiation time, and the designed pattern of alginate PDA struts, whereas the temperature gradient formed between the upper and lower layers under NIR irradiation induces bending toward the light source. Dome-shaped calvarial defects, maxillary sinus floor lift and horizontal bone augmentation surgeries demonstrate the PASN scaffold markedly enhances bone regeneration. Collectively, the personalised and bioactive scaffold with NIR-responsive shape-morphing may be a promising biomaterial for clinical-size and irregular bone defect regeneration. Four-dimensional Printing Osteoimmunomodulation Guided Bone Regeneration Mechanotranduction RhoA/ROCK Full Text Additional Declarations No competing interests reported. Supplementary Files SI3.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 09 Dec, 2025 Reviews received at journal 08 Dec, 2025 Reviews received at journal 07 Dec, 2025 Reviews received at journal 06 Dec, 2025 Reviews received at journal 02 Dec, 2025 Reviewers agreed at journal 02 Dec, 2025 Reviews received at journal 28 Nov, 2025 Reviewers agreed at journal 27 Nov, 2025 Reviewers agreed at journal 27 Nov, 2025 Reviewers agreed at journal 27 Nov, 2025 Reviewers agreed at journal 26 Nov, 2025 Reviewers agreed at journal 25 Nov, 2025 Reviewers agreed at journal 25 Nov, 2025 Reviewers agreed at journal 25 Nov, 2025 Reviewers agreed at journal 25 Nov, 2025 Reviewers invited by journal 25 Nov, 2025 Editor assigned by journal 16 Nov, 2025 Submission checks completed at journal 16 Nov, 2025 First submitted to journal 15 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8124694","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":552418679,"identity":"3ac78654-be7e-49bb-93c4-5b429cdaa794","order_by":0,"name":"Chuqiao Wei","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Chuqiao","middleName":"","lastName":"Wei","suffix":""},{"id":552418680,"identity":"b7b81f19-9268-4b50-b100-ac9a6a139aec","order_by":1,"name":"Jingjie Zhai","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Jingjie","middleName":"","lastName":"Zhai","suffix":""},{"id":552418681,"identity":"5d782b8b-55fc-4511-9340-b88b7884521b","order_by":2,"name":"Yidi Zhang","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Yidi","middleName":"","lastName":"Zhang","suffix":""},{"id":552418682,"identity":"3c32d8f9-d889-4499-89c6-fb9d321b20c3","order_by":3,"name":"Yuemeng Zhu","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Yuemeng","middleName":"","lastName":"Zhu","suffix":""},{"id":552418683,"identity":"dd0392d6-a8ca-4724-9900-e1a84af12607","order_by":4,"name":"Yuzhu Han","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Yuzhu","middleName":"","lastName":"Han","suffix":""},{"id":552418685,"identity":"8afa0bde-50aa-4d98-9477-993b5d5dda5d","order_by":5,"name":"Yangyang Li","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Yangyang","middleName":"","lastName":"Li","suffix":""},{"id":552418686,"identity":"0783583d-a75f-4f03-9452-3b84fc191e76","order_by":6,"name":"Sicong Ren","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Sicong","middleName":"","lastName":"Ren","suffix":""},{"id":552418687,"identity":"6740e460-ab04-4dca-a567-d06082507e50","order_by":7,"name":"Quan Lin","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Quan","middleName":"","lastName":"Lin","suffix":""},{"id":552418688,"identity":"f58cec36-5411-4b56-ac30-201b37f5fbf9","order_by":8,"name":"Hanchi Wang","email":"","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":false,"prefix":"","firstName":"Hanchi","middleName":"","lastName":"Wang","suffix":""},{"id":552418689,"identity":"a59f4f91-d15f-4b03-bcde-f85b434a9897","order_by":9,"name":"Yanmin Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIiWNgGAWjYDACCTBpw8wHonhI0JLGzEaqlsMMxGuRn918TJo35zw7m0QC44O3bQzy5oS0MM45libNu+02M1ALs+HcNgbDnQ0EtDBL5JjBtLBJ87YxJBgcIKCFDaLlHEgL+2+itPBAtBwA28JMlBYJibRky7nbkpnZeB42S845J2G4gZAW+RnJB2+83WaXzM+efPDDmzIbeYK2gAATMDqSgYHXwACLJoKA8QcDgx1xSkfBKBgFo2BEAgC6GDKVr180VwAAAABJRU5ErkJggg==","orcid":"","institution":"Jilin University Hospital of stomotology","correspondingAuthor":true,"prefix":"","firstName":"Yanmin","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-11-16 02:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8124694/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8124694/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97249814,"identity":"ca40dcf7-61dd-4614-b4fc-25eb020d27d0","added_by":"auto","created_at":"2025-12-02 13:13:29","extension":"png","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":25579451,"visible":true,"origin":"","legend":"","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/f1c4e3699198396be53443f2.png"},{"id":97248719,"identity":"486947b3-93dd-48d6-8739-609360966cea","added_by":"auto","created_at":"2025-12-02 