Hydrogels for osteosarcoma treatment: Bioprinting strategies and local tumor eradication–bone regeneration
Osteosarcoma remains a clinically challenging primary bone malignancy because effective postoperative treatment must both eradicate residual tumor cells and restore function after tumor resection. Hydrogel-based platforms have emerged as versatile local therapeutic systems because of their injectability, tunable physicochemical properties, cavity-conforming capacity, high local retention, and ability to integrate antitumor and osteoregenerative functions. This review summarizes recent advances and design principles in hydrogel-based osteosarcoma treatment and bioprinting Strategies, with emphasis on local tumor eradication–bone regeneration. The reviewed platforms include architecturally programmed three-dimensional-printed hydrogel and scaffold–hydrogel hybrid constructs, postoperative locoregional depots, tumor microenvironment-responsive hydrogels, chemoimmunotherapeutic and sonodynamic systems, photothermally actuated theragenerative platforms, and externally regulated magnetic and piezoelectric depots. Particular attention is given to the complementary clinical roles of injectable hydrogels and patient-specific printed constructs. Hydrogels are thus evolving from passive drug reservoirs into programmable biomaterial systems capable of spatiotemporal treatment control, immune–stromal modulation, molecularly targeted delivery, and functional reconstruction. Key translational barriers include the limited relevance of current preclinical models, normal-tissue safety of field-regulated therapies, degradation and long-term biocompatibility of multifunctional materials, sterilization, quality assurance, regulatory classification, manufacturability, and integration into surgical workflows. Overall, the most clinically realistic direction is a staged and adaptable platform that provides early local tumor control while progressively supporting bone regeneration and structural reconstruction.
- Liu W, Li L, Bai X, et al. Osteosarcoma Cell-Derived Migrasomes Promote Macrophage M2 Polarization to Aggravate Osteosarcoma Proliferation and Metastasis. Adv Sci. 2025;12(17):e2409870. doi: 10.1002/advs.202409870
- Liu B, Li W, Zhang W, et al. PKMYT1 kinase ameliorates cisplatin sensitivity in osteosarcoma. Signal Transduct Target Ther. 2025;10(1):165. doi: 10.1038/s41392-025-02250-7
- Zhang Y, Jiang S, Lv J, Feng W, Yu Y, Zhao H. Osteosarcoma immune microenvironment: cellular struggle and novel therapeutic insights. Front Immunol. 2025;16:1584450. doi: 10.3389/fimmu.2025.1584450
- López-Fuentes E, Clugston AS, Lee AG, et al. Epigenetic and Transcriptional Programs Define Osteosarcoma Subtypes and Establish Targetable Vulnerabilities. Cancer Discov. 2026;16(2):296-319. doi: 10.1158/2159-8290.Cd-25-0237
- Meazza C, Scanagatta P. Metastatic osteosarcoma: a challenging multidisciplinary treatment. Expert Rev Anticancer Ther. 2016;16(5):543-556. doi: 10.1586/14737140.2016.1168697
- Bishop MW. Osteosarcoma: Diagnosis, Treatment, and Emerging Opportunities. Hematol Oncol Clin North Am. 2025;39(4):749-760. doi: 10.1016/j.hoc.2025.04.005
