{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:58:51Z","timestamp":1790740731966,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"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":["52473115"],"award-info":[{"award-number":["52473115"]}],"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":["52673157"],"award-info":[{"award-number":["52673157"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Materials"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Decoupling molecular\u2010scale mechanical signaling from bulk substrate stiffness remains a fundamental challenge in biomaterial design. Here, we develop a soft\u2010yet\u2010active hyaluronic acid hydrogel (\u223c3\u00a0kPa) grafted with near\u2010infrared\u2010driven CD\u2010PNIPAM\u2010RGD molecular actuators to apply programmable, piconewton\u2010scale forces directly to integrins without altering the bulk modulus. By isolating force history as an independent variable, we reveal that human mesenchymal stem cells act as cumulative mechanical integrators. A cumulative force dose of just 7\u00a0h (1\u2010h daily pulses) drives irreversible osteogenic commitment on this classically non\u2010permissive substrate. Mechanistically, each pulse bypasses canonical tension\u2010based signaling. Despite negligible cytoplasmic traction, localized molecular pulling drives G\u2010actin nuclear import, intranuclear F\u2010actin polymerization, and rapid YAP activation. By recasting mechanotransduction from a continuous analog response into a discrete, cumulative integration of mechanical inputs, this work establishes active force dosing as a quantitative design principle for next\u2010generation soft biomaterials.<\/jats:p>","DOI":"10.1002\/adma.75184","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:23:19Z","timestamp":1790738599000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Active Soft Hydrogels Reveal Cumulative Molecular Force Dosing in Stem Cell Fate Programming"],"prefix":"10.1002","author":[{"given":"Bohan","family":"Li","sequence":"first","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyu","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoliang","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2380-2869","authenticated-orcid":false,"given":"Peng","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwen","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicheng","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingshuai","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaowen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongrui","family":"Ran","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5194-8262","authenticated-orcid":false,"given":"Qiang","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Polymer Science and Engineering State Key Laboratory of Polymer Materials and Engineering Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7135-8438","authenticated-orcid":false,"given":"Yijun","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology &amp; State Key Laboratory of Advanced Medical Materials and Devices ShanghaiTech University  Shanghai China"},{"name":"Shanghai Clinical Research and Trial Center  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201001134\u20104"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2021.08.009"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.201909874"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u201000279\u2010w"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.044"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1116995"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2014.11.017"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.7b05339"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2021.08.026"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2020.120543"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2017.04.039"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adr5023"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1792"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmat3889"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.09.016"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2406787121"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010018\u20102830\u2010z"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202103466"},{"key":"e_1_2_9_20_1","doi-asserted-by":"crossref","DOI":"10.1002\/adhm.201700192","article-title":"The Potential of Liquid Marbles for Biomedical Applications: A Critical Review","volume":"6","author":"Oliveira N. M.","year":"2017","journal-title":"Advanced Healthcare Materials"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12217\u2010019\u20109687\u20100"},{"key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"9596","DOI":"10.3390\/ijms21249596","article-title":"Tissue Engineering of Cartilage Using a Random Positioning Machine","volume":"21","author":"Wehland M.","year":"2020","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","DOI":"10.1002\/adhm.202202163","article-title":"Transcriptomic Changes Toward Osteogenic Differentiation of Mesenchymal Stem Cells on 3D\u2010Printed Gelma\/Cnc Hydrogel Under Pulsatile Pressure Environment","volume":"12","author":"Ganguly K.","year":"2023","journal-title":"Advanced Healthcare Materials"},{"key":"e_1_2_9_24_1","doi-asserted-by":"crossref","DOI":"10.1155\/2018\/2174824","article-title":"Cyclic Stretch Enhances Osteogenic Differentiation of Human Periodontal Ligament Cells via YAP Activation","volume":"2018","author":"Yang Y.","year":"2018","journal-title":"BioMed Research International"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7333"},{"key":"e_1_2_9_26_1","doi-asserted-by":"crossref","first-page":"4229","DOI":"10.1038\/s41467-021-24383-3","article-title":"The Force Loading Rate Drives Cell Mechanosensing Through Both Reinforcement and Cytoskeletal Softening","volume":"12","author":"Andreu I.","year":"2021","journal-title":"Nature Communications"},{"key":"e_1_2_9_27_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202110267","article-title":"Delivering Mechanical Stimulation to Cells: State of the Art in Materials and Devices Design","volume":"34","author":"Zhang Y. G.","year":"2022","journal-title":"Advanced Materials"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201023815\u20104"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201609483"},{"key":"e_1_2_9_30_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nmeth.3689","article-title":"Nanoscale Optomechanical Actuators for Controlling Mechanotransduction in Living Cells","volume":"13","author":"Liu Z.","year":"2016","journal-title":"Nature Methods"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201060062\u20103"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2022.100476"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202306554"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2006765117"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules17044047"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2015.05.010"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e12\u201009\u20100685"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201024383\u20103"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.01.136"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.2090"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.02.019"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202509860"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010024\u201003775\u20104"}],"container-title":["Advanced Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adma.75184","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/adma.75184","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adma.75184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:23:23Z","timestamp":1790738603000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adma.75184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":42,"alternative-id":["10.1002\/adma.75184"],"URL":"https:\/\/doi.org\/10.1002\/adma.75184","archive":["Portico"],"relation":{},"ISSN":["0935-9648","1521-4095"],"issn-type":[{"value":"0935-9648","type":"print"},{"value":"1521-4095","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"assertion":[{"value":"2026-04-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e75184"}}