Research progress of bioactive scaffolds in repair and regeneration of osteoporotic bone defects_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WU Yuangang , SUN Kaibo , ZENG Yi ,  SHEN Bin

Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P. R. China;

Corresponding author：

SHEN Bin, Email: shenbin_1971@163.com

Keywords：

Osteoporosis; bone defect; bioactive scaffold; regenerative medicine; osteogenic differentiation; biotechnology

DOI：

10.7507/1002-1892.202410018

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the research progress of bioactive scaffolds in the repair and regeneration of osteoporotic bone defects. Methods Recent literature on bioactive scaffolds for the repair of osteoporotic bone defects was reviewed to summarize various types of bioactive scaffolds and their associated repair methods. Results The application of bioactive scaffolds provides a new idea for the repair and regeneration of osteoporotic bone defects. For example, calcium phosphate ceramics scaffolds, hydrogel scaffolds, three-dimensional (3D)-printed biological scaffolds, metal scaffolds, as well as polymer material scaffolds and bone organoids, have all demonstrated good bone repair-promoting effects. However, in the pathological bone microenvironment of osteoporosis, the function of single-material scaffolds to promote bone regeneration is insufficient. Therefore, the design of bioactive scaffolds must consider multiple factors, including material biocompatibility, mechanical properties, bioactivity, bone conductivity, and osteogenic induction. Furthermore, physical and chemical surface modifications, along with advanced biotechnological approaches, can help improve the osteogenic microenvironment and promote the differentiation of bone cells. Conclusion With advancements in technology, the synergistic application of 3D bioprinting, bone organoids technologies, and advanced biotechnologies holds promise for providing more efficient bioactive scaffolds for the repair and regeneration of osteoporotic bone defects.

1.	中华医学会骨质疏松和骨矿盐疾病分会. 原发性骨质疏松症诊疗指南(2022). 中国全科医学, 2023, 26(14): 1671-1691.
2.	Walker MD, Shane E. Postmenopausal osteoporosis. N Engl J Med, 2023, 389(21): 1979-1991.
3.	邓淼月, 郭懿, 沈思雨, 等. 定量CT应用于绝经后女性骨质疏松症的研究进展. 临床医学进展, 2024, 14(1): 597-605.
4.	Wang L, Yu W, Yin X, et al. Prevalence of osteoporosis and fracture in China: The China osteoporosis prevalence study. JAMA Netw Open, 2021, 4(8): e2121106. doi: 10.1001/jamanetworkopen.2021.21106.
5.	Lo JC, Yang W, Park-Sigal JJ, et al. Osteoporosis and fracture risk among older US Asian adults. Curr Osteoporos Rep, 2023, 21(5): 592-608.
6.	Yu B, Wang CY. Osteoporosis and periodontal diseases—An update on their association and mechanistic links. Periodontol 2000, 2022, 89(1): 99-113.
7.	Muñoz M, Robinson K, Shibli-Rahhal A. Bone health and osteoporosis prevention and treatment. Clin Obstet Gynecol, 2020, 63(4): 770-787.
8.	Zhang H, Hu Y, Chen X, et al. Expert consensus on the bone repair strategy for osteoporotic fractures in China. Front Endocrinol (Lausanne), 2022, 13: 989648. doi: 10.3389/fendo.2022.989648.
9.	Zhang YY, Xie N, Sun XD, et al. Insights and implications of sexual dimorphism in osteoporosis. Bone Res, 2024, 12(1): 8. doi: 10.1038/s41413-023-00306-4.
10.	Chen YS, Lian WS, Kuo CW, et al. Epigenetic regulation of skeletal tissue integrity and osteoporosis development. Int J Mol Sci, 2020, 21(14): 4923. doi: 10.3390/ijms21144923.
11.	Sivakumar PM, Yetisgin AA, Sahin SB, et al. Bone tissue engineering: Anionic polysaccharides as promising scaffolds. Carbohydr Polym, 2022, 283: 119142. doi: 10.1016/j.carbpol.2022.119142.
12.	Peng Z, Zhao T, Zhou Y, et al. Bone tissue engineering via carbon-based nanomaterials. Adv Healthc Mater, 2020, 9(5): e1901495. doi: 10.1002/adhm.201901495.
