Skip to main content
SpringerLink
Log in

PEG-based bioresponsive hydrogels with redox-mediated formation and degradation

  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

A hydrogel which will undergo macroscopic transition responding to redox stimuli is prepared. Mercapto precursors are prepared from 4-armed polyethylene glycol and after deprotection of thiolate anions, they can transform into disulfide crosslinked hydrogels within 3 min by responding to oxidant H2O2. Desirable elasticity is exhibited with a wide range of storage modulus from 50 Pa to 14 kPa through rheological investigation. In addition, the hydrogels are found to be hydrolytically stable but degrade within 75 days when exposed to reductant such as glutathione (GSH). So gelation time and degradation behavior can be regulated by concentrations of precursor, oxidant, reductant, temperature, and pH value. Notably, interest arises from the long-period degradation under low GSH concentration of 0.01 mM that is similar to extracellular level, but not the fast disintegration under high concentration intracellular, providing the possibility of “smart” degradation responding to those cell-secreted biomacromolecules during the process of tissue regeneration. Furthermore, both hydrogels and their degradation products show cell viability above 90% culturing with C2C12 cells, representing nontoxic properties. Such a stimuli-responsive degradation strategy will give promising application in tissue repair and regeneration; especially enable the achievement of matching the degradation kinetics with physiological environment.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Scheme 2

Similar content being viewed by others

References

  1. Nguyen MK, Lee DS. Ingectable biodegradable hydrogels. Macromol Biosci. 2010;10:563–79.

    Article  CAS  Google Scholar 

  2. Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49:1993–2007.

    Article  CAS  Google Scholar 

  3. Hiemstra C, Van der Aa LJ, Zhong Z, Dijkstra PJ, Feijen J. Rapidly in situ-forming degradable hydrogels from dextran thiols through michael addition. Biomacromolecules. 2007;8:1548–56.

    Article  CAS  Google Scholar 

  4. Ulijn RV, Bibi N, Jayawarna V, Thornto PD, Todd SJ, Mart RJ, et al. Bioresponsive hydrogels. Mater Today. 2007;10:40–8.

    Article  CAS  Google Scholar 

  5. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–6.

    Article  CAS  Google Scholar 

  6. Kraehenbuehl TP, Zammaretti P, Van der Vlies AJ, Schoenmakers RG, Lutolf MP, Jaconi ME, et al. Three-dimensional extracellular matrix-directed cardioprogenitor differentiation: systematic modulation of a synthetic cell-responsive PEG hydrogel. Biomaterials. 2008;29:2757–66.

    Article  CAS  Google Scholar 

  7. Lutolf MP, Hubbell JA. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol. 2005;23:47–55.

    Article  CAS  Google Scholar 

  8. Lei Y, Segura T. DNA delivery from matrix metalloproteinase degradable poly(ethylene glycol) hydrogels to mouse cloned mesenchymal stem cells. Biomaterials. 2009;30:254–65.

    Article  CAS  Google Scholar 

  9. Jo YS, Gants J, Hubbell JA, Lutolf MP. Tailoring hydrogel degradation and drug release via neighboring amio acid controlled ester hydrolysis. Soft Matter. 2009;5:440–6.

    Article  CAS  Google Scholar 

  10. Lévesque SG, Shoichet MS. Synthesis of enzyme-degradable, peptide-cross-linked dextran hydrogels. Bioconjug Chem. 2007;18:874–85.

    Article  Google Scholar 

  11. Lutolf MP, Raeber GP, Zisch AH, Tirelli N, Hubbell JA. Cell-responsive synthetic hydrogels. Adv Mater. 2003;15:888–92.

    Article  CAS  Google Scholar 

  12. Seliktar D, Zisch AH, Lutolf MP, Wrana L, Hubbelle JA. MMP-2 sensitive, VEGF-bearing bioactive hydrogels for promotion of vascular healing. J Biomed Mater Res. 2004;68A:704–16.

