Differential regulation of angiogenesis using degradable VEGF-binding microspheres.
Differential regulation of angiogenesis using degradable VEGF-binding microspheres.
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DOI：
10.1016/j.biomaterials.2016.03.021
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发表时间：
2016-07
期刊：
影响因子：
14
通讯作者：
Murphy WL
中科院分区：
文献类型：
--
作者：
Belair DG;Miller MJ;Wang S;Darjatmoko SR;Binder BYK;Sheibani N;Murphy WL
在血管生成过程中，必须严格控制血管内皮生长因子 (VEGF) 的空间和时间活性，以在愈合伤口中形成可灌注的脉管系统。天然细胞外基质 (ECM) 通过隔离来局部调节生长因子活性，研究人员使用 ECM 模拟方法来调节细胞培养物和体内 VEGF 的活性。然而，尚未用生物材料详细探讨动态亲和介导的生长因子隔离的影响。在这里，我们试图使用含有 VEGF 结合肽 (VBP) 并表现出不同降解率的聚乙二醇微球随时间动态调节 VEGF 活性。 VBP 微球的降解率赋予了在原代人内皮细胞培养物中上调或下调 VEGF 活性的差异能力。具有快速降解交联的 VBP 微球降低了 VEGF 活性和信号传导，而没有固有降解性的 VBP 微球则在内皮细胞培养物中隔离并促进了 VEGF 活性。具有可降解交联的VBP微球显着减少体内新血管形成，但不可降解VBP微球和可溶性VBP的推注均不减少新血管形成。在体内脉络膜新生血管形成的小鼠模型中，需要将VBP共价掺入可降解微球来减少新生血管形成，这证明了可降解VBP微球在减少病理性血管生成方面的潜在临床应用。本文的结果强调了通过改变PEG水凝胶微球内的交联剂特性来调节隔离生长因子的活性的能力。这里获得的见解可以指导用于再生医学应用的基于亲和力的生长因子隔离生物材料的设计和转化。
Vascular endothelial growth factor (VEGF) spatial and temporal activity must be tightly controlled during angiogenesis to form perfusable vasculature in a healing wound. The native extracellular matrix (ECM) regulates growth factor activity locally via sequestering, and researchers have used ECM-mimicking approaches to regulate the activity of VEGF in cell culture and in vivo. However, the impact of dynamic, affinity-mediated growth factor sequestering has not been explored in detail with biomaterials. Here, we sought to modulate VEGF activity dynamically over time using poly(ethylene glycol) microspheres containing VEGF-binding peptides (VBPs) and exhibiting varying degradation rates. The degradation rate of VBP microspheres conferred a differential ability to up- or down-regulate VEGF activity in culture with primary human endothelial cells. VBP microspheres with fast-degrading crosslinks reduced VEGF activity and signaling, while VBP microspheres with no inherent degradability sequestered and promoted VEGF activity in culture with endothelial cells. VBP microspheres with degradable crosslinks significantly reduced neovascularization in vivo, but neither non-degradable VBP microspheres nor bolus delivery of soluble VBP reduced neovascularization. The covalent incorporation of VBP to degradable microspheres was required to reduce neovascularization in a mouse model of choroidal neovascularization in vivo, which demonstrates a potential clinical application of degradable VBP microspheres to reduce pathological angiogenesis. The results herein highlight the ability to modulate the activity of a sequestered growth factor by changing the crosslinker identity within PEG hydrogel microspheres. The insights gained here may instruct the design and translation of affinity-based growth factor sequestering biomaterials for regenerative medicine applications.