Research progress on 3D printing ceramic-polymer composite for bone repair_West China Medical Journal

Authors：

ZENG Zhimou ^1,2 , ZHU Ce ¹ , WANG Linnan ¹ ,  SONG Yueming ¹

1. Department of Orthopedic Surgery and Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Orthopedic Surgery, the First Afliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, P. R. China;

Corresponding author：

SONG Yueming, Email: hx_sym@163.com

Keywords：

Ceramics; polymers; bone repair; modification

DOI：

10.7507/1002-0179.202310133

Video：

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Abstract Full text Figures/Tables Video References Cited by

Traditional bone repair materials, such as titanium, polyetheretherketone, and calcium phosphate, exhibit limitations, including poor biocompatibility and incongruent mechanical properties. In contrast, ceramic-polymer composite materials combine the robust mechanical strength of ceramics with the flexibility of polymers, resulting in enhanced biocompatibility and mechanical performance. In recent years, researchers worldwide have conducted extensive studies to develop innovative composite materials and manufacturing processes, with the aim of enhancing the bone repair capabilities of implants. This article provides a comprehensive overview of the advancements in ceramic-polymer composite materials, as well as in 3D printing and surface modification techniques for composite materials, with the objective of offering valuable insights to improve and facilitate the clinical application of ceramic-polymer composite materials in the future.

Citation： ZENG Zhimou, ZHU Ce, WANG Linnan, SONG Yueming. Research progress on 3D printing ceramic-polymer composite for bone repair. West China Medical Journal, 2023, 38(10): 1449-1455. doi: 10.7507/1002-0179.202310133 Copy

