Bifunctional biomaterials: An innovative strategy for synergistic bone tumor therapy and bone regeneration_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

FENG Weike ¹ , CHANG Bin ¹ , WANG Chunyang ¹ ,  FAN Bo ²

1. First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou Gansu, 730030, P. R. China;
2. Department of Spinal Surgery, the 940th Hospital of the Joint Logistic Support Force of Chinese PLA, Lanzhou Gansu, 730050, P. R. China;

Corresponding?author：

FAN Bo, Email: borger123@163.com

Keywords：

Bifunctional biomaterials; bone tumors; bone regeneration; synergistic therapy; antitumor; bone defect repair

DOI：

10.7507/1002-1892.202510084

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review research progress of bifunctional biomaterials in the treatment of bone tumors and bone defects in recent years, aiming to provide assistance for the further research of bifunctional biomaterials. Methods A wide range of domestic and international literature on the preparation and properties of novel bifunctional biomaterials in recent years was reviewed, followed by summary and analysis. Carrier-functionalized materials, intrinsically active materials, and immune-engineered materials were summarized respectively, and discussions were conducted from aspects such as anti-tumor effects and controlled drug release. Results Studies have revealed that, unlike traditional biomaterials, the novel bifunctional biomaterials can effectively inhibit the in-situ recurrence of bone tumors through precise drug delivery, external field-responsive tumor killing and immunomodulatory anti-tumor effects. Meanwhile, relying on osteoconduction, osteoinduction, and tissue engineering technologies, they promote new bone formation and bone functional reconstruction in bone defect areas. Conclusion Novel multifunctional biomaterials can inhibit bone tumor cells and promote new bone formation at the site of bone defects.

Citation： FENG Weike, CHANG Bin, WANG Chunyang, FAN Bo. Bifunctional biomaterials: An innovative strategy for synergistic bone tumor therapy and bone regeneration. Chinese Journal of Reparative and Reconstructive Surgery, 2026, 40(4): 681-688. doi: 10.7507/1002-1892.202510084 Copy

