Dynamic Molecular Design of Force-responsive Hydrogels

Abstract

Force-responsive hydrogels are dynamic soft materials that convert mechanical stimuli into energy dissipation, network reconstruction, functional adaptation, or mechanochemical transduction. This review discusses how molecular interactions and network architectures enable such responses, focusing on dynamic covalent bonds, noncovalent and supramolecular interactions, hierarchical and topological structures, and protein mechanophores. We summarize key mechanisms including sacrificial-bond dissociation, self-healing, stress relaxation, strain stiffening, fatigue resistance, mechanical training, self-reinforcement, self-growth, and force-induced chemical activation. The potential implications of these design principles for adaptive biomedical and engineering systems are briefly considered. Finally, we discuss challenges in balancing robustness and adaptability, improving fatigue durability, enhancing predictability, and integrating multiple functions. By framing hydrogels through a structure-force-response relationship, this review provides a cross-scale perspective for designing adaptive, reconfigurable, and intelligent soft materials.

Keywords

Force-responsive hydrogel / Dynamic network / Supramolecular interaction / Protein mechanophore / Mechanochemical transduction

References

[1] Peppas N A, Huang Y, Torres-Lugo M, Ward J H, Zhang J. Annu. Rev. Biomed. Eng., 2000, 2: 9

[2] Li Y, Rodrigues J, Tomás H. Chem. Soc. Rev., 2012, 41: 2193

[3] Hoffman A S. Adv. Drug Delivery Rev., 2012, 64: 18

[4] Yu L, Ding J. Chem. Soc. Rev., 2008, 37: 1473

[5] Nam S, Mooney D. Chem. Rev., 2021, 121: 11336

[6] Cui C, Liu W. Prog. Polym. Sci., 2021, 116: 101388

[7] Yang C, Suo Z. Nat. Rev. Mater., 2018, 3: 125

[8] Ray T R, Choi J, Bandodkar A J, Krishnan S, Gutruf P, Tian L, Ghaffari R, Rogers J A. Chem. Rev., 2019, 119: 5461

[9] Cianchetti M, Laschi C, Menciassi A, Dario P. Nat. Rev. Mater., 2018, 3: 143

[10] Xue B, Gu J, Li L, Yu W, Yin S, Qin M, Jiang Q, Wang W, Cao Y. Nat. Commun., 2021, 12: 7156

[11] Li J, Mooney D J. Nat. Rev. Mater., 2016, 1: 16071

[12] Liu W, Xie R, Zhu J, Wu J, Hui J, Zheng X, Huo F, Fan D. NPJ Flexible Electron., 2022, 6: 68

[13] Lee Y, Song W J, Sun J Y. Mater. Today Phys., 2020, 15: 100258

[14] Lee K Y, Mooney D J. Chem. Rev., 2001, 101: 1869

[15] Sreepadmanabh M, Arun A B, Bhattacharjee T. Biophys. Rev., 2024, 5: 021304

[16] Yadav S, Nguyen N T. Biophys. Rev., 2025, 6: 031303

[17] Zhang X, Wang C, Niu J, Wang Y, Wang W, Yang H, Ye X, Yang H. Chem. Res. Chinese Universities, 2025, 41: 1607

[18] Meng D, Zhou X, Zheng K, Miao C, Sheng Y, Zou H. Chem. Res. Chinese Universities, 2019, 35: 521

[19] Engler A J, Sen S, Sweeney H L, Discher D E. Cell, 2006, 126: 677

[20] Huebsch N, Arany P R, Mao A S, Shvartsman D, Ali O A, Bencherif S A, Rivera-Feliciano J, Mooney D J. Nat. Mater., 2010, 9: 518

[21] Tibbitt M W, Anseth K S. Biotechnol. Bioeng., 2009, 103: 655

[22] Wang X Q, Xie A Q, Cao P, Yang J, Ong W L, Zhang K Q, Ho G W. Adv. Mater., 2024, 36: 2309952