1.	Liu Y, Luo D, Wang T. Hierarchical structures of bone and bioinspired bone tissue engineering. Small, 2016, 12(34): 4611-4632.
2.	Eryildiz M. Fabrication of drug-loaded 3D-printed bone scaffolds with radial gradient porosity. J Mater Eng Perform, 2022, 10(19): 32.
3.	Sahu KK, Modi YK. Multi response optimization for compressive strength, porosity and dimensional accuracy of binder jetting 3D printed ceramic bone scaffolds. Ceram Int, 2022, 48(18): 26772-26783.
4.	Yunna C, Mengru H, Lei W, et al. Macrophage M1/M2 polarization. Eur J Pharmacol, 2020, 877: 173090.
5.	Civantos A, Martinez-Campos E, Ramos V, et al. Titanium coatings and surface modifications: toward clinically useful bioactive implants. ACS Biomater Sci Eng, 2017, 3(7): 1245-1261.
6.	Memarian P, Sartor F, Bernardo E, et al. Osteogenic properties of 3D-printed silica-carbon-calcite composite scaffolds: novel approach for personalized bone tissue regeneration. Int J Mol Sci, 2021, 22(2): 475.
7.	Zafar MJ, Zhu D, Zhang Z. 3D printing of bioceramics for bone tissue engineering. Materials (Basel), 2019, 12(20): 3361.
8.	Suto M, Nemoto E, Kanaya S, et al. Nanohydroxyapatite increases BMP-2 expression via a p38 MAP kinase dependent pathway in periodontal ligament cells. Arch Oral Biol, 2013, 58(8): 1021-1028.
9.	Ozeki K, Aoki H, Fukui Y. The effect of adsorbed vitamin D and K to hydroxyapatite on ALP activity of MC3T3-E1 cell. J Mater Sci Mater Med, 2008, 19(4): 1753-1757.
10.	Esposito Corcione C, Gervaso F, Scalera F, et al. 3D printing of hydroxyapatite polymer-based composites for bone tissue engineering. j Polym Eng, 2017, 37(8): 741-746.
11.	Kosik-Koziol A, Costantini M, Mroz A, et al. 3D bioprinted hydrogel model incorporating beta-tricalcium phosphate for calcified cartilage tissue engineering. Biofabrication, 2019, 11(3): 35016.
12.	沈红裕, 宋珂. 双相磷酸钙陶瓷在口腔种植的应用及研究进展. 口腔医学研究, 2022, 38(5): 404-407.
13.	姜达君, 贾伟涛, 张长青. 生物玻璃在骨修复中的研究进展. 中国修复重建外科杂志, 2017, 31(12): 1512-1516.
14.	Gerhardt LC, Boccaccini AR. Bioactive glass and glass-ceramic scaffolds for bone tissue engineering. Materials (Basel), 2010, 3(7): 3867-3910.
15.	Simorgh S, Alasvand N, Khodadadi M, et al. Additive manufacturing of bioactive glass biomaterials. Methods, 2022, 208: 75-91.
16.	Ding Y, Liu X, Zhang J, et al. 3D printing polylactic acid polymer-bioactive glass loaded with bone cement for bone defect in weight-bearing area. Front Bioeng Biotechnol, 2022, 10: 947521.
17.	Kim BS, Jang J, Chae S, et al. Three-dimensional bioprinting of cell-laden constructs with polycaprolactone protective layers for using various thermoplastic polymers. Biofabrication, 2016, 8(3): 35013.
18.	Murariu M, Dubois P. PLA composites: from production to properties. Adv Drug Deliv Rev, 2016, 107: 17-46.
19.	Mei F, Peng Y, Lu S, et al. Synthesis and characterization of biodegradable poly(lactic-co-glycolic acid). J Macromol Sci B, 2015, 54(5): 562-570.
20.	Schliecker G, Schmidt C, Fuchs S, et al. Characterization of a homologous series of D, L-lactic acid oligomers; a mechanistic study on the degradation kinetics in vitro. Biomaterials, 2003, 24(21): 3835-3844.
21.	Babilotte J, Martin B, Guduric V, et al. Development and characterization of a PLGA-HA composite material to fabricate 3D-printed scaffolds for bone tissue engineering. Mater Sci Eng C Mater Biol Appl, 2021, 118: 111334.
22.	Panayotov IV, Orti V, Cuisinier F, et al. Polyetheretherketone (PEEK) for medical applications. J Mater Sci Mater Med, 2016, 27(7): 118.