1.	Zhang H, Wang Y, Qiang H, et al. Exploring the frontiers: The potential and challenges of bioactive scaffolds in osteosarcoma treatment and bone regeneration. Mater Today Bio, 2024, 29: 101276. doi: 10.1016/j.mtbio.2024.101276.
2.	Liu WB, Dong SH, Hu WH, et al. A simple, universal and multifunctional template agent for personalized treatment of bone tumors. Bioact Mater, 2021, 12: 292-302.
3.	Park JB, Lakes RS. Biomaterials. An introduction. New York: Springer , 2007: 99-100.
4.	Niinomi M, Nakai M, Hieda J. Development of new metallic alloys for biomedical applications. Acta Biomater, 2012, 8(11): 3888-3903.
5.	Wang X, Xu S, Zhou S, et al. Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review. Biomaterials, 2016, 83: 127-141.
6.	Vaiani L, Boccaccio A, Uva AE, et al. Ceramic materials for biomedical applications: an overview on properties and fabrication processes. J Funct Biomater, 2023, 14(3): 146. doi: 10.3390/jfb14030146.
7.	Belluomo R, Khodaei A, Amin Yavari S. Additively manufactured Bi-functionalized bioceramics for reconstruction of bone tumor defects. Acta Biomater, 2023, 156: 234-249.
8.	Han Y, Jia B, Lian M, et al. High-precision, gelatin-based, hybrid, bilayer scaffolds using melt electro-writing to repair cartilage injury. Bioact Mater, 2021, 6(7): 2173-2186.
9.	Cyphert EL, Kanagasegar N, Zhang N, et al. PMMA bone cement composite functions as an adjuvant chemotherapeutic platform for localized and multi-window release during bone reconstruction. Macromol Biosci, 2022, 22(5): e2100415. doi: 10.1002/mabi.202100415.
10.	Sun L, Berndt CC, Gross KA, et al. Material fundamentals and clinical performance of plasma-sprayed hydroxyapatite coatings: a review. J Biomed Mater Res, 2001, 58(5): 570-592.
11.	Ma R, Tang T. Current strategies to improve the bioactivity of PEEK. Int J Mol Sci, 2014, 15(4): 5426-5445.
12.	LeGeros RZ. Calcium phosphate-based osteoinductive materials. Chem Rev, 2008, 108(11): 4742-4753.
13.	Liu Y, Raina DB, Sebastian S, et al. Sustained and controlled delivery of doxorubicin from an in-situ setting biphasic hydroxyapatite carrier for local treatment of a highly proliferative human osteosarcoma. Acta Biomater, 2021, 131: 555-571.
14.	Gao J, Huang J, Shi R, et al. Loading and releasing behavior of selenium and doxorubicin hydrochloride in hydroxyapatite with different morphologies. ACS Omega, 2021, 6(12): 8365-8375.
15.	Zhou J, Huo T, Miu J, et al. Bone-adhesive peptide hydrogel loaded with cisplatin for postoperative treatment of osteosarcoma. ACS Appl Mater Interfaces, 2025, 17(7): 11073-11084.
16.	Sowjanya M, Debnath S, Lavanya P, et al. Polymers used in the designing of controlled drug delivery system. Research Journal of Pharmacy and Technology, 2017, 10(3): 903-912.
17.	Jing Z, Yuan W, Wang J, et al. Simvastatin/hydrogel-loaded 3D-printed titanium alloy scaffolds suppress osteosarcoma via TF/NOX2-associated ferroptosis while repairing bone defects. Bioact Mater, 2023, 33: 223-241.
18.	Tan W, Gao C, Feng P, et al. Dual-functional scaffolds of poly(L-lactic acid)/nanohydroxyapatite encapsulated with metformin: Simultaneous enhancement of bone repair and bone tumor inhibition. Mater Sci Eng C Mater Biol Appl, 2021, 120: 111592. doi: 10.1016/j.msec.2020.111592.
19.	Zeng Y, Yuan J, Ran Z, et al. Chitosan/NH₂-MIL-125 (Ti) scaffold loaded with doxorubicin for postoperative bone tumor clearance and osteogenesis: An in vitro study. Int J Biol Macromol, 2024, 263(Pt 2): 130368. doi: 10.1016/j.ijbiomac.2024.130368.
20.	Bauer L, Hadzhieva Z, Bazina I, et al. Chitosan/bioactive glass microparticles enriched with therapeutic metal ions for bone tissue engineering. ACS Appl Bio Mater, 2025, 8(8): 7201-7215.