13.	Heng BC, Bai Y, Li X, et al. Electroactive biomaterials for facilitating bone defect repair under pathological conditions. Adv Sci (Weinh), 2023, 10(2): e2204502. doi: 10.1002/advs.202204502.
14.	Tan B, Tang Q, Zhong Y, et al. Biomaterial-based strategies for maxillofacial tumour therapy and bone defect regeneration. Int J Oral Sci, 2021, 13(1): 9. doi: 10.1038/s41368-021-00113-9.
15.	Fan L, Chen S, Yang M, et al. Metallic materials for bone repair. Adv Healthc Mater, 2024, 13(3): e2302132. doi: 10.1002/adhm.202302132.
16.	Khare D, Basu B, Dubey AK. Electrical stimulation and piezoelectric biomaterials for bone tissue engineering applications. Biomaterials, 2020, 258: 120280. doi: 10.1016/j.biomaterials.2020.120280.
17.	Ren Y, Fan L, Alkildani S, et al. Barrier Membranes for Guided Bone Regeneration (GBR): A focus on recent advances in collagen membranes. Int J Mol Sci, 2022, 23(23): 14987. doi: 10.3390/ijms232314987.
18.	Sadowska JM, Ginebra MP. Inflammation and biomaterials: role of the immune response in bone regeneration by inorganic scaffolds. J Mater Chem B, 2020, 8(41): 9404-9427.
19.	Donos N, Akcali A, Padhye N, et al. Bone regeneration in implant dentistry: Which are the factors affecting the clinical outcome? Periodontol 2000, 2023, 93(1): 26-55.
20.	Patel D, Wairkar S. Bone regeneration in osteoporosis: opportunities and challenges. Drug Deliv Transl Res, 2023, 13(2): 419-432.
21.	Zhao X, Ma H, Han H, et al. Precision medicine strategies for spinal degenerative diseases: Injectable biomaterials with in situ repair and regeneration. Mater Today Bio, 2022, 16: 100336. doi: 10.1016/j.mtbio.2022.100336.
22.	Liu X, Ma Y, Chen M, et al. Ba/Mg co-doped hydroxyapatite/PLGA composites enhance X-ray imaging and bone defect regeneration. J Mater Chem B, 2021, 9(33): 6691-6702.
23.	Mofakhami S, Salahinejad E. Biphasic calcium phosphate microspheres in biomedical applications. J Control Release, 2021, 338: 527-536.
24.	Mo X, Zhang D, Liu K, et al. Nano-hydroxyapatite composite scaffolds loaded with bioactive factors and drugs for bone tissue engineering. Int J Mol Sci, 2023, 24(2): 1291. doi: 10.3390/ijms24021291.
25.	Wang X, Huang S, Peng Q. Metal ion-doped hydroxyapatite-based materials for bone defect restoration. Bioengineering (Basel), 2023, 10(12): 1367. doi: 10.3390/bioengineering10121367.
26.	Zhao R, Chen S, Zhao W, et al. A bioceramic scaffold composed of strontium-doped three-dimensional hydroxyapatite whiskers for enhanced bone regeneration in osteoporotic defects. Theranostics, 2020, 10(4): 1572-1589.
27.	Li J, Xia T, Zhao Q, et al. Biphasic calcium phosphate recruits Tregs to promote bone regeneration. Acta Biomater, 2024, 176: 432-444.
28.	Rana N, Suliman S, Mohamed-Ahmed S, et al. Systemic and local innate immune responses to surgical co-transplantation of mesenchymal stromal cells and biphasic calcium phosphate for bone regeneration. Acta Biomater, 2022, 141: 440-453.
29.	彭双麟, 姚志浩, 罗道文, 等. 多孔双相磷酸钙陶瓷修复骨质疏松症大鼠颅骨极量缺损的实验研究. 口腔医学研究, 2019, 35(4): 377-381.
30.	Zheng S, Li D, Liu Q, et al. Surface-modified nano-hydroxyapatite uniformly dispersed on high-porous gelma scaffold surfaces for enhanced osteochondral regeneration. Int J Nanomedicine, 2023, 18: 5907-5923.
