Preparation and bone repair capability of a new plastic bone filler material_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LI Jing , REN Xiaoqi , QIAO Wei , SHI Hao , YANG Ting , MA Shaoying , LI Baoxing ,  ZHAO Yaping

Biomaterial R&D Center of China Institute for Radiation Protection, Shanxi Osteorad Biomaterial Co., Ltd, Taiyuan Shanxi, 030006, P. R. China;

Corresponding author：

ZHAO Yaping, Email: zypsir@qq.com

Keywords：

Plastic bone filler material; demineralized bone matrix; bone matrix gelatin; osteoinduction

DOI：

10.7507/1002-1892.202210022

Video：

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Objective To prepare a new plastic bone filler material with adhesive carrier and matrix particles derived from human bone, and evaluate its safety and osteoinductive ability through animal tests. Methods The human long bones donated voluntarily were prepared into decalcified bone matrix (DBM) by crushing, cleaning, and demineralization, and then the DBM was prepared into bone matrix gelatin (BMG) by warm bath method, and the BMG and DBM were mixed to prepare the experimental group’s plastic bone filler material; DBM was used as control group. Fifteen healthy male thymus-free nude mice aged 6-9 weeks were used to prepare intermuscular space between gluteus medius and gluteus maximus muscles, and all of them were implanted with experimental group materials. The animals were sacrificed at 1, 4, and 6 weeks after operation, and the ectopic osteogenic effect was evaluated by HE staining. Eight 9-month-old Japanese large-ear rabbits were selected to prepare 6-mm-diameter defects at the condyles of both hind legs, and the left and right sides were filled with the materials of the experimental group and the control group respectively. The animals were sacrificed at 12 and 26 weeks after operation, and the effect of bone defect repair were evaluated by Micro-CT and HE staining. Results In ectopic osteogenesis experiment, HE staining showed that a large number of chondrocytes could be observed at 1 week after operation, and obvious newly formed cartilage tissue could be observed at 4 and 6 weeks after operation. For the rabbit condyle bone filling experiment, HE staining showed that at 12 weeks after operation, part of the materials were absorbed, and new cartilage could be observed in both experimental and control groups; at 26 weeks after operation, the most of the materials were absorbed, and large amount of new bone could be observed in the 2 groups, while new bone unit structure could be observed in the experimental group. Micro-CT observation showed that the bone formation rate and area of the experimental group were better than those of the control group. The measurement of bone morphometric parameters showed that the parameters at 26 weeks after operation in both groups were significantly higher than those at 12 weeks after operation (P<0.05). At 12 weeks after operation, the bone mineral density and bone volume fraction in the experimental group were significantly higher than those in the control group (P<0.05), and there was no significant difference between the two groups in trabecular thickness (P>0.05). At 26 weeks after operation, the bone mineral density of the experimental group was significantly higher than that of the control group (P<0.05). There was no significant difference in bone volume fraction and trabecular thickness between the two groups (P>0.05). Conclusion The new plastic bone filler material is an excellent bone filler material with good biosafety and osteoinductive activity.

Citation： LI Jing, REN Xiaoqi, QIAO Wei, SHI Hao, YANG Ting, MA Shaoying, LI Baoxing, ZHAO Yaping. Preparation and bone repair capability of a new plastic bone filler material. Chinese Journal of Reparative and Reconstructive Surgery, 2023, 37(3): 302-307. doi: 10.7507/1002-1892.202210022 Copy