21.	Vladu AF, Albu Kaya MG, Ficai A, et al. Localized combination therapy using collagen-hydroxyapatite bone grafts for simultaneous bone cancer inhibition and tissue regeneration. Polymers (Basel), 2025, 17(16): 2239. doi: 10.3390/polym17162239.
22.	Rezk AI, Lee J, Kim BS, et al. Strategically designed bifunctional polydopamine enwrapping polycaprolactone-hydroxyapatite-doxorubicin composite nanofibers for osteosarcoma treatment and bone regeneration. ACS Appl Mater Interfaces, 2024, 16(18): 22946-22957.
23.	Liu J, Lin S, Dang J, et al. Anticancer and bone-enhanced nano-hydroxyapatite/gelatin/polylactic acid fibrous membrane with dual drug delivery and sequential release for osteosarcoma. Int J Biol Macromol, 2023, 240: 124406. doi: 10.1016/j.ijbiomac.2023.124406.
24.	Liu X, Zhang P, Xu M, et al. Mixed-valence vanadium-doped mesoporous bioactive glass for treatment of tumor-associated bone defects. J Mater Chem B, 2025, 13(9): 3138-3160.
25.	Li C, Zhang W, Nie Y, et al. Time-sequential and multi-functional 3D printed MgO₂/PLGA scaffold developed as a novel biodegradable and bioactive bone substitute for challenging postsurgical osteosarcoma treatment. Adv Mater, 2024, 36(34): e2308875. doi: 10.1002/adma.202308875.
26.	Huang H, Qiang L, Fan M, et al. 3D-printed tri-element-doped hydroxyapatite/ polycaprolactone composite scaffolds with antibacterial potential for osteosarcoma therapy and bone regeneration. Bioact Mater, 2023, 31: 18-37.
27.	Gao M, Feng K, Zhang X, et al. Nanoassembly with self-regulated magnetic thermal therapy and controlled immuno-modulating agent release for improved immune response. J Control Release, 2023, 357: 40-51.
28.	Tavares FJTM, Soares PIP, Silva JC, et al. Preparation and in vitro characterization of magnetic CS/PVA/HA/pSPIONs scaffolds for magnetic hyperthermia and bone regeneration. Int J Mol Sci, 2023, 24(2): 1128. doi: 10.3390/ijms24021128.
29.	Kesse X, Adam A, Begin-Colin S, et al. Elaboration of superparamagnetic and bioactive multicore-shell nanoparticles (γ-Fe₂O₃@SiO₂-CaO): A promising material for bone cancer treatment. ACS Appl Mater Interfaces, 2020, 12(42): 47820-47830.
30.	Tithito T, Sillapaprayoon S, Chantho V, et al. Evaluation of magnetic hyperthermia, drug delivery and biocompatibility (bone cell adhesion and zebrafish assays) of trace element co-doped hydroxyapatite combined with Mn-Zn ferrite for bone tissue applications. RSC Adv, 2024, 14(40): 29242-29253.
31.	Wang J, Zhou J, Xie Z, et al. Multifunctional 4D printed shape memory composite scaffolds with photothermal and magnetothermal effects for multimodal tumor therapy and bone repair. Biofabrication, 2025, 17(2). doi: 10.1088/1758-5090/adc29e.
32.	Xu C, Xia Y, Zhuang P, et al. FePSe₃-nanosheets-integrated cryogenic-3D-printed multifunctional calcium phosphate scaffolds for synergistic therapy of osteosarcoma. Small, 2023, 19(38): e2303636. doi: 10.1002/smll.202303636.
33.	Du J, Ding H, Fu S, et al. Bismuth-coated 80S15C bioactive glass scaffolds for photothermal antitumor therapy and bone regeneration. Front Bioeng Biotechnol, 2023, 10: 1098923. doi: 10.3389/fbioe.2022.1098923.
34.	Jian G, Wang S, Wang X, et al. Enhanced sequential osteosarcoma therapy using a 3D-Printed bioceramic scaffold combined with 2D nanosheets via NIR-Ⅱ photothermal-chemodynamic synergy. Bioact Mater, 2025, 50: 540-555.
35.	Cheung EC, Vousden KH. The role of ROS in tumour development and progression. Nat Rev Cancer, 2022, 22(5): 280-297.
36.	Zhang D, Tan J, Xu R, et al. Collaborative design of MgO/FeOx nanosheets on titanium: Combining therapy with regeneration. Small, 2023, 19(5): e2204852. doi: 10.1002/smll.202204852.
