Experiment of porous calcium phosphate/bone matrix gelatin composite cement for repairing lumbar vertebral bone defect in rabbit_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WANG Song ¹ , YANG Han ¹ , YANG Jian ¹ , KANG Jianping ¹ , WANG Qing ¹ ,  SONG Yueming ²

1. Department of Spine Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China;
2. Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;

Corresponding author：

SONG Yueming, Email: hx_sym@163.com

Keywords：

Calcium phosphate cement; bone matrix gelatin; poly (lactic-co-glycolic) acid; composite cement; rabbit

DOI：

10.7507/1002-1892.201707097

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Objective To investigate the effect of a porous calcium phosphate/bone matrix gelatin (BMG) composite cement (hereinafter referred to as the " porous composite cement”) for repairing lumbar vertebral bone defect in a rabbit model. Methods BMG was extracted from adult New Zealand rabbits according to the Urist’s method. Poly (lactic-co-glycolic) acid (PLGA) microsphere was prepared by W/O/W double emulsion method. The porous composite cement was developed by using calcium phosphate cement (CPC) composited with BMG and PLGA microsphere. The physicochemical characterizations of the porous composite cement were assessed by anti-washout property, porosity, and biomechanical experiment, also compared with the CPC. Thirty 2-month-old New Zealand rabbits were used to construct vertebral bone defect at L₃ in size of 4 mm×3 mm×3 mm. Then, the bone defect was repaired with porous composite cement (experimental group, n=15) or CPC (control group, n=15). At 4, 8, and 12 weeks after implantation, each bone specimen was assessed by X-ray films for bone fusion, micro-CT for bone mineral density (BMD), bone volume fraction (BVF), trabecular thickness (Tb. Th.), trabecular number (Tb.N.), and trabecular spacing (Tb. Sp.), and histological section with toluidine blue staining for new-born bone formation. Results The study demonstrated well anti-washout property in 2 groups. The porous composite cement has 55.06%±1.18% of porosity and (51.63±6.73) MPa of compressive strength. The CPC has 49.38%±1.75% of porosity and (63.34±3.27) MPa of compressive strength. There were significant differences in porosity and compressive strength between different cements (t=4.254, P=0.006; t=2.476, P=0.034). X-ray films revealed that the zone between the cement and host bone gradually blurred with the time extending. At 12 weeks after implantation, the zone was disappeared in the experimental group, but clear in the control group. There were significant differences in BMD, BVF, Tb. Th., Tb. N., and Tb. Sp. between 2 groups at each time point (P<0.05). Histological observation revealed that there was new-born bone in the cement with the time extending in 2 groups. Among them, bony connection was observed between the new-born bone and the host in the experimental group, which was prior to the control group. Conclusion The porous composite cement has dual bioactivity of osteoinductivity and osteoconductivity, which are effective to promote bone defect healing and reconstruction.

Citation： WANG Song, YANG Han, YANG Jian, KANG Jianping, WANG Qing, SONG Yueming. Experiment of porous calcium phosphate/bone matrix gelatin composite cement for repairing lumbar vertebral bone defect in rabbit. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(12): 1462-1467. doi: 10.7507/1002-1892.201707097 Copy