    Article  CAS  Google Scholar 

  13. Ehrbar M, Rizzi SC, Schoenmakers RG, Miguel BS, Hubbell JA, Weber FE, Lutolf MP. Biomolecular hydrogels formed and degraded via site-specific enzymatic reactions. Biomacromolecules. 2007;8:3000–7.

    Article  CAS  Google Scholar 

  14. Plunkett KN, Berkowski KL, Moore JS. Chymotrypsin responsive hydrogel: application of a disulfide exchange protocol for the preparation of methacrylamide containing peptides. Biomacromolecules. 2005;6:632–7.

    Article  CAS  Google Scholar 

  15. Thornton PD, McConnell G, Ulijn RV. Enzyme responsive polymer hydrogel beads. Chem Commun. 2005;47:5913–5.

    Article  Google Scholar 

  16. Saito G, Swanson JA, Lee KD. Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities. Adv Drug Deliv Rev. 2003;55:199–215.

    Article  CAS  Google Scholar 

  17. Li C, Madsen J, Armes SP, Lewis AL. A new class of biochemically degradable, stimulus-responsive triblock copolymer gelators. Angew Chem Int Ed. 2006;45:3510–3.

    Article  CAS  Google Scholar 

  18. Cline DJ, Redding SE, Brohawn SG, Psathas JN, Schneider JP, Thorpe C. New water-soluble phosphines as reductants of peptide and protein disulfide bonds: reactivity and membrane permeability. Biochemistry. 2004;43:15195–203.

    Article  CAS  Google Scholar 

  19. Kurtoglu YE, Navath RS, Wang B, Kannan S, Romero R, Kannan RM. Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery. Biomaterials. 2009;30:2112–21.

    Article  CAS  Google Scholar 

  20. Zalipsky S, Qazen M, Walker JA, Mullah N, Quinn YP, Huang SK. New detachable poly(ethylene glycol) conjugates: cysteine-cleavable lipopolymers regenerating natural phospholipid, diacyl phosphatidylethanolamine. Bioconjug Chem. 1999;10:703–7.

    Article  CAS  Google Scholar 

  21. Zalipskym S, Kiwan R, Qazen M. In: Proceedings of the International Symposium Control Rel Bioact Mater Controlled Release Society: San Diego; 2001; pp. 437.

  22. Meng F, Hennink WE, Zhong Z. Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials. 2009;30:2180–98.

    Article  CAS  Google Scholar 

  23. Yang J, Jacobsen MT, Pan H, Kopecek J. Synthesis and characterization of enzymatically degradable PEG-based peptide-containing hydrogels. Macromol Biosci. 2010;10:445–54.

    Article  CAS  Google Scholar 

  24. Hiemstra C, Van der Aa LJ, Zhong Z, Dijkstra PJ, Feijen J. Novel in situ forming, degradable dextran hydrogels by michael addition chemistry: synthesis, rheology, and degradation. Macromolecules. 2007;40:1165–73.

    Article  CAS  Google Scholar 

  25. Ellman GL. A colorimetric method for determining low concentrations of mercaptans. Arch Biochem Biophys. 1958;74:443–50.

    Article  CAS  Google Scholar 

  26. Jin R, Hiemstra C, Zhong Z, Feijen J. Enzyme-mediated fast in situ formation of hydrogels from dextran-tyramine conjugates. Biomaterials. 2007;28:2791–800.

    Article  CAS  Google Scholar 

  27. Goessl A, Tirelli N, Hubbell JA. A hydrogel system for stimulus-responsive, oxygen-sensitive in situ gelation. J Biomater Sci Polym Ed. 2004;15:895–904.

    Article  CAS  Google Scholar 

  28. Mather BD, Viswanathan K, Miller KM, Long TE. Michael addition reactions in macromolecular design for emerging technologies. Prog Polym Sci. 2006;31:487–531.