- Wang X, Zhu K, Hu J, Zhang C. Advances and challenges in the treatment of osteosarcoma. Prog Biophys Mol Biol. 2025;197:60-74. doi: 10.1016/j.pbiomolbio.2025.07.001
- Su W, Li Y, Yang G, et al. Nanotechnology-Driven Strategies in Osteosarcoma Advances in Treatment: Immunotherapy and Drug Delivery. Int J Nanomedicine. 2025;20:12913-12937. doi: 10.2147/ijn.S549587
- Mu H, Liu C, Zhang Q, et al. Magnetic-Driven Hydrogel Microrobots Selectively Enhance Synthetic Lethality in MTAP-Deleted Osteosarcoma. Front Bioeng Biotechnol. 2022;10:911455. doi: 10.3389/fbioe.2022.911455
- Liu X, Zhang Y, Wu H, et al. A conductive gelatin methacrylamide hydrogel for synergistic therapy of osteosarcoma and potential bone regeneration. Int J Biol Macromol. 2023;228:111-122. doi: 10.1016/j.ijbiomac.2022.12.185
- Su H, Chen Y, Xuan Z, et al. Permeable Hydrogel Encapsulated Osteosarcoma-on-a-Chip for High-Throughput Multi-Drugs Screening. Smart Med. 2025;4(3):e70013. doi: 10.1002/smmd.70013
- Tian H, Wu R, Feng N, Zhang J, Zuo J. Recent advances in hydrogels-based osteosarcoma therapy. Front Bioeng Biotechnol. 2022;10:1042625. doi: 10.3389/fbioe.2022.1042625
- Cao J, Zhu C, Cao Z, Ke X. CPPs-modified chitosan as permeability-enhancing chemotherapeutic combined with gene therapy nanosystem by thermosensitive hydrogel for the treatment of osteosarcoma. Int J Biol Macromol. 2024;267(Pt 2):130915. doi: 10.1016/j.ijbiomac.2024.130915
- Cao J, Du X, Zhao H, et al. Sequentially degradable hydrogel-microsphere loaded with doxorubicin and pioglitazone synergistically inhibits cancer stemness of osteosarcoma. Biomed Pharmacother. 2023;165:115096. doi: 10.1016/j.biopha.2023.115096
- Chen H, Ye K, Zhang C. Paclitaxel-loaded Bone Acellular Extracellular Matrix Injectable Hydrogel for Osteosarcoma Treatment. J Drug Target. 2026:1-14. doi: 10.1080/1061186x.2026.2666805
- Murugan D, Ezhilan M, Kumar A, Dhayalan A, Kannan S. Interfacial Engineering of a NaGdF(4)@NaYF(4):Nd(3+)-Reinforced PVA/Chitosan Janus Hydrogel for Osteosarcoma and Osseointegration via the Entrapment of Strontium in Bisphosphonates. Bioconjug Chem. 2025;36(8):1838-1853. doi: 10.1021/acs.bioconjchem.5c00302
- Zhang Q, Zhang Y, Chen H, et al. Dual-functional injectable adhesive hydrogel delivering ginger-derived doxorubicin vesicles for osteosarcoma recurrence suppression and post-resection wound healing. Front Bioeng Biotechnol. 2025;13:1609673. doi: 10.3389/fbioe.2025.1609673
- Fu J, Chen H, Zhao Y, et al. Self-assembled injectable Icariin@ Ti(3)C(2)Tx/doxorubicin hydrogel preserving osteogenesis while synergizing photodynamic and chemodynamic therapy for osteosarcoma. J Mater Sci Mater Med. 2025;36(1):28. doi: 10.1007/s10856-025-06874-7
- Jing S, Lian L, Hou Y, et al. Advances in volumetric bioprinting. Biofabrication. 2024;16(1):012004. doi: 10.1088/1758-5090/ad0978
- Ashammakhi N, Hasan A, Kaarela O, et al. Advancing Frontiers in Bone Bioprinting. Adv Healthc Mater. 2019;8(7):e1801048. doi: 10.1002/adhm.201801048
- Abdollahiyan P, Oroojalian F, Mokhtarzadeh A, de la Guardia M. Hydrogel-Based 3D Bioprinting for Bone and Cartilage Tissue Engineering. Biotechnol J. 2020;15(12):e2000095. doi: 10.1002/biot.202000095
