Skip to main content
Log in

Controlled cross-linking strategy for formation of hydrogels, microgels and nanogels

  • Feature Article
  • Published:
Chinese Journal of Polymer Science Aims and scope Submit manuscript

Abstract

Hydrogels are a kind of unique cross-linking polymeric materials with three-dimensional networks. Various efforts have been devoted to manipulate the formation of functional hydrogels in situ and enrich the production of hydrogels, microgels and nanogels with improved modulation capacity. However, these methods always fail to tune the gel properties because of the difficulty in achieving the precise control of cross-linking extents once the gel formation is initiated. Therefore, the preparation of tailor-made hydrogels remains a great challenge. Herein, we summarize a controlled cross-linking strategy towards not only fabrication of hydrogels at nano-, micro- and macro-scales, but also achievement of controlled assembly of nanoparticles into multifunctional materials in macroscopic and microscopic scales. The strategy is conducted by controllably activating and terminating the disulfide reshuffling reactions of disulfide-linked core/shell materials with selective core/shell separation using system pH or UV triggers. So it provides a facile approach to producing hydrogels, hydrogel particles and nanoparticle aggregates with tunable structures and properties, opening up the design possibility, flexibility and complexity of hydrogels, microgels/nanogels and nanoparticle aggregates from nanoscopic components to macroscopic objects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Murthy, N.; Thng, Y. X.; Schuck, S.; Xu, M. C.; Fréchet, J. M. A novel strategy for encapsulation and release of proteins: hydrogels and microgels with acid-labile acetal cross-linkers. J. Am. Chem. Soc. 2002, 124(42), 12398–12399.

    Article  CAS  Google Scholar 

  2. Murthy, N.; Xu, M. C.; Schuck, S.; Kunisawa, J.; Shastri, N.; Fréchet, J. M. A macromolecular delivery vehicle for proteinbased vaccines: acid-degradable protein-loaded microgels. J. Proc. Matl. Acad. Sci. 2003, 100(9), 4995–5000.

    Article  CAS  Google Scholar 

  3. Wang, J. Z.; Loh, K. P.; Wang, Z.; Yan, Y. L.; Zhong, Y. L.; Xu, Q. H.; Ho, P. C. Fluorescent nanogel of arsenic sulfide nanoclusters. Angew. Chem. Int. Ed. 2009, 48(34), 6282–6285.

    Article  CAS  Google Scholar 

  4. Gota, C.; Okabe, K.; Funatsu, T.; Harada, Y.; Uchiyama, S. Hydrophilic fluorescent nanogel thermometer for intracellular thermometry. J. Am. Chem. Soc. 2009, 131(8), 2766–2767.

    Article  CAS  Google Scholar 

  5. Nayak, S.; Lyon, L. A. Ligand-functionalized core/shell microgels with permselective shells. Angew. Chem. Int. Ed. 2004, 43(48), 6706–6709.

    Article  CAS  Google Scholar 

  6. Terashima, T.; Nomura, A.; Ito, M.; Ouchi, M.; Sawamoto, M. Star-polymer-catalyzed living radical polymerization: microgelcore reaction vessel by tandem catalyst interchange. Angew. Chem. Int. Ed. 2011, 50(34), 7892–7895.

    Article  CAS  Google Scholar 

  7. Lu, Y.; Mei, Y.; Drechsler, M.; Ballauff, M. Thermosensitive core-shell particles as carriers for Ag nanoparticles: modulating the catalytic activity by a phase transition in networks. Angew. Chem. Int. Ed. 2006, 45(5), 813–816.

    Article  CAS  Google Scholar 

  8. Ladet, S.; David, L.; Domard, A. Multi-membrane hydrogels. Nature 2008, 452(7183), 76–79.

    Article  CAS  Google Scholar 

  9. Cheng, E. J.; Xing, Y. Z.; Chen, P.; Yang, Y.; Sun, Y. W.; Zhou, D. J.; Xu, L. J.; Fan, Q. H.; Liu, D. S. A pH-triggered, fastresponding DNA hydrogel. Angew. Chem. Int. Ed. 2009, 121(41), 7796–7799.