13:06:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":24323052,"visible":true,"origin":"","legend":"","description":"","filename":"journalofnanobiotechnology.docx","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/7284c2f7f4cfca2f03108271.docx"},{"id":97160455,"identity":"2d0fa0da-53c5-44a2-a996-9b063b3db7e0","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16157941,"visible":true,"origin":"","legend":"","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/c4a4db4f25ee35e0a11a41e4.png"},{"id":97248933,"identity":"6b89aa9c-111f-4199-986f-7573a2a8e1e3","added_by":"auto","created_at":"2025-12-02 13:08:32","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3939956,"visible":true,"origin":"","legend":"","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/c9b3905f6b0a5f0029ec22b9.png"},{"id":97248542,"identity":"2005ab3d-73f4-42f7-ab7d-d18159a5b7e8","added_by":"auto","created_at":"2025-12-02 13:03:01","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":41031252,"visible":true,"origin":"","legend":"","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/89951b6fe547dc33e94ff512.png"},{"id":97160452,"identity":"5e6de2c0-9ae4-4fc5-b2e3-4b246dd0bb2a","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":976149,"visible":true,"origin":"","legend":"","description":"","filename":"figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/91a376d06843de270f3f3738.png"},{"id":97248861,"identity":"c68fa581-9cc6-4ce8-b4c1-3199e54c81cb","added_by":"auto","created_at":"2025-12-02 13:07:42","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20938644,"visible":true,"origin":"","legend":"","description":"","filename":"figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/85720567f78ab867250141b0.png"},{"id":97248561,"identity":"9908e4e0-3a0c-465d-a7c4-f44fac28d633","added_by":"auto","created_at":"2025-12-02 13:03:27","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17157573,"visible":true,"origin":"","legend":"","description":"","filename":"figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/de5226fe2f69fa162ba09573.png"},{"id":97249596,"identity":"51e3b054-4a5a-48fa-be04-60a0ac311751","added_by":"auto","created_at":"2025-12-02 13:12:59","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20334951,"visible":true,"origin":"","legend":"","description":"","filename":"figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/9d2e6787a646d4096a5c8b45.png"},{"id":97160453,"identity":"e0f0c179-f716-4ef5-b2aa-f005757d7f9b","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"json","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10377,"visible":true,"origin":"","legend":"","description":"","filename":"dc29efd715fa4b8caf33951cafc1b246.json","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/ddd902747472745423ec952f.json"},{"id":97160464,"identity":"271c8633-4b60-44c1-8db1-cb2160fd6d9f","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14029971,"visible":true,"origin":"","legend":"","description":"","filename":"SI3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/21424a1577fd7fc2ff55ae5e.docx"},{"id":97160459,"identity":"578a3b1a-65e3-4b94-bdc3-a6efe2974eb4","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":177808,"visible":true,"origin":"","legend":"","description":"","filename":"dc29efd715fa4b8caf33951cafc1b2461enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/d180111e563546ebea62af8b.xml"},{"id":97160469,"identity":"fcc58dc9-9795-4b75-a79f-6006e8b8562e","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":25579451,"visible":true,"origin":"","legend":"","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/94ca6c0bd02ab7271dac6e7e.png"},{"id":97160462,"identity":"c39d1144-28da-4a8c-b4f4-7969d07a0d5d","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16157941,"visible":true,"origin":"","legend":"","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/2021eef0d6ab856f8602ad3d.png"},{"id":97160457,"identity":"ed2eaa79-04cc-45ec-8910-ccb9edbf0d13","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3939956,"visible":true,"origin":"","legend":"","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/d7c975115f88c555ffc87b40.png"},{"id":97248947,"identity":"86e10d7b-f615-4c89-bdef-cd7b578b1ba1","added_by":"auto","created_at":"2025-12-02 13:08:47","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":41031252,"visible":true,"origin":"","legend":"","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/47a2bc37d6289086c8f3f4fc.png"},{"id":97160461,"identity":"baa110b2-6bf2-4bf5-ae6a-71b005da9d5f","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":976149,"visible":true,"origin":"","legend":"","description":"","filename":"figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/8d67afb003f28b8cc758dc2f.png"},{"id":97160480,"identity":"85894602-cdeb-4484-aa83-7762f82c1fdb","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20938644,"visible":true,"origin":"","legend":"","description":"","filename":"figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/dec806ff6cbb665231981399.png"},{"id":97248905,"identity":"6fbe1342-4478-460d-ba2a-6b302681bb4f","added_by":"auto","created_at":"2025-12-02 