37.	Xu X, Wang H, Mei X, et al. “Antenna Effect”-enhanced AuNPs@rGO photothermal coating promotes 3D printing of osteogenic active scaffolds to repair bone defects after malignant tumor surgery. Adv Sci (Weinh), 2025, 12(15): e2417346. doi: 10.1002/advs.202417346.
38.	Chen Z, Sang L, Liu Y, et al. Sono-Piezo dynamic therapy: Utilizing piezoelectric materials as sonosensitizer for sonodynamic therapy. Adv Sci (Weinh), 2025, 12(12): e2417439. doi: 10.1002/advs.202417439.
39.	Shuai C, Zhang Z, Chen M, et al. 3D-printed scaffold achieves synergistic chemo-sonodynamic therapy for tumorous bone defect. ACS Appl Bio Mater, 2025, 8(5): 3920-3931.
40.	Fang H, Zhu D, Chen Y, et al. Ultrasound-responsive 4D bioscaffold for synergistic sonopiezoelectric-gaseous osteosarcoma therapy and enhanced bone regeneration. Adv Sci (Weinh), 2025, 12(22): e2417208. doi: 10.1002/advs.202417208.
41.	Zhang Z, Wang F, Huang X, et al. Engineered sensory nerve guides self-adaptive bone healing via NGF-TrkA signaling pathway. Adv Sci (Weinh), 2023, 10(10): e2206155. doi: 10.1002/advs.202206155.
42.	Ma YX, Jiao K, Wan QQ, et al. Silicified collagen scaffold induces semaphorin 3A secretion by sensory nerves to improve in-situ bone regeneration. Bioact Mater, 2021, 9: 475-490.
43.	Li Z, Meyers CA, Chang L, et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest, 2019, 129(12): 5137-5150.
44.	Leit?o L, Neto E, Concei??o F, et al. Osteoblasts are inherently programmed to repel sensory innervation. Bone Res, 2020, 8: 20. doi: 10.1038/s41413-020-0096-1.
45.	Tomlinson RE, Li Z, Zhang Q, et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep, 2016, 16(10): 2723-2735.
46.	Xu Y, Xu C, Song H, et al. Biomimetic bone-periosteum scaffold for spatiotemporal regulated innervated bone regeneration and therapy of osteosarcoma. J Nanobiotechnology, 2024, 22(1): 250. doi: 10.1186/s12951-024-02430-7.
47.	Xiao C, Wang R, Fu R, et al. Piezo-enhanced near infrared photocatalytic nanoheterojunction integrated injectable biopolymer hydrogel for anti-osteosarcoma and osteogenesis combination therapy. Bioact Mater, 2024, 34: 381-400.
48.	Wang X, Guo X, Ren H, et al. An “Outer Piezoelectric and Inner Epigenetic” logic-gated panoptosis for osteosarcoma sono-immunotherapy and bone regeneration. Adv Mater, 2025, 37(7): e2415814. doi: 10.1002/adma.202415814.
49.	Cheng Z, Xue C, Liu M, et al. Injectable microenvironment-responsive hydrogels with redox-activatable supramolecular prodrugs mediate ferroptosis-immunotherapy for postoperative tumor treatment. Acta Biomater, 2023, 169: 289-305.
50.	An L, Wang CB, Tian QW, et al. NIR-Ⅱ laser-mediated photo-Fenton-like reaction via plasmonic Cu9S8 for immunotherapy enhancement. Nano Today, 2022, 43: 101397. doi: 10.1016/j.nantod.2022.101397.
51.	Ouyang ZJ, Gao Y, Shen SY, et al. A minimalist dendrimer nanodrug for autophagy inhibition-amplified tumor photothermo-immunotherapy. Nano Today, 2023, 51: 101936. doi: 10.1016/j.nantod.2023.101936.
52.	Wang S, Wang Z, Li Z, et al. Amelioration of systemic antitumor immune responses in cocktail therapy by immunomodulatory nanozymes. Sci Adv, 2022, 8(21): eabn3883. doi: 10.1126/sciadv.abn3883.
53.	Ma Q, Xu S, Wang Q, et al. Controllable all-in-one biomimetic hollow nanoscaffold initiating pyroptosis-mediated antiosteosarcoma targeted therapy and bone defect repair. ACS Appl Mater Interfaces, 2024, 16(49): 67424-67443.
54.	Liu X, Zhang H, Guan S, et al. Electron pump and photon trap effect-derived selective antitumor of Fe-Ppy@CaO₂-modified polyetheretherketone for bone tumor therapy. ACS Nano, 2025, 19(15): 14954-14971.

