Application of Microspheres in Calcium Phosphate Cement System_Journal of Biomedical Engineering

Authors：

1. Clinical Engineering Department, The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical College, Wenzhou 325000, China;
2. Key Lab of Advanced Technologies of Materials, Ministry of Education, School of Material Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;

Corresponding author：

Keywords：

calcium phosphate cement (CPC); microspheres; drug release; porous structure

DOI：

10.7507/1001-5515.20160130

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Calcium phosphate cement (CPC) has been widely used as bone fillers because of its excellent bioactivity and biocompatibility. Meanwhile, CPC is also an attractive candidate for the incorporation of drug or microspheres, because the preparing procedure avoids sintering and heating release. This paper summarizes the clinical applications of microspheres incorporated in CPC from the aspects of sustained drug release, accelerated degradation, porous structure and improved mechanical properties. The paper is aimed to analyze the methods and principles of microspheres loaded CPC, and so as to lay a foundation for the further research of improving and manufacturing the CPC with ideal properties.

Citation： LINSunzhong, QUShuxin, XUEJixin, LINChanjuan, XUXiaopu, WENGJie. Application of Microspheres in Calcium Phosphate Cement System. Journal of Biomedical Engineering, 2016, 33(4): 806-811. doi: 10.7507/1001-5515.20160130 Copy