31.	Jeuken RM, Roth AK, Peters MJM, et al. In vitro and in vivo study on the osseointegration of BCP-coated versus uncoated nondegradable thermoplastic polyurethane focal knee resurfacing implants. J Biomed Mater Res B Appl Biomater, 2020, 108(8): 3370-3382.
32.	Xue X, Hu Y, Wang S, et al. Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering. Bioact Mater, 2021, 12: 327-339.
33.	Zhou B, Jiang X, Zhou X, et al. GelMA-based bioactive hydrogel scaffolds with multiple bone defect repair functions: therapeutic strategies and recent advances. Biomater Res, 2023, 27(1): 86. doi: 10.1186/s40824-023-00422-6.
34.	Gao Y, Zhang X, Zhou H. Biomimetic hydrogel applications and challenges in bone, cartilage, and nerve repair. Pharmaceutics, 2023, 15(10): 2405. doi: 10.3390/pharmaceutics15102405.
35.	Zhang H, Wu S, Chen W, et al. Bone/cartilage targeted hydrogel: Strategies and applications. Bioact Mater, 2022, 23: 156-169.
36.	韩晶媛, 李欣玲, 韩金煜, 等. 载药温敏水凝胶调节巨噬细胞M2极化促进骨质疏松骨缺损修复. 牙体牙髓牙周病学杂志, 2024, 29(2): 74-79.
37.	Li J, Li L, Wu T, et al. An injectable thermosensitive hydrogel containing resveratrol and dexamethasone-loaded carbonated hydroxyapatite microspheres for the regeneration of osteoporotic bone defects. Small Methods, 2024, 8(1): e2300843. doi: 10.1002/smtd.202300843.
38.	Nie L, Wu Q, Long H, et al. Development of chitosan/gelatin hydrogels incorporation of biphasic calcium phosphate nanoparticles for bone tissue engineering. J Biomater Sci Polym Ed, 2019, 30(17): 1636-1657.
39.	Sen KS, Duarte Campos DF, Köpf M, et al. The effect of addition of calcium phosphate particles to hydrogel-based composite materials on stiffness and differentiation of mesenchymal stromal cells toward osteogenesis. Adv Healthc Mater, 2018, 7(18): e1800343. doi: 10.1002/adhm.201800343.
40.	Wu N, Li J, Li X, et al. 3D printed biopolymer/black phosphorus nanoscaffolds for bone implants: A review. Int J Biol Macromol, 2024, 279(Pt 3): 135227. doi: 10.1016/j.ijbiomac.2024.135227.
41.	Ren Y, Zhang C, Liu Y, et al. Advances in 3D printing of highly bioadaptive bone tissue engineering scaffolds. ACS Biomater Sci Eng, 2024, 10(1): 255-270.
42.	Yan C, Zhang P, Qin Q, et al. 3D-printed bone regeneration scaffolds modulate bone metabolic homeostasis through vascularization for osteoporotic bone defects. Biomaterials, 2024, 311: 122699. doi: 10.1016/j.biomaterials.2024.122699.
43.	Li Z, Zhao Y, Wang Z, et al. Engineering multifunctional hydrogel-integrated 3D printed bioactive prosthetic interfaces for osteoporotic osseointegration. Adv Healthc Mater, 2022, 11(11): e2102535. doi: 10.1002/adhm.202102535.
44.	Xie Y, Li S, Zhang T, et al. Titanium mesh for bone augmentation in oral implantology: current application and progress. Int J Oral Sci, 2020, 12(1): 37. doi: 10.1038/s41368-020-00107-z.
45.	Qian H, Yao Q, Pi L, et al. Current advances and applications of tantalum element in infected bone defects. ACS Biomater Sci Eng, 2023, 9(1): 1-19.
46.	Wu Y, Liu J, Kang L, et al. An overview of 3D printed metal implants in orthopedic applications: Present and future perspectives. Heliyon, 2023, 9(7): e17718. doi: 10.1016/j.heliyon.2023.e17718.