[23] Li X, Gong J P. Nat. Rev. Mater., 2024, 9: 380

[24] Zhang Y S, Khademhosseini A. Science, 2017, 356: eaaf3627

[25] Rowan S J, Cantrill S J, Cousins G R L, Sanders J K M, Stoddart J F. Angew. Chem. Int. Ed., 2002, 41: 898

[26] Chakma P, Konkolewicz D. Angew. Chem. Int. Ed., 2019, 58: 9682

[27] Webber M J, Appel E A, Meijer E W, Langer R. Nat. Mater., 2016, 15: 13

[28] Sun W, Xue B, Fan Q, Tao R, Wang C, Wang X, Li Y, Qin M, Wang W, Chen B, Cao Y. Sci. Adv., 2020, 6: eaaz9531

[29] Grindy S C, Learsch R, Mozhdehi D, Cheng J, Barrett D G, Guan Z, Messersmith P B, Holten-Andersen N. Nat. Mater., 2015, 14: 1210

[30] Zou L, Braegelman A S, Webber M J. ACS Appl. Mater. Interfaces, 2019, 11: 5695

[31] Mantooth S M, Munoz-Robles B G, Webber M J. Macromol. Biosci., 2019, 19: 1800281

[32] Rodell C B, Kaminski A L, Burdick J A. Biomacromolecules, 2013, 14: 4125

[33] Hu X, Vatankhah-Varnoosfaderani M, Zhou J, Li Q, Sheiko S S. Adv. Mater., 2015, 27: 6899

[34] Bai T, Zhang P, Han Y, Liu Y, Liu W, Zhao X, Lu W. Soft Matter, 2011, 7: 2825

[35] Appel E A, Tibbitt M W, Greer J M, Fenton O S, Kreuels K, Anderson D G, Langer R. ACS Macro Lett., 2015, 4: 848

[36] Senebandith H, Li D, Srivastava S. Langmuir, 2023, 39: 16965

[37] Gong J P, Katsuyama Y, Kurokawa T, Osada Y. Adv. Mater., 2003, 15: 1155

[38] Sun J Y, Zhao X, Illeperuma W R K, Chaudhuri O, Oh K H, Mooney D J, Vlassak J J, Suo Z. Nature, 2012, 489: 133

[39] Dong L, Li L, Chen H, Cao Y, Lei H. Adv. Sci., 2025, 12: 2403949

[40] Ollier R C, Webber M J. Adv. Mater., 2025, 37: 2507397

[41] Yuk H, Lu B, Zhao X. Chem. Soc. Rev., 2019, 48: 1642

[42] Cong Y, Fu J. Langmuir, 2022, 38: 11503

[43] Mirvakili S M, Hunter I W. Adv. Mater., 2018, 30: 1704407

[44] Little C J, Bawolin N K, Chen X. Tissue Eng. B: Rev., 2011, 17: 213

[45] Johnson G A, Tramaglini D M, Levine R E, Ohno K, Choi N Y, Woo S L Y. J. Orthop. Res., 1994, 12: 796

[46] Chan B P, Leong K W. Eur. Spine J., 2008, 17: 467

[47] Liu C, Morimoto N, Jiang L, Kawahara S, Noritomi T, Yokoyama H, Mayumi K, Ito K. Science, 2021, 372: 1078

[48] Xiong X, Chen Y, Wang Z, Liu H, Le M, Lin C, Wu G, Wang L, Shi X, Jia Y G, Zhao Y. Nat. Commun., 2023, 14: 1331

[49] Fu L, Li L, Bian Q, Xue B, Jin J, Li J, Cao Y, Jiang Q, Li H. Nature, 2023, 618: 740

[50] Chaudhuri O, Gu L, Klumpers D, Darnell M, Bencherif S A, Weaver J C, Huebsch N, Lee H P, Lippens E, Duda G N, Mooney D J. Nat. Mater., 2016, 15: 326

[51] Gong J P. Soft Matter, 2010, 6: 2583

[52] Bai R, Yang Q, Tang J, Morelle X P, Vlassak J, Suo Z. Extreme Mech. Lett., 2017, 15: 91