1.	CHEN Changkeng, JU C P, LIN J. Setting solution concentration effect on properties of a TTCP/DCPA-derived calcium phosphate cement[J]. J Mater Sci Mater Med, 2012, 23(9):2109-2114.
2.	林孙忠.可时序控释双组分药物磷酸钙骨水泥的研究[D].成都:西南交通大学, 2012.
3.	ZHANG Jingtao, LIU Weizhen, SCHNITZLER V, et al. Calcium phosphate cements for bone substitution:chemistry, handling and mechanical properties[J]. Acta Biomater, 2014, 10(3):1035-1049.
4.	RENNO A, VAN DE WATERING F, NEJADNIK M, et al. Incorporation of bioactive glass in calcium phosphate cement:An evaluation[J]. Acta Biomater, 2013, 9(3):5728-5739.
5.	XIE Xiangyang, LIN Wen, XING Chuan-feng, et al. In vitro and in vivo evaluations of PLGA microspheres containing nalmefene[J]. PLoS One, 2015, 10(5):0125953.
6.	POOVI G, ARUL J J, LAKSHMI S, et al. Review on microsphere[J]. American Journal of Drug Discovery and Development, 2014, 4:153-179.
7.	SUSAN D S, JABAR A F, STEFANO G, et al. Development of risperidone PLGA microspheres[J]. J Drug Deliv, 2014, 11:1-11.
8.	SIMON C J, KHATRI C A, WIGHT S A, et al. Preliminary report on the biocompatibility of a moldable, resorbable, composite bone graft consisting of calcium phosphate cement and poly(lactide-co-glycolide)microspheres[J]. J Orthop Res, 2002, 20(3):473-482.
9.	HOEKSTRA J W, VAN DEN BEUCKEN J J, BRONKHORST E M, et al. Tantalum oxide and Barium sulfate as radiopacifiers in injectable calcium phosphate-poly(lactic-co-glycolic acid) cements for monitoring in vivo degradation[J]. J Biomed Mater Res A, 2014, 102(1):141-149.
10.	PEREZ R A, KIM H W, GINEBRA M P. Polymeric additives to enhance the functional properties of Calcium phosphate cements[J]. Tissue Eng, 2012, 3(1):2041731412439555.
11.	ZHONG Meiling, CHEN Xiaoqin, FAN Hongsong, et al. Incorporation of salmon calcitonin-loaded poly(lactide-co-glycolide) (PLGA) microspheres into calcium phosphate bone cement and the biocompatibility evaluation in vitro[J]. J Bioact Compat Polym, 2012, 27(2):133-147.
12.	LOCA D, SOKOLOVA M, LOCS J, et al. Calcium phosphate bone cements for local vancomycin delivery[J]. Mater Sci Eng C Mater Biol Appl, 2015, 49:106-113.
13.	HABRAKEN W M, LIAO H-b, ZHANG Z, et al. In vivo degradation of calcium phosphate cement incorporated into biodegradable microspheres[J]. Acta Biomater, 2010, 6:2200-2211.
14.	IWAKURA T, LEE Sangyang, NⅡKURA T, et al. Gentamycin-impregnated calcium phosphate cement for calcaneal osteomyelitis:a case report[J]. J Orthop Surg Res, 2014, 22(3):437-439.
15.	BAIER M, STAUDT P, KLEIN R, et al. Strontium enhances osseointegration of calcium phosphate cement:a histomorphometric pilot study in ovariectomized rats[J]. J Orthop Surg Res, 2013, 8(16):1749.
16.	WATERING F D, MOLKENBOER K D, BOERMAN O C, et al. Differential loading methods for BMP-2 within injectable calcium phosphate cement[J]. J Control Release, 2012, 164(3):283-290.
17.	HABRAKEN W M, WOLKE J C, MIKOS A G, et al. PLGA microsphere/calcium phosphate cement composites for tissue engineering:in vitro release and degradation characteristics[J]. Journal of Biomaterials Science-Polymer Edition, 2008, 19(9):1171-1188.
18.	HABRAKEN W M, BOERMAN O C, WOLKE J C, et al. In vitro growth factor release from injectable calcium phosphate cements containing gelatin microspheres[J]. J Biomed Mater Res A, 2009, 91A(2):614-622.
19.	LI Meng, LIU Xing-yan, LIU Xu-dong, et al. Calcium phosphate cement with BMP-2-loaded gelatin microspheres enhances bone healing in osteoporosis:a pilot study[J]. Clin Orthop Relat Res, 2010, 468(7):1978-1985.
20.	FÉLIX LANAO R P, BOSCO R, LEEUWENBURGH S C, et al. RANKL delivery from calcium phosphate containing PLGA microspheres[J]. J Biomed Mater Res A, 2013, 101(11):3123-3130.
21.	LIAO H B, FELIX L P, BEUCKEN J D, et al. Size matters:effects of PLGA-microsphere size in injectable CPC/PLGA on bone formation[J]. J Tissue Eng Regen Med, 2013:1840.