47.	Wang X, Li Z, Wang Z, et al. Incorporation of bone morphogenetic protein-2 and osteoprotegerin in 3D-printed Ti6Al4V scaffolds enhances osseointegration under osteoporotic conditions. Front Bioeng Biotechnol, 2021, 9: 754205. doi: 10.3389/fbioe.2021.754205.
48.	Zhao Z, Li G, Ruan H, et al. Capturing magnesium ions via microfluidic hydrogel microspheres for promoting cancellous bone regeneration. ACS Nano, 2021, 15(8): 13041-13054.
49.	Ma L, Wang X, Zhao N, et al. Integrating 3D printing and biomimetic mineralization for personalized enhanced osteogenesis, angiogenesis, and osteointegration. ACS Appl Mater Interfaces, 2018, 10(49): 42146-42154.
50.	Meng M, Wang J, Huang H, et al. 3D printing metal implants in orthopedic surgery: Methods, applications and future prospects. J Orthop Translat, 2023, 42: 94-112.
51.	蔡兴博, 董艳, 王斌, 等. 金属基3D打印支架的构建与功能化研究进展. 生物骨科材料与临床研究, 2022, 19(6): 82-87.
52.	Ye B, Wu B, Su Y, et al. Recent advances in the application of natural and synthetic polymer-based scaffolds in musculoskeletal regeneration. Polymers (Basel), 2022, 14(21): 4566. doi: 10.3390/polym14214566.
53.	Rajan RK, Chandran S, Sreelatha HV, et al. Pamidronate-encapsulated electrospun polycaprolactone-based composite scaffolds for osteoporotic bone defect repair. ACS Appl Bio Mater, 2020, 3(4): 1924-1933.
54.	Yu S, Sun T, Liu W, et al. PLGA cage-like structures loaded with Sr/Mg-doped hydroxyapatite for repairing osteoporotic bone defects. Macromol Biosci, 2022, 22(8): e2200092. doi: 10.1002/mabi.202200092.
55.	Liao C, Li Y, Tjong SC. Polyetheretherketone and its composites for bone replacement and regeneration. Polymers (Basel), 2020, 12(12): 2858. doi: 10.3390/polym12122858.
56.	Zhang Y, Wang L, Long X, et al. Multi-functional PEEK implants enhance osseointegration in OVX rat by remodeling the bone immune microenvironment. Colloids Surf B Biointerfaces, 2025, 245: 114219. doi: 10.1016/j.colsurfb.2024.114219.
57.	Chen S, Chen X, Geng Z, Su J. The horizon of bone organoid: A perspective on construction and application. Bioact Mater, 2022, 18: 15-25.
58.	Wang J, Wu Y, Li G, et al. Engineering large-scale self-mineralizing bone organoids with bone matrix-inspired hydroxyapatite hybrid bioinks. Adv Mater, 2024, 36(30): e2309875. doi: 10.1002/adma.202309875.
59.	Zhao D, Saiding Q, Li Y, et al. Bone organoids: Recent advances and future challenges. Adv Healthc Mater, 2024, 13(5): e2302088. doi: 10.1002/adhm.202302088.

1. 中华医学会骨质疏松和骨矿盐疾病分会. 原发性骨质疏松症诊疗指南(2022). 中国全科医学, 2023, 26(14): 1671-1691.
2. Walker MD, Shane E. Postmenopausal osteoporosis. N Engl J Med, 2023, 389(21): 1979-1991.
3. 邓淼月, 郭懿, 沈思雨, 等. 定量CT应用于绝经后女性骨质疏松症的研究进展. 临床医学进展, 2024, 14(1): 597-605.
4. Wang L, Yu W, Yin X, et al. Prevalence of osteoporosis and fracture in China: The China osteoporosis prevalence study. JAMA Netw Open, 2021, 4(8): e2121106. doi: 10.1001/jamanetworkopen.2021.21106.
5. Lo JC, Yang W, Park-Sigal JJ, et al. Osteoporosis and fracture risk among older US Asian adults. Curr Osteoporos Rep, 2023, 21(5): 592-608.
6. Yu B, Wang CY. Osteoporosis and periodontal diseases—An update on their association and mechanistic links. Periodontol 2000, 2022, 89(1): 99-113.