[53] Bai R, Yang J, Suo Z. Eur. J. Mech. A Solids, 2019, 74: 337

[54] Webber M J, Tibbitt M W. Nat. Rev. Mater., 2022, 7: 541

[55] Xian S, Webber M J. J. Mater. Chem. B, 2020, 8: 9197

[56] Marco-Dufort B, Tibbitt M W. Mater. Today Chem., 2019, 12: 16

[57] Correa S, Grosskopf A K, Lopez Hernandez H, Chan D, Yu A C, Stapleton L M, Appel E A. Chem. Rev., 2021, 121: 11385

[58] Tang S, Richardson B M, Anseth K S. Prog. Mater Sci., 2021, 120: 100738

[59] Lin S, Liu J, Liu X, Zhao X. Proc. Natl. Acad. Sci., 2019, 116: 10244

[60] Matsuda T, Kawakami R, Namba R, Nakajima T, Gong J P. Science, 2019, 363: 504

[61] Cao Y, Li H. Nat. Mater., 2007, 6: 109

[62] Rosales A M, Anseth K S. Nat. Rev. Mater., 2016, 1: 15012

[63] Hu X, Zhang Y. Biophys. Rev., 2021, 2: 041302

[64] Buchmann B, Fernández P, Bausch A R. Biophys. Rev., 2021, 2: 021401

[65] Li T, Huang Y, Lu C, Gu L, Cao Y, Yin S. Chem. Res. Chinese Universities, 2022, 38: 1512

[66] Peng Y, Liu Q J, He T, Ye K, Yao X, Ding J. Biomaterials, 2018, 178: 467

[67] Han Y, Cao Y, Lei H. Gels, 2022, 8: 577

[68] Chen J, Peng Q, Peng X, Han L, Wang X, Wang J, Zeng H. ACS Appl. Polym. Mater., 2020, 2: 1092

[69] Hall M S, Alisafaei F, Ban E, Feng X, Hui C Y, Shenoy V B, Wu M. Proc. Natl. Acad. Sci., 2016, 113: 14043

[70] Xu J, Jiang Y, Gao L. J. Mater. Chem. B, 2023, 11: 221

[71] Cui J, Chen J, Ni Z, Dong W, Chen M, Shi D. ACS Appl. Mater. Interfaces, 2022, 14: 47148

[72] Cui J, Xu R, Dong W, Kaneko T, Chen M, Shi D. ACS Appl. Mater. Interfaces, 2023, 15: 48736

[73] Liu H, Li M, Ouyang C, Lu T J, Li F, Xu F. Small, 2018, 14: 1801711

[74] Huang Z, Chen X, O’Neill S J K, Wu G, Whitaker D J, Li J, McCune J A, Scherman O A. Nat. Mater., 2022, 21: 103

[75] Ge G, Lu Y, Qu X, Zhao W, Ren Y, Wang W, Wang Q, Huang W, Dong X. ACS Nano, 2020, 14: 218

[76] Talebian S, Mehrali M, Taebnia N, Pennisi C P, Kadumudi F B, Foroughi J, Hasany M, Nikkhah M, Akbari M, Orive G, Dolatshahi-Pirouz A. Adv. Sci., 2019, 6: 1801664

[77] Su G, Yin S, Guo Y, Zhao F, Guo Q, Zhang X, Zhou T, Yu G. Mater. Horiz., 2021, 8: 1795

[78] Bertsch P, Diba M, Mooney D J, Leeuwenburgh S C G. Chem. Rev., 2023, 123: 834

[79] Lehn J M. Chem. Eur. J., 1999, 5: 2455

[80] Zhao R, Wang Y, Wang S, Zhao C, Gong X. Polymer, 2020, 210: 122995

[81] Huang S, Kong X, Xiong Y, Zhang X, Chen H, Jiang W, Niu Y, Xu W, Ren C. Eur. Polym. J., 2020, 141: 110094

[82] Zhang V, Accardo J V, Kevlishvili I, Woods E F, Chapman S J, Eckdahl C T, Stern C L, Kulik H J, Kalow J A. Chem, 2023, 9: 2298

[83] Brown T E, Carberry B J, Worrell B T, Dudaryeva O Y, McBride M K, Bowman C N, Anseth K S. Biomaterials, 2018, 178: 496

