Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

In Vivo Characterization of Poly(ethylene glycol) Hydrogels with Thio-β Esters


Resorbable hydrogels have numerous potential applications in tissue engineering and drug delivery due to their highly tunable properties and soft tissue-like mechanical properties. The incorporation of esters into the backbone of poly(ethylene glycol) hydrogels has been used to develop libraries of hydrogels with tunable degradation rates. However, these synthetic strategies used to increase degradation rate often result in undesired changes in the hydrogel physical properties such as matrix modulus or swelling. In an effort to decouple degradation rate from other hydrogel properties, we inserted thio-β esters into the poly(ethylene glycol)-diacrylate backbone to introduce labile bonds without changing macromer molecular weight. This allowed the number of hydrolytically labile thio-β esters to be controlled through changing the ratios of this modified macromer to the original macromer without affecting network properties. The retention of hydrogel properties at different macromer ratios was confirmed by measuring gel fraction, swelling ratio, and compressive modulus. The tunable degradation profiles were characterized both in vitro and in vivo. Following confirmation of cytocompatibility after exposure to the hydrogel degradation products, the in vivo host response was evaluated in comparison to medical grade silicone. Collectively, this work demonstrates the utility and tunability of these hydrolytically degradable hydrogels for a wide variety of tissue engineering applications.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8


  1. 1.

    Anderson, D. G., C. A. Tweedie, N. Hossain, S. M. Navarro, D. M. Brey, K. J. Van Vliet, R. Langer, and J. A. Burdick. A combinatorial library of photocrosslinkable and degradable materials. Adv. Mater. 18:2614–2618, 2006.

  2. 2.

    Anseth, K. S., C. N. Bowman, and L. Brannon-Peppas. Mechanical properties of hydrogels and their experimental determination. Biomaterials 17:1647–1657, 1996.

  3. 3.

    Anseth, K. S., A. T. Metters, S. J. Bryant, P. J. Martens, J. H. Elisseeff, and C. N. Bowman. In situ forming degradable networks and their application in tissue engineering and drug delivery. J. Control. Release 78:199–209, 2002.

  4. 4.

    Basu, A., K. R. Kunduru, S. Doppalapudi, A. J. Domb, and W. Khan. Poly(lactic acid) based hydrogels. Adv. Drug Deliv. Rev. 107:192–205, 2016.

  5. 5.

    Bencherif, S. A., J. A. Sheehan, J. O. Hollinger, L. M. Walker, K. Matyjaszewski, and N. R. Washburn. Influence of cross-linker chemistry on release kinetics of PEG-co-PGA hydrogels. J. Biomed. Mater. Res. A 90:142–153, 2009.

  6. 6.

    Benoit, D. S., A. R. Durney, and K. S. Anseth. Manipulations in hydrogel degradation behavior enhance osteoblast function and mineralized tissue formation. Tissue Eng. 12:1663–1673, 2006.

  7. 7.

    Biswal, D., P. P. Wattamwar, T. D. Dziubla, and J. Z. Hilt. A single-step polymerization method for poly (β-amino ester) biodegradable hydrogels. Polymer 52:5985–5992, 2011.

  8. 8.

    Brandl, F. P., A. K. Seitz, J. K. Teßmar, T. Blunk, and A. M. Göpferich. Enzymatically degradable poly (ethylene glycol) based hydrogels for adipose tissue engineering. Biomaterials 31:3957–3966, 2010.

  9. 9.

    Brey, D. M., I. Erickson, and J. A. Burdick. Influence of macromer molecular weight and chemistry on poly (β-amino ester) network properties and initial cell interactions. J. Biomed. Mater. Res. A 85:731–741, 2008.

  10. 10.

    Browning, M. B., S. Cereceres, P. Luong, and E. Cosgriff-Hernandez. Determination of the in vivo degradation mechanism of PEGDA hydrogels. J. Biomed. Mater. Res. A 102:4244–4251, 2014.

  11. 11.

    Browning, M. B., and E. Cosgriff-Hernandez. Development of a biostable replacement for PEGDA hydrogels. Biomacromolecules 13:779–786, 2012.

  12. 12.

    Browning, M. B., B. Russell, J. Rivera, M. Hook, and E. M. Cosgriff-Hernandez. Bioactive hydrogels with enhanced initial and sustained cell interactions. Biomacromolecules 14:2225–2233, 2013.

  13. 13.

    Browning, M. B., T. Wilems, M. Hahn, and E. Cosgriff-Hernandez. Compositional control of poly (ethylene glycol) hydrogel modulus independent of mesh size. J. Biomed. Mater. Res. A 98:268–273, 2011.

  14. 14.