13:08:05","extension":"png","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17157573,"visible":true,"origin":"","legend":"","description":"","filename":"figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/98272157ab126c9354f18085.png"},{"id":97248628,"identity":"b983d7d0-f260-4121-a092-38b7fd4b31b1","added_by":"auto","created_at":"2025-12-02 13:04:27","extension":"png","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20334951,"visible":true,"origin":"","legend":"","description":"","filename":"figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/d079301d8a37ed4b1ef1620f.png"},{"id":97160472,"identity":"eeca407c-3a61-497a-b779-3fee950a532c","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"jpeg","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":880022,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/081b92039bae70de332c5c3a.jpeg"},{"id":97248517,"identity":"e66b7d78-d4ed-4310-8e92-e2f40b8c868b","added_by":"auto","created_at":"2025-12-02 13:02:18","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3691738,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/a4afbda1d27751955083a659.png"},{"id":97248729,"identity":"e680e0e5-f014-48be-a154-fad1fc084971","added_by":"auto","created_at":"2025-12-02 13:06:36","extension":"png","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3409117,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/2ae99cb9d50fcde2b390569d.png"},{"id":97160489,"identity":"878192db-4ebe-4e49-a49b-e78ac3e81046","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1487782,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/4e2330a4e379f3ec781b4764.png"},{"id":97160492,"identity":"ccfb3c51-864f-49e4-901f-8c29e091eedf","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2460373,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/ed1d4f9666772284f015c846.png"},{"id":97248775,"identity":"25b3cfab-834a-4e5c-9cef-c2f00e82684b","added_by":"auto","created_at":"2025-12-02 13:07:08","extension":"png","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":280913,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/a56d6f0675e23c55ed773047.png"},{"id":97160465,"identity":"0d79c410-26f9-46b4-96e1-7cdc4a6c859f","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3855665,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/040cdfffa39f4fc7d2e03ba6.png"},{"id":97160495,"identity":"3c62b537-77a7-431b-b5c2-789dfc5dabeb","added_by":"auto","created_at":"2025-12-01 12:28:55","extension":"png","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3563204,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/79f61dead367a3635515ae4c.png"},{"id":97160486,"identity":"eb7e8b2d-5dda-440e-ad62-637df808e928","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4576578,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/0f25ac8186dd1436f174285d.png"},{"id":97248618,"identity":"75143cde-c6a0-48cf-946e-e3c852a85b22","added_by":"auto","created_at":"2025-12-02 13:04:18","extension":"png","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4088816,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/cd0203f4b30b90e50799d970.png"},{"id":97248424,"identity":"9062e31b-9f5f-4e08-ad06-154c4af5ff02","added_by":"auto","created_at":"2025-12-02 12:58:14","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2774741,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/4aa67d6e7c38d39c2070c036.png"},{"id":97249786,"identity":"f2830fef-dfcd-49e9-8400-66fe74e831be","added_by":"auto","created_at":"2025-12-02 13:13:25","extension":"png","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":620919,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/b523e03ab1225e88074e0ce7.png"},{"id":97250081,"identity":"ee63ba0b-95e8-4ff1-a3dd-85750aa76651","added_by":"auto","created_at":"2025-12-02 13:13:54","extension":"png","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6720468,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/ad744ce0a830712beb8c1be5.png"},{"id":97160473,"identity":"28274607-e8cc-495c-a5c1-d3499befbdb1","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":278754,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/e2beacc8ba898ca7a837d60b.png"},{"id":97160485,"identity":"ccdedae0-55cb-4f1e-9d0a-298f3de32384","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3401442,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure6.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/00bc1ae8de686242ae1dcb1a.png"},{"id":97160499,"identity":"ae92a52a-aa73-45a8-8f89-9ce5af7cddb3","added_by":"auto","created_at":"2025-12-01 12:28:55","extension":"png","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2354702,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure7.