1.	Rattanachan ST, Srakaew NL, Thaitalay P, et al. Development of injectable chitosan/biphasic calcium phosphate bone cement and in vitro and in vivo evaluation. Biomed Mater, 2020, 15(5): 055038. doi: 10.1088/1748-605X/ab8441.
2.	Tran NM, Dang NT, Nguyen NT, et al. Fabrication of injectable bone substitute loading porous simvastatin-loaded poly (lactic-co-glycolicacid) microspheres. International Journal of Polymeric Materials and Polymeric Biomaterials, 2020, 69(6): 351-362.
3.	Chang DG, Park JB, Han Y. Surgical outcomes of two kinds of demineralized bone matrix putties/local autograft composites in instrumented posterolateral lumbar fusion. BMC Musculoskelet Disord, 2021, 22(1): 200. doi: 10.1186/s12891-021-04073-3.
4.	张乃丽, 李宝兴, 张育敏, 等. 可塑形骨泥的研究进展. 中国修复重建外科杂志, 2012, 26(11): 1391-1397.
5.	Chandra RV, Rachala MR, Madhavi K, et al. Periodontally accelerated osteogenic orthodontics combined with recombinant human bone morphogenetic protein-2: An outcome assessment. J Indian Soc Periodontol, 2019, 23(3): 257-263.
6.	孙婷, 张秀华, 邵华荣, 等. 含重组人骨形态发生蛋白2复合材料的制备及体内外成骨实验研究. 药物生物技术, 2021, 28(3): 221-226.
7.	李淼, 白玉龙, 潘小亮, 等. 脱钙骨基质中BMP-2含量与其体内/外成骨活性的相关性研究. 中国修复重建外科杂志, 2021, 35(5): 620-626.
8.	Dadgar N, Ghiaseddin A, Irani S, et al. Bioartificial injectable cartilage implants from demineralized bone matrix/PVA and related studies in rabbit animal model. J Biomater Appl, 2021, 35(10): 1315-1326.
9.	慈政, 张起新, 王雅慧, 等. 成骨微环境仿生支架用于骨组织工程的可行性分析. 组织工程与重建外科, 2020, 16(6): 437-441.
10.	Yang Z, Chen L, Hao Y, et al. Synthesis and characterization of an injectable and hydrophilous expandable bone cement based on poly (methyl methacrylate). ACS Appl Mater Interfaces, 2017, 9(46): 40846-40856.
11.	Ramis JM, Blasco-Ferrer M, Calvo J, et al. Improved physical and osteoinductive properties of demineralized bone matrix by gelatin methacryloyl formulation. J Tissue Eng Regen Med, 2020, 14(3): 475-485.
12.	Thitiset T, Damrongsakkul S, Yodmuang S, et al. A novel gelatin/chitooligosaccharide/demineralized bone matrix composite scaffold and periosteum-derived mesenchymal stem cells for bone tissue engineering. Biomater Res, 2021, 25(1): 19. doi: 10.1186/s40824-021-00220-y.
13.	李忠海, 赵彦涛, 侯树勋. 新型甘油基溶胶凝胶赋形材料: 性能及体内评价. 中国组织工程研究, 2015, 19(53): 8637-8638.
14.	Bellar A, Kessler SP, Obery DR, et al. Safety of hyaluronan 35 in healthy human subjects: A pilot study. Nutrients, 2019, 11(5): 1135. doi: 10.3390/nu11051135.
15.	张乃丽, 张育敏, 周沫, 等. 可塑形脱矿骨基质/透明质酸骨泥的制备与细胞相容性. 中国组织工程研究, 2013, 17(47): 8182-8188.
16.	王松, 杨函, 杨剑, 等. 多孔磷酸钙/骨基质明胶复合骨水泥的构建及理化特性. 中国组织工程研究, 2018, 22(34): 5419-5425.
17.	王松, 杨函, 杨剑, 等. 多孔磷酸钙/骨基质明胶复合骨水泥修复兔腰椎骨缺损的实验研究. 中国修复重建外科杂志, 2017, 31(12): 1462-1467.
18.	浙江大学, 中国食品药品检定研究院, 浙江星月生物科技股份有限公司, 等. YYT1680-2020 同种异体修复材料脱钙骨材料的体内成骨诱导性能评价. 国家药品监督管理局, 2020.
19.	Chen Z, Yan X, Yin S, et al. Influence of the pore size and porosity of selective laser melted Ti6Al4V ELI porous scaffold on cell proliferation, osteogenesis and bone ingrowth. Mater Sci Eng C Mater Biol Appl, 2020, 106: 110289. doi: 10.1016/j.msec.2019.110289.
20.	Keller L, Regiel-Futyra A, Gimeno M, et al. Chitosan-based nanocomposites for the repair of bone defects. Nanomedicine, 2017, 13(7): 2231-2240.
21.	陈海霞, 谢志刚. 骨组织工程支架材料: 脱矿骨基质. 中国组织工程研究, 2014, 18(3): 426-431.
22.	Pietrzak WS, Ali SN, Chitturi D, et al. BMP depletion occurs during prolonged acid demineralization of bone: characterization and implications for graft preparation. Cell Tissue Bank, 2011, 12(2): 81-88.
23.	Duan H, Cao C, Wang X, et al. Magnesium-alloy rods reinforced bioglass bone cement composite scaffolds with cortical bone-matching mechanical properties and excellent osteoconductivity for load-bearing bone in vivo regeneration. Sci Rep, 2020, 10(1): 18193. doi: 10.1038/s41598-020-75328-7.
24.	付海洋, 李敏, 姜爱莉, 等. 脱矿同种异体骨纤维小鼠异位诱导成骨试验的研究. 中国骨与关节损伤杂志, 2020, 35(9): 928-931.
25.	Kim SK, Huh CK, Lee JH, et al. Histologic study of bone-forming capacity on polydeoxyribonucleotide combined with demineralized dentin matrix. Maxillofac Plast Reconstr Surg, 2016, 38(1): 7. doi: 10.1186/s40902-016-0053-5.
26.	Dozza B, Lesci IG, Duchi S, et al. When size matters: differences in demineralized bone matrix particles affect collagen structure, mesenchymal stem cell behavior, and osteogenic potential. J Biomed Mater Res A, 2017, 105(4): 1019-1033.
27.	Sutha K, Schwartz Z, Wang Y, et al. Osteogenic embryoid body-derived material induces bone formation in vivo. Sci Rep, 2015, 5: 9960. doi: 10.1038/srep09960.

1. Rattanachan ST, Srakaew NL, Thaitalay P, et al. Development of injectable chitosan/biphasic calcium phosphate bone cement and in vitro and in vivo evaluation. Biomed Mater, 2020, 15(5): 055038. doi: 10.1088/1748-605X/ab8441.
2. Tran NM, Dang NT, Nguyen NT, et al. Fabrication of injectable bone substitute loading porous simvastatin-loaded poly (lactic-co-glycolicacid) microspheres. International Journal of Polymeric Materials and Polymeric Biomaterials, 2020, 69(6): 351-362.
3. Chang DG, Park JB, Han Y. Surgical outcomes of two kinds of demineralized bone matrix putties/local autograft composites in instrumented posterolateral lumbar fusion. BMC Musculoskelet Disord, 2021, 22(1): 200. doi: 10.1186/s12891-021-04073-3.
4. 张乃丽, 李宝兴, 张育敏, 等. 可塑形骨泥的研究进展. 中国修复重建外科杂志, 2012, 26(11): 1391-1397.
5. Chandra RV, Rachala MR, Madhavi K, et al. Periodontally accelerated osteogenic orthodontics combined with recombinant human bone morphogenetic protein-2: An outcome assessment. J Indian Soc Periodontol, 2019, 23(3): 257-263.
6. 孙婷, 张秀华, 邵华荣, 等. 含重组人骨形态发生蛋白2复合材料的制备及体内外成骨实验研究. 药物生物技术, 2021, 28(3): 221-226.
7. 李淼, 白玉龙, 潘小亮, 等. 脱钙骨基质中BMP-2含量与其体内/外成骨活性的相关性研究. 中国修复重建外科杂志, 2021, 35(5): 620-626.
8. Dadgar N, Ghiaseddin A, Irani S, et al. Bioartificial injectable cartilage implants from demineralized bone matrix/PVA and related studies in rabbit animal model. J Biomater Appl, 2021, 35(10): 1315-1326.
9. 慈政, 张起新, 王雅慧, 等. 成骨微环境仿生支架用于骨组织工程的可行性分析. 组织工程与重建外科, 2020, 16(6): 437-441.
10. Yang Z, Chen L, Hao Y, et al. Synthesis and characterization of an injectable and hydrophilous expandable bone cement based on poly (methyl methacrylate). ACS Appl Mater Interfaces, 2017, 9(46): 40846-40856.
11. Ramis JM, Blasco-Ferrer M, Calvo J, et al. Improved physical and osteoinductive properties of demineralized bone matrix by gelatin methacryloyl formulation. J Tissue Eng Regen Med, 2020, 14(3): 475-485.
12. Thitiset T, Damrongsakkul S, Yodmuang S, et al. A novel gelatin/chitooligosaccharide/demineralized bone matrix composite scaffold and periosteum-derived mesenchymal stem cells for bone tissue engineering. Biomater Res, 2021, 25(1): 19. doi: 10.1186/s40824-021-00220-y.
13. 李忠海, 赵彦涛, 侯树勋. 新型甘油基溶胶凝胶赋形材料: 性能及体内评价. 中国组织工程研究, 2015, 19(53): 8637-8638.
14. Bellar A, Kessler SP, Obery DR, et al. Safety of hyaluronan 35 in healthy human subjects: A pilot study. Nutrients, 2019, 11(5): 1135. doi: 10.3390/nu11051135.
15. 张乃丽, 张育敏, 周沫, 等. 可塑形脱矿骨基质/透明质酸骨泥的制备与细胞相容性. 中国组织工程研究, 2013, 17(47): 8182-8188.
16. 王松, 杨函, 杨剑, 等. 多孔磷酸钙/骨基质明胶复合骨水泥的构建及理化特性. 中国组织工程研究, 2018, 22(34): 5419-5425.
17. 王松, 杨函, 杨剑, 等. 多孔磷酸钙/骨基质明胶复合骨水泥修复兔腰椎骨缺损的实验研究. 中国修复重建外科杂志, 2017, 31(12): 1462-1467.
18. 浙江大学, 中国食品药品检定研究院, 浙江星月生物科技股份有限公司, 等. YYT1680-2020 同种异体修复材料脱钙骨材料的体内成骨诱导性能评价. 国家药品监督管理局, 2020.
19. Chen Z, Yan X, Yin S, et al. Influence of the pore size and porosity of selective laser melted Ti6Al4V ELI porous scaffold on cell proliferation, osteogenesis and bone ingrowth. Mater Sci Eng C Mater Biol Appl, 2020, 106: 110289. doi: 10.1016/j.msec.2019.110289.
20. Keller L, Regiel-Futyra A, Gimeno M, et al. Chitosan-based nanocomposites for the repair of bone defects. Nanomedicine, 2017, 13(7): 2231-2240.
21. 陈海霞, 谢志刚. 骨组织工程支架材料: 脱矿骨基质. 中国组织工程研究, 2014, 18(3): 426-431.
22. Pietrzak WS, Ali SN, Chitturi D, et al. BMP depletion occurs during prolonged acid demineralization of bone: characterization and implications for graft preparation. Cell Tissue Bank, 2011, 12(2): 81-88.
23. Duan H, Cao C, Wang X, et al. Magnesium-alloy rods reinforced bioglass bone cement composite scaffolds with cortical bone-matching mechanical properties and excellent osteoconductivity for load-bearing bone in vivo regeneration. Sci Rep, 2020, 10(1): 18193. doi: 10.1038/s41598-020-75328-7.
24. 付海洋, 李敏, 姜爱莉, 等. 脱矿同种异体骨纤维小鼠异位诱导成骨试验的研究. 中国骨与关节损伤杂志, 2020, 35(9): 928-931.
25. Kim SK, Huh CK, Lee JH, et al. Histologic study of bone-forming capacity on polydeoxyribonucleotide combined with demineralized dentin matrix. Maxillofac Plast Reconstr Surg, 2016, 38(1): 7. doi: 10.1186/s40902-016-0053-5.
26. Dozza B, Lesci IG, Duchi S, et al. When size matters: differences in demineralized bone matrix particles affect collagen structure, mesenchymal stem cell behavior, and osteogenic potential. J Biomed Mater Res A, 2017, 105(4): 1019-1033.
27. Sutha K, Schwartz Z, Wang Y, et al. Osteogenic embryoid body-derived material induces bone formation in vivo. Sci Rep, 2015, 5: 9960. doi: 10.1038/srep09960.

Chinese Journal of Reparative and Reconstructive Surgery

Preparation and bone repair capability of a new plastic bone filler material

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