[84] Carberry B J, Rao V V, Anseth K S. Ann. Biomed. Eng., 2020, 48: 2053

[85] Zhang V, Ou C, Kevlishvili I, Hemmingsen C M, Accardo J V, Kulik H J, Kalow J A. ACS Macro Lett., 2024, 13: 621

[86] Bell G I. Science, 1978, 200: 618

[87] Evans E, Ritchie K. Biophys. J., 1997, 72: 1541

[88] Wang Z J, Wang S, Jiang J, Hu Y, Nakajima T, Maeda S, Craig S L, Gong J P. J. Am. Chem. Soc., 2024, 146: 13336

[89] Tang L, Liu W, Liu G. Adv. Mater., 2010, 22: 2652

[90] Haque M A, Kurokawa T, Kamita G, Gong J P. Macromolecules, 2011, 44: 8916

[91] Li C, Rowland M J, Shao Y, Cao T, Chen C, Jia H, Zhou X, Yang Z, Scherman O A, Liu D. Adv. Mater., 2015, 27: 3298

[92] Taylor D L, In Het Panhuis M. Adv. Mater., 2016, 28: 9060

[93] Wei Z, Yang J H, Zhou J, Xu F, Zrínyi M, Dussault P H, Osada Y, Chen Y M. Chem. Soc. Rev., 2014, 43: 8114

[94] Bai R, Yang J, Morelle X P, Yang C, Suo Z. ACS Macro Lett., 2018, 7: 312

[95] Zhang Y, Hu C, Xiang X, Diao Y, Li B, Shi L, Ran R. RSC Adv., 2017, 7: 12063

[96] Dimitriou C J, McKinley G H. Soft Matter, 2014, 10: 6619

[97] Feldman K E, Kade M J, Meijer E W, Hawker C J, Kramer E J. Macromolecules, 2009, 42: 9072

[98] Zhang Z, Chen Q, Colby R H. Soft Matter, 2018, 14: 2961

[99] Lopez Hernandez H, Souza J W, Appel E A. Macromol. Biosci., 2021, 21: 2000295

[100] Lin Y H, Lou J, Xia Y, Chaudhuri O. Adv. Healthcare Mater., 2024, 13: 2402059

[101] Crowell A D, FitzSimons T M, Anslyn E V, Schultz K M, Rosales A M. Macromolecules, 2023, 56: 7795

[102] Lu L, Zhou W, Chen Z, Hu Y, Yang Y, Zhang G, Yang Z. Gels, 2022, 8: 244

[103] Grosskopf A K, Mann J L, Baillet J, Lopez Hernandez H, Autzen A A A, Yu A C, Appel E A. Macromolecules, 2022, 55: 7498

[104] Rodell C B, MacArthur J W, Dorsey S M, Wade R J, Wang L L, Woo Y J, Burdick J A. Adv. Funct. Mater., 2015, 25: 636

[105] Zhu R, Zhu D, Zheng Z, Wang X. Nat. Commun., 2024, 15: 1344

[106] Bin Imran A, Esaki K, Gotoh H, Seki T, Ito K, Sakai Y, Takeoka Y. Nat. Commun., 2014, 5: 5124

[107] Li X, Cui K, Sun T L, Meng L, Yu C, Li L, Creton C, Kurokawa T, Gong J P. Proc. Natl. Acad. Sci., 2020, 117: 7606

[108] Ni J, Lin S, Qin Z, Veysset D, Liu X, Sun Y, Hsieh A J, Radovitzky R, Nelson K A, Zhao X. Matter, 2021, 4: 1919

[109] Zhang S, Ren D, Zhao Q, Peng M, Wang X, Zhang Z, Liu W, Huang F. Nat. Commun., 2025, 16: 2371

[110] Matsuura K, Inaba H. Biophys. Rev., 2023, 4: 041303

[111] Li L, Lei H, Cao Y. Chem. Res. Chinese Universities, 2024, 40: 64

[112] Liu J, Lin S, Liu X, Qin Z, Yang Y, Zang J, Zhao X. Nat. Commun., 2020, 11: 1071

[113] Xue B, Bashir Z, Guo Y, Yu W, Sun W, Li Y, Zhang Y, Qin M, Wang W, Cao Y. Nat. Commun., 2023, 14: 2583

[114] Rief M, Gautel M, Oesterhelt F, Fernandez J M, Gaub H E. Science, 1997, 276: 1109

[115] Li H, Bian Q. Supramol. Mater., 2025, 4: 100120

[116] Lv S, Dudek D M, Cao Y, Balamurali M M, Gosline J, Li H. Nature, 2010, 465: 69

[117] Wu J, Li P, Dong C, Jiang H, Xue B, Gao X, Qin M, Wang W, Chen B, Cao Y. Nat. Commun., 2018, 9: 620

[118] Lei H, Dong L, Li Y, Zhang J, Chen H, Wu J, Zhang Y, Fan Q, Xue B, Qin M, Chen B, Cao Y, Wang W. Nat. Commun., 2020, 11: 4032

[119] Ma T, Sun W, Qin M, Yin S, Li Y, Cao Y, Xue B, Wang W. Adv. Mater., 2026, 38: e23636

[120] Zhang J, Lei H, Qin M, Wang W, Cao Y. Supramol. Mater., 2022, 1: 100005

[121] Rizwan M, Baker A E G, Shoichet M S. Adv. Healthcare Mater., 2021, 10: 2100234

[122] Deng G, Li F, Yu H, Liu F, Liu C, Sun W, Jiang H, Chen Y. ACS Macro Lett., 2012, 1: 275

[123] Zhang Y, Tao L, Li S, Wei Y. Biomacromolecules, 2011, 12: 2894

[124] Deng G, Tang C, Li F, Jiang H, Chen Y. Macromolecules, 2010, 43: 1191

[125] Roberts M C, Hanson M C, Massey A P, Karren E A, Kiser P F. Adv. Mater., 2007, 19: 2503

[126] Wei Z, Yang J H, Du X J, Xu F, Zrinyi M, Osada Y, Li F, Chen Y M. Macromol. Rapid Commun., 2013, 34: 1464

[127] Han Y, Liu C, Xu H, Cao Y. Chin. J. Chem., 2022, 40: 1578

[128] Liu C, Xia J, Ji S, Fan Z, Xu H. Chem. Commun., 2019, 55: 2813

[129] Yi Y, Xu H, Wang L, Cao W, Zhang X. Chem. Eur. J., 2013, 19: 9506

[130] Huang X, Fang R, Wang D, Wang J, Xu H, Wang Y, Zhang X. Small, 2015, 11: 1537

[131] Hupe D J, Jencks W P. J. Am. Chem. Soc., 1977, 99: 451

[132] Chen X, Dam M A, Ono K, Mal A, Shen H, Nutt S R, Sheran K, Wudl F. Science, 2002, 295: 1698

[133] Duan H Y, Wang Y X, Wang L J, Min Y Q, Zhang X H, Du B Y. Macromolecules, 2017, 50: 1353

[134] Ollier R C, Xiang Y, Yacovelli A M, Webber M J. Chem. Sci., 2023, 14: 4796

[135] FitzSimons T M, Anslyn E V, Rosales A M. ACS Polym. Au, 2022, 2: 129

[136] Guan Y, Zhang Y. Chem. Soc. Rev., 2013, 42: 8106

[137] He L, Fullenkamp D E, Rivera J G, Messersmith P B. Chem. Commun., 2011, 47: 7497

[138] Wang R, Bian Z, Zhan D, Wu Z, Yao Q, Zhang G. Dyes Pigm., 2021, 185: 108885

[139] Williams G T, Sedgwick A C, Sen S, Gwynne L, Gardiner J E, Brewster J T, Hiscock J R, James T D, Jenkins A T A, Sessler J L. Chem. Commun., 2020, 56: 5516

[140] Springsteen G, Wang B. Tetrahedron, 2002, 58: 5291

[141] Tseng T C, Hsieh F Y, Theato P, Wei Y, Hsu S H. Biomaterials, 2017, 133: 20