    Article  CAS  Google Scholar 

  29. Kurisawa M, Chung JE, Yang YY, Gao SJ, Uyama H. Injectable biodegradable tyramine conjugates for drug delivery and tissue engineering. Hydrogels composed of hyaluronic acid. Chem Commun. 2005;34:4312–4.

    Article  Google Scholar 

  30. Wang LS, Chung JE, Chan PP, Kurisawa M. Injectable biodegradable hydrogels with tunable mechanical properties for the stimulation of neurogenic differentiation of human mesenchymal stem cells in 3D culture. Biomaterials. 2010;31:1148–57.

    Article  Google Scholar 

  31. Kim SH, Won CY, Chu CC. Synthesis and characterization of dextran-based hydrogel prepared by photocrosslinking. Carbohydr Polym. 1999;40:183–90.

    Article  CAS  Google Scholar 

  32. Dennis WH, Rosenblatt DH, Simcox JR. Synthesis of nitrotoluenesulfonic acids by oxidative cleavage of disulfides. Synthesis. 1974;(4):295–6.

  33. Kakizama Y, Harada A, Kataoka K. Glutathione-sensitive stabilization of block copolymer micelles composed of antisense DNA and thiolated poly(ethylene glycol)-block-poly(l-lysine): a potential carrier for systemic delivery of antisense DNA. Biomacromolecular. 2001;2:491–7.

    Article  Google Scholar 

  34. Kakizama Y, Harada A, Kataoka K. Environment-sensitive stabilization of core-shell structured polyion complex micelle by reversible cross-linking of the core through disulfide bond. J Am Chem Soc. 1999;121:11247–8.

    Article  Google Scholar 

  35. Wang Y, Chen P, Shen J. The development and characterization of a glutathione-sensitive cross-linked polyethylenimine gene vector. Biomaterials. 2006;27:5292–8.

    Article  CAS  Google Scholar 

  36. Zhu Y, Tong W, Gao C, Möhwald H. Fabrication of bovine serum albumin microcapsules by desolvation and destroyable cross-linking. J Mater Chem. 2008;18:1153–8.

    Article  CAS  Google Scholar 

  37. Bayramoğlu G, Kayaman-Apohan N, Akcakaya H, Kahraman MV, Kuruca SE, Güngör A. Preparation of collagen modified photopolymers: a new type of biodegradable gel for cell growth. J Mater Sci Mater Med. 2010;21:761–5.

    Article  Google Scholar 

  38. Hu C, Zhang L, Wu D, Cheng S, Zhang X, Zhuo R. Heparin-modified PEI encapsulated in thermosensitive hydrogels for efficient gene delivery and expression. J Mater Chem. 2009;19:3189–97.

    Article  CAS  Google Scholar 

  39. Bae KH, Mok H, Park TG. Synthesis, characterization, and intracellular delivery of reducible heparin nanogels for apoptotic cell death. Biomaterials. 2008;29:3376–83.

    Article  CAS  Google Scholar 

Download references

Acknowledgment

The authors wish to express their gratitude to the financial supports from the State Key Program of National Natural Science of China (No. 50732002), National Natural Science Foundation of China (No. 50973029), and Program for Chang Jiang Scholars and Innovative Research Team. The State Key Laboratory of Bioreactor Engineering is also gratefully acknowledged.

Author information

Authors and Affiliations

  1. Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, 130 Meilong Road, P.O. Box 112, Shanghai, 200237, People’s Republic of China

    Fan Yang, Jing Wang, Geng Peng, Sichao Fu, Shuo Zhang & Changsheng Liu

Authors
  1. Fan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geng Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sichao Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Changsheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jing Wang or Changsheng Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, F., Wang, J., Peng, G. et al. PEG-based bioresponsive hydrogels with redox-mediated formation and degradation. J Mater Sci: Mater Med 23, 697–710 (2012). https://doi.org/10.1007/s10856-012-4555-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10856-012-4555-0

Keywords

Search

Navigation