7. Muñoz M, Robinson K, Shibli-Rahhal A. Bone health and osteoporosis prevention and treatment. Clin Obstet Gynecol, 2020, 63(4): 770-787.
8. Zhang H, Hu Y, Chen X, et al. Expert consensus on the bone repair strategy for osteoporotic fractures in China. Front Endocrinol (Lausanne), 2022, 13: 989648. doi: 10.3389/fendo.2022.989648.
9. Zhang YY, Xie N, Sun XD, et al. Insights and implications of sexual dimorphism in osteoporosis. Bone Res, 2024, 12(1): 8. doi: 10.1038/s41413-023-00306-4.
10. Chen YS, Lian WS, Kuo CW, et al. Epigenetic regulation of skeletal tissue integrity and osteoporosis development. Int J Mol Sci, 2020, 21(14): 4923. doi: 10.3390/ijms21144923.
11. Sivakumar PM, Yetisgin AA, Sahin SB, et al. Bone tissue engineering: Anionic polysaccharides as promising scaffolds. Carbohydr Polym, 2022, 283: 119142. doi: 10.1016/j.carbpol.2022.119142.
12. Peng Z, Zhao T, Zhou Y, et al. Bone tissue engineering via carbon-based nanomaterials. Adv Healthc Mater, 2020, 9(5): e1901495. doi: 10.1002/adhm.201901495.
13. Heng BC, Bai Y, Li X, et al. Electroactive biomaterials for facilitating bone defect repair under pathological conditions. Adv Sci (Weinh), 2023, 10(2): e2204502. doi: 10.1002/advs.202204502.
14. Tan B, Tang Q, Zhong Y, et al. Biomaterial-based strategies for maxillofacial tumour therapy and bone defect regeneration. Int J Oral Sci, 2021, 13(1): 9. doi: 10.1038/s41368-021-00113-9.
15. Fan L, Chen S, Yang M, et al. Metallic materials for bone repair. Adv Healthc Mater, 2024, 13(3): e2302132. doi: 10.1002/adhm.202302132.
16. Khare D, Basu B, Dubey AK. Electrical stimulation and piezoelectric biomaterials for bone tissue engineering applications. Biomaterials, 2020, 258: 120280. doi: 10.1016/j.biomaterials.2020.120280.
17. Ren Y, Fan L, Alkildani S, et al. Barrier Membranes for Guided Bone Regeneration (GBR): A focus on recent advances in collagen membranes. Int J Mol Sci, 2022, 23(23): 14987. doi: 10.3390/ijms232314987.
18. Sadowska JM, Ginebra MP. Inflammation and biomaterials: role of the immune response in bone regeneration by inorganic scaffolds. J Mater Chem B, 2020, 8(41): 9404-9427.
19. Donos N, Akcali A, Padhye N, et al. Bone regeneration in implant dentistry: Which are the factors affecting the clinical outcome? Periodontol 2000, 2023, 93(1): 26-55.
20. Patel D, Wairkar S. Bone regeneration in osteoporosis: opportunities and challenges. Drug Deliv Transl Res, 2023, 13(2): 419-432.
21. Zhao X, Ma H, Han H, et al. Precision medicine strategies for spinal degenerative diseases: Injectable biomaterials with in situ repair and regeneration. Mater Today Bio, 2022, 16: 100336. doi: 10.1016/j.mtbio.2022.100336.
22. Liu X, Ma Y, Chen M, et al. Ba/Mg co-doped hydroxyapatite/PLGA composites enhance X-ray imaging and bone defect regeneration. J Mater Chem B, 2021, 9(33): 6691-6702.
23. Mofakhami S, Salahinejad E. Biphasic calcium phosphate microspheres in biomedical applications. J Control Release, 2021, 338: 527-536.
24. Mo X, Zhang D, Liu K, et al. Nano-hydroxyapatite composite scaffolds loaded with bioactive factors and drugs for bone tissue engineering. Int J Mol Sci, 2023, 24(2): 1291. doi: 10.3390/ijms24021291.
25. Wang X, Huang S, Peng Q. Metal ion-doped hydroxyapatite-based materials for bone defect restoration. Bioengineering (Basel), 2023, 10(12): 1367. doi: 10.3390/bioengineering10121367.