[142] Chen Y, Wang W, Wu D, Nagao M, Hall D G, Thundat T, Narain R. Biomacromolecules, 2018, 19: 596

[143] Wang W, Xiang L, Diaz-Dussan D, Zhang J, Yang W, Gong L, Chen J, Narain R, Zeng H. Chem. Mater., 2020, 32: 10545

[144] Wang Z J, Li W, Li X, Nakajima T, Rubinstein M, Gong J P. Nat. Mater., 2025, 24: 607

[145] He G, Lei H, Sun W, Gu J, Yu W, Zhang D, Chen H, Li Y, Qin M, Xue B, Wang W, Cao Y. Angew. Chem. Int. Ed., 2022, 61: e202201765

[146] Yu W, Xue B, Zhu Z, Shen Z, Qin M, Wang W, Cao Y. Chem. Res. Chinese Universities, 2020, 36: 962

[147] Yuk H, Zhang T, Parada G A, Liu X, Zhao X. Nat. Commun., 2016, 7: 12028

[148] Van Hest J C M, Tirrell D A. Chem. Commun., 2001, 37: 1897

[149] Li H. Adv. NanoBiomed Res., 2021, 1: 2100028

[150] Cai L, Heilshorn S C. Acta Biomater., 2014, 10: 1751

[151] Li Y, Xue B, Cao Y. ACS Macro Lett., 2020, 9: 512

[152] Davari N, Bakhtiary N, Khajehmohammadi M, Sarkari S, Tolabi H, Ghorbani F, Ghalandari B. Polymers, 2022, 14: 986

[153] Lee K Z, Jeon J, Jiang B, Subramani S V, Li J, Zhang F. Molecules, 2023, 28: 4988

[154] Murphy W L, Dillmore W S, Modica J, Mrksich M. Angew. Chem. Int. Ed., 2007, 46: 3066

[155] Yuan W, Yang J, Kopečková P, Kopeček J. J. Am. Chem. Soc., 2008, 130: 15760

[156] Ehrick J D, Luckett M R, Khatwani S, Wei Y, Deo S K, Bachas L G, Daunert S. Macromol. Biosci., 2009, 9: 864

[157] Cai Z, Luck L A, Punihaole D, Madura J D, Asher S A. Chem. Sci., 2016, 7: 4557

[158] Fang J, Mehlich A, Koga N, Huang J, Koga R, Gao X, Hu C, Jin C, Rief M, Kast J, Baker D, Li H. Nat. Commun., 2013, 4: 2974

[159] Chalkley M J, Mann S I, DeGrado W F. Nat. Rev. Chem., 2021, 6: 31

[160] Khare E, Holten-Andersen N, Buehler M J. Nat. Rev. Mater., 2021, 6: 421

[161] Permyakov E A. Encyclopedia, 2021, 1: 261

[162] Lu Y, Yeung N, Sieracki N, Marshall N M. Nature, 2009, 460: 855

[163] Jagannathan B, Marqusee S. Biopolymers, 2013, 99: 860

[164] Seckler R, Jaenicke R. FASEB J., 1992, 6: 2545

[165] Popa I, Berkovich R. Emerging Top. Life Sci., 2018, 2: 687

[166] Cao Y, Kuske R, Li H. Biophys. J., 2008, 95: 782

[167] Wang L J, Yang K X, Zhou Q, Yang H Y, He J Q, Zhang X Y. Chin. J. Polym. Sci., 2020, 38: 24

[168] Ouchi T, Bowser B H, Kouznetsova T B, Zheng X, Craig S L. Mater. Horiz., 2023, 10: 585

[169] Arenhart Soares F, Besenius P. Org. Chem. Front., 2025, 12: 3107

[170] Luo J, Chen J, Huang Y, You L, Dai Z. Biophys. Rev., 2023, 4: 011305

Rights & permissions

Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH

Just Accepted

This article has successfully passed peer review and final editorial review, and will soon enter typesetting, proofreading and other publishing processes. The currently displayed version is the accepted final manuscript. The officially published version will be updated with format, DOI and citation information upon launch. We recommend that you pay attention to subsequent journal notifications and preferentially cite the officially published version. Thank you for your support and cooperation.