1.	Brown WE, Chow LC. A new calcium phosphate setting cement. J Dent Res, 1983, 62: 672-679.
2.	Stiller M, Kluk E, Bohner M, et al. Performance of β-tricalcium phosphate granules and putty, bone grafting materials after bilateral sinus flooraugmentation in humans. Biomaterials, 2014, 35(10): 3154-3163.
3.	Bohner M. Physical and chemical aspects of calcium phosphates used in spinal surgery. Eur Spine J, 2001, 10 Suppl 2: S114-121.
4.	O’Neill R, McCarthy HO, Montufar EB, et al. Critical review: Injectability of calcium phosphate pastes and cements. Acta Biomater, 2017, 50: 1-19.
5.	Niu LN, Jiao K, Wang TD, et al. A review of the bioactivity of hydraulic calcium silicate cements. J Dent, 2014, 42(5): 517-533.
6.	Urist MR, DeLange RJ, Finerman GA. Bone cell differentiation and growth factors. Science, 1983, 220(4598): 680-686.
7.	袁清霞, 赵龙岩, 程杰, 等. W/O/W 复乳溶剂蒸发法制备水溶性药物微球研究进展. 中国生化药物杂志, 2012, 33(6):920-923.
8.	丁裕明. 新型磷酸钙复合骨水泥的制备及性能研究. 泸州: 西南医科大学, 2016.
9.	Lee DJ, Padilla R, Zhang H, et al. Biological assessment of a calcium silicate incorporated hydroxyapatite-gelatin nanocomposite: a comparison to decellularized bone matrix. Biomed Res Int, 2014, 2014: 837524.
10.	Roy A, Jhunjhunwala S, Bayer E, et al. Porous calcium phosphate-poly (lactic-co-glycolic) acid composite bone cement: A viable tunable drug delivery system. Mater Sci Eng C Mater Biol Appl, 2016, 59: 92-101.
11.	Habraken WJ, Wolke JG, Mikos AG, et al. PLGA microsphere/calcium phosphate cement composites for tissue engineering: in vitro release and degradation characteristics. J Biomater Sci Polym Ed, 2008, 19(9): 1171-1188.
12.	Wagoner-Johnson AJ, Herschler BA. A review of the mechanical behavior of CaP and CaP/polymer composites for applications in bone replacement and repair. Acta Biomater, 2011, 7(1): 16-30.
13.	Fernández E, Sarda S, Hamcerencu M, et al. High-strength apatitic cement by modification with superplasticizers. Biomaterials, 2005, 26(15): 2289-2296.
14.	张淑娴, 郭新全, 邱玉金, 等. 兔椎体骨折动物模型制备的初步探讨. 动物医学进展, 2013, 34(7): 131-134.
15.	Maenz S, Brinkmann O, Kunisch E, et al. Enhanced bone formation in sheep vertebral bodies after minimally invasive treatment with a novel, PLGA fiber-reinforced brushite cement. Spine J, 2016, 17(5): 709-719.
16.	Palmer I, Nelson J, Schatton W, et al. Biocompatibility of calcium phosphate bone cement with optimised mechanical properties: an in vivo study. J Mater Sci Mater Med, 2016, 27(12): 91.
17.	Wang ZH, Zhang J, Zhang Q, et al. Evaluation of bone matrix gelatin/fibrin glue and chitosan/gelatin composite scaffolds for cartilage tissue engineering. Genet Mol Res, 2016, 15(3): 1-8.
18.	张育敏, 李晶, 牛晓军, 等. 聚乳酸/骨基质明胶多孔复合材料的生物相容性研究. 中国修复重建外科杂志, 2016, 30(2): 251-257.
19.	Lamghari M, Berland S, Laurent A, et al. Bone reactions to nacre injected percutaneously into the vertebrae of sheep. Biomaterials, 2001, 22(6): 555-562.
20.	Lamghari M, Antonietti P, Berland S, et al. Arthrodesis of lumbar spine transverse processes using nacre in rabbit. J Bone Miner Res, 2001, 16(12): 2232-2237.
21.	Parker RM, Malham GM. Comparison of a calcium phosphate bone substitute with recombinant human bone morphogenetic protein-2: a prospective study of fusion rates, clinical outcomes and complications with 24-month follow-up. Eur Spine J, 2017, 26(3): 754-763.
22.	Zheng YX, Wang J, Lin HT, et al. Reconstruction of orbital defect in rabbits with composite of calcium phosphate cement and recombinant human bone morphogenetic protein-2. Chin Med J (Engl), 2010, 123(24): 3658-3662.
23.	Perrier M, Lu Y, Nemke B, et al. Acceleration of second and fourth metatarsal fracture healing with recombinant human bone morphogenetic protein-2/calcium phosphate cement in horses. Vet Surg, 2008, 37(7): 648-655.
24.	Lovasik BP, Holland CM, Howard BM, et al. Anterior Cervical Discectomy and Fusion: Comparison of Fusion, Dysphagia, and Complication Rates Between Recombinant Human Bone Morphogenetic Protein-2 and Beta-Tricalcium Phosphate. World Neurosurg, 2017, 97: 674-683.e1.
25.	Villavicencio AT, Burneikiene S. RhBMP-2-induced radiculitis in patients undergoing transforaminal lumbar interbody fusion: relationship to dose. Spine J, 2016, 16(10): 1208-1213.
26.	Yu T, Dong C, Shen Z, et al. Vascularization of plastic calcium phosphate cement in vivo induced by in-situ-generated hollow channels. Mater Sci Eng C Mater Biol Appl, 2016, 68: 153-162.
27.	Kasuya A, Sobajima S, Kinoshita M. In vivo degradation and new bone formation of calcium phosphate cement-gelatin powder composite related to macroporosity after in situ gelatin degradation. J Orthop Res, 2012, 30(7): 1103-1111.
28.	Palmer I, Nelson J, Schatton W, et al. Biocompatibility of calcium phosphate bone cement with optimised mechanical properties: an in vivo study. J Mater Sci Mater Med, 2016, 27(12): 191.
29.	Toth JM, Wang M, Lawson J, et al. Radiographic, biomechanical, and histological evaluation of rhBMP-2 in a 3-level intertransverse process spine fusion: an ovine study. J Neurosurg Spine, 2016, 25(6): 733-739.