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/a4a36d647dd9c1792571b4f9.png"},{"id":97248724,"identity":"6550f653-aaba-4438-b5ac-1c38969f48d9","added_by":"auto","created_at":"2025-12-02 13:06:35","extension":"png","order_by":36,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3011432,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure8.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/0a3fe0cf7b7a2603d85c959a.png"},{"id":97249743,"identity":"68c493af-880c-4cf7-81cb-0b425d8baee5","added_by":"auto","created_at":"2025-12-02 13:13:18","extension":"png","order_by":37,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":467716,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/fa40913838fe482c14524340.png"},{"id":97160500,"identity":"b516dea5-25c8-4e7b-9005-6aeb55eaf922","added_by":"auto","created_at":"2025-12-01 12:28:55","extension":"png","order_by":38,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":327708,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/e3ca2e73365ca37c7c40e27f.png"},{"id":97160494,"identity":"49c7729c-42b1-4ade-b0c0-78358024eff6","added_by":"auto","created_at":"2025-12-01 12:28:55","extension":"png","order_by":39,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":550849,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/fa8ca3c12c916573f0ffe2af.png"},{"id":97160483,"identity":"283a946c-1f01-4bec-a018-80ae5dd95145","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":40,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":218462,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/83502b20b5dd0d37effec273.png"},{"id":97160491,"identity":"a8d5302b-3c81-41c7-a47a-7da316a1f2b1","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":41,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":463418,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/233262ca8edcd192c9709eac.png"},{"id":97249908,"identity":"f22a0a82-63af-40a6-ae54-c7a6a4a5c612","added_by":"auto","created_at":"2025-12-02 13:13:36","extension":"png","order_by":42,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65890,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/a14972c8512e5686a8fcd87a.png"},{"id":97160488,"identity":"ac271014-9a23-4737-8302-330730c915e0","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":43,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":657079,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/fd5c2ca47165feac3bb2b6e7.png"},{"id":97160475,"identity":"3a23e7f0-0893-49a9-805e-7a2112a75dab","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"png","order_by":44,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":484750,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/b903c84c99374481eed888ae.png"},{"id":97249950,"identity":"c92d23a3-c9ab-4009-9b63-52334a4870fd","added_by":"auto","created_at":"2025-12-02 13:13:42","extension":"png","order_by":45,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":641132,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/61570622f396dbc186b6da51.png"},{"id":97160478,"identity":"0a3c9d12-c37c-49e8-9cc6-aa97ea7e377f","added_by":"auto","created_at":"2025-12-01 12:28:54","extension":"xml","order_by":46,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":176198,"visible":true,"origin":"","legend":"","description":"","filename":"dc29efd715fa4b8caf33951cafc1b2461structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/8b5e7faa2644de30730e56f9.xml"},{"id":97248691,"identity":"4f833962-eec3-4db8-9171-7d5a0530fd2a","added_by":"auto","created_at":"2025-12-02 13:05:29","extension":"html","order_by":47,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":188708,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/800f43a5ea9c4275c4dcbeef.html"},{"id":97366659,"identity":"7912c02e-3988-4782-820d-77ad08e3ef1b","added_by":"auto","created_at":"2025-12-03 15:53:49","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2717764,"visible":true,"origin":"","legend":"","description":"","filename":"journalofnanobiotechnology.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1_covered_89bf8dbc-9bb9-4699-8e87-2ed0923d57c3.pdf"},{"id":97249863,"identity":"4bea5a69-e09b-425f-a42b-d7044213a9e6","added_by":"auto","created_at":"2025-12-02 13:13:33","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":14029971,"visible":true,"origin":"","legend":"","description":"","filename":"SI3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8124694/v1/e7e10c282ddc56e0f88259ca.