Research progress on hydroxyapatite/graphene oxide composite scaffolds in the treatment of bone defect repair
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摘要: 骨缺损引起的骨疾病是现代医学非常棘手的一种疾病，正常的骨组织发生病变或外部因素的物理损伤都会形成难愈合的骨缺损；骨缺损部位复杂的微环境决定其治疗条件也更苛刻。构建可以用于骨缺损的支架是骨组织工程技术的一个重要方向，也是解决骨缺损疾病难题的重要手段。本文简单介绍了羟基磷灰石/氧化石墨烯(HA/GO)复合材料的制备原理和方法，细胞实验表明HA/GO对骨细胞没有明显的毒性，粗糙的表面结构更有利于骨细胞的增殖分化，在此基础上详细介绍了用于治疗骨缺损疾病HA/GO复合支架的构建方式及其性能。最后讨论了HA/GO复合支架在骨疾病治疗中的发展前景和面临的挑战。Abstract: Bone defects caused by bone diseases are a very challenging issue in modern medicine. Both pathological changes in normal bone tissue and physical damage caused by external factors can lead to difficult-to-heal bone defects. The complex microenvironment of the bone defect site makes treatment conditions more demanding. Constructing scaffolds for bone defects is an important direction in bone tissue engineering technology and a crucial means to solve the problem of bone defect diseases. This article briefly introduces the preparation principles and methods of hydroxyapatite/graphene oxide (HA/GO) composite materials. HA/GO has no apparent toxicity to bone cells, and its rough surface structure is more conducive to the proliferation and differentiation of bone cells. Based on this, the construction methods and performance of HA/GO composite scaffolds for treating bone defect diseases are described in detail. Finally, the development prospects and challenges of HA/GO composite scaffolds in the treatment of bone diseases are discussed.
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Key words:
- graphene oxide /
- hydroxyapatite /
- bone diseases /
- composite brackets /
- tissue engineering
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图 4 具有不同孔径大小的3D打印支架[30-32]：(a) 3D打印磷酸三钙(TCP)支架；(b) 1250℃烧结支架的抗压强度比较；(c) 细胞在支架表面和3D互连大孔内的黏附和增殖；(d) 纯TCP支架的SEM图像；(e) 植入物的显微照片；(f) 类骨面积分数的组织形态计量学分析
Figure 4. 3D printed brackets with different aperture sizes[30-32]: (a) 3D printing tricalcium phosphate (TCP) scaffolds; (b) Comparison of compressive strength of 1250℃ sintered scaffolds; (c) Adhesion and proliferation of cells on the surface of scaffolds and within 3D interconnected macropores; (d) SEM image of pure TCP scaffolds; (e) Microscopic photos of implants; (f) Histomorphometric analysis of osteoid area fraction
图 2 不同构建方式HA/GO复合支架形貌：(a) 壳聚糖基复合支架[21]；(b) 明胶基复合支架[22]；(c) 纳米纤维基复合支架[29]；(d) 自组装法制备的HA/GO复合支架[35]
Figure 2. HA/GO composite scaffold morphology with different construction methods: (a) Chitosan based composite scaffold[21]; (b) Gelatin based composite scaffold[22]; (c) Nanofiber based composite scaffold[29]; (d) HA/GO composite scaffold prepared by self-assembly method[35]
GHA—Gelatin-HA scaffold; GOGHA0.5—GHA scaffold with 0.5wt%GO; nHA—Nano-hydroxyapatite; rGO—Reduced graphene oxide
图 6 HA/GO复合支架的力学性能：(a) 不同聚己内酯(PCL)含量的HA/GO应力-应变行为[5]；(b) 不同含量HA/GO纳米压痕测试[18]；(c) 不同海藻酸钠(SA)含量的应力-应变曲线[39]
Figure 6. Mechanical properties of HA/GO composite scaffolds: (a) Stress-strain behavior of HA/GO with different poly(ε-caprolactone) (PCL) contents[5]; (b) HA/GO nanoindentation testing with different contents[18]; (c) Stress-strain curves of different sodium alginate (SA) contents[39]
HAP—Hydroxyapatite; Gs—Graphene nanosheets; SHA—Spherical porous hydroxyapatite; M—Elastic modulus; H—Hardness; σe1*—Elastic collapse stress; E*—Calculate the linear elastic modulus; Δσ/Δε—Collapse plateau modulus; εe1*—Elastic collapse strain
图 7 HA/GO复合支架的细胞毒性[2, 4, 18, 33, 40]：(a) 小鼠胚胎成骨细胞前体细胞 (MC3T3-E1)在不同材料上的噻唑蓝检测 (MTT)检测结果；(b) Saos-2成骨样细胞在不同材料上的细胞增殖率；(c) 人骨髓间充斥干细胞 (hMSCs)在不同材料上的细胞活性；(d) 人骨肉瘤细胞(MG-63)在不同材料上的增殖情况；(e) hMSCs细胞代谢情况；(f) 不同HA含量的复合材料形貌；(g) MC3T3-E1细胞形态；(h) MC3T3-E1细胞的增殖情况；(i) 培养不同天数MC3T3-E1细胞细胞增值状况
Figure 7. Cytotoxicity of HA/GO composite scaffolds[2, 4, 18, 33, 40]: (a) 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) monitoring results of mouse osteoblast (MC3T3-E1) cells on different materials; (b) Cell proliferation rate of Saos-2 osteoblast like cells on different materials; (c) Cellular activity of human mesenchymal stem cells (hMSCs) cells on different materials; (d) The proliferation of Human osteosarcoma cells (MG-63) cells on different materials; (e) Metabolism of hMSCs cells; (f) Morphology of composite materials with different HA contents; (g) MC3T3-E1 cell morphology; (h) The proliferation of MC3T3-E1 cells; (i) Cell proliferation status of MC3T3-E1 cells cultured for different days
OD—Optical density; CTR—Control group; SBF—Simulated body fluid; FGO—Functional GO; FGHA—Functional GO/HA; RHA—Rod HA; SHA—Spherical HA
图 8 HA/GO复合支架的细胞增殖附着实验：(a)大鼠骨髓间充质干细胞(rBMSCs)活细胞密度[33]；(b) MC3T3-E1细胞增值情况[29]；(c) 人骨肉瘤细胞(MG-63)细胞增值情况[39]；(d) MC3T3-E1细胞增值情况[50]
Figure 8. Cell proliferation and attachment assay for HA/GO composite scaffolds: (a) Rat bone mesenchymal stem cells (rBMSCs) live cell density[33]; (b) MC3T3-E1 cell proliferation status[29]; (c) Human osteosarcoma cells (MG-63) proliferation status[39]; (d) MC3T3-E1 cell proliferation status[50]
p—Significance level; PLA—Polylactic acid
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