Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2
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- 作者：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
- 关键词：Bone morphogenetic protein-2 ; Growth factor ; Burst release ; Glycosaminoglycan ; Mesenchymal cell ; Osteogenesis
- 刊名：Biomaterials
- 出版年：2012
- 出版时间：September, 2012
- 年：2012
- 卷：33
- 期：26
- 页码：6113-6122
- 全文大小：1254 K
文摘
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 ¦Ì-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.