- Loi G, Stucchi G, Scocozza F, et al. Characterization of a Bioink Combining Extracellular Matrix-like Hydrogel with Osteosarcoma Cells: Preliminary Results. Gels. 2023;9(2);129. doi: 10.3390/gels9020129
- Yang Z, Yi P, Liu Z, et al. Stem Cell-Laden Hydrogel-Based 3D Bioprinting for Bone and Cartilage Tissue Engineering. Front Bioeng Biotechnol. 2022;10:865770. doi: 10.3389/fbioe.2022.865770
- Mandrycky C, Wang Z, Kim K, Kim DH. 3D bioprinting for engineering complex tissues. Biotechnol Adv. 2016;34(4):422-434. doi: 10.1016/j.biotechadv.2015.12.011
- Delgrosso E, Scocozza F, Cansolino L, et al. 3D bioprinted osteosarcoma model for experimental boron neutron capture therapy (BNCT) applications: Preliminary assessment. J Biomed Mater Res B Appl Biomater. 2023;111(8):1571-1580. doi: 10.1002/jbm.b.35255
- Zhang YS, Haghiashtiani G, Hübscher T, et al. 3D extrusion bioprinting. Nature Reviews Methods Primers. 2021;1(1):75. doi: 10.1038/s43586-021-00073-8
- Zhang X, Wei H, Dong C, et al. 3D printed hydrogel/bioceramics core/shell scaffold with NIR-II triggered drug release for chemo-photothermal therapy of bone tumors and enhanced bone repair. Chemical Engineering Journal. 2023;461:141855. doi: 10.1016/j.cej.2023.141855
- Jing Z, Ni R, Wang J, et al. Practical strategy to construct anti-osteosarcoma bone substitutes by loading cisplatin into 3D-printed titanium alloy implants using a thermosensitive hydrogel. Bioact Mater. 2021;6(12):4542-4557. doi: 10.1016/j.bioactmat.2021.05.007
- Ji Z, Wan Y, Zou Y, Wang H, Liang X, Liu P. Dual-release 3D-printed porous Ti-6Al-4V implant with drug-eluting photothermal micro-nanotopographies: combating osteosarcoma recurrence, infections, and enhancing osteogenesis. Biomaterials. 2026;327:123749. doi: 10.1016/j.biomaterials.2025.123749
- Khaled Wassif R, Daihom BA, Maniruzzaman M. FRESH 3D printing of zoledronic acid-loaded chitosan/alginate/hydroxyapatite composite thermosensitive hydrogel for promoting bone regeneration. Int J Pharm. 2024;667(Pt A):124898. doi: 10.1016/j.ijpharm.2024.124898
- Dutta SD, Ganguly K, Hexiu J, Randhawa A, Moniruzzaman M, Lim KT. A 3D Bioprinted Nanoengineered Hydrogel with Photoactivated Drug Delivery for Tumor Apoptosis and Simultaneous Bone Regeneration via Macrophage Immunomodulation. Macromol Biosci. 2023;23(9):e2300096. doi: 10.1002/mabi.202300096
- Su S, Chen WC, Dang W, et al. 3D-Printed Hydrogel Scaffolds with Sandwich Architecture for Multimodal Therapy of Postoperative Osteosarcoma. ACS Appl Mater Interfaces. 2025;17(36):50534-50547. doi: 10.1021/acsami.5c14641
- Abie N, Ünlü C, Pinho AR, et al. Designing of a Multifunctional 3D-Printed Biomimetic Theragenerative Aerogel Scaffold via Mussel-Inspired Chemistry: Bioactive Glass Nanofiber-Incorporated Self-Assembled Silk Fibroin with Antibacterial, Antiosteosarcoma, and Osteoinductive Properties. ACS Appl Mater Interfaces. 2024;16(18):22809-22827. doi: 10.1021/acsami.4c00065