26. Zhao R, Chen S, Zhao W, et al. A bioceramic scaffold composed of strontium-doped three-dimensional hydroxyapatite whiskers for enhanced bone regeneration in osteoporotic defects. Theranostics, 2020, 10(4): 1572-1589.
27. Li J, Xia T, Zhao Q, et al. Biphasic calcium phosphate recruits Tregs to promote bone regeneration. Acta Biomater, 2024, 176: 432-444.
28. Rana N, Suliman S, Mohamed-Ahmed S, et al. Systemic and local innate immune responses to surgical co-transplantation of mesenchymal stromal cells and biphasic calcium phosphate for bone regeneration. Acta Biomater, 2022, 141: 440-453.
29. 彭双麟, 姚志浩, 罗道文, 等. 多孔双相磷酸钙陶瓷修复骨质疏松症大鼠颅骨极量缺损的实验研究. 口腔医学研究, 2019, 35(4): 377-381.
30. Zheng S, Li D, Liu Q, et al. Surface-modified nano-hydroxyapatite uniformly dispersed on high-porous gelma scaffold surfaces for enhanced osteochondral regeneration. Int J Nanomedicine, 2023, 18: 5907-5923.
31. Jeuken RM, Roth AK, Peters MJM, et al. In vitro and in vivo study on the osseointegration of BCP-coated versus uncoated nondegradable thermoplastic polyurethane focal knee resurfacing implants. J Biomed Mater Res B Appl Biomater, 2020, 108(8): 3370-3382.
32. Xue X, Hu Y, Wang S, et al. Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering. Bioact Mater, 2021, 12: 327-339.
33. Zhou B, Jiang X, Zhou X, et al. GelMA-based bioactive hydrogel scaffolds with multiple bone defect repair functions: therapeutic strategies and recent advances. Biomater Res, 2023, 27(1): 86. doi: 10.1186/s40824-023-00422-6.
34. Gao Y, Zhang X, Zhou H. Biomimetic hydrogel applications and challenges in bone, cartilage, and nerve repair. Pharmaceutics, 2023, 15(10): 2405. doi: 10.3390/pharmaceutics15102405.
35. Zhang H, Wu S, Chen W, et al. Bone/cartilage targeted hydrogel: Strategies and applications. Bioact Mater, 2022, 23: 156-169.
36. 韩晶媛, 李欣玲, 韩金煜, 等. 载药温敏水凝胶调节巨噬细胞M2极化促进骨质疏松骨缺损修复. 牙体牙髓牙周病学杂志, 2024, 29(2): 74-79.
37. Li J, Li L, Wu T, et al. An injectable thermosensitive hydrogel containing resveratrol and dexamethasone-loaded carbonated hydroxyapatite microspheres for the regeneration of osteoporotic bone defects. Small Methods, 2024, 8(1): e2300843. doi: 10.1002/smtd.202300843.
38. Nie L, Wu Q, Long H, et al. Development of chitosan/gelatin hydrogels incorporation of biphasic calcium phosphate nanoparticles for bone tissue engineering. J Biomater Sci Polym Ed, 2019, 30(17): 1636-1657.
39. Sen KS, Duarte Campos DF, Köpf M, et al. The effect of addition of calcium phosphate particles to hydrogel-based composite materials on stiffness and differentiation of mesenchymal stromal cells toward osteogenesis. Adv Healthc Mater, 2018, 7(18): e1800343. doi: 10.1002/adhm.201800343.
40. Wu N, Li J, Li X, et al. 3D printed biopolymer/black phosphorus nanoscaffolds for bone implants: A review. Int J Biol Macromol, 2024, 279(Pt 3): 135227. doi: 10.1016/j.ijbiomac.2024.135227.
41. Ren Y, Zhang C, Liu Y, et al. Advances in 3D printing of highly bioadaptive bone tissue engineering scaffolds. ACS Biomater Sci Eng, 2024, 10(1): 255-270.
42. Yan C, Zhang P, Qin Q, et al. 3D-printed bone regeneration scaffolds modulate bone metabolic homeostasis through vascularization for osteoporotic bone defects. Biomaterials, 2024, 311: 122699. doi: 10.1016/j.biomaterials.2024.122699.