    Article  Google Scholar 

  10. Nowak, A. P.; Breedveld, V.; Pakstis, L. M.; Ozbas, B.; Pine, D. J.; Pochan, D.; Deming, T. J. Rapidly recovering hydrogel scaffolds from self-assembling diblock copolypeptide amphiphiles. Nature 2002, 417(6887), 424–428.

    Article  CAS  Google Scholar 

  11. Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Biodegradable block copolymers as injectable drug-delivery systems. Nature 1997, 388(6645), 860–862.

    Article  CAS  Google Scholar 

  12. Murdan, S. Electro-responsive drug delivery from hydrogels. J. Control. Release 2003, 92(12), 1–17.

    Article  CAS  Google Scholar 

  13. Moriyama, K.; Minamihata, K.; Wakabayashi, R.; Goto, M.; Kamiya, N. Enzymatic preparation of a redox-responsive hydrogel for encapsulating and releasing living cells. Chem. Commun. 2014, 50(44), 5895–5898.

    Article  CAS  Google Scholar 

  14. Nakahata, M.; Takashima, Y.; Harada, A. Redox-responsive macroscopic gel assembly based on discrete dual interactions. Angew. Chem. Int. Ed. 2014, 53(14), 3617–3621.

    Article  CAS  Google Scholar 

  15. Collier, J. H.; Hu, B. H.; Ruberti, J. W.; Zhang, J.; Shum, P.; Thompson, D. H.; Messersmith, P. B. Thermally and photochemically triggered self-assembly of peptide hydrogels. J. Am. Chem. Soc. 2001, 123(38), 9463–9464.

    Article  CAS  Google Scholar 

  16. Haines, L. A.; Rajagopal, K.; Ozbas, B.; Salick, D. A.; Pochan, D. J.; Schneider, J. P. Light-activated hydrogel formation via the triggered folding and self-assembly of a designed peptide. J. Am. Chem. Soc. 2005, 127(48), 17025–17029.

    Article  CAS  Google Scholar 

  17. Naficy, S.; Brown, H. R.; Razal, J. M.; Spinks, G. M.; Whitten, P. G. Progress toward robust polymer hydrogels. Aust. J. Chem. 2011, 64(8), 1007–1025.

    Article  CAS  Google Scholar 

  18. Cohen, Y.; Ramon, O.; Kopelman, I. J.; Mizrahi, S. Characterization of inhomogeneous polyacrylamide hydrogels. J. Polym. Sci., Part B: Polym. Phys. 1992, 30(9), 1055–1067.

    Article  CAS  Google Scholar 

  19. Hsu, T. P.; Ma, D. S.; Cohen, C. Effects of inhomogeneities in polyacrylamide gels on thermodynamic and transport properties. Polymer 1983, 24(10), 1273–1278.

    Article  CAS  Google Scholar 

  20. Wu, D. C.; Loh, X. J.; Wu, Y. L.; Lay, C. L.; Liu, Y. ‘Living’ controlled in situ gelling systems: thiol-disulfide exchange method toward tailor-made biodegradable hydrogels. J. Am. Chem. Soc. 2010, 132(43), 15140–15143.

    Article  CAS  Google Scholar 

  21. Fernandes, P. A.; Ramos, M. J. Theoretical insights into the mechanism for thiol/disulfide exchange. Chem-Eur. J. 2004, 10(1), 257–266.

    Article  CAS  Google Scholar 

  22. You, Y. Z.; Yu, Z. Q.; Cui, M. M.; Hong, C. Y. Preparation of photoluminescent nanorings with controllable bioreducibility and stimuli-responsiveness. Angew. Chem. Int. Ed. 2010, 49(6), 1099–1102.

    Article  CAS  Google Scholar 

  23. Cheng, W. R.; Wu, D. C.; Liu, Y. Michael addition polymerization of trifunctional amine and acrylic monomer: a versatile platform for development of biomaterials. Biomacromolecules 2016, 17(10), 3115–3126.

    Article  CAS  Google Scholar 

  24. Drury, J. L.; Mooney, D. J. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 2003, 24(24), 4337–4351.

    Article  CAS  Google Scholar 

  25. Meng, F. H.; Hennink, W. E.; Zhong, Z. Y. Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials 2009, 30(12), 2180–2198.