- Kanwal F, Al-Almadi AA, Khurshid M, Chen S, He C. Natural Medicine and 3D Printing for Tissue Repair, Drug Delivery, and Wound Healing: Integrating Traditional Chinese Medicine Bio-Actives with Advanced Biomaterials. Macromol Biosci. 2025;25(11):e00173. doi: 10.1002/mabi.202500173
- Hernández-Sosa A, Ramírez-Jiménez RA, Rojo L, et al. Optimization of the Rheological Properties of Self-Assembled Tripeptide/Alginate/Cellulose Hydrogels for 3D Printing. Polymers. 2022;14(11):2229. doi: 10.3390/polym14112229
- 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. 2024;33:223-241. doi: 10.1016/j.bioactmat.2023.11.001
- Fischetti T, Graziani G, Borciani G, et al. Development of novel organic/inorganic osteomimetic inks for 3D bioprinted in vitro bone models. Biomater Adv. 2026;180:214608. doi: 10.1016/j.bioadv.2025.214608
- Chu X, Mi B, Xiong Y, et al. Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment. Biomaterials. 2025;312:122714. doi: 10.1016/j.biomaterials.2024.122714
- Zhang Y, Wang Y, Zhang X, et al. Nanohydroxyapatite-Stabilized Pickering-Emulsion-Incorporated Hydrogel Prevents Postoperative Osteosarcoma Recurrence and Promotes Bone Repair. Nano Lett. 2025;25(26):10487-10496. doi: 10.1021/acs.nanolett.5c01949
- 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. doi: 10.1021/acsami.4c19608
- Zhou J, Lin G, Fu X, et al. ZIF-8-Modified Multifunctional Hydrogel Loading siRNA and DOX for Postoperative Therapy of Maxillofacial Osteosarcoma and Bone Repair. ACS Appl Mater Interfaces. 2025;17(12):17990-18002. doi: 10.1021/acsami.4c21331
- Zhang W, Li L, Wang Z, et al. Injectable and adhesive MgO(2)-potentiated hydrogel with sequential tumor synergistic therapy and osteogenesis for challenging postsurgical osteosarcoma treatment. Biomaterials. 2025;315:122959. doi: 10.1016/j.biomaterials.2024.122959
- Ma Y, Lai P, Sha Z, et al. TME-responsive nanocomposite hydrogel with targeted capacity for enhanced synergistic chemoimmunotherapy of MYC-amplified osteosarcoma. Bioact Mater. 2025;47:83-99. doi: 10.1016/j.bioactmat.2025.01.006
- Lin H, Jin X, Cao Y, et al. Self-Adaptive Hydrogel with Cascade Microenvironments-Responsiveness to Inhibit Osteosarcoma Progression and Augment Bone Reconstruction. Advanced Functional Materials. 2025;35(40):2421470. doi: 10.1002/adfm.202421470
- Xie D, Hu C, Zhu Y, et al. Sequential Therapy for Osteosarcoma and Bone Regeneration via Chemodynamic Effect and Cuproptosis Using a 3D-Printed Scaffold with TME-Responsive Hydrogel. Small. 2025;21(5):e2406639. doi: 10.1002/smll.202406639
- Liao J, Shi K, Jia Y, Wu Y, Qian Z. Gold nanorods and nanohydroxyapatite hybrid hydrogel for preventing bone tumor recurrence via postoperative photothermal therapy and bone regeneration promotion. Bioact Mater. 2021;6(8):2221-2230. doi: 10.1016/j.bioactmat.2021.01.006
- Li L, Lin Y, Liu K, et al. Multiple-Effect Combined Hydrogels: "Temporal Regulation" Treatment of Osteosarcoma-Associated Bone Defects with Switchable Hyperthermia and Bioactive Agents. Adv Healthc Mater. 2024;13(31):e2402505. doi: 10.1002/adhm.202402505
- Zhu J, Zhou T, Tang X, et al. Injectable Cu(2+) loaded rhein hydrogel for cross-amplifying osteosarcoma apoptosis and cuproptosis epitranscriptomically. Biomaterials. 2026;332:124170. doi: 10.1016/j.biomaterials.2026.124170