23.	Qi D, Wang N, Wang S, et al. High-strength porous polyetheretherketone/hydroxyapatite composite for the treatment of bone defect. Compos Commun, 2023, 38: 101473.
24.	唐鹿. 3D 打印聚酰胺材料的研究进展. 化工新型材料, 2021, 49(1): 28-31.
25.	Zhang Y, Deng X, Jiang D, et al. Long-term results of anterior cervical corpectomy and fusion with nano-hydroxyapatite/polyamide 66 strut for cervical spondylotic myelopathy. Sci Rep, 2016, 6: 26751.
26.	Li J, Hsu Y, Luo E, et al. Computer-aided design and manufacturing and rapid prototyped nanoscale hydroxyapatite/polyamide (n-HA/PA) construction for condylar defect caused by mandibular angle ostectomy. Aesthetic Plast Surg, 2011, 35(4): 636-640.
27.	Turnbull G, Clarke J, Picard F, et al. 3D bioactive composite scaffolds for bone tissue engineering. Bioact Mater, 2018, 3(3): 278-314.
28.	Bandyopadhyay A, Mitra I, Bose S. 3D printing for bone regeneration. Curr Osteoporos Rep, 2020, 18(5): 505-514.
29.	Garzon-Hernandez S, Arias A, Garcia-Gonzalez D. A continuum constitutive model for FDM 3D printed thermoplastics. Compos B Eng, 2020, 201: 108373.
30.	Thavornyutikarn B, Chantarapanich N, Sitthiseripratip K, et al. Bone tissue engineering scaffolding: computer-aided scaffolding techniques. Prog Biomater, 2014, 3: 61-102.
31.	Ligon SC, Liska R, Stampfl J, et al. Polymers for 3D printing and customized additive manufacturing. Chem Rev, 2017, 117(15): 10212-10290.
32.	Manzoor F, Golbang A, Jindal S, et al. 3D printed PEEK/HA composites for bone tissue engineering applications: effect of material formulation on mechanical performance and bioactive potential. J Mech Behav Biomed Mater, 2021, 121: 104601.
33.	Wang WZ, Zhang BQ, Li MX, et al. 3D printing of PLA/n-HA composite scaffolds with customized mechanical properties and biological functions for bone tissue engineering. Compos B Eng, 2021, 224: 10192.
34.	Charoo NA, Barakh Ali SF, Mohamed EM, et al. Selective laser sintering 3D printing - an overview of the technology and pharmaceutical applications. Drug Dev Ind Pharm, 2020, 46(6): 869-877.
35.	Fina F, Madla CM, Goyanes A, et al. Fabricating 3D printed orally disintegrating printlets using selective laser sintering. Int J Pharm, 2018, 541(1/2): 101-107.
36.	Feng P, Qiu X, Yang L, et al. Polydopamine constructed interfacial molecular bridge in nano-hydroxylapatite/polycaprolactone composite scaffold. Colloids Surf B Biointerfaces, 2022, 217: 112668.
37.	Martin-Montal J, Pernas-Sanchez J, Varas D. Experimental characterization framework for SLA additive manufacturing materials. Polymers (Basel), 2021, 13(7): 1147.
38.	Melchels FP, Feijen J, Grijpma DW. A review on stereolithography and its applications in biomedical engineering. Biomaterials, 2010, 31(24): 6121-6130.
39.	Lee E, Sim J, Kweon H, et al. Determination of process parameters in stereolithography using neural network. J Mech Sci Technol, 2004, 18(3): 443-452.
40.	Skoog SA, Goering PL, Narayan RJ. Stereolithography in tissue engineering. J Mater Sci Mater Med, 2014, 25(3): 845-856.
41.	Kim K, Yeatts A, Dean D, et al. Stereolithographic bone scaffold design parameters: osteogenic differentiation and signal expression. Tissue Eng Part B Rev, 2010, 16(5): 523-539.
42.	Tsang CHA, Zhakeyev A, Leung DYC, et al. GO-modified flexible polymer nanocomposites fabricated via 3D stereolithography. Front Chem Sci Eng, 2019, 13(4): 736-743.