43. Li Z, Zhao Y, Wang Z, et al. Engineering multifunctional hydrogel-integrated 3D printed bioactive prosthetic interfaces for osteoporotic osseointegration. Adv Healthc Mater, 2022, 11(11): e2102535. doi: 10.1002/adhm.202102535.
44. Xie Y, Li S, Zhang T, et al. Titanium mesh for bone augmentation in oral implantology: current application and progress. Int J Oral Sci, 2020, 12(1): 37. doi: 10.1038/s41368-020-00107-z.
45. Qian H, Yao Q, Pi L, et al. Current advances and applications of tantalum element in infected bone defects. ACS Biomater Sci Eng, 2023, 9(1): 1-19.
46. Wu Y, Liu J, Kang L, et al. An overview of 3D printed metal implants in orthopedic applications: Present and future perspectives. Heliyon, 2023, 9(7): e17718. doi: 10.1016/j.heliyon.2023.e17718.
47. Wang X, Li Z, Wang Z, et al. Incorporation of bone morphogenetic protein-2 and osteoprotegerin in 3D-printed Ti6Al4V scaffolds enhances osseointegration under osteoporotic conditions. Front Bioeng Biotechnol, 2021, 9: 754205. doi: 10.3389/fbioe.2021.754205.
48. Zhao Z, Li G, Ruan H, et al. Capturing magnesium ions via microfluidic hydrogel microspheres for promoting cancellous bone regeneration. ACS Nano, 2021, 15(8): 13041-13054.
49. Ma L, Wang X, Zhao N, et al. Integrating 3D printing and biomimetic mineralization for personalized enhanced osteogenesis, angiogenesis, and osteointegration. ACS Appl Mater Interfaces, 2018, 10(49): 42146-42154.
50. Meng M, Wang J, Huang H, et al. 3D printing metal implants in orthopedic surgery: Methods, applications and future prospects. J Orthop Translat, 2023, 42: 94-112.
51. 蔡兴博, 董艳, 王斌, 等. 金属基3D打印支架的构建与功能化研究进展. 生物骨科材料与临床研究, 2022, 19(6): 82-87.
52. Ye B, Wu B, Su Y, et al. Recent advances in the application of natural and synthetic polymer-based scaffolds in musculoskeletal regeneration. Polymers (Basel), 2022, 14(21): 4566. doi: 10.3390/polym14214566.
53. Rajan RK, Chandran S, Sreelatha HV, et al. Pamidronate-encapsulated electrospun polycaprolactone-based composite scaffolds for osteoporotic bone defect repair. ACS Appl Bio Mater, 2020, 3(4): 1924-1933.
54. Yu S, Sun T, Liu W, et al. PLGA cage-like structures loaded with Sr/Mg-doped hydroxyapatite for repairing osteoporotic bone defects. Macromol Biosci, 2022, 22(8): e2200092. doi: 10.1002/mabi.202200092.
55. Liao C, Li Y, Tjong SC. Polyetheretherketone and its composites for bone replacement and regeneration. Polymers (Basel), 2020, 12(12): 2858. doi: 10.3390/polym12122858.
56. Zhang Y, Wang L, Long X, et al. Multi-functional PEEK implants enhance osseointegration in OVX rat by remodeling the bone immune microenvironment. Colloids Surf B Biointerfaces, 2025, 245: 114219. doi: 10.1016/j.colsurfb.2024.114219.
57. Chen S, Chen X, Geng Z, Su J. The horizon of bone organoid: A perspective on construction and application. Bioact Mater, 2022, 18: 15-25.
58. Wang J, Wu Y, Li G, et al. Engineering large-scale self-mineralizing bone organoids with bone matrix-inspired hydroxyapatite hybrid bioinks. Adv Mater, 2024, 36(30): e2309875. doi: 10.1002/adma.202309875.
59. Zhao D, Saiding Q, Li Y, et al. Bone organoids: Recent advances and future challenges. Adv Healthc Mater, 2024, 13(5): e2302088. doi: 10.1002/adhm.202302088.

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