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Tuning the Bioactivity of Bone Morphogenetic Protein-2 with Surface Immobilization Strategies
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2018-09-13 , DOI: 10.1016/j.actbio.2018.09.011
Rui Chen , Yuanman Yu , Wenjing Zhang , Yuanzhong Pan , Jing Wang , Yin Xiao , Changsheng Liu

Bone morphogenetic protein-2 (BMP-2) involved therapy is of great potential for bone regeneration. However, its clinical application is restricted due to the undesirable bioactivity and relevant complications in vivo. Immobilization of recombinant BMP-2 (rhBMP-2) is an efficient strategy to mimic natural microenvironment and retain its bioactivity. Herein, we present evidences indicating that osteoinductive capacity of rhBMP-2 can be regulated via variant immobilizing approaches. Three representative superficial immobilizing models were employed to fabricate rhBMP-2-immobilized surfaces including physical adsorption (Au/rhBMP-2), covalent grafting (rhBMP-2-SAM-Au) and heparin binding (Hep-SAM-Au/rhBMP-2) (SAM: self-assembled monolayer). Loading capacity, releasing behavior, osteogenic differentiation and signaling pathways involved, as well as the cellular recognition of rhBMP-2 under various immobilization modes were systematically investigated. As a result, disparate immobilizing approaches not only have effects on loading capacity, but also lead to disparity of osteoinduction at the same dosage. Notably, heparin could reinforce the recognition between rhBMP-2 and its receptors (BMPRs) whereas weaken its binding to its antagonist Noggin. Owing to this “selective” binding feature, the favorable osteoinduction and maximum ectopic bone formation can be achieved with the heparin-binding approach. In particular, manipulation of orientation-mediated BMP-2-cell recognition efficiency may be a potential target to design more therapeutic efficient rhBMP-2 delivery system.

Statement of significance

Bone morphogenetic protein-2 (BMP-2) is crucial in bone regeneration. However, its clinical application is challenged due to its shorten half-life and supra-physiological dose associated complications. In this study, three representative superficial immobilizing patterns were fabricated through physical adsorption, covalent grafting and electrostatic interaction with heparin respectively. We provided evidences indicating an dose-dependent osteoinductive capacity of immobilized BMP-2. Further, a possible mechanism of rhBMP-2-cell recognition at the interface was presented, highlighting the superior effect of heparin on rhBMP-2 bioactivity. Finally, We proposed a dual mechanism of tuning the bioactivity of immobilized rhBMP-2 through surface immobilization approaches: regulation of the saturated loading capacity and orientation-mediated rhBMP-2-cell recognition. These results provide novel insights into designing criterion of efficient delivery vehicle for rhBMP-2.



中文翻译:

通过表面固定策略调节骨形态发生蛋白2的生物活性

涉及骨形态发生蛋白2(BMP-2)的治疗具有巨大的骨再生潜力。然而,由于不良的生物活性和体内相关的并发症,其临床应用受到限制。重组BMP-2(rhBMP-2)的固定化是模仿天然微环境并保留其生物活性的有效策略。在这里,我们提供的证据表明,可以通过变体固定方法来调节rhBMP-2的骨诱导能力。使用三种代表性的表面固定模型来制备rhBMP-2固定的表面,包括物理吸附(Au / rhBMP-2),共价接枝(rhBMP-2-SAM-Au)和肝素结合(Hep-SAM-Au / rhBMP-2) )(SAM:自组装单层)。系统地研究了负载能力,释放行为,成骨分化和信号通路,以及在各种固定模式下对rhBMP-2的细胞识别。结果,不同的固定方法不仅会对负载能力产生影响,但也会导致相同剂量的骨诱导差异。值得注意的是,肝素可以增强rhBMP-2及其受体(BMPR)之间的识别,而削弱其与其拮抗剂Noggin的结合。由于这种“选择性”结合特征,可以通过肝素结合方法实现良好的骨诱导和最大的异位骨形成。特别地,定向介导的BMP-2-细胞识别效率的操纵可能是设计更具治疗效率的rhBMP-2递送系统的潜在目标。肝素结合方法可以实现良好的骨诱导作用和最大的异位骨形成。特别地,定向介导的BMP-2-细胞识别效率的操纵可能是设计更具治疗效率的rhBMP-2递送系统的潜在目标。肝素结合方法可以实现良好的骨诱导作用和最大的异位骨形成。特别地,定向介导的BMP-2-细胞识别效率的操纵可能是设计更具治疗效率的rhBMP-2递送系统的潜在目标。

重要声明

骨形态发生蛋白2(BMP-2)在骨骼再生中至关重要。然而,由于其半衰期短和超生理剂量相关的并发症,其临床应用受到了挑战。在这项研究中,分别通过物理吸附,共价接枝和与肝素的静电相互作用制备了三种具有代表性的表面固定模式。我们提供的证据表明固定的BMP-2具有剂量依赖性的骨诱导能力。此外,提出了在界面处rhBMP-2-细胞识别的可能机制,突出了肝素对rhBMP-2生物活性的优异作用。最后,我们提出了一种通过表面固定方法调节固定化rhBMP-2生物活性的双重机制:饱和负荷能力的调节和定向介导的rhBMP-2-细胞识别。这些结果为rhBMP-2高效传递载体的设计标准提供了新颖的见解。

更新日期:2018-09-13
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