43.	Guillaume O, Geven MA, Sprecher CM, et al. Surface-enrichment with hydroxyapatite nanoparticles in stereolithography-fabricated composite polymer scaffolds promotes bone repair. Acta Biomater, 2017, 54: 386-398.
44.	Bai L, Gong C, Chen W, et al. Additive manufacturing of customized metallic orthopedic implants: materials, structures, and surface modifications. Metals (Basel), 2019, 9(9): 1004.
45.	Zhao Y, Chen H, Ran K, et al. Porous hydroxyapatite scaffold orchestrated with bioactive coatings for rapid bone repair. Biomater Adv, 2023, 144: 213202.
46.	Hou J, Gao H, Wang Y, et al. Effect of mineralized layer topographies on stem cell behavior in microsphere scaffold. J Mater Sci, 2016, 32(9): 971-977.
47.	Lu RJ, Wang X, He HX, et al. Tantalum-incorporated hydroxyapatite coating on titanium implants: its mechanical and in vitro osteogenic properties. J Mater Sci Mater Med, 2019, 30(10): 111.
48.	Auclair-Daigle C, Bureau MN, Legoux JG, et al. Bioactive hydroxyapatite coatings on polymer composites for orthopedic implants. J Biomed Mater Res A, 2005, 73(4): 398-408.
49.	Wu C, Zeng B, Shen D, et al. Biomechanical and osteointegration study of 3D-printed porous PEEK hydroxyapatite-coated scaffolds. J Biomater Sci Polym Ed, 2023, 34(4): 435-448.
50.	Lett A, Sagadevan S, Paiman S, et al. Exploring the thumbprints of Ag-hydroxyapatite composite as a surface coating bone material for the implants. J Mater Res Technol, 2020, 9(6): 12824-12833.
51.	Liu Y, Zhang Z, Lv H, et al. Surface modification of chitosan film via polydopamine coating to promote biomineralization in bone tissue engineering. J Bioact Compat Polym, 2018, 33(2): 134-145.
52.	Zhao X, Han Y, Li J, et al. BMP-2 immobilized PLGA/hydroxyapatite fibrous scaffold via polydopamine stimulates osteoblast growth. Mater Sci Eng C Mater Biol Appl, 2017, 78: 658-666.
53.	Wang W, Yeung K. Bone grafts and biomaterials substitutes for bone defect repair: a review. Bioact Mater, 2017, 2(4): 224-247.
54.	Huang B, Yuan Y, Liu C. Biomaterial-guided immobilization and osteoactivity of bone morphogenetic protein-2. Appl Mater Today, 2020, 19: 100599.
55.	Sun Z, Ouyang L, Ma X, et al. Controllable and durable release of BMP-2-loaded 3D porous sulfonated polyetheretherketone (PEEK) for osteogenic activity enhancement. Colloids Surf B Biointerfaces, 2018, 171: 668-674.
56.	Sivaraj KK, Adams RH. Blood vessel formation and function in bone. Development, 2016, 143(15): 2706-2715.
57.	Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone, 2016, 91: 30-38.
58.	Yu H, Zeng X, Deng C, et al. Exogenous VEGF introduced by bioceramic composite materials promotes the restoration of bone defect in rabbits. Biomed Pharmacother, 2018, 98: 325-332.
59.	Aspenberg P. Annotation: parathyroid hormone and fracture healing. Acta Orthop, 2013, 84(1): 4-6.
60.	Jiang L, Zhang W, Wei L, et al. Early effects of parathyroid hormone on vascularized bone regeneration and implant osseointegration in aged rats. Biomaterials, 2018, 179: 15-28.
61.	Lombardi G, Ziemann E, Banfi G, et al. Physical activity-dependent regulation of parathyroid hormone and calcium-phosphorous metabolism. Int J Mol Sci, 2020, 21(15): 5388.
62.	Liang B, Huang J, Xu J, et al. Local delivery of a novel PTHrP via mesoporous bioactive glass scaffolds to improve bone regeneration in a rat posterolateral spinal fusion model. RSC advances, 2018, 8(22): 12484-12493.

