Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2

Gajadhar Bhakta, Bina Rai, Zophia X.H. Lim, James H. Hui, Gary S. Stein, Andre J. van Wijnen, Victor Nurcombe, Glenn D. Prestwich, Simon M. Cool

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive factor, yet its clinical use is limited by a short biological half-life, rapid local clearance and propensity for side effects. Heparin (HP), a highly sulfated glycosaminoglycan (GAG) that avidly binds BMP-2, has inherent biological properties that may circumvent these limitations. Here, we compared hyaluronan-based hydrogels formulated to include heparin (Heprasil™) with similar gels without heparin (Glycosil™) for their ability to deliver bioactive BMP-2 in vitro and in vivo. The osteogenic activity of BMP-2 released from the hydrogels was evaluated by monitoring alkaline phosphatase (ALP) activity and SMAD 1/5/8 phosphorylation in mesenchymal precursor cells. The osteoinductive ability of these hydrogels was determined in a rat ectopic bone model by 2D radiography, 3D μ-CT and histological analyses at 8 weeks post-implantation. Both hydrogels sustain the release of BMP-2. Importantly, the inclusion of a small amount of heparin (0.3% w/w) attenuated release of BMP-2 and sustained its osteogenic activity for up to 28 days. In contrast, hydrogels lacking heparin released more BMP-2 initially but were unable to maintain BMP-2 activity at later time points. Ectopic bone-forming assays using transplanted hydrogels emphasized the therapeutic importance of the initial burst of BMP-2 rather than its long-term osteogenic activity. Thus, tuning the burst release phase of BMP-2 from hydrogels may be advantageous for optimal bone formation.

Original languageEnglish (US)
Pages (from-to)6113-6122
Number of pages10
JournalBiomaterials
Volume33
Issue number26
DOIs
StatePublished - Sep 2012

Keywords

  • Bone morphogenetic protein-2
  • Burst release
  • Glycosaminoglycan
  • Growth factor
  • Mesenchymal cell
  • Osteogenesis

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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