Kang Fei, Yi Qiying, Gu Pengcheng, Dong Yuhan, Zhang Ziyang, Zhang Lijuan, Bai Yan
Department of Biomedical Materials Science, Third Military Medical University, Chongqing, 400038, China.
School of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
J Orthop Translat. 2021 Dec 11;31:110-125. doi: 10.1016/j.jot.2021.11.004. eCollection 2021 Nov.
Bone regeneration involves a coordinated cascade of events that are regulated by several cytokines and growth factors, among which bone morphogenic protein-2 (BMP-2), vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) play important roles. In this study, we investigated the effects of dual release of the three growth factors on bone regeneration in femur defects.
A composite consisting of Gelatin microparticles loaded with VEGF/FGF-2 and poly(lactic-co-glycolic acid)-poly(ethylene glycol)-carboxyl (PLGA-PEG-COOH) microparticles loaded with BMP-2 encapsulated in a nano hydroxyapatite-poly actic-co-glycolic acid (nHA-PLGA) scaffold was prepared for the dual release of the growth factors.
On the 14th day, decreased release rate of BMP-2 compared with FGF-2 and VEGF was observed. However, after 14 days, compared to FGF-2 and VEGF, BMP-2 showed an increased release rate. Controlled dual release of BMP-2 and VEGF, FGF-2 resulted in a significant osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Moreover, effects of the composite scaffold on functional connection of osteoblast-vascular cells during bone development were evaluated. The synergistic effects of dual delivery of growth factors were shown to promote the expression of VEGF in BMSCs. Increased secretion of VEGF from BMSCs promoted the proliferation and angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) in the co-culture system. At 12 weeks after implantation, blood vessel and bone formation were analyzed by micro-CT and histology. The composite scaffold significantly promoted the formation of blood vessels and new bone in femur defects.
These findings demonstrate that dual delivery of angiogenic factors and osteogenic factors from Gelatin and PLGA-PEG-COOH microparticles-based composite scaffolds exerted an osteogenic-angiogenic coupling effect on bone regeneration. This approach will inform on the development of appropriate designs of high-performance bioscaffolds for bone tissue engineering.
骨再生涉及一系列由多种细胞因子和生长因子调控的协同事件，其中骨形态发生蛋白-2（BMP-2）、血管内皮生长因子（VEGF）和成纤维细胞生长因子-2（FGF-2）发挥着重要作用。在本研究中，我们调查了三种生长因子的双重释放对股骨缺损处骨再生的影响。
制备了一种复合材料，该材料由负载VEGF/FGF-2的明胶微粒和负载BMP-2的聚乳酸-乙醇酸共聚物-聚乙二醇-羧基（PLGA-PEG-COOH）微粒组成，并包裹在纳米羟基磷灰石-聚乳酸-乙醇酸共聚物（nHA-PLGA）支架中，用于生长因子的双重释放。
在第14天，观察到BMP-2的释放速率低于FGF-2和VEGF。然而，14天后，与FGF-2和VEGF相比，BMP-2的释放速率有所增加。BMP-2与VEGF、FGF-2的可控双重释放导致骨间充质干细胞（BMSC）发生显著的成骨分化。此外，评估了复合支架在骨发育过程中对成骨细胞-血管细胞功能连接的影响。生长因子双重递送的协同作用显示可促进BMSC中VEGF的表达。BMSC中VEGF分泌增加促进了共培养系统中人类脐静脉内皮细胞（HUVEC）的增殖和血管生成分化。植入后12周，通过显微CT和组织学分析血管和骨形成情况。复合支架显著促进了股骨缺损处的血管和新骨形成。
这些发现表明，基于明胶和PLGA-PEG-COOH微粒的复合支架中血管生成因子和成骨因子的双重递送对骨再生产生了成骨-血管生成耦合效应。这种方法将为骨组织工程高性能生物支架的适当设计开发提供信息。
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