    Article  CAS  Google Scholar 

  26. Li, D. W.; Bu, Y. Z.; Zhang, L. N.; Wang, X.; Yang, Y. Y.; Zhuang, Y. P.; Yang, F.; Shen, H.; Wu, D. C. Facile construction of pH-and redox-responsive micelles from a biodegradable poly(beta-hydroxyl amine) for drug delivery. Biomacromolecules 2016, 17(1), 291–300.

    Article  CAS  Google Scholar 

  27. Zhang, J.; Yang, F.; Shen, H.; Wu, D. C. Controlled formation of microgels/nanogels from a disulfide-linked core/shell hyperbranched polymer. ACS Macro Lett. 2012, 1(11), 1295–1299.

    Article  CAS  Google Scholar 

  28. Hu, X. B.; Tong, Z.; Lyon, L. A. Multicompartment core/shell microgels. J. Am. Chem. Soc. 2010, 132(33), 11470–11472.

    Article  CAS  Google Scholar 

  29. Lu, Y.; Ballauff, M. Thermosensitive core-shell microgels: from colloidal model systems to nanoreactors. Prog. Polym. Sci. 2011, 36(6), 767–792.

    Article  CAS  Google Scholar 

  30. Xiong, M. H.; Bao, Y.; Yang, X.; Wang, Y. Z.; Sun, B. L.; Wang, J. Lipase-sensitive polymeric triple-layered nanogel for “ondemand” drug delivery. J. Am. Chem. Soc. 2012, 134(9), 4355–4362.

    Article  CAS  Google Scholar 

  31. Chen, Y.; Chen, H. R.; Zeng, D. P.; Tian, Y. B.; Chen, F.; Feng, J. W.; Shi, J. L. Core/shell structured hollow mesoporous nanocapsules: a potential platform for simultaneous cell imaging and anticancer drug delivery. ACS Nano 2010, 4(10), 6001–6013.

    Article  CAS  Google Scholar 

  32. Mitragotri, S.; Anderson, D. G.; Chen, X. Y.; Chow, E. K.; Ho, D.; Kabanov, A. V.; Karp, J. M.; Kataoka, K.; Mirkin, C. A.; Petrosko, S. H. Accelerating the translation of nanomaterials in biomedicine. ACS Nano 2015, 9(7), 6644–6654.

    Article  CAS  Google Scholar 

  33. Zhang, J.; Jia, J. P.; Kim, J. P.; Yang, F.; Wang, X.; Shen, H.; Xu, S. J.; Yang, J.; Wu, D. C. Construction of versatile multilayered composite nanoparticles from a customized nanogel template. Bioactive Materials 2017, DOI: 10.1016/j.bioactmat.2017.06.003

    Google Scholar 

  34. Zhang, J.; Jia, J. P.; Kim, J. P.; Shen, H.; Yang, F.; Zhang, Q.; Xu, M.; Bi, W. Z.; Wang, X.; Yang, J.; Wu, D. C. Ionic colloidal molding as a biomimetic scaffolding strategy for uniform bone tissue regeneration. Adv. Mater. 2017, 29(17), 1605546.

    Article  Google Scholar 

  35. Xu, S. J.; Liu, J. H.; Zhang, L. C.; Yang, F.; Tang, P. F.; Wu, D. C. Effects of HAp and TCP in constructing tissue engineering scaffolds for bone repair. J. Mater. Chem. B 2017, 5(30), 6110–6118.

    Article  CAS  Google Scholar 

  36. Zhuang, Y. P.; Shen, H.; Yang, F.; Wang, X.; Wu, D. C. Synthesis and characterization of PLGA nanoparticle/4-arm-PEG hybrid hydrogels with controlled porous structures. RSC Adv. 2016, 6(59), 53804–53812.

    Article  CAS  Google Scholar 

  37. Huang, D.; Yang, F.; Wang, X.; Shen, H.; You, Y. Z.; Wu, D. C. Facile synthesis and self-assembly behaviour of pH-responsive degradable polyacetal dendrimers. Polym. Chem. 2016, 7(40), 6154–6158.