1. Zhang H, Wang Y, Qiang H, et al. Exploring the frontiers: The potential and challenges of bioactive scaffolds in osteosarcoma treatment and bone regeneration. Mater Today Bio, 2024, 29: 101276. doi: 10.1016/j.mtbio.2024.101276.
2. Liu WB, Dong SH, Hu WH, et al. A simple, universal and multifunctional template agent for personalized treatment of bone tumors. Bioact Mater, 2021, 12: 292-302.
3. Park JB, Lakes RS. Biomaterials. An introduction. New York: Springer , 2007: 99-100.
4. Niinomi M, Nakai M, Hieda J. Development of new metallic alloys for biomedical applications. Acta Biomater, 2012, 8(11): 3888-3903.
5. Wang X, Xu S, Zhou S, et al. Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review. Biomaterials, 2016, 83: 127-141.
6. Vaiani L, Boccaccio A, Uva AE, et al. Ceramic materials for biomedical applications: an overview on properties and fabrication processes. J Funct Biomater, 2023, 14(3): 146. doi: 10.3390/jfb14030146.
7. Belluomo R, Khodaei A, Amin Yavari S. Additively manufactured Bi-functionalized bioceramics for reconstruction of bone tumor defects. Acta Biomater, 2023, 156: 234-249.
8. Han Y, Jia B, Lian M, et al. High-precision, gelatin-based, hybrid, bilayer scaffolds using melt electro-writing to repair cartilage injury. Bioact Mater, 2021, 6(7): 2173-2186.
9. Cyphert EL, Kanagasegar N, Zhang N, et al. PMMA bone cement composite functions as an adjuvant chemotherapeutic platform for localized and multi-window release during bone reconstruction. Macromol Biosci, 2022, 22(5): e2100415. doi: 10.1002/mabi.202100415.
10. Sun L, Berndt CC, Gross KA, et al. Material fundamentals and clinical performance of plasma-sprayed hydroxyapatite coatings: a review. J Biomed Mater Res, 2001, 58(5): 570-592.
11. Ma R, Tang T. Current strategies to improve the bioactivity of PEEK. Int J Mol Sci, 2014, 15(4): 5426-5445.
12. LeGeros RZ. Calcium phosphate-based osteoinductive materials. Chem Rev, 2008, 108(11): 4742-4753.
13. Liu Y, Raina DB, Sebastian S, et al. Sustained and controlled delivery of doxorubicin from an in-situ setting biphasic hydroxyapatite carrier for local treatment of a highly proliferative human osteosarcoma. Acta Biomater, 2021, 131: 555-571.
14. Gao J, Huang J, Shi R, et al. Loading and releasing behavior of selenium and doxorubicin hydrochloride in hydroxyapatite with different morphologies. ACS Omega, 2021, 6(12): 8365-8375.
15. Zhou J, Huo T, Miu J, et al. Bone-adhesive peptide hydrogel loaded with cisplatin for postoperative treatment of osteosarcoma. ACS Appl Mater Interfaces, 2025, 17(7): 11073-11084.
16. Sowjanya M, Debnath S, Lavanya P, et al. Polymers used in the designing of controlled drug delivery system. Research Journal of Pharmacy and Technology, 2017, 10(3): 903-912.
17. Jing Z, Yuan W, Wang J, et al. Simvastatin/hydrogel-loaded 3D-printed titanium alloy scaffolds suppress osteosarcoma via TF/NOX2-associated ferroptosis while repairing bone defects. Bioact Mater, 2023, 33: 223-241.
18. Tan W, Gao C, Feng P, et al. Dual-functional scaffolds of poly(L-lactic acid)/nanohydroxyapatite encapsulated with metformin: Simultaneous enhancement of bone repair and bone tumor inhibition. Mater Sci Eng C Mater Biol Appl, 2021, 120: 111592. doi: 10.1016/j.msec.2020.111592.
19. Zeng Y, Yuan J, Ran Z, et al. Chitosan/NH₂-MIL-125 (Ti) scaffold loaded with doxorubicin for postoperative bone tumor clearance and osteogenesis: An in vitro study. Int J Biol Macromol, 2024, 263(Pt 2): 130368. doi: 10.1016/j.ijbiomac.2024.130368.
20. Bauer L, Hadzhieva Z, Bazina I, et al. Chitosan/bioactive glass microparticles enriched with therapeutic metal ions for bone tissue engineering. ACS Appl Bio Mater, 2025, 8(8): 7201-7215.
