Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2.
Hyaluronic acid-based hydrogels functionalized with heparin that support controlled release of bioactive BMP-2.
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DOI：
10.1016/j.biomaterials.2012.05.030
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发表时间：
2012-09
期刊：
影响因子：
14
通讯作者：
Cool, Simon M.
中科院分区：
文献类型：
--
作者：
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.
关键词：
骨形态发生蛋白-2（BMP-2）是一种有效的骨诱导因子，但其生物半衰期短、局部清除快和易产生副作用等限制了其临床应用。肝素（HP）是一种高度硫酸化的糖胺聚糖（GAG），可与BMP-2结合，具有固有的生物学特性，可以规避这些限制。在这里，我们比较了配制成包含肝素的基于透明质酸的水凝胶（Heprasil™）与不含肝素的类似凝胶（Glycosil™）在体外和体内递送生物活性BMP-2的能力。通过监测间充质前体细胞中的碱性磷酸酶（ALP）活性和SMAD 1/5/8磷酸化来评价从水凝胶释放的BMP-2的成骨活性。在植入后8周，通过2D射线照相术、3D µ-CT和组织学分析，在大鼠异位骨模型中测定这些水凝胶的骨诱导能力。两种水凝胶都能维持BMP-2的释放。重要的是，包含少量肝素（0.3%w/w）会减弱BMP-2的释放并维持其成骨活性长达28天。相比之下，缺乏肝素的水凝胶最初释放更多的BMP-2，但在随后的时间点不能维持BMP-2活性。使用移植水凝胶的异位骨形成试验强调BMP-2的初始爆发而不是其长期成骨活性的治疗重要性。因此，调整BMP-2从水凝胶的突释阶段可能有利于最佳骨形成。
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.
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影响因子：
10.8
作者：
Martinez-Sanz, Elena;Ossipov, Dmitri A.;Varghese, Oommen P.
通讯作者：
Varghese, Oommen P.
影响因子：
4.1
作者：
Brown, Kate V.;Li, Bing;Wenke, Joseph C.
通讯作者：
Wenke, Joseph C.
DOI：
10.1002/jbm.10011
发表时间：
2002-03-05
期刊：
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH
影响因子：
--
作者：
Kim, HD;Valentini, RF
通讯作者：
Valentini, RF
影响因子：
4
作者：
Chang, Eun-Ju;Kim, Hyon Jong;Kim, Hong-Hee
通讯作者：
Kim, Hong-Hee
影响因子：
14
作者：
Cai, SS;Liu, YC;Prestwich, GD
通讯作者：
Prestwich, GD