22.	WATERING F D, BEUCKEN J D, WALBOOMERS X F, et al. Calcium phosphate/poly(D, L-lactic-co-glycolic acid)composite bone substitute materials:evaluation of temporal degradation and bone ingrowth in a rat critical-sized cranial defect[J]. Clin Oral Implan Res, 2012, 23(2):151-159.
23.	HABRAKEN W M, WOLKE J C, MIKOS A G, et al. Injectable PLGA microsphere/calcium phosphate cements:physical properties and degradation characteristics[J]. Journal of Biomaterials Science-Polymer Edition, 2006, 17(9):1057-1074.
24.	SARⅡBRAHIMOGLU K, AN Jie, VAN OIRSCHOT B A, et al. Tuning the degradation rate of calcium phosphate cements by incorporating mixtures of polylactic-co-glycolic acid microspheres and glucono-delta-lactone microparticles[J]. Tissue Eng Part A, 2014, 20(21/22):2870-2882.
25.	FÉLIX LANAO R P, LEEUWENBURGH S C, WOLKE J G, et al. In vitro degradation rate of apatitic calcium phosphate cement with incorporated PLGA microspheres[J]. Acta Biomater, 2011, 7(9):3459-3468.
26.	LANAO R P, LEEUWENBURGH S C, WOLKE J G, et al. Bone response to fast-degrading, injectable calcium phosphate cements containing PLGA microparticles[J]. Biomaterials, 2011, 32(34):8839-8847.
27.	KLIJN R J, VAN DEN BEUCKEN J J, FÉLIX LANAO R P, et al. Three different strategies to obtain porous calcium phosphate cements:comparison of performance in a rat skull bone augmentation model[J]. Tissue Eng Part A, 2012, 18(11/12):1171-1182.
28.	QI Xiaopeng, YE Jiandong. Mechanical and rheological properties and injectability of calcium phosphate cement containing poly (lactic-co-glycolic acid) microspheres[J]. Mater Sci Eng C Mater Biol Appl, 2009, 29(6):1901-1906.
29.	AN Jie, LEEUWENBURGH S C, WOLKE J G, et al. Effects of stirring and fluid perfusion on the in vitro degradation of calcium phosphate cement/PLGA composites[J]. Tissue Eng Part C Methods, 2015, 21(11):1171-1177.
30.	MENG D, DONG L M, WEN Y, et al. Effects of adding resorbable chitosan microspheres to calcium phosphate cements for bone regeneration[J]. Mater Sci Eng C Mater Biol Appl, 2015, 47:266-272.
31.	FÉLIX LANAO R P, SARⅡBRAHIMOGLU K, WANG Huanan, et al. Accelerated calcium phosphate cement degradation due to incorporation of glucono-delta-lactone microparticles[J]. Tissue Eng Part A, 2014, 20(1/2):378-388.
32.	THEINHAN W, WEIR M D, SIMON C G, et al. Non-rigid calcium phosphate cement containing hydrogel microbeads and absorbable fibres seeded with umbilical cord stem cells for bone engineering[J]. J Tissue Eng Regen Med, 2013, 7(10):777-787.
33.	MAI Y Y, WU H H, MAI Z S, et al. Preliminary application of injectable calcium phosphate cement/poly (lactic-co-glycolic acid) microspheres for extraction site preservation[J]. Zhonghua Kou Qiang Yi Xue Za Zhi, 2014, 49(3):180-183.
34.	WU Tingting, SHI Haishan, YE Jiandong. Effect of PLGA/lecithin hybrid microspheres and beta-tricalcium phosphate granules on the physicochemical properties, in vitro degradation and biocompatibility of Calcium phosphate cement[J]. RSC Adv, 2015, 5(59):47749-47756.
35.	CAI Shu, ZHAI Yujia, XU Guohua, et al. Preparation and properties of calcium phosphate cements incorporated gelatin microspheres and calcium sulfate dihydrate as controlled local drug delivery system[J]. J Mater Sci Mater Med, 2011, 22(11):2487-2496.
36.	LI Yuhua, WANG Zhendong, WANG Wei, et al. The biocompatibility of calcium phosphate cements containing alendronate-loaded PLGA microparticles in vitro.[J]. Exp Biol Med, 2015, 240(11):1465-1471.
37.	WATERING F D, LAVERMAN P, CUIJPERS V M, et al. The biological performance of injectable calcium phosphate/PLGA cement in osteoporotic rats[J]. Biomed Mater, 2013, 8(3):035012.
38.	LANAO R, HOEKSTRA J, WOLKE J, et al. Porous calcium phosphate cement for alveolar bone regeneration[J]. J Tissue Eng Regen Med, 2014, 8(6):473-482.