1. Liu Y, Luo D, Wang T. Hierarchical structures of bone and bioinspired bone tissue engineering. Small, 2016, 12(34): 4611-4632.
2. Eryildiz M. Fabrication of drug-loaded 3D-printed bone scaffolds with radial gradient porosity. J Mater Eng Perform, 2022, 10(19): 32.
3. Sahu KK, Modi YK. Multi response optimization for compressive strength, porosity and dimensional accuracy of binder jetting 3D printed ceramic bone scaffolds. Ceram Int, 2022, 48(18): 26772-26783.
4. Yunna C, Mengru H, Lei W, et al. Macrophage M1/M2 polarization. Eur J Pharmacol, 2020, 877: 173090.
5. Civantos A, Martinez-Campos E, Ramos V, et al. Titanium coatings and surface modifications: toward clinically useful bioactive implants. ACS Biomater Sci Eng, 2017, 3(7): 1245-1261.
6. Memarian P, Sartor F, Bernardo E, et al. Osteogenic properties of 3D-printed silica-carbon-calcite composite scaffolds: novel approach for personalized bone tissue regeneration. Int J Mol Sci, 2021, 22(2): 475.
7. Zafar MJ, Zhu D, Zhang Z. 3D printing of bioceramics for bone tissue engineering. Materials (Basel), 2019, 12(20): 3361.
8. Suto M, Nemoto E, Kanaya S, et al. Nanohydroxyapatite increases BMP-2 expression via a p38 MAP kinase dependent pathway in periodontal ligament cells. Arch Oral Biol, 2013, 58(8): 1021-1028.
9. Ozeki K, Aoki H, Fukui Y. The effect of adsorbed vitamin D and K to hydroxyapatite on ALP activity of MC3T3-E1 cell. J Mater Sci Mater Med, 2008, 19(4): 1753-1757.
10. Esposito Corcione C, Gervaso F, Scalera F, et al. 3D printing of hydroxyapatite polymer-based composites for bone tissue engineering. j Polym Eng, 2017, 37(8): 741-746.
11. Kosik-Koziol A, Costantini M, Mroz A, et al. 3D bioprinted hydrogel model incorporating beta-tricalcium phosphate for calcified cartilage tissue engineering. Biofabrication, 2019, 11(3): 35016.
12. 沈红裕, 宋珂. 双相磷酸钙陶瓷在口腔种植的应用及研究进展. 口腔医学研究, 2022, 38(5): 404-407.
13. 姜达君, 贾伟涛, 张长青. 生物玻璃在骨修复中的研究进展. 中国修复重建外科杂志, 2017, 31(12): 1512-1516.
14. Gerhardt LC, Boccaccini AR. Bioactive glass and glass-ceramic scaffolds for bone tissue engineering. Materials (Basel), 2010, 3(7): 3867-3910.
15. Simorgh S, Alasvand N, Khodadadi M, et al. Additive manufacturing of bioactive glass biomaterials. Methods, 2022, 208: 75-91.
16. Ding Y, Liu X, Zhang J, et al. 3D printing polylactic acid polymer-bioactive glass loaded with bone cement for bone defect in weight-bearing area. Front Bioeng Biotechnol, 2022, 10: 947521.
17. Kim BS, Jang J, Chae S, et al. Three-dimensional bioprinting of cell-laden constructs with polycaprolactone protective layers for using various thermoplastic polymers. Biofabrication, 2016, 8(3): 35013.
18. Murariu M, Dubois P. PLA composites: from production to properties. Adv Drug Deliv Rev, 2016, 107: 17-46.
19. Mei F, Peng Y, Lu S, et al. Synthesis and characterization of biodegradable poly(lactic-co-glycolic acid). J Macromol Sci B, 2015, 54(5): 562-570.
20. Schliecker G, Schmidt C, Fuchs S, et al. Characterization of a homologous series of D, L-lactic acid oligomers; a mechanistic study on the degradation kinetics in vitro. Biomaterials, 2003, 24(21): 3835-3844.
21. Babilotte J, Martin B, Guduric V, et al. Development and characterization of a PLGA-HA composite material to fabricate 3D-printed scaffolds for bone tissue engineering. Mater Sci Eng C Mater Biol Appl, 2021, 118: 111334.
22. Panayotov IV, Orti V, Cuisinier F, et al. Polyetheretherketone (PEEK) for medical applications. J Mater Sci Mater Med, 2016, 27(7): 118.
23. Qi D, Wang N, Wang S, et al. High-strength porous polyetheretherketone/hydroxyapatite composite for the treatment of bone defect. Compos Commun, 2023, 38: 101473.
24. 唐鹿. 3D 打印聚酰胺材料的研究进展. 化工新型材料, 2021, 49(1): 28-31.
25. Zhang Y, Deng X, Jiang D, et al. Long-term results of anterior cervical corpectomy and fusion with nano-hydroxyapatite/polyamide 66 strut for cervical spondylotic myelopathy. Sci Rep, 2016, 6: 26751.
26. Li J, Hsu Y, Luo E, et al. Computer-aided design and manufacturing and rapid prototyped nanoscale hydroxyapatite/polyamide (n-HA/PA) construction for condylar defect caused by mandibular angle ostectomy. Aesthetic Plast Surg, 2011, 35(4): 636-640.
27. Turnbull G, Clarke J, Picard F, et al. 3D bioactive composite scaffolds for bone tissue engineering. Bioact Mater, 2018, 3(3): 278-314.
28. Bandyopadhyay A, Mitra I, Bose S. 3D printing for bone regeneration. Curr Osteoporos Rep, 2020, 18(5): 505-514.
29. Garzon-Hernandez S, Arias A, Garcia-Gonzalez D. A continuum constitutive model for FDM 3D printed thermoplastics. Compos B Eng, 2020, 201: 108373.
30. Thavornyutikarn B, Chantarapanich N, Sitthiseripratip K, et al. Bone tissue engineering scaffolding: computer-aided scaffolding techniques. Prog Biomater, 2014, 3: 61-102.
31. Ligon SC, Liska R, Stampfl J, et al. Polymers for 3D printing and customized additive manufacturing. Chem Rev, 2017, 117(15): 10212-10290.
32. Manzoor F, Golbang A, Jindal S, et al. 3D printed PEEK/HA composites for bone tissue engineering applications: effect of material formulation on mechanical performance and bioactive potential. J Mech Behav Biomed Mater, 2021, 121: 104601.