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"4D printed hydrogel scaffolds with shape morphing by near-infrared to promote bone regeneration through immune and vascular coupling","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-nanobiotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jnan","sideBox":"Learn more about [Journal of Nanobiotechnology](http://jnanobiotechnology.biomedcentral.com)","snPcode":"12951","submissionUrl":"https://submission.nature.com/new-submission/12951/3","title":"Journal of Nanobiotechnology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Four-dimensional Printing, Osteoimmunomodulation, Guided Bone Regeneration, Mechanotranduction, RhoA/ROCK","lastPublishedDoi":"10.21203/rs.3.rs-8124694/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8124694/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe regeneration of critical-size irregular bone defects, especially those with irregular shapes, remains clinically challenging due to inadequate shape-conformability, immune dysregulation, poor vascularization and the unsatisfied osteogenic bioactivity. Self-fitting tissue scaffolds that can be implanted by minimally invasive procedures are a promising solution. Herein, we present a 4D-printed hydrogel scaffold (PASN) composed of polydopamine (PDA), alginate (Alg), and strontium ions (Sr\u0026sup2;⁺), that is 3D-printed and NIR-induced shape-morphing to match defect and orchestrate both immunomodulation and osteogenesis. By eliminating reactive oxygen species and driving M2 macrophage polarization through PDA, PASN improves immune regulation through the PI3K signaling pathway as well as stimulates osteogenesis and angiogenesis through release of Sr\u0026sup2;⁺. The deformation angle of the scaffold is adjusted by the laser power, irradiation time, and the designed pattern of alginate PDA struts, whereas the temperature gradient formed between the upper and lower layers under NIR irradiation induces bending toward the light source. Dome-shaped calvarial defects, maxillary sinus floor lift and horizontal bone augmentation surgeries demonstrate the PASN scaffold markedly enhances bone regeneration. Collectively, the personalised and bioactive scaffold with NIR-responsive shape-morphing may be a promising biomaterial for clinical-size and irregular bone defect regeneration.\u003c/p\u003e","manuscriptTitle":"4D printed hydrogel scaffolds with shape morphing by near-infrared to promote bone regeneration through immune and vascular coupling","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 12:28:48","doi":"10.21203/rs.3.rs-8124694/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-09T15:33:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-09T01:28:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-07T12:43:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-06T18:49:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-03T04:39:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"266788625824967752957873401537810202984","date":"2025-12-03T04:28:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-28T16:02:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279239834977305121251493587001794297828","date":"2025-11-27T15:24:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"177432325745171343087351170321341162958","date":"2025-11-27T08:41:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300347272548894917339643973302746790682","date":"2025-11-27T08:05:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78394067053804846364170588948133564969","date":"2025-11-26T10:58:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"324978549828740227360908665217650835138","date":"2025-11-25T22:29:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"133566746938117959576916675207122167037","date":"2025-11-25T19:04:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158566033746572992036853603470890034019","date":"2025-11-25T16:41:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87586099190184444560684026722114274467","date":"2025-11-25T15:36:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-25T15:21:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-16T14:17:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-16T14:17:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Nanobiotechnology","date":"2025-11-16T02:01:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-nanobiotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jnan","sideBox":"Learn more about [Journal of Nanobiotechnology](http://jnanobiotechnology.biomedcentral.com)","snPcode":"12951","submissionUrl":"https://submission.nature.com/new-submission/12951/3","title":"Journal of Nanobiotechnology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5edd3856-bea6-4398-a9ea-6d562000a92e","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-31T15:41:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 12:28:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8124694","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8124694","identity":"rs-8124694","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}