Functional Biomaterials: Hyaluronic Acid–Based Hydrogel Particles and Doubly Crosslinked Networks

Hyaluronic acid (HA) is a ubiquitous nonsulfated glycosaminoglycan (GAG) in ECM. It is naturally biocompatible and biodegradable. It plays critical roles in cell adhesion, differentiation, motility, morphogenesis and wound healing. We have pioneered techniques for the production of HA–based hydrogel particles (HGPs) of micron to submicron dimensions. HA HGPs with an average diameter of 10 µm (HGP10) and 0.9 µm (HGP0.9) have been successfully synthesized via inverse emulsion polymerization processes employing different crosslinking chemistries, organic solvents and surfactants. The presence of nanoscale pores (average mesh size 6–10 nm) within the HA HGPs makes them ideal candidates as release depots for protein–based, biomacromolecular drugs, such as growth factors. Using straightforward chemical conjugation methods, we have successfully immobilized recombinantly produced, heparan sulfate–bearing perlecan domain I (PlnDI) to HA HGPs (HGP–P1). The immobilized PlnDI not only maintains its ability to bind and sequester human recombinant bone morphogenic protein 2 (rhBMP–2) but also mediates its release. We believe that the PlnDI–conjugated, HA HGPs provide an improved BMP–2 delivery system for stimulating chondrogenic differentiation in vitro, with potential therapeutic application for cartilage repair and regeneration. In vivo assessment of HGP–P1–B2 on cartilage repair is currently underway.

Hydrogels are macroscopic polymer networks that imbibe large amounts of water. Traditional hydrogels are derived from molecularly–dispersed, soluble precursors (monomers and multifunctional crosslinkers or macromers) that are randomly interconnected, lacking the structural complexity, mechanical integrity and functional diversity seen in the natural ECM. In an effort to improve the structural complexity, biological activities and mechanical properties of hydrogels, we have created a novel class of hybrid hydrogels using hydrogel particles as the microscopic crosslinkers. Towards this end, we have synthesized HA–based doubly crosslinked networks (DXN) with densely crosslinked, nanoporous HA hydrogel particles covalently interconnected by a loose secondary network that is also HA–based. The viscoelasticity of the DXNs can be readily tuned by varying the particle size, their surface functional group, intra– and inter–particle crosslinking. The covalent coupling between the particles and the secondary matrix ensures that the external mechanical stress can be readily transmitted to the particles, effectively dissipating energy through particle deformation. Such hierarchically–structured hydrogels permit the controlled release of hydrophilic molecules of both low and high molecular weight with reduced initial bursts and a linear release afterwards over a prolonged period of time. Finally, the HA DXNs provide a 3D microenvironment that not only facilitates the maintenance of the chondrocyte phenotype but also fosters the production of cartilage–specific ECM components.

Collaborators:

  • Mary C. Farach–Carson, Department of Biochemistry and Cell Biology, Rice University

Selected Publications:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.