    Censi, R., W. Schuurman, J. Malda, G. Di Dato, P. E. Burgisser, W. J. Dhert, C. F. Van Nostrum, P. Di Martino, T. Vermonden, and W. E. Hennink. A printable photopolymerizable thermosensitive p (HPMAm-lactate)-PEG hydrogel for tissue engineering. Adv. Funct. Mater. 21:1833–1842, 2011.

  15. 15.

    Cereceres, S., T. Touchet, M. B. Browning, C. Smith, J. Rivera, M. Höök, C. Whitfield-Cargile, B. Russell, and E. Cosgriff-Hernandez. Chronic wound dressings based on collagen-mimetic proteins. Adv. Wound Care 4:444–456, 2015.

  16. 16.

    Chen, J., H. Park, and K. Park. Synthesis of superporous hydrogels: hydrogels with fast swelling and superabsorbent properties. J. Biomed. Mater. Res. 44:53–62, 1999.

  17. 17.

    Chiu, Y.-C., M.-H. Cheng, H. Engel, S.-W. Kao, J. C. Larson, S. Gupta, and E. M. Brey. The role of pore size on vascularization and tissue remodeling in PEG hydrogels. Biomaterials 32:6045–6051, 2011.

  18. 18.

    Cosgriff-Hernandez, E., M. Hahn, B. Russell, T. Wilems, D. Munoz-Pinto, M. Browning, J. Rivera, and M. Höök. Bioactive hydrogels based on designer collagens. Acta Biomater. 6:3969–3977, 2010.

  19. 19.

    DeFail, A. J., C. R. Chu, N. Izzo, and K. G. Marra. Controlled release of bioactive TGF-β1 from microspheres embedded within biodegradable hydrogels. Biomaterials 27:1579–1585, 2006.

  20. 20.

    Franssen, O., O. P. Vos, and W. E. Hennink. Delayed release of a model protein from enzymatically-degrading dextran hydrogels. J. Control. Release 44:237–245, 1997.

  21. 21.

    Hahn, M. S., L. J. Taite, J. J. Moon, M. C. Rowland, K. A. Ruffino, and J. L. West. Photolithographic patterning of polyethylene glycol hydrogels. Biomaterials 27:2519–2524, 2006.

  22. 22.

    Hao, Y., and C. C. Lin. Degradable thiol-acrylate hydrogels as tunable matrices for three-dimensional hepatic culture. J. Biomed. Mater. Res. A 102:3813–3827, 2014.

  23. 23.

    Hoffman, A. S. Hydrogels for biomedical applications. Adv. Drug Deliv. Rev. 64:18–23, 2012.

  24. 24.

    Hubbell, J. A. Bioactive biomaterials. Curr. Opin. Biotechnol. 10:123–129, 1999.

  25. 25.

    Hudalla, G. A., T. S. Eng, and W. L. Murphy. An approach to modulate degradation and mesenchymal stem cell behavior in poly (ethylene glycol) networks. Biomacromolecules 9:842–849, 2008.

  26. 26.

    Jongpaiboonkit, L., W. J. King, G. E. Lyons, A. L. Paguirigan, J. W. Warrick, D. J. Beebe, and W. L. Murphy. An adaptable hydrogel array format for 3-dimensional cell culture and analysis. Biomaterials 29:3346–3356, 2008.

  27. 27.

    Jongpaiboonkit, L., W. J. King, and W. L. Murphy. Screening for 3D environments that support human mesenchymal stem cell viability using hydrogel arrays. Tissue Eng. A 15:343–353, 2008.

  28. 28.

    Kharkar, P. M., K. L. Kiick, and A. M. Kloxin. Designing degradable hydrogels for orthogonal control of cell microenvironments. Chem. Soc. Rev. 42:7335–7372, 2013.

  29. 29.

    King, W. J., L. Jongpaiboonkit, and W. L. Murphy. Influence of FGF2 and PEG hydrogel matrix properties on hMSC viability and spreading. J. Biomed. Mater. Res. A 93:1110–1123, 2010.

  30. 30.

    Lee, K. Y., and D. J. Mooney. Hydrogels for tissue engineering. Chem. Rev. 101:1869–1880, 2001.

  31. 31.

    Li, Q., J. Wang, S. Shahani, D. D. Sun, B. Sharma, J. H. Elisseeff, and K. W. Leong. Biodegradable and photocrosslinkable polyphosphoester hydrogel. Biomaterials 27:1027–1034, 2006.

  32. 32.

    Lutolf, M., J. Lauer-Fields, H. Schmoekel, A. T. Metters, F. Weber, G. Fields, and J. A. Hubbell. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc. Natl. Acad. Sci. U.S.A. 100:5413–5418, 2003.

  33. 33.

    Lynn, A. D., T. R. Kyriakides, and S. J. Bryant. Characterization of the in vitro macrophage response and in vivo host response to poly(ethylene glycol)-based hydrogels. J. Biomed. Mater. Res. A 93:941–953, 2010.

  34. 34.

