Functional Biomaterials: Hyaluronic Acid–Based Complex Networks

Rapid and bioorthogonal reactions, when combined with modular building blocks of molecular and microscopic dimensions, enable the construction of synthetic matrices with complex structures and controlled heterogeneity. Using hyaluronic acid (HA) as the starting material, we have created various HA–based bulk gels, hydrogel particles (HGPs) and HGP–integrated doubly crosslinked networks. Successful installation of orthogonal functional groups to HA has led to the development of various in situ crosslinkable HA bulk gels. The same crosslinking reactions, when restricted to microscopic compartments, have allowed for the production of HA HGPs via an inverse emulsion process. When the crosslinking kinetics exceeds the molecular diffusion, HA HGPs with spatially tagged chemical cues can be readily prepared via an interfacial crosslinking process through an instantaneous reaction at the gel/liquid interface. Physical entrapment or covalent integration of HA HGPs in a secondary HA network give rise to hybrid networks that are hierarchically structured and mechanically robust, capable of mediating cellular activities through the spatial and temporal presentation of biological cues. These HA–based hydrogels are conducive matrices for the engineering of soft connective tissues, as well as the creation of prostate cancer tumor models.


  • Mary C. Farach–Carson, Department of Biochemistry and Cell Biology, Rice University
  • Joseph M. Fox, Department of Chemistry and Biochemistry, University of Delaware

Selected Publications:

  1. Zhang, H.; Dicker, K. T.; Xu, X.; Jia, X.*; Fox, J. M.* "Interfacial Bioorthogonal Crosslinking", ACS Macro Lett, 2014, 3, 727–731.
  2. Jha, A. K.; Xu, X.; Duncan, R. L.; Jia, X.* "Controlling the Adhesion and Differentiation of Mesenchymal Stem Cells Using Hyaluronic Acid–based, Doubly Crosslinked Networks", Biomaterials, 2011, 32, 2466–2478.
  3. Jha, A. K.; Malik, M. S.; Farach–Carson, M. C.; Duncan, R. L.; Jia, X.* "Hierarchically Structured, Hyaluronic Acid–Based Hydrogel Matrices via the Covalent Integration of Microgels into Macroscopic Networks", Soft Matter, 2010, 6, 5045–5055.
  4. Jha, A. K.; Yang, W.; Kirn–Safarn, C. B.; Farach–Carson, M. C.; Jia, X.* "Perlecan Domain I–Conjugated, Hyaluronic Acid–Based Hydrogel Particles for Enhanced Chondrogenic Differentiation via BMP–2 Release" Biomaterials, 2009, 30, 6964–6974.
  5. Jha, A. K.; Hule, R. A.; Jiao, T.; Teller, S. S.; Clifton, R. J.; Duncan, R. L.; Pochan, D. J.; Jia, X.* "Structural Analysis and Mechanical Characterization of Hyaluronic Acid–Based Doubly Crosslinked Networks" Macromolecules, 2009, 42, 537–546.
  6. Sahiner, N.; Jha, A. K.; Nguyen, D.; Jia, X.* "Fabrication and Characterization of Crosslinkable Hydrogel Particles Based on Hyaluronic Acid: Potential Application in Vocal Fold Regeneration" J. Biomat. Sci.–Polym. E., 2008, 19, 223–243.
  7. Jia, X.*; Yeo, Y.; Clifton, R. J.; Jiao, T.; Kohane, D. S.; Kobler, J.; Zeitels, S. M.; Langer, R. "Hyaluronic Acid–Based Microgels and Microgel Networks for Vocal Fold Regeneration" Biomacromolecules, 2006, 7, 3336-3344.