Annals of Biomedical Engineering

, Volume 43, Issue 10, pp 2569–2576 | Cite as

Enabling Surgical Placement of Hydrogels Through Achieving Paste-Like Rheological Behavior in Hydrogel Precursor Solutions

  • Emily C. Beck
  • Brooke L. Lohman
  • Daniel B. Tabakh
  • Sarah L. Kieweg
  • Stevin H. Gehrke
  • Cory J. Berkland
  • Michael S. DetamoreEmail author


Hydrogels are a promising class of materials for tissue regeneration, but they lack the ability to be molded into a defect site by a surgeon because hydrogel precursors are liquid solutions that are prone to leaking during placement. Therefore, although the main focus of hydrogel technology and developments are on hydrogels in their crosslinked form, our primary focus is on improving the fluid behavior of hydrogel precursor solutions. In this work, we introduce a method to achieve paste-like hydrogel precursor solutions by combining hyaluronic acid nanoparticles with traditional crosslinked hyaluronic acid hydrogels. Prior to crosslinking, the samples underwent rheological testing to assess yield stress and recovery using linear hyaluronic acid as a control. The experimental groups containing nanoparticles were the only solutions that exhibited a yield stress, demonstrating that the nanoparticulate rather than the linear form of hyaluronic acid was necessary to achieve paste-like behavior. The gels were also photocrosslinked and further characterized as solids, where it was demonstrated that the inclusion of nanoparticles did not adversely affect the compressive modulus and that encapsulated bone marrow-derived mesenchymal stem cells remained viable. Overall, this nanoparticle-based approach provides a platform hydrogel system that exhibits a yield stress prior to crosslinking, and can then be crosslinked into a hydrogel that is capable of encapsulating cells that remain viable. This behavior may hold significant impact for hydrogel applications where a paste-like behavior is desired in the hydrogel precursor solution.


Colloidal gel Yield stress Hyaluronic acid Nanoparticles 



We acknowledge funding support from the NIH (R01 DE022472 to C.J.B, S10 RR024664) and the NSF for a Graduate Research Fellowship (E.B.), a Major Research Instrumentation Grant (0320648), and an NSF CAREER Award (DMR 0847759) (M.D.). We also gratefully acknowledge the Tertiary Oil Recovery Program for the use of equipment, the Microscopy Laboratory for assistance with imaging, and the KU NMR lab for their assistance.


