Review of a new bone tumor therapy strategy based on bifunctional biomaterials

Abstract

Bone tumors, especially those in osteosarcoma, usually occur in adolescents. The standard clinical treatment includes chemotherapy, surgical therapy, and radiation therapy. Unfortunately, surgical resection often fails to completely remove the tumor, which is the main cause of postoperative recurrence and metastasis, resulting in a high mortality rate. Moreover, bone tumors often invade large areas of bone, which cannot repair itself, and causes a serious effect on the quality of life of patients. Thus, bone tumor therapy and bone regeneration are challenging in the clinic. Herein, this review presents the recent developments in bifunctional biomaterials to achieve a new strategy for bone tumor therapy. The selected bifunctional materials include 3D-printed scaffolds, nano/microparticle-containing scaffolds, hydrogels, and bone-targeting nanomaterials. Numerous related studies on bifunctional biomaterials combining tumor photothermal therapy with enhanced bone regeneration were reviewed. Finally, a perspective on the future development of biomaterials for tumor therapy and bone tissue engineering is discussed. This review will provide a useful reference for bone tumor-related disease and the field of complex diseases to combine tumor therapy and tissue engineering.

References

[1] Siclari VA, Qin L. Targeting the osteosarcoma cancer stem cell. J. Orthop. Surg. Res., 2010, 5: 78

[2] Kansara M, Teng MW, Smyth MJ, Thomas DM. Translational biology of osteosarcoma. Nat. Rev. Cancer, 2014, 14: 722-735

[3] Chen D et al. Super enhancer inbibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma. Bone Res., 2018, 6: 11

[4] Gianferante DM, Mirabello L, Savage SA. Germline and somatic genetics of osteosarcoma-connecting aetiology, biology and therapy. Nat. Rev. Endocrinol., 2017, 13: 480-491

[5] Bosma SE, Wong KC, Paul L, Gerbers JG, Jutte PC. A cadaveric comparative study on the surgical accuracy of freehand, computer navigation, and patient-specific instruments in joint-preserving bone tumor resection. Sarcoma, 2018, 11: 4065846

[6] Friesenbichler J et al. Clinical experience with the artificial bone graft substitute Calcibon used following curettage of benign and low-grade malignant bone tumors. Sci. Rep., 2017, 7

[7] Anderson ME. Update on survival in osteosarcoma. Orthop. Clin. N. Am., 2016, 47: 283-292

[8] Ballatori SE, Hinds PW. Osteosarcoma: prognosis plateau warrants retinoblastma pathway targeted therapy. Signal Transduct. Target. Ther., 2016, 1: 16001

[9] Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer, 2002, 2: 584-593

[10] Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat. Rev. Cancer, 2011, 11: 411-425

[11] Thibaudeau L et al. A tissue-engineered human xenograft model of human breast cancer metastasis to bone. Dis. Models Mech., 2014, 7: 299-309

[12] Kuchimaru T et al. A reliable murine model for bone matastasis by injecting cancer cells through caudal arteries. Nat. Commun., 2018, 9

[13] Adjei IM, Sharma B, Peetla C, Labhasetwar V. Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer. J. Control. Release, 2016, 232: 83-92

[14] Cortini M, Baldini N, Avnet S. New advances in the study of bone tumors: a lesson from the 3D environment. Front. Physiol., 2019, 10: 814

[15] Ando K et al. Current therapeutic strategies and novel approaches in osteosarcoma. Cancers, 2013, 5: 591-616

[16] Liu Y, Yu Q, Chang J, Wu C. Nanobiomaterials: from 0D to 3D for tumor therapy and tissue engineering. Nanoscale, 2019, 11: 13678-13708

[17] Xue Y et al. Engineering a biodegradable multifunctional antibacterial bioactive nanosystem for enhancing tumor photothermo-chemotherapy and bone regeneration. ACS Nano, 2020, 14: 442-453

[18] Fan D, Tian Y, Liu Z. Injectable hydrogels for localized caner therapy. Front. Chem., 2019, 7: 675

[19] Zhao M et al. Codelivery of paclitaxel and temozolomide through a photopolymerizable hydrogel prevents glioblastoma recurrence after surgical resection. J. Control. Release, 2019, 309: 72-81

[20] Liao, J. et al. Physical-, chemical-, and biological-responsive nanomedicine for cancer therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 12, e1581 (2020).

[21] Shao J et al. Black-phosphorus-incorporated hydrogel as a sprayable and biodegradable photothermal platform for postsurgical treatment of cancer. Adv. Sci., 2018, 5: 1700848

[22] Du C et al. Efficient suppression of liver metastasis cancers by paclitaxel loaded nanoparticles in PDLLA-PEG-PDLLA thermosensitive hydrogel composites. J. Biomed. Nanotechnol., 2017, 13: 1545-1556

[23] luo Y et al. 3D printing of hydrogel scaffolds for future application in photothermal therapy of breast cancer and tissue repair. Acta Biomater., 2019, 92: 37-47

[24] Darge HF et al. Locailized controlled release of bevacizumab and doxorubicin by thermo-sensitive hydrogel for normalization of tumor vasculature and to enhance the efficacy of chemotherapy. Int. J. Pharm., 2019, 572: 118799

[25] Qu Y et al. A biodegradable thermo-responsive hybrid hydrogel: therapeutic applications in preventing the post-operative recurrence of breast cancer. NPG Asia Mater., 2015, 7

[26] Wang H et al. Biocompatible iodine-starch-alginate hydrogel for tumor photothermal therapy. ACS Biomater. Sci. Eng., 2019, 5: 3654-3662

[27] Chu KF, Dupuy DE. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat. Rev. Cancer, 2014, 14: 199-208

[28] Liu Y, Bhattarai P, Dai Z, Chen X. Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer. Chem. Soc. Rev., 2019, 48: 2053-2108

[29] Wang Z et al. Construction of Bi/phthalocyanine manganese nanocomposite for trimodal imaging directed photodynamic and photothermal therapy mediated by 808 nm light. Biomaterials, 2010, 28: 119569

[30] Chen Q et al. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat. Commun., 2016, 7: 13193

[31] Zhang W et al. A hydrogenated black TiO₂ coating with excellent effects for photothermal of bone tumor and bone regeneration. Mater. Sci. Eng. C., 2019, 102: 458-470

[32] Liu Y et al. Preparation of therapeutic-laden konjac hydrogel for tumor combination therapy. Chem. Eng. J., 2019, 375: 122048

[33] Liao J et al. Polymer hybrid magnetic nanocapsules encapsulating IR820 and PTX for external magnetic field-guided tumor targeting and multifunctional theranostics. Nanoscale, 2017, 9: 2479-2491

[34] Zhang B, Xu C, Sun C, Yu C. Polyphosphoester-based nanocarrier for combined radio-photothermal therapy of breast cancer. ACS Biomater. Sci. Eng., 2019, 5: 1868-1877

[35] Hu L et al. Oxygen-generating hybrid polymeric nanoparticles with encapsulated doxorubicin and chlorin e6 for trimodal imaging-guided combined chemo-photodynamic therapy. Theranostics, 2018, 8: 1558-1574

[36] Mahmoodzadeh F, Abbasian M, Jaymand M, Salehi R, Bagherzadh-Khajehmarjan E. A novel gold-based stimuli-responsive theranostic nanomedicine for chemophotothermal therapy of solid tumors. Mater. Sci. Eng. C., 2018, 93: 880-889

[37] Liao J et al. Magnetic/gold core-shell hybrid particles for targeting and imaging-guided photothermal cancer therapy. J. Biomed. Nanotechnol., 2019, 15: 2072-2089