- Salama AM, Hardy JG, Yessuf AM, et al. Injectable Hydrogel Technologies for Bone Disease Treatment. ACS Appl Bio Mater. 2025;8(4):2691-2715. doi: 10.1021/acsabm.4c01968
- 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
- He J, Niu J, Wang L, et al. An injectable hydrogel microsphere-integrated training court to inspire tumor-infiltrating T lymphocyte potential. Biomaterials. 2024;306:122475. doi: 10.1016/j.biomaterials.2024.122475
- Wang S, Zhang H, Chen T, et al. Injectable hyaluronate-L- cysteine gel potentiates photothermal therapy in osteosarcoma via vorinostat-copper cell death. Mater Today Bio. 2024;29:101368. doi: 10.1016/j.mtbio.2024.101368
- Chen Y, Cheng X, Zhu C, et al. A microsphere-vesicle hybrid system for tumor treatment through enhancement of innate and adaptive immune responses. Biomaterials. 2026;325:123587. doi: 10.1016/j.biomaterials.2025.123587
- Luo G, Xu Z, Zhong H, et al. Biodegradable photothermal thermosensitive hydrogels treat osteosarcoma by reprogramming macrophages. Biomater Sci. 2023;11(8):2818-2827. doi: 10.1039/d2bm01900k
- Yang L, Sun Q, Chen S, et al. pH-responsive hydrogel with gambogic acid and calcium nanowires for promoting mitochondrial apoptosis in osteosarcoma. J Control Release. 2025;377:563-577. doi: 10.1016/j.jconrel.2024.11.055
- Yang Z, Li Z, Zhao Y, et al. Lotus Seedpod-Inspired Crosslinking-Assembled Hydrogels Based on Gold Nanoclusters for Synergistic Osteosarcoma Multimode Imaging and Therapy. ACS Appl Mater Interfaces. 2022;14(30):34377-34387. doi: 10.1021/acsami.2c06890
- Monteiro CF, Custódio CA, Mano JF. Bioengineering a humanized 3D tri-culture osteosarcoma model to assess tumor invasiveness and therapy response. Acta Biomater. 2021;134:204-214. doi: 10.1016/j.actbio.2021.07.034
- Yu K, Zhou H, Xu Y, Cao Y, Zheng Y, Liang B. Engineering a triple-functional magnetic gel driving mutually-synergistic mild hyperthermia-starvation therapy for osteosarcoma treatment and augmented bone regeneration. J Nanobiotechnology. 2023;21(1):201. doi: 10.1186/s12951-023-01955-7
- Wang J, Yu N, Tang Y, Cheng Y, Li H. FDA-Approved Hydrogel-Mediated In Situ Sonodynamic and Chemotherapeutic Therapy for Pancreatic Cancer. Pharmaceuticals. 2024;17(12):1666. doi: 10.3390/ph17121666
- Yu S, Yao X. Advances on immunotherapy for osteosarcoma. Mol Cancer. 2024;23(1):192. doi: 10.1186/s12943-024-02105-9
- Lian H, Zhang J, Hou S, et al. Immunotherapy of osteosarcoma based on immune microenvironment modulation. Front Immunol. 2025;15:1498060. doi: 10.3389/fimmu.2024.1498060
- Sun C, Li S, Ding J. Biomaterials-Boosted Immunotherapy for Osteosarcoma. Adv Healthc Mater. 2024;13(23):e2400864. doi: 10.1002/adhm.202400864
- Wang H, Chen Y, Wei R, et al. Synergistic Chemoimmunotherapy Augmentation via Sequential Nanocomposite Hydrogel-Mediated Reprogramming of Cancer-Associated Fibroblasts in Osteosarcoma. Adv Mater. 2024;36(15):e2309591. doi: 10.1002/adma.202309591
- Lin S, Liu H, Lv L, et al. Hydrogel delivering antifibrotic agent and nano-sonosensitizer enhances efficacy of sonodynamic therapy in osteosarcoma treatment. Bioact Mater. 2026;56:77-94. doi: 10.1016/j.bioactmat.2025.10.001
