Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2.
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.
Institute of Medical Biology, A*STAR, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore.
Gajadhar
G
Bhakta
Bina
B
Rai
Zophia X H
ZX
Lim
James H
JH
Hui
Gary S
GS
Stein
Andre J
AJ
van Wijnen
Victor
V
Nurcombe
Glenn D
GD
Prestwich
Simon M
SM
Cool
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry*; D005260:Female; D006493:Heparin / Q000737:chemistry*; D006820:Hyaluronic Acid / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry*; D010012:Osteogenesis / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023822:Tissue Engineering / Q000379:methods
D055396:Bone Morphogenetic Protein 2; D020100:Hydrogels; D006820:Hyaluronic Acid; D006493:Heparin