Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Fast-forming hydrogel with ultralow polymeric content as an artificial vitreous body


Degradation-induced swelling in implanted hydrogels can cause severe adverse reactions in surrounding tissues. Here, we report a new class of hydrogel with extremely low swelling pressure, and demonstrate its use as an artificial vitreous body. The hydrogel has ultralow polymer content (4.0 g l−1), low cytotoxicity, and forms in situ in 10 minutes via the crosslinking of clusters of highly branched polymers of tetra-armed poly(ethylene glycol) prepolymers. After injection and gelation in the eyes of rabbits, the hydrogel functioned as an artificial vitreous body for over a year without adverse effects, and proved effective for the treatment of retinal detachment. The properties of the hydrogel make it a promising candidate as an infill biomaterial for a range of biomedical applications.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Gelation process and properties of the conventional Tetra-PEG hydrogel and of the oligo-Tetra-PEG hydrogel.
Figure 2: Synthesis and phase diagram of the oligo-Tetra-PEG hydrogel.
Figure 3: Characterization of the oligo-Tetra-PEG and Tetra-PEG hydrogels.
Figure 4: Biocompatibility of the oligo-Tetra-PEG hydrogels.
Figure 5: Applicability of the oligo-Tetra-PEG hydrogels as artificial vitreous bodies.
Figure 6: Fundus photography of rabbit eyes, with or without retinal detachment, after injection of the oligo-Tetra-PEG hydrogel.


  1. Li, Y. L., Rodrigues, J. & Tomas, H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chem. Soc. Rev. 41, 2193–2221 (2012).

    Article  CAS  Google Scholar 

  2. Anseth, K. S. In situ forming degradable networks and their application in tissue engineering and drug delivery. J. Control. Release 78, 199–209 (2002).

    Article  CAS  Google Scholar 

  3. Ranga, A., Lutolf, M. P., Hilborn H. & Ossipov, D. A. Hyaluronic acid hydrogels formed in situ by transglutaminase-catalyzed reaction. Biomacromolecules 17, 1553–1560 (2016).

    Article  CAS  Google Scholar 

  4. Pritchard, C. D . An infectable thiol-acrylate poly(ethylene glycol) hydrogel for sustained release of methylprednisolone sodium succinate. Biomaterials 32, 587–597 (2011).

    Article  CAS  Google Scholar 

  5. Kamata, H., Chung, U., Shibayama, M. & Sakai, T. Anomalous volume phase transition in a polymer gel with alternative hydrophilic-amphiphilic sequence. Soft Matter 8, 6876–6879 (2012).

    Article  CAS  Google Scholar 

  6. Li, X., Kondo, S., Chung, U.-i. & Sakai, T. Degradation behavior of polymer gels caused by nonspecific cleavages of network strands. Chem. Mater. 26, 5352–5357 (2014).

    Article  CAS  Google Scholar 

  7. Kamata, H., Li, X., Chung, U.-i. & Sakai, T. Design of hydrogels for biomedical applications. Adv. Healthcare Mater. 4, 2360–2374 (2015).

    Article  CAS  Google Scholar 

  8. Kamata, H., Akagi, Y., Kayasuga-Kariya, Y., Chung, U.-i. & Sakai, T. “Nonswellable” hydrogel without mechanical hysteresis. Science 343, 873–875 (2014).

    Article  CAS  Google Scholar 

  9. Ho, P. C., Chan, I. M., Refojo, M. F. & Tolentino, F. I. The MAI hydrophilic implant for scleral buckling: a review. Ophthalmic Surg. 15, 511–515 (1984).

    CAS  PubMed  Google Scholar 

  10. Tolentino, F. I., Roldan, M., Nassif, J. & Refojo, M. F. Hydrogel implant for scleral buckling. Long-term observations. Retina 5, 38–41 (1985).

    Article  CAS  Google Scholar 

  11. Marin, J. F., Tolentino, F. I., Refojo, M. F. & Schepens, C. L. Long-term complications of the MAI hydrogel intrascleral buckling implant. Arch. Ophthalmol. 110, 86–88 (1992).

    Article  CAS  Google Scholar 

  12. Roldan-Pallares, M., Hernandez-Montero, J., Llanes, F., Fernandez-Rubio, J. E. & Ortega, F. MIRAgel: hydrolytic degradation and long-term observations. Arch. Ophthalmol. 125, 511–514 (2007).

    Article  Google Scholar 

  13. Flory, P. J. & Rehner, J. Statistical mechanics of cross-linked polymer networks II. Swelling. J. Chem. Phys. 11, 521–526 (1943).

    Article  CAS  Google Scholar 

  14. Gennes, P.-G. Scaling Concepts in Polymer Physics (Cornell Univ. Press, 1979).

    Google Scholar 

  15. Sakai, T. et al. Design and fabrication of a high-strength hydrogel with ideally homogeneous network structure from tetrahedron-like macromonomers. Macromolecules 41, 5379–5384 (2008).