21. Vladu AF, Albu Kaya MG, Ficai A, et al. Localized combination therapy using collagen-hydroxyapatite bone grafts for simultaneous bone cancer inhibition and tissue regeneration. Polymers (Basel), 2025, 17(16): 2239. doi: 10.3390/polym17162239.
22. Rezk AI, Lee J, Kim BS, et al. Strategically designed bifunctional polydopamine enwrapping polycaprolactone-hydroxyapatite-doxorubicin composite nanofibers for osteosarcoma treatment and bone regeneration. ACS Appl Mater Interfaces, 2024, 16(18): 22946-22957.
23. Liu J, Lin S, Dang J, et al. Anticancer and bone-enhanced nano-hydroxyapatite/gelatin/polylactic acid fibrous membrane with dual drug delivery and sequential release for osteosarcoma. Int J Biol Macromol, 2023, 240: 124406. doi: 10.1016/j.ijbiomac.2023.124406.
24. Liu X, Zhang P, Xu M, et al. Mixed-valence vanadium-doped mesoporous bioactive glass for treatment of tumor-associated bone defects. J Mater Chem B, 2025, 13(9): 3138-3160.
25. Li C, Zhang W, Nie Y, et al. Time-sequential and multi-functional 3D printed MgO₂/PLGA scaffold developed as a novel biodegradable and bioactive bone substitute for challenging postsurgical osteosarcoma treatment. Adv Mater, 2024, 36(34): e2308875. doi: 10.1002/adma.202308875.
26. Huang H, Qiang L, Fan M, et al. 3D-printed tri-element-doped hydroxyapatite/ polycaprolactone composite scaffolds with antibacterial potential for osteosarcoma therapy and bone regeneration. Bioact Mater, 2023, 31: 18-37.
27. Gao M, Feng K, Zhang X, et al. Nanoassembly with self-regulated magnetic thermal therapy and controlled immuno-modulating agent release for improved immune response. J Control Release, 2023, 357: 40-51.
28. Tavares FJTM, Soares PIP, Silva JC, et al. Preparation and in vitro characterization of magnetic CS/PVA/HA/pSPIONs scaffolds for magnetic hyperthermia and bone regeneration. Int J Mol Sci, 2023, 24(2): 1128. doi: 10.3390/ijms24021128.
29. Kesse X, Adam A, Begin-Colin S, et al. Elaboration of superparamagnetic and bioactive multicore-shell nanoparticles (γ-Fe₂O₃@SiO₂-CaO): A promising material for bone cancer treatment. ACS Appl Mater Interfaces, 2020, 12(42): 47820-47830.
30. Tithito T, Sillapaprayoon S, Chantho V, et al. Evaluation of magnetic hyperthermia, drug delivery and biocompatibility (bone cell adhesion and zebrafish assays) of trace element co-doped hydroxyapatite combined with Mn-Zn ferrite for bone tissue applications. RSC Adv, 2024, 14(40): 29242-29253.
31. Wang J, Zhou J, Xie Z, et al. Multifunctional 4D printed shape memory composite scaffolds with photothermal and magnetothermal effects for multimodal tumor therapy and bone repair. Biofabrication, 2025, 17(2). doi: 10.1088/1758-5090/adc29e.
32. Xu C, Xia Y, Zhuang P, et al. FePSe₃-nanosheets-integrated cryogenic-3D-printed multifunctional calcium phosphate scaffolds for synergistic therapy of osteosarcoma. Small, 2023, 19(38): e2303636. doi: 10.1002/smll.202303636.
33. Du J, Ding H, Fu S, et al. Bismuth-coated 80S15C bioactive glass scaffolds for photothermal antitumor therapy and bone regeneration. Front Bioeng Biotechnol, 2023, 10: 1098923. doi: 10.3389/fbioe.2022.1098923.
34. Jian G, Wang S, Wang X, et al. Enhanced sequential osteosarcoma therapy using a 3D-Printed bioceramic scaffold combined with 2D nanosheets via NIR-Ⅱ photothermal-chemodynamic synergy. Bioact Mater, 2025, 50: 540-555.
35. Cheung EC, Vousden KH. The role of ROS in tumour development and progression. Nat Rev Cancer, 2022, 22(5): 280-297.
36. Zhang D, Tan J, Xu R, et al. Collaborative design of MgO/FeOx nanosheets on titanium: Combining therapy with regeneration. Small, 2023, 19(5): e2204852. doi: 10.1002/smll.202204852.