- Luo H, Ma J, Yang H, et al. Functionalized Photoimmune Hydrogel Microspheres for Inside-Out Eradication of Osteosarcoma via a PD-L1 PROTAC Strategy. Adv Healthc Mater. 2026;15(8):e03988. doi: 10.1002/adhm.202503988
- Adewuyi E, Chorya H, Muili A, et al. Chemotherapy, immunotherapy, and targeted therapy for osteosarcoma: Recent advancements. Crit Rev Oncol Hematol. 2025;206:104575. doi: 10.1016/j.critrevonc.2024.104575
- Li S, Qing Y, Lou Y, et al. Injectable thermosensitive black phosphorus nanosheet- and doxorubicin-loaded hydrogel for synergistic bone tumor photothermal-chemotherapy and osteogenesis enhancement. Int J Biol Macromol. 2023;239:124209. doi: 10.1016/j.ijbiomac.2023.124209
- Wu F, Yin W, Shan H, et al. A nano-bio-coordination dynamic hydrogel with photothermal effects and osteogenic activity for the treatment of osteosarcoma. Materials & Design. 2025;260:115092. doi: 10.1016/j.matdes.2025.115092
- Yao J, He Q, Zheng X, Shen S, Hui J, Fan D. An Injectable Hydrogel System with Mild Photothermal Effects Combined with Ion Release for Osteosarcoma-Related Bone Defect Repair. Advanced Functional Materials. 2024;34(30):2315217. doi: 10.1002/adfm.202315217
- Chen S, Hassan N, Kopp A, et al. Theragenerative injectable bone-adhesive hydrogels for combined photothermal osteosarcoma therapy and bone repair. Biomater Sci. 2025;13(13):3544-3560. doi: 10.1039/d5bm00559k
- Ye B, Jing X, Su Y, et al. FePS3-Nanosheets-Integrated multifunctional nanocomposite hydrogel for multimodal synergistic osteosarcoma therapy and enhanced bone regeneration. Chemical Engineering Journal. 2025;511:162175. doi: 10.1016/j.cej.2025.162175
- Tao Y, Li L, Yang X, et al. Magnetic-driven hydrogel microrobots for promoting osteosarcoma chemo-therapy with synthetic lethality strategy. Front Chem. 2024;12:1386076. doi: 10.3389/fchem.2024.1386076
- Wang H, Jiang H, Tao Y, et al. Magnetically driven hydrogel microrobots for enhancing the therapeutic effect of anlotinib on osteosarcoma. Front Bioeng Biotechnol. 2024;12:1409988. doi: 10.3389/fbioe.2024.1409988
- 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. doi: 10.1016/j.bioactmat.2024.01.003
- Byun H, Hwang T, Lee H, et al. Comprehensive Osteosarcoma Treatment with Multifunctional Composite Hydrogels Enabling Combined Photothermal Cancer Ablation and Osteoinductive Tissue Regeneration. Small Methods. 2026;10(2):e2500617. doi: 10.1002/smtd.202500617
- Zhu J, Gao R, Wang Z, et al. Sustained and Targeted Delivery of Self-Assembled Doxorubicin Nonapeptides Using pH-Responsive Hydrogels for Osteosarcoma Chemotherapy. Pharmaceutics. 2023;15(2):668. doi: 10.3390/pharmaceutics15020668
- Tian H, Zhou T, Chen H, et al. Bone morphogenetic protein-2 promotes osteosarcoma growth by promoting epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin signaling pathway. J Orthop Res. 2019;37(7):1638-1648. doi: 10.1002/jor.24244
- Kendal JK, Singla A, Affan A, et al. Is Use of BMP-2 Associated with Tumor Growth and Osteoblastic Differentiation in Murine Models of Osteosarcoma? Clin Orthop Relat Res. 2020;478(12):2921-2933. doi: 10.1097/corr.0000000000001422