    Mann, B. K., A. S. Gobin, A. T. Tsai, R. H. Schmedlen, and J. L. West. Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering. Biomaterials 22:3045–3051, 2001.

  35. 35.

    Mawad, D., L. A. Poole-Warren, P. Martens, L. H. Koole, T. L. Slots, and C. S. van Hooy-Corstjens. Synthesis and characterization of radiopaque iodine-containing degradable PVA hydrogels. Biomacromolecules 9:263–268, 2008.

  36. 36.

    Metters, A. T., K. S. Anseth, and C. N. Bowman. Fundamental studies of a novel, biodegradable PEG-b-PLA hydrogel. Polymer 41:3993–4004, 2000.

  37. 37.

    Metters, A. T., and J. Hubbell. Network formation and degradation behavior of hydrogels formed by Michael-type addition reactions. Biomacromolecules 6:290–301, 2005.

  38. 38.

    Nicodemus, G. D., and S. J. Bryant. Cell encapsulation in biodegradable hydrogels for tissue engineering applications. Tissue Eng. B 14:149–165, 2008.

  39. 39.

    Parlato, M., S. Reichert, N. Barney, and W. L. Murphy. Poly(ethylene glycol) hydrogels with adaptable mechanical and degradation properties for use in biomedical applications. Macromol. Biosci. 14:687–698, 2014.

  40. 40.

    Peppas, N. A., P. Bures, W. Leobandung, and H. Ichikawa. Hydrogels in pharmaceutical formulations. Eur. J. Pharm. Biopharm. 50:27–46, 2000.

  41. 41.

    Peppas, N. A., J. Z. Hilt, A. Khademhosseini, and R. Langer. Hydrogels in biology and medicine: from molecular principles to bionanotechnology. Adv. Mater. 18:1345–1360, 2006.

  42. 42.

    Qiu, Y., J. J. Lim, L. Scott, R. C. Adams, H. T. Bui, and J. S. Temenoff. PEG-based hydrogels with tunable degradation characteristics to control delivery of marrow stromal cells for tendon overuse injuries. Acta Biomater. 7:959–966, 2011.

  43. 43.

    Safranski, D. L., D. Weiss, J. B. Clark, B. S. Caspersen, W. R. Taylor, and K. Gall. Effect of poly (ethylene glycol) diacrylate concentration on network properties and in vivo response of poly (β-amino ester) networks. J. Biomed. Mater. Res. A 96:320–329, 2011.

  44. 44.

    Sebra, R. P., K. S. Masters, C. N. Bowman, and K. S. Anseth. Surface grafted antibodies: controlled architecture permits enhanced antigen detection. Langmuir 21:10907–10911, 2005.

  45. 45.

    Slaughter, B. V., S. S. Khurshid, O. Z. Fisher, A. Khademhosseini, and N. A. Peppas. Hydrogels in regenerative medicine. Adv. Mater. 21:3307–3329, 2009.

  46. 46.

    Suggs, L. J., R. S. Krishnan, C. A. Garcia, S. J. Peter, J. M. Anderson, and A. G. Mikos. In vitro and in vivo degradation of poly (propylene fumarate-co-ethylene glycol) hydrogels. J. Biomed. Mater. Res. 42:312–320, 1998.

  47. 47.

    Van de Wetering, P., A. T. Metters, R. G. Schoenmakers, and J. A. Hubbell. Poly(ethylene glycol) hydrogels formed by conjugate addition with controllable swelling, degradation, and release of pharmaceutically active proteins. J. Control. Release 102:619–627, 2005.

  48. 48.

    West, J. L., and J. A. Hubbell. Polymeric biomaterials with degradation sites for proteases involved in cell migration. Macromolecules 32:241–244, 1999.

  49. 49.

    Zaquen, N., B. Wenn, K. Ranieri, J. Vandenbergh, and T. Junkers. Facile design of degradable poly (β-thioester)s with tunable structure and functionality. J. Polym. Sci. A 52:178–187, 2014.

  50. 50.

    Zhu, J. Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. Biomaterials 31:4639–4656, 2010.

  51. 51.

    Zustiak, S. P., and J. B. Leach. Hydrolytically degradable poly (ethylene glycol) hydrogel scaffolds with tunable degradation and mechanical properties. Biomacromolecules 11:1348–1357, 2010.

Download references

Author information

Correspondence to Elizabeth Cosgriff-Hernandez.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Associate Editor Emmanuel Opara oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 617 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cereceres, S., Lan, Z., Bryan, L. et al. In Vivo Characterization of Poly(ethylene glycol) Hydrogels with Thio-β Esters. Ann Biomed Eng 48, 953–967 (2020). https://doi.org/10.1007/s10439-019-02271-8

Download citation


  • Biodegradation
  • Cytocompatibility
  • Resorbable hydrogels
  • Hydrolysis