1. Brown WE, Chow LC. A new calcium phosphate setting cement. J Dent Res, 1983, 62: 672-679.
2. Stiller M, Kluk E, Bohner M, et al. Performance of β-tricalcium phosphate granules and putty, bone grafting materials after bilateral sinus flooraugmentation in humans. Biomaterials, 2014, 35(10): 3154-3163.
3. Bohner M. Physical and chemical aspects of calcium phosphates used in spinal surgery. Eur Spine J, 2001, 10 Suppl 2: S114-121.
4. O’Neill R, McCarthy HO, Montufar EB, et al. Critical review: Injectability of calcium phosphate pastes and cements. Acta Biomater, 2017, 50: 1-19.
5. Niu LN, Jiao K, Wang TD, et al. A review of the bioactivity of hydraulic calcium silicate cements. J Dent, 2014, 42(5): 517-533.
6. Urist MR, DeLange RJ, Finerman GA. Bone cell differentiation and growth factors. Science, 1983, 220(4598): 680-686.
7. 袁清霞, 赵龙岩, 程杰, 等. W/O/W 复乳溶剂蒸发法制备水溶性药物微球研究进展. 中国生化药物杂志, 2012, 33(6):920-923.
8. 丁裕明. 新型磷酸钙复合骨水泥的制备及性能研究. 泸州: 西南医科大学, 2016.
9. Lee DJ, Padilla R, Zhang H, et al. Biological assessment of a calcium silicate incorporated hydroxyapatite-gelatin nanocomposite: a comparison to decellularized bone matrix. Biomed Res Int, 2014, 2014: 837524.
10. Roy A, Jhunjhunwala S, Bayer E, et al. Porous calcium phosphate-poly (lactic-co-glycolic) acid composite bone cement: A viable tunable drug delivery system. Mater Sci Eng C Mater Biol Appl, 2016, 59: 92-101.
11. Habraken WJ, Wolke JG, Mikos AG, et al. PLGA microsphere/calcium phosphate cement composites for tissue engineering: in vitro release and degradation characteristics. J Biomater Sci Polym Ed, 2008, 19(9): 1171-1188.
12. Wagoner-Johnson AJ, Herschler BA. A review of the mechanical behavior of CaP and CaP/polymer composites for applications in bone replacement and repair. Acta Biomater, 2011, 7(1): 16-30.
13. Fernández E, Sarda S, Hamcerencu M, et al. High-strength apatitic cement by modification with superplasticizers. Biomaterials, 2005, 26(15): 2289-2296.
14. 张淑娴, 郭新全, 邱玉金, 等. 兔椎体骨折动物模型制备的初步探讨. 动物医学进展, 2013, 34(7): 131-134.
15. Maenz S, Brinkmann O, Kunisch E, et al. Enhanced bone formation in sheep vertebral bodies after minimally invasive treatment with a novel, PLGA fiber-reinforced brushite cement. Spine J, 2016, 17(5): 709-719.
16. Palmer I, Nelson J, Schatton W, et al. Biocompatibility of calcium phosphate bone cement with optimised mechanical properties: an in vivo study. J Mater Sci Mater Med, 2016, 27(12): 91.
17. Wang ZH, Zhang J, Zhang Q, et al. Evaluation of bone matrix gelatin/fibrin glue and chitosan/gelatin composite scaffolds for cartilage tissue engineering. Genet Mol Res, 2016, 15(3): 1-8.
18. 张育敏, 李晶, 牛晓军, 等. 聚乳酸/骨基质明胶多孔复合材料的生物相容性研究. 中国修复重建外科杂志, 2016, 30(2): 251-257.
19. Lamghari M, Berland S, Laurent A, et al. Bone reactions to nacre injected percutaneously into the vertebrae of sheep. Biomaterials, 2001, 22(6): 555-562.
20. Lamghari M, Antonietti P, Berland S, et al. Arthrodesis of lumbar spine transverse processes using nacre in rabbit. J Bone Miner Res, 2001, 16(12): 2232-2237.
21. Parker RM, Malham GM. Comparison of a calcium phosphate bone substitute with recombinant human bone morphogenetic protein-2: a prospective study of fusion rates, clinical outcomes and complications with 24-month follow-up. Eur Spine J, 2017, 26(3): 754-763.
22. Zheng YX, Wang J, Lin HT, et al. Reconstruction of orbital defect in rabbits with composite of calcium phosphate cement and recombinant human bone morphogenetic protein-2. Chin Med J (Engl), 2010, 123(24): 3658-3662.
23. Perrier M, Lu Y, Nemke B, et al. Acceleration of second and fourth metatarsal fracture healing with recombinant human bone morphogenetic protein-2/calcium phosphate cement in horses. Vet Surg, 2008, 37(7): 648-655.
24. Lovasik BP, Holland CM, Howard BM, et al. Anterior Cervical Discectomy and Fusion: Comparison of Fusion, Dysphagia, and Complication Rates Between Recombinant Human Bone Morphogenetic Protein-2 and Beta-Tricalcium Phosphate. World Neurosurg, 2017, 97: 674-683.e1.
25. Villavicencio AT, Burneikiene S. RhBMP-2-induced radiculitis in patients undergoing transforaminal lumbar interbody fusion: relationship to dose. Spine J, 2016, 16(10): 1208-1213.
26. Yu T, Dong C, Shen Z, et al. Vascularization of plastic calcium phosphate cement in vivo induced by in-situ-generated hollow channels. Mater Sci Eng C Mater Biol Appl, 2016, 68: 153-162.
27. Kasuya A, Sobajima S, Kinoshita M. In vivo degradation and new bone formation of calcium phosphate cement-gelatin powder composite related to macroporosity after in situ gelatin degradation. J Orthop Res, 2012, 30(7): 1103-1111.
28. Palmer I, Nelson J, Schatton W, et al. Biocompatibility of calcium phosphate bone cement with optimised mechanical properties: an in vivo study. J Mater Sci Mater Med, 2016, 27(12): 191.
29. Toth JM, Wang M, Lawson J, et al. Radiographic, biomechanical, and histological evaluation of rhBMP-2 in a 3-level intertransverse process spine fusion: an ovine study. J Neurosurg Spine, 2016, 25(6): 733-739.

Chinese Journal of Reparative and Reconstructive Surgery

Experiment of porous calcium phosphate/bone matrix gelatin composite cement for repairing lumbar vertebral bone defect in rabbit

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