Three-dimensional bioprinting of multicell-laden scaffolds containing bone morphogenic protein-4 for promoting M2 macrophage polarization and accelerating bone defect repair in diabetes mellitus.
Three-dimensional bioprinting of multicell-laden scaffolds containing bone morphogenic protein-4 for promoting M2 macrophage polarization and accelerating bone defect repair in diabetes mellitus.
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含有骨形态发生蛋白4的多细胞支架的三维生物打印促进M2巨噬细胞极化并加速糖尿病骨缺损修复
DOI：
10.1016/j.bioactmat.2020.08.030
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发表时间：
2021-03
影响因子：
18.9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Sun X;Ma Z;Zhao X;Jin W;Zhang C;Ma J;Qiang L;Wang W;Deng Q;Yang H;Zhao J;Liang Q;Zhou X;Li T;Wang J
由于骨缺损区巨噬细胞极化功能障碍和炎症微环境的影响，糖尿病患者的临界骨缺损修复仍然是临床治疗的一个挑战。装载有活细胞和生物活性因子的三维（3D）生物打印支架可以提高细胞活力和炎症微环境，并进一步加速骨修复。在这里，我们使用包含明胶、明胶甲基丙烯酰基（GelMA）和4臂聚（乙二醇）丙烯酸酯（PEG）的改性生物墨水来制造含有BMSC、RAW 264.7巨噬细胞和BMP-4负载的介孔二氧化硅纳米颗粒（MSN）的3D生物打印支架。MSNs的加入有效地提高了GelMA/明胶/PEG支架的机械强度。此外，MSN可持续地释放BMP-4以获得长期有效性。在3D生物打印支架中，BMP-4促进RAW 264.7向M2巨噬细胞的极化，M2巨噬细胞分泌抗炎因子，从而降低促炎因子的水平。从MSN释放的BMP-4和从M2巨噬细胞分泌的BMP-2共同刺激了3D生物打印支架中BMSC的成骨分化。此外，在糖尿病大鼠的颅骨临界尺寸缺损模型中，装载有MSN/BMP-4的3D生物打印支架诱导了M2巨噬细胞极化并改善了炎症微环境。含有MSN/BMP-4、BMSC和RAW 264.7细胞的3D生物打印支架显著加速了骨修复。总之，我们的研究结果表明，在骨缺损中植入含有MSNs/BMP-4、BMSCs和RAW264.7细胞的3D生物打印支架可能是改善糖尿病骨修复的有效方法，这是由于BMP-4直接促进BMSCs的成骨作用和调节M2型巨噬细胞极化以改善炎症微环境并分泌BMP-2。GelMA/明胶/PEG/MSN复合生物油墨显示出令人满意的可印刷性、机械稳定性和生物相容性。从MSN持续释放BMP-4诱导M2巨噬细胞极化，从而抑制炎症反应。M2型巨噬细胞负载BMP-4和分泌BMP-2促进DM骨缺损的修复。
Critical-sized bone defect repair in patients with diabetes mellitus remains a challenge in clinical treatment because of dysfunction of macrophage polarization and the inflammatory microenvironment in the bone defect region. Three-dimensional (3D) bioprinted scaffolds loaded with live cells and bioactive factors can improve cell viability and the inflammatory microenvironment and further accelerating bone repair. Here, we used modified bioinks comprising gelatin, gelatin methacryloyl (GelMA), and 4-arm poly (ethylene glycol) acrylate (PEG) to fabricate 3D bioprinted scaffolds containing BMSCs, RAW264.7 macrophages, and BMP-4-loaded mesoporous silica nanoparticles (MSNs). Addition of MSNs effectively improved the mechanical strength of GelMA/gelatin/PEG scaffolds. Moreover, MSNs sustainably released BMP-4 for long-term effectiveness. In 3D bioprinted scaffolds, BMP-4 promoted the polarization of RAW264.7 to M2 macrophages, which secrete anti-inflammatory factors and thereby reduce the levels of pro-inflammatory factors. BMP-4 released from MSNs and BMP-2 secreted from M2 macrophages collectively stimulated the osteogenic differentiation of BMSCs in the 3D bioprinted scaffolds. Furthermore, in calvarial critical-size defect models of diabetic rats, 3D bioprinted scaffolds loaded with MSNs/BMP-4 induced M2 macrophage polarization and improved the inflammatory microenvironment. And 3D bioprinted scaffolds with MSNs/BMP-4, BMSCs, and RAW264.7 cells significantly accelerated bone repair. In conclusion, our results indicated that implanting 3D bioprinted scaffolds containing MSNs/BMP-4, BMSCs, and RAW264.7 cells in bone defects may be an effective method for improving diabetic bone repair, owing to the direct effects of BMP-4 on promoting osteogenesis of BMSCs and regulating M2 type macrophage polarization to improve the inflammatory microenvironment and secrete BMP-2. The GelMA/gelatin/PEG/MSN composite bioinks showed satisfactory printability, mechanical stability, and biocompatibility. The sustained release of BMP-4 from MSNs induced M2 macrophage polarization and thereby inhibited inflammatory reactions. Loading of BMP-4 and secretion of BMP-2 by M2 type macrophages accelerated bone repair in DM bone defects.
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影响因子：
9.5
作者：
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通讯作者：
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