    Article  CAS  Google Scholar 

  38. Wang, L. H.; Wu, D. C.; Xu, H. X.; You, Y. Z. High DNAbinding affinity and gene-transfection efficacy of bioreducible cationic nanomicelles with a fluorinated core. Angew. Chem. Int. Ed. 2016, 55(2), 755–759.

    Article  CAS  Google Scholar 

  39. Liu, B. X.; Zhou, X.; Yang, F.; Shen, H.; Wang, S. G.; Zhang, B.; Zhi, G.; Wu, D. C. Fabrication of uniform sized polylactone microcapsules by premix membrane emulsification for ultrasound imaging. Polym. Chem. 2014, 5(5), 1693–1701.

    Article  CAS  Google Scholar 

  40. Wang, X.; Wang, J.; Yang, Y. Y.; Yang, F.; Wu, D. C. Fabrication of multi-stimuli responsive supramolecular hydrogels based on host-guest inclusion complexation of a tadpole-shaped cyclodextrin derivative with the azobenzene dimer. Polym. Chem. 2017, 8(26), 3901–3909.

    Article  CAS  Google Scholar 

  41. Li, D. W.; Niu, Y. G.; Yang, Y. Y.; Wang, X.; Yang, F.; Shen, H.; Wu, D. C. Synthesis and self-assembly behavior of POSSembedded hyperbranched polymers. Chem. Commun. 2015, 51(39), 8296–8299.

    Article  CAS  Google Scholar 

  42. Wang, X.; Li, D.; Yang, F.; Shen, H.; Li, Z. B.; Wu, D. C. Controlled cross-linking strategy: from hybrid hydrogels to nanoparticle macroscopic aggregates. Polym. Chem. 2013, 4(17), 4596–4600.

    Article  CAS  Google Scholar 

  43. Yang, Y. Y.; Wang, X.; Hu, Y.; Hu, H.; Wu, D. C.; Xu, F. J. Bioreducible POSS-cored star-shaped polycation for efficient gene delivery. ACS Appl. Mater. Interfaces 2014, 6(2), 1044–1052.

    Article  CAS  Google Scholar 

  44. Wang, X.; Yang, Y. Y.; Gao, P. Y.; Li, D.; Yang, F.; Shen, H.; Guo, H. X.; Xu, F. J.; Wu, D. C. POSS dendrimers constructed from a 1 → 7 branching monomer. Chem. Commun. 2014, 50(46), 6126–6129.

    Article  CAS  Google Scholar 

  45. Bu, Y. Z.; Sun, G. F.; Zhang, L. C.; Liu, J. H.; Yang, F.; Tang, P. F.; Wu, D. C. POSS-modified PEG adhesives for wound closure. Chinese J. Polym. Sci. 2017, 35(10), 1231–1242.

    Article  CAS  Google Scholar 

  46. Wang, X.; Yang, Y. Y.; Zhuang, Y. P.; Gao, P. Y.; Yang, F.; Shen, H.; Guo, H. X.; Wu, D. C. Fabrication of pH-responsive nanoparticles with an AIE feature for imaging intracellular drug delivery. Biomacromolecules 2016, 17(9), 2920–2929.

    Article  CAS  Google Scholar 

  47. Wang, X.; Yang, Y. Y.; Zuo, Y. F.; Yang, F.; Shen, H.; Wu, D. C. Facile creation of FRET systems from a pH-responsive AIE fluorescent vesicle. Chem. Commun. 2016, 52(30), 5320–5323.

    Article  CAS  Google Scholar 

  48. Li, L. Y.; Song, C. F.; Jennings, M.; Thayumanavan, S. Photoinduced heterodisulfide metathesis for reagent-free synthesis of polymer nanoparticles. Chem. Commun. 2015, 51(8), 1425–1428.

    Article  CAS  Google Scholar 

  49. Wang, L. L.; Li, L.; Wang, X.; Huang, D.; Yang, F.; Shen, H.; Li, Z. C.; Wu, D. C. UV-triggered thiol-disulfide exchange reaction towards tailored biodegradable hydrogels. Polym. Chem. 2016, 7(7), 1429–1438.