  1. 1.
    Beck E., C. Berkland, S. Gehrke, and M. Detamore. Novel hyaluronic acid nanocomposite hydrogel for cartilage tissue engineering: utilizing yield stress for ease of implantation. In: ASME 2013 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2013.Google Scholar
  2. 2.
    Brigham, M., A. Bick, E. Lo, A. Bendali, J. Burdick, and A. Khademhosseini. Mechanically robust and bioadhesive collagen and photocrosslinkable hyaluronic acid semi-interpenetrating networks. Tissue Eng. Part A 15:1645–1653, 2009.CrossRefPubMedGoogle Scholar
  3. 3.
    DeKosky, B., N. Dormer, G. Ingavle, C. Roatch, J. Lomakin, M. Detamore, and S. Gehrke. Hierarchically designed agarose and poly(ethylene glycol) interpenetrating network hydrogels for cartilage tissue engineering. Tissue Eng. Part C Methods 16:1533–1542, 2010.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Dennis, S., M. Detamore, S. Kieweg, and C. Berkland. Mapping glycosaminoglycan-hydroxyapatite colloidal gels as potential tissue defect fillers. Langmuir 30(12):3528–3537, 2014.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Elder, A., N. Dangelo, S. Kim, and N. Washburn. Conjugation of β-sheet peptides to modify the rheological properties of hyaluronic acid. Biomacromolecules 12:2610–2616, 2011.CrossRefPubMedGoogle Scholar
  6. 6.
    Elisseeff, J., C. Puleo, F. Yang, and B. Sharma. Advances in skeletal tissue engineering with hydrogels. Orthod. Craniofac. Res. 8:150–161, 2005.CrossRefPubMedGoogle Scholar
  7. 7.
    Fakhari, A., Q. Phan, and C. Berkland. Hyaluronic acid colloidal gels as self-assembling elastic biomaterials. J. Biomed. Mater. Res. B Appl. Biomater. 102:612–618, 2014.Google Scholar
  8. 8.
    Fakhari, A., Q. Phan, S. Thakkar, C. Middaugh, and C. Berkland. Hyaluronic acid nanoparticles titrate the viscoelastic properties of viscosupplements. Langmuir 29:5123–5131, 2013.CrossRefPubMedGoogle Scholar
  9. 9.
    Jha, A., R. Hule, T. Jiao, S. Teller, R. Clifton, R. Duncan, D. Pochan, and X. Jia. Structural analysis and mechanical characterization of hyaluronic acid-based doubly cross-linked networks. Macromolecules 42:537–546, 2009.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Jha, A., M. Malik, M. Farach-Carson, R. Duncan, and X. Jia. Hierarchically structured, hyaluronic acid-based hydrogel matrices via the covalent integration of microgels into macroscopic networks. Soft Matter 6:5045–5055, 2010.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Jha, A., X. Xu, R. Duncan, and X. Jia. Controlling the adhesion and differentiation of mesenchymal stem cells using hyaluronic acid-based, doubly crosslinked networks. Biomaterials 32:2466–2478, 2011.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Jia, X., and K. Kiick. Hybrid multicomponent hydrogels for tissue engineering. Macromol. Biosci. 9:140–156, 2009.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Jia, X., Y. Yeo, R. Clifton, T. Jiao, D. Kohane, J. Kobler, S. Zeitels, and R. Langer. Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration. Biomacromolecules 7:3336–3344, 2006.CrossRefPubMedGoogle Scholar
  14. 14.
    Khanlari, A., M. S. Detamore, and S. H. Gehrke. Increasing cross-linking efficiency of methacrylated chondroitin sulfate hydrogels by copolymerization with oligo (ethylene glycol) diacrylates. Macromolecules 46:9609–9617, 2013.CrossRefGoogle Scholar
  15. 15.
    Lu, H., M. Charati, I. Kim, and J. Burdick. Injectable shear-thinning hydrogels engineered with a self-assembling Dock-and-Lock mechanism. Biomaterials 33:2145–2153, 2012.CrossRefPubMedGoogle Scholar
  16. 16.
    Murat, G., D. L. Hoang, and A. B. Jason. Shear-thinning hydrogels for biomedical applications. Soft Matter 8:260–272, 2012.CrossRefGoogle Scholar
  17. 17.
    Nettles, D. L., T. P. Vail, M. T. Morgan, M. W. Grinstaff, and L. A. Setton. Photocrosslinkable hyaluronan as a scaffold for articular cartilage repair. Ann. Biomed. Eng. 32:391–397, 2004.CrossRefPubMedGoogle Scholar
  18. 18.
    Prata, J., T. Barth, S. Bencherif, and N. Washburn. Complex fluids based on methacrylated hyaluronic acid. Biomacromolecules 11:769–775, 2010.CrossRefPubMedGoogle Scholar
  19. 19.
    Rughani, R. V., M. C. Branco, D. J. Pochan, and J. P. Schneider. De novo design of a shear-thin recoverable peptide-based hydrogel capable of intrafibrillar photopolymerization. Macromolecules 43:7924–7930, 2010.CrossRefGoogle Scholar
  20. 20.
    Sahiner, N., A. Jha, D. Nguyen, and X. Jia. Fabrication and characterization of cross-linkable hydrogel particles based on hyaluronic acid: potential application in vocal fold regeneration. J. Biomater. Sci. Polym. Ed. 19:223–243, 2008.CrossRefPubMedGoogle Scholar
  21. 21.
    Tezel, A., and G. H. Fredrickson. The science of hyaluronic acid dermal fillers. J. Cosmet. Laser Ther. 10:35–42, 2008.CrossRefPubMedGoogle Scholar
  22. 22.
    Todd, R. H., and S. K. Daniel. Hydrogels in drug delivery: progress and challenges. Polymer 49:1993–2007, 2008.CrossRefGoogle Scholar
  23. 23.
    Wang, Q., Z. Gu, S. Jamal, M. S. Detamore, and C. Berkland. Hybrid hydroxyapatite nanoparticle colloidal gels are injectable fillers for bone tissue engineering. Tissue Eng. Part A 19:2586–2593, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang, Q., S. Jamal, M. Detamore, and C. Berkland. PLGA-chitosan/PLGA-alginate nanoparticle blends as biodegradable colloidal gels for seeding human umbilical cord mesenchymal stem cells. J. Biomed. Mater. Res. Part A 96:520–527, 2011.CrossRefGoogle Scholar
  25. 25.
    Wang, Q., L. Wang, M. S. Detamore, and C. Berkland. Biodegradable colloidal gels as moldable tissue engineering scaffolds. Adv. Mater. 20:236–239, 2008.CrossRefGoogle Scholar
  26. 26.
    Wang, Q., J. Wang, Q. Lu, M. Detamore, and C. Berkland. Injectable PLGA based colloidal gels for zero-order dexamethasone release in cranial defects. Biomaterials 31:4980–4986, 2010.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Biomedical Engineering Society 2015

Authors and Affiliations

  • Emily C. Beck
    • 1
  • Brooke L. Lohman
    • 2
  • Daniel B. Tabakh
    • 2
  • Sarah L. Kieweg
    • 1
    • 3
  • Stevin H. Gehrke
    • 1
    • 2
  • Cory J. Berkland
    • 1
    • 2
    • 4
  • Michael S. Detamore
    • 1
    • 2
    Email author
  1. 1.Bioengineering ProgramUniversity of KansasLawrenceUSA
  2. 2.Department of Chemical and Petroleum EngineeringUniversity of KansasLawrenceUSA
  3. 3.Department of Mechanical EngineeringUniversity of KansasLawrenceUSA
  4. 4.Department of Pharmaceutical ChemistryUniversity of KansasLawrenceUSA

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