33. Wang WZ, Zhang BQ, Li MX, et al. 3D printing of PLA/n-HA composite scaffolds with customized mechanical properties and biological functions for bone tissue engineering. Compos B Eng, 2021, 224: 10192.
34. Charoo NA, Barakh Ali SF, Mohamed EM, et al. Selective laser sintering 3D printing - an overview of the technology and pharmaceutical applications. Drug Dev Ind Pharm, 2020, 46(6): 869-877.
35. Fina F, Madla CM, Goyanes A, et al. Fabricating 3D printed orally disintegrating printlets using selective laser sintering. Int J Pharm, 2018, 541(1/2): 101-107.
36. Feng P, Qiu X, Yang L, et al. Polydopamine constructed interfacial molecular bridge in nano-hydroxylapatite/polycaprolactone composite scaffold. Colloids Surf B Biointerfaces, 2022, 217: 112668.
37. Martin-Montal J, Pernas-Sanchez J, Varas D. Experimental characterization framework for SLA additive manufacturing materials. Polymers (Basel), 2021, 13(7): 1147.
38. Melchels FP, Feijen J, Grijpma DW. A review on stereolithography and its applications in biomedical engineering. Biomaterials, 2010, 31(24): 6121-6130.
39. Lee E, Sim J, Kweon H, et al. Determination of process parameters in stereolithography using neural network. J Mech Sci Technol, 2004, 18(3): 443-452.
40. Skoog SA, Goering PL, Narayan RJ. Stereolithography in tissue engineering. J Mater Sci Mater Med, 2014, 25(3): 845-856.
41. Kim K, Yeatts A, Dean D, et al. Stereolithographic bone scaffold design parameters: osteogenic differentiation and signal expression. Tissue Eng Part B Rev, 2010, 16(5): 523-539.
42. Tsang CHA, Zhakeyev A, Leung DYC, et al. GO-modified flexible polymer nanocomposites fabricated via 3D stereolithography. Front Chem Sci Eng, 2019, 13(4): 736-743.
43. Guillaume O, Geven MA, Sprecher CM, et al. Surface-enrichment with hydroxyapatite nanoparticles in stereolithography-fabricated composite polymer scaffolds promotes bone repair. Acta Biomater, 2017, 54: 386-398.
44. Bai L, Gong C, Chen W, et al. Additive manufacturing of customized metallic orthopedic implants: materials, structures, and surface modifications. Metals (Basel), 2019, 9(9): 1004.
45. Zhao Y, Chen H, Ran K, et al. Porous hydroxyapatite scaffold orchestrated with bioactive coatings for rapid bone repair. Biomater Adv, 2023, 144: 213202.
46. Hou J, Gao H, Wang Y, et al. Effect of mineralized layer topographies on stem cell behavior in microsphere scaffold. J Mater Sci, 2016, 32(9): 971-977.
47. Lu RJ, Wang X, He HX, et al. Tantalum-incorporated hydroxyapatite coating on titanium implants: its mechanical and in vitro osteogenic properties. J Mater Sci Mater Med, 2019, 30(10): 111.
48. Auclair-Daigle C, Bureau MN, Legoux JG, et al. Bioactive hydroxyapatite coatings on polymer composites for orthopedic implants. J Biomed Mater Res A, 2005, 73(4): 398-408.
49. Wu C, Zeng B, Shen D, et al. Biomechanical and osteointegration study of 3D-printed porous PEEK hydroxyapatite-coated scaffolds. J Biomater Sci Polym Ed, 2023, 34(4): 435-448.
50. Lett A, Sagadevan S, Paiman S, et al. Exploring the thumbprints of Ag-hydroxyapatite composite as a surface coating bone material for the implants. J Mater Res Technol, 2020, 9(6): 12824-12833.
51. Liu Y, Zhang Z, Lv H, et al. Surface modification of chitosan film via polydopamine coating to promote biomineralization in bone tissue engineering. J Bioact Compat Polym, 2018, 33(2): 134-145.
52. Zhao X, Han Y, Li J, et al. BMP-2 immobilized PLGA/hydroxyapatite fibrous scaffold via polydopamine stimulates osteoblast growth. Mater Sci Eng C Mater Biol Appl, 2017, 78: 658-666.
53. Wang W, Yeung K. Bone grafts and biomaterials substitutes for bone defect repair: a review. Bioact Mater, 2017, 2(4): 224-247.
54. Huang B, Yuan Y, Liu C. Biomaterial-guided immobilization and osteoactivity of bone morphogenetic protein-2. Appl Mater Today, 2020, 19: 100599.
55. Sun Z, Ouyang L, Ma X, et al. Controllable and durable release of BMP-2-loaded 3D porous sulfonated polyetheretherketone (PEEK) for osteogenic activity enhancement. Colloids Surf B Biointerfaces, 2018, 171: 668-674.
56. Sivaraj KK, Adams RH. Blood vessel formation and function in bone. Development, 2016, 143(15): 2706-2715.
57. Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone, 2016, 91: 30-38.
58. Yu H, Zeng X, Deng C, et al. Exogenous VEGF introduced by bioceramic composite materials promotes the restoration of bone defect in rabbits. Biomed Pharmacother, 2018, 98: 325-332.
59. Aspenberg P. Annotation: parathyroid hormone and fracture healing. Acta Orthop, 2013, 84(1): 4-6.
60. Jiang L, Zhang W, Wei L, et al. Early effects of parathyroid hormone on vascularized bone regeneration and implant osseointegration in aged rats. Biomaterials, 2018, 179: 15-28.
61. Lombardi G, Ziemann E, Banfi G, et al. Physical activity-dependent regulation of parathyroid hormone and calcium-phosphorous metabolism. Int J Mol Sci, 2020, 21(15): 5388.
62. Liang B, Huang J, Xu J, et al. Local delivery of a novel PTHrP via mesoporous bioactive glass scaffolds to improve bone regeneration in a rat posterolateral spinal fusion model. RSC advances, 2018, 8(22): 12484-12493.

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