    Article  CAS  Google Scholar 

  50. Wang, J.; Wang, X.; Yang, F.; Shen, H.; You, Y. Z.; Wu, D. C. Effect of topological structures on the self-assembly behavior of supramolecular amphiphiles. Langmuir 2015, 31(51), 13834–13841.

    Article  CAS  Google Scholar 

  51. Wang, J.; Wang, X.; Yang, F.; Shen, H.; You, Y. Z.; Wu, D. C. Self-assembly behavior of a linear-star supramolecular amphiphile based on host-guest complexation. Langmuir 2014, 30(43), 13014–13020.

    Article  CAS  Google Scholar 

  52. Wang, J.; Li, B. X.; Wang, X.; Yang, F.; Shen, H.; Wu, D. C. Morphological evolution of self-assembled structures induced by the molecular architecture of supra-amphiphiles. Langmuir 2016, 32(51), 13706–13715.

    Article  CAS  Google Scholar 

  53. Wang, X.; Yang, Y. Y.; Yang, F.; Shen, H.; Wu, D. C. pHtriggered decomposition of polymeric fluorescent vesicles to induce growth of tetraphenylethylene nanoparticles for longterm live cell imaging. Polymer 2017, 118(2), 75–84.

    Article  Google Scholar 

  54. Wang, X.; Yang, Y. Y.; Gao, P. Y.; Yang, F.; Shen, H.; Guo, H. X.; Wu, D. C. Synthesis, self-assembly, and photoresponsive behavior of tadpole-shaped azobenzene polymers. ACS Macro Lett. 2015, 4(12), 1321–1326.

    Article  CAS  Google Scholar 

  55. Gong, J. P.; Katsuyama, Y.; Kurokawa, T.; Osada, Y. Doublenetwork hydrogels with extremely high mechanical strength. Adv. Mater. 2003, 15(14), 1155–1158.

    Article  CAS  Google Scholar 

  56. Liu, X. Y.; Zhong, M.; Shi, F. K.; Xu, H.; Xie, X. M. Multi-bond network hydrogels with robust mechanical and self-healable properties. Chinese J. Polym. Sci. 2017, 35(10), 1253–1267.

    Article  CAS  Google Scholar 

  57. Shi, F. K.; Zhong, M.; Zhang, L. Q.; Liu, X. Y.; Xie, X. M. Toughening mechanism of nanocomposite physical hydrogels fabricated by a single gel network with dual crosslinking—the roles of the dual crosslinking points. Chinese J. Polym. Sci. 2017, 35(1), 25–35.

    Article  CAS  Google Scholar 

  58. Yang, Y. Y.; Wang, X.; Yang, F.; Shen, H.; Wu, D. C. A universal soaking strategy to convert composite hydrogels into extremely tough and rapidly recoverable double-network hydrogels. Adv. Mater. 2016, 28(33), 7178–7184.

    Article  CAS  Google Scholar 

  59. Bu, Y. Z.; Shen, H.; Yang, F.; Yang, Y. Y.; Wang, X.; Wu, D. C. Construction of tough, in situ forming double-network hydrogels with good biocompatibility. ACS Appl. Mater. Interfaces 2017, 9(3), 2205–2212.

    Article  CAS  Google Scholar 

  60. Bu, Y. Z.; Zhang, L. C.; Liu, J. H.; Zhang, L. H.; Li, T. T.; Shen, H.; Wang, X.; Yang, F.; Tang, P. F.; Wu, D. C. Synthesis and properties of hemostatic and bacteria-responsive in situ hydrogels for emergency treatment in critical situations. ACS Appl. Mater. Interfaces 2016, 8(20), 12674–12683.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Nos. 21674120, 21504096, 21474115 and 21174147) and the ‘Young Thousand Talents Program’.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Xing Wang or De-Cheng Wu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, QC., Wang, X. & Wu, DC. Controlled cross-linking strategy for formation of hydrogels, microgels and nanogels. Chin J Polym Sci 36, 8–17 (2018). https://doi.org/10.1007/s10118-018-2061-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10118-018-2061-7

Keywords

Navigation