    Article  CAS  Google Scholar 

  16. Sakai, T. Experimental verification of homogeneity in polymer gels. Polym. J. 46, 517–523 (2014).

    Article  CAS  Google Scholar 

  17. Mours, M. & Winter, H. H. Relaxation patterns of nearly critical gels. Macromolecules 29, 7221–7229 (1996).

    Article  CAS  Google Scholar 

  18. Winter, H. H. & Mours, M. Rheology of polymers near liquid-solid transitions. Adv. Polym. Sci. 134, 165–234 (1997).

    Article  CAS  Google Scholar 

  19. Zheng, Y. C., Li, S. P., Weng, Z. L. & Gao, C. Hyperbranched polymers: advances from synthesis to applications. Chem. Soc. Rev. 44, 4091–4130 (2015).

    Article  CAS  Google Scholar 

  20. Kainthan, R. K., Muliawan, E. B., Hatzikiriakos, S. G. & Brooks, D. E. Synthesis, characterization, and viscoelastic properties of high molecular weight hyperbranched polyglycerols. Macromolecules 39, 7708–7717 (2006).

    Article  CAS  Google Scholar 

  21. Sakai, T., Katashima, T., Matsushita, T. & Chung, U.-i. Sol-gel transition behavior near critical concentration and connectivity. Polymer J. 48, 629–634 (2016).

    Article  CAS  Google Scholar 

  22. Wang, Q. et al. High-water-content mouldable hydrogels by mixing clay and a dendritic molecular binder. Nature 463, 339–343 (2010).

    Article  CAS  Google Scholar 

  23. Denlinger, J. L. & Balazs, E. A. Replacement of the liquid vitreous with sodium hyaluronate in monkeys. I. Short-term evaluation. Exp. Eye Res. 31, 81–99 (1980).

    Article  CAS  Google Scholar 

  24. Swindle-Reilly, K. E. et al. Rabbit study of an in situ forming hydrogel vitreous substitute. Invest. Ophth. Vis. Sci. 50, 4840–4846 (2009).

    Article  Google Scholar 

  25. Pritchard, C. D. et al. Evaluation of viscoelastic poly(ethylene glycol) sols as vitreous substitutes in an experimental vitrectomy model in rabbits. Acta Biomater. 7, 936–943 (2011).

    Article  CAS  Google Scholar 

  26. Tao, Y. et al. Evaluation of an in situ chemically crosslinked hydrogel as a long-term vitreous substitute material. Acta Biomater. 9, 5022–5030 (2013).

    Article  CAS  Google Scholar 

  27. Crafoord, S., Andreasson, S. & Ghosh, F. Experimental vitreous tamponade using polyalkylimide hydrogel. Graef. Arch. Clin. Exp. 249, 1167–1174 (2011).

    Article  CAS  Google Scholar 

  28. Hoshi, S. et al. In vivo and in vitro feasibility studies of intraocular use of polyethylene glycol-based synthetic sealant to close retinal breaks in porcine and rabbit eyes. Invest. Ophthalmol. Vis. Sci. 56, 4705–4711 (2015).

    Article  CAS  Google Scholar 

  29. Vink, H. Precision measurements of osmotic pressure in concentrated polymer solutions. Eur. Polym. J. 7, 1411–1419 (1971).

    Article  CAS  Google Scholar 

  30. Horkay, F., Tasaki, I. & Basser, P. J. Osmotic swelling of polyacrylate hydrogels in physiological salt solutions. Biomacromolecules 1, 84–91 (2000).

    Article  CAS  Google Scholar 

Download references


This work was supported by the Japan Society for the Promotion of Science (JSPS) through Grants-in-Aid for the Graduate Program for Leaders in Life Innovation (GPLLI), by the International Core Research Center for Nanobio, Core-to-Core Program A. Advanced Research Networks, and Grants-in-Aid for Young Scientists (A) grant number 23700555 to T.S., Scientific Research (S) grant number 16H06312 to U.C., and Scientific Research (C) grant number 26462631 to F.O. This work was also supported by the Japan Science and Technology Agency (JST) through the S-innovation program and Center of Innovation program (to U.C.) and PREST (to T.S.).

Author information

Authors and Affiliations



T.S. planned and supervised the project. K.H., F.O., S.H., T.K., D.C.Z., X.L., M.S., E.G. and S.O. designed and performed the experiments. U.C. and T.O. contributed to discussions throughout the project.

Corresponding authors

Correspondence to Fumiki Okamoto or Takamasa Sakai.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures and video captions. (PDF 1513 kb)

Supplementary Video 1

Oligo-TetraPEG hydrogel in a glass vial. (MOV 25225 kb)

Supplementary Video 2

Surgical procedures in the left eye of a normal Dutch pigmented rabbit model. (MOV 64484 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hayashi, K., Okamoto, F., Hoshi, S. et al. Fast-forming hydrogel with ultralow polymeric content as an artificial vitreous body. Nat Biomed Eng 1, 0044 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing