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.	張乃麗, 李寶興, 張育敏, 等. 可塑形骨泥的研究進展. 中國修復重建外科雜志, 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.	孫婷, 張秀華, 邵華榮, 等. 含重組人骨形態發生蛋白2復合材料的制備及體內外成骨實驗研究. 藥物生物技術, 2021, 28(3): 221-226.
7.	李淼, 白玉龍, 潘小亮, 等. 脫鈣骨基質中BMP-2含量與其體內/外成骨活性的相關性研究. 中國修復重建外科雜志, 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, 張起新, 王雅慧, 等. 成骨微環境仿生支架用于骨組織工程的可行性分析. 組織工程與重建外科, 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, 趙彥濤, 侯樹勛. 新型甘油基溶膠凝膠賦形材料: 性能及體內評價. 中國組織工程研究, 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.	張乃麗, 張育敏, 周沫, 等. 可塑形脫礦骨基質/透明質酸骨泥的制備與細胞相容性. 中國組織工程研究, 2013, 17(47): 8182-8188.
16.	王松, 楊函, 楊劍, 等. 多孔磷酸鈣/骨基質明膠復合骨水泥的構建及理化特性. 中國組織工程研究, 2018, 22(34): 5419-5425.
17.	王松, 楊函, 楊劍, 等. 多孔磷酸鈣/骨基質明膠復合骨水泥修復兔腰椎骨缺損的實驗研究. 中國修復重建外科雜志, 2017, 31(12): 1462-1467.
18.	浙江大學, 中國食品藥品檢定研究院, 浙江星月生物科技股份有限公司, 等. YYT1680-2020 同種異體修復材料脫鈣骨材料的體內成骨誘導性能評價. 國家藥品監督管理局, 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.	陳海霞, 謝志剛. 骨組織工程支架材料: 脫礦骨基質. 中國組織工程研究, 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, 姜愛莉, 等. 脫礦同種異體骨纖維小鼠異位誘導成骨試驗的研究. 中國骨與關節損傷雜志, 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. 張乃麗, 李寶興, 張育敏, 等. 可塑形骨泥的研究進展. 中國修復重建外科雜志, 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. 孫婷, 張秀華, 邵華榮, 等. 含重組人骨形態發生蛋白2復合材料的制備及體內外成骨實驗研究. 藥物生物技術, 2021, 28(3): 221-226.
7. 李淼, 白玉龍, 潘小亮, 等. 脫鈣骨基質中BMP-2含量與其體內/外成骨活性的相關性研究. 中國修復重建外科雜志, 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, 張起新, 王雅慧, 等. 成骨微環境仿生支架用于骨組織工程的可行性分析. 組織工程與重建外科, 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, 趙彥濤, 侯樹勛. 新型甘油基溶膠凝膠賦形材料: 性能及體內評價. 中國組織工程研究, 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. 張乃麗, 張育敏, 周沫, 等. 可塑形脫礦骨基質/透明質酸骨泥的制備與細胞相容性. 中國組織工程研究, 2013, 17(47): 8182-8188.
16. 王松, 楊函, 楊劍, 等. 多孔磷酸鈣/骨基質明膠復合骨水泥的構建及理化特性. 中國組織工程研究, 2018, 22(34): 5419-5425.
17. 王松, 楊函, 楊劍, 等. 多孔磷酸鈣/骨基質明膠復合骨水泥修復兔腰椎骨缺損的實驗研究. 中國修復重建外科雜志, 2017, 31(12): 1462-1467.
18. 浙江大學, 中國食品藥品檢定研究院, 浙江星月生物科技股份有限公司, 等. YYT1680-2020 同種異體修復材料脫鈣骨材料的體內成骨誘導性能評價. 國家藥品監督管理局, 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. 陳海霞, 謝志剛. 骨組織工程支架材料: 脫礦骨基質. 中國組織工程研究, 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, 姜愛莉, 等. 脫礦同種異體骨纖維小鼠異位誘導成骨試驗的研究. 中國骨與關節損傷雜志, 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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