37. Xu X, Wang H, Mei X, et al. “Antenna Effect”-enhanced AuNPs@rGO photothermal coating promotes 3D printing of osteogenic active scaffolds to repair bone defects after malignant tumor surgery. Adv Sci (Weinh), 2025, 12(15): e2417346. doi: 10.1002/advs.202417346.
38. Chen Z, Sang L, Liu Y, et al. Sono-Piezo dynamic therapy: Utilizing piezoelectric materials as sonosensitizer for sonodynamic therapy. Adv Sci (Weinh), 2025, 12(12): e2417439. doi: 10.1002/advs.202417439.
39. Shuai C, Zhang Z, Chen M, et al. 3D-printed scaffold achieves synergistic chemo-sonodynamic therapy for tumorous bone defect. ACS Appl Bio Mater, 2025, 8(5): 3920-3931.
40. Fang H, Zhu D, Chen Y, et al. Ultrasound-responsive 4D bioscaffold for synergistic sonopiezoelectric-gaseous osteosarcoma therapy and enhanced bone regeneration. Adv Sci (Weinh), 2025, 12(22): e2417208. doi: 10.1002/advs.202417208.
41. Zhang Z, Wang F, Huang X, et al. Engineered sensory nerve guides self-adaptive bone healing via NGF-TrkA signaling pathway. Adv Sci (Weinh), 2023, 10(10): e2206155. doi: 10.1002/advs.202206155.
42. Ma YX, Jiao K, Wan QQ, et al. Silicified collagen scaffold induces semaphorin 3A secretion by sensory nerves to improve in-situ bone regeneration. Bioact Mater, 2021, 9: 475-490.
43. Li Z, Meyers CA, Chang L, et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J Clin Invest, 2019, 129(12): 5137-5150.
44. Leit?o L, Neto E, Concei??o F, et al. Osteoblasts are inherently programmed to repel sensory innervation. Bone Res, 2020, 8: 20. doi: 10.1038/s41413-020-0096-1.
45. Tomlinson RE, Li Z, Zhang Q, et al. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep, 2016, 16(10): 2723-2735.
46. Xu Y, Xu C, Song H, et al. Biomimetic bone-periosteum scaffold for spatiotemporal regulated innervated bone regeneration and therapy of osteosarcoma. J Nanobiotechnology, 2024, 22(1): 250. doi: 10.1186/s12951-024-02430-7.
47. Xiao C, Wang R, Fu R, et al. Piezo-enhanced near infrared photocatalytic nanoheterojunction integrated injectable biopolymer hydrogel for anti-osteosarcoma and osteogenesis combination therapy. Bioact Mater, 2024, 34: 381-400.
48. Wang X, Guo X, Ren H, et al. An “Outer Piezoelectric and Inner Epigenetic” logic-gated panoptosis for osteosarcoma sono-immunotherapy and bone regeneration. Adv Mater, 2025, 37(7): e2415814. doi: 10.1002/adma.202415814.
49. Cheng Z, Xue C, Liu M, et al. Injectable microenvironment-responsive hydrogels with redox-activatable supramolecular prodrugs mediate ferroptosis-immunotherapy for postoperative tumor treatment. Acta Biomater, 2023, 169: 289-305.
50. An L, Wang CB, Tian QW, et al. NIR-Ⅱ laser-mediated photo-Fenton-like reaction via plasmonic Cu9S8 for immunotherapy enhancement. Nano Today, 2022, 43: 101397. doi: 10.1016/j.nantod.2022.101397.
51. Ouyang ZJ, Gao Y, Shen SY, et al. A minimalist dendrimer nanodrug for autophagy inhibition-amplified tumor photothermo-immunotherapy. Nano Today, 2023, 51: 101936. doi: 10.1016/j.nantod.2023.101936.
52. Wang S, Wang Z, Li Z, et al. Amelioration of systemic antitumor immune responses in cocktail therapy by immunomodulatory nanozymes. Sci Adv, 2022, 8(21): eabn3883. doi: 10.1126/sciadv.abn3883.
53. Ma Q, Xu S, Wang Q, et al. Controllable all-in-one biomimetic hollow nanoscaffold initiating pyroptosis-mediated antiosteosarcoma targeted therapy and bone defect repair. ACS Appl Mater Interfaces, 2024, 16(49): 67424-67443.
54. Liu X, Zhang H, Guan S, et al. Electron pump and photon trap effect-derived selective antitumor of Fe-Ppy@CaO₂-modified polyetheretherketone for bone tumor therapy. ACS Nano, 2025, 19(15): 14954-14971.

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