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

117 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Hyaluronic acid
Bone Morphogenetic Protein 2
Hydrogels
Hyaluronic Acid
Heparin
Bone
Proteins
A73025
Bone and Bones
Phosphorylation
Radiography
Osteogenesis
Alkaline Phosphatase
Half-Life
Rats
Phosphatases
Assays
Tuning
Gels

Keywords

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

ASJC Scopus subject areas

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

Cite this

Bhakta, G., Rai, B., Lim, Z. X. H., Hui, J. H., Stein, G. S., van Wijnen, A. J., ... Cool, S. M. (2012). Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2. Biomaterials, 33(26), 6113-6122. https://doi.org/10.1016/j.biomaterials.2012.05.030

Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2. / Bhakta, Gajadhar; Rai, Bina; Lim, Zophia X H; Hui, James H.; Stein, Gary S.; van Wijnen, Andre J; Nurcombe, Victor; Prestwich, Glenn D.; Cool, Simon M.

In: Biomaterials, Vol. 33, No. 26, 09.2012, p. 6113-6122.

Research output: Contribution to journalArticle

Bhakta, G, Rai, B, Lim, ZXH, Hui, JH, Stein, GS, van Wijnen, AJ, Nurcombe, V, Prestwich, GD & Cool, SM 2012, 'Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2', Biomaterials, vol. 33, no. 26, pp. 6113-6122. https://doi.org/10.1016/j.biomaterials.2012.05.030
Bhakta, Gajadhar ; Rai, Bina ; Lim, Zophia X H ; Hui, James H. ; Stein, Gary S. ; van Wijnen, Andre J ; Nurcombe, Victor ; Prestwich, Glenn D. ; Cool, Simon M. / Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2. In: Biomaterials. 2012 ; Vol. 33, No. 26. pp. 6113-6122.
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