1. CHEN Changkeng, JU C P, LIN J. Setting solution concentration effect on properties of a TTCP/DCPA-derived calcium phosphate cement[J]. J Mater Sci Mater Med, 2012, 23(9):2109-2114.
2. 林孙忠.可时序控释双组分药物磷酸钙骨水泥的研究[D].成都:西南交通大学, 2012.
3. ZHANG Jingtao, LIU Weizhen, SCHNITZLER V, et al. Calcium phosphate cements for bone substitution:chemistry, handling and mechanical properties[J]. Acta Biomater, 2014, 10(3):1035-1049.
4. RENNO A, VAN DE WATERING F, NEJADNIK M, et al. Incorporation of bioactive glass in calcium phosphate cement:An evaluation[J]. Acta Biomater, 2013, 9(3):5728-5739.
5. XIE Xiangyang, LIN Wen, XING Chuan-feng, et al. In vitro and in vivo evaluations of PLGA microspheres containing nalmefene[J]. PLoS One, 2015, 10(5):0125953.
6. POOVI G, ARUL J J, LAKSHMI S, et al. Review on microsphere[J]. American Journal of Drug Discovery and Development, 2014, 4:153-179.
7. SUSAN D S, JABAR A F, STEFANO G, et al. Development of risperidone PLGA microspheres[J]. J Drug Deliv, 2014, 11:1-11.
8. SIMON C J, KHATRI C A, WIGHT S A, et al. Preliminary report on the biocompatibility of a moldable, resorbable, composite bone graft consisting of calcium phosphate cement and poly(lactide-co-glycolide)microspheres[J]. J Orthop Res, 2002, 20(3):473-482.
9. HOEKSTRA J W, VAN DEN BEUCKEN J J, BRONKHORST E M, et al. Tantalum oxide and Barium sulfate as radiopacifiers in injectable calcium phosphate-poly(lactic-co-glycolic acid) cements for monitoring in vivo degradation[J]. J Biomed Mater Res A, 2014, 102(1):141-149.
10. PEREZ R A, KIM H W, GINEBRA M P. Polymeric additives to enhance the functional properties of Calcium phosphate cements[J]. Tissue Eng, 2012, 3(1):2041731412439555.
11. ZHONG Meiling, CHEN Xiaoqin, FAN Hongsong, et al. Incorporation of salmon calcitonin-loaded poly(lactide-co-glycolide) (PLGA) microspheres into calcium phosphate bone cement and the biocompatibility evaluation in vitro[J]. J Bioact Compat Polym, 2012, 27(2):133-147.
12. LOCA D, SOKOLOVA M, LOCS J, et al. Calcium phosphate bone cements for local vancomycin delivery[J]. Mater Sci Eng C Mater Biol Appl, 2015, 49:106-113.
13. HABRAKEN W M, LIAO H-b, ZHANG Z, et al. In vivo degradation of calcium phosphate cement incorporated into biodegradable microspheres[J]. Acta Biomater, 2010, 6:2200-2211.
14. IWAKURA T, LEE Sangyang, NⅡKURA T, et al. Gentamycin-impregnated calcium phosphate cement for calcaneal osteomyelitis:a case report[J]. J Orthop Surg Res, 2014, 22(3):437-439.
15. BAIER M, STAUDT P, KLEIN R, et al. Strontium enhances osseointegration of calcium phosphate cement:a histomorphometric pilot study in ovariectomized rats[J]. J Orthop Surg Res, 2013, 8(16):1749.
16. WATERING F D, MOLKENBOER K D, BOERMAN O C, et al. Differential loading methods for BMP-2 within injectable calcium phosphate cement[J]. J Control Release, 2012, 164(3):283-290.
17. HABRAKEN W M, WOLKE J C, MIKOS A G, et al. PLGA microsphere/calcium phosphate cement composites for tissue engineering:in vitro release and degradation characteristics[J]. Journal of Biomaterials Science-Polymer Edition, 2008, 19(9):1171-1188.
18. HABRAKEN W M, BOERMAN O C, WOLKE J C, et al. In vitro growth factor release from injectable calcium phosphate cements containing gelatin microspheres[J]. J Biomed Mater Res A, 2009, 91A(2):614-622.
19. LI Meng, LIU Xing-yan, LIU Xu-dong, et al. Calcium phosphate cement with BMP-2-loaded gelatin microspheres enhances bone healing in osteoporosis:a pilot study[J]. Clin Orthop Relat Res, 2010, 468(7):1978-1985.
20. FÉLIX LANAO R P, BOSCO R, LEEUWENBURGH S C, et al. RANKL delivery from calcium phosphate containing PLGA microspheres[J]. J Biomed Mater Res A, 2013, 101(11):3123-3130.
21. LIAO H B, FELIX L P, BEUCKEN J D, et al. Size matters:effects of PLGA-microsphere size in injectable CPC/PLGA on bone formation[J]. J Tissue Eng Regen Med, 2013:1840.
22. WATERING F D, BEUCKEN J D, WALBOOMERS X F, et al. Calcium phosphate/poly(D, L-lactic-co-glycolic acid)composite bone substitute materials:evaluation of temporal degradation and bone ingrowth in a rat critical-sized cranial defect[J]. Clin Oral Implan Res, 2012, 23(2):151-159.
23. HABRAKEN W M, WOLKE J C, MIKOS A G, et al. Injectable PLGA microsphere/calcium phosphate cements:physical properties and degradation characteristics[J]. Journal of Biomaterials Science-Polymer Edition, 2006, 17(9):1057-1074.
24. SARⅡBRAHIMOGLU K, AN Jie, VAN OIRSCHOT B A, et al. Tuning the degradation rate of calcium phosphate cements by incorporating mixtures of polylactic-co-glycolic acid microspheres and glucono-delta-lactone microparticles[J]. Tissue Eng Part A, 2014, 20(21/22):2870-2882.
25. FÉLIX LANAO R P, LEEUWENBURGH S C, WOLKE J G, et al. In vitro degradation rate of apatitic calcium phosphate cement with incorporated PLGA microspheres[J]. Acta Biomater, 2011, 7(9):3459-3468.
26. LANAO R P, LEEUWENBURGH S C, WOLKE J G, et al. Bone response to fast-degrading, injectable calcium phosphate cements containing PLGA microparticles[J]. Biomaterials, 2011, 32(34):8839-8847.
27. KLIJN R J, VAN DEN BEUCKEN J J, FÉLIX LANAO R P, et al. Three different strategies to obtain porous calcium phosphate cements:comparison of performance in a rat skull bone augmentation model[J]. Tissue Eng Part A, 2012, 18(11/12):1171-1182.
28. QI Xiaopeng, YE Jiandong. Mechanical and rheological properties and injectability of calcium phosphate cement containing poly (lactic-co-glycolic acid) microspheres[J]. Mater Sci Eng C Mater Biol Appl, 2009, 29(6):1901-1906.
29. AN Jie, LEEUWENBURGH S C, WOLKE J G, et al. Effects of stirring and fluid perfusion on the in vitro degradation of calcium phosphate cement/PLGA composites[J]. Tissue Eng Part C Methods, 2015, 21(11):1171-1177.
30. MENG D, DONG L M, WEN Y, et al. Effects of adding resorbable chitosan microspheres to calcium phosphate cements for bone regeneration[J]. Mater Sci Eng C Mater Biol Appl, 2015, 47:266-272.
31. FÉLIX LANAO R P, SARⅡBRAHIMOGLU K, WANG Huanan, et al. Accelerated calcium phosphate cement degradation due to incorporation of glucono-delta-lactone microparticles[J]. Tissue Eng Part A, 2014, 20(1/2):378-388.
32. THEINHAN W, WEIR M D, SIMON C G, et al. Non-rigid calcium phosphate cement containing hydrogel microbeads and absorbable fibres seeded with umbilical cord stem cells for bone engineering[J]. J Tissue Eng Regen Med, 2013, 7(10):777-787.
33. MAI Y Y, WU H H, MAI Z S, et al. Preliminary application of injectable calcium phosphate cement/poly (lactic-co-glycolic acid) microspheres for extraction site preservation[J]. Zhonghua Kou Qiang Yi Xue Za Zhi, 2014, 49(3):180-183.
34. WU Tingting, SHI Haishan, YE Jiandong. Effect of PLGA/lecithin hybrid microspheres and beta-tricalcium phosphate granules on the physicochemical properties, in vitro degradation and biocompatibility of Calcium phosphate cement[J]. RSC Adv, 2015, 5(59):47749-47756.
35. CAI Shu, ZHAI Yujia, XU Guohua, et al. Preparation and properties of calcium phosphate cements incorporated gelatin microspheres and calcium sulfate dihydrate as controlled local drug delivery system[J]. J Mater Sci Mater Med, 2011, 22(11):2487-2496.
36. LI Yuhua, WANG Zhendong, WANG Wei, et al. The biocompatibility of calcium phosphate cements containing alendronate-loaded PLGA microparticles in vitro.[J]. Exp Biol Med, 2015, 240(11):1465-1471.
37. WATERING F D, LAVERMAN P, CUIJPERS V M, et al. The biological performance of injectable calcium phosphate/PLGA cement in osteoporotic rats[J]. Biomed Mater, 2013, 8(3):035012.
38. LANAO R, HOEKSTRA J, WOLKE J, et al. Porous calcium phosphate cement for alveolar bone regeneration[J]. J Tissue Eng Regen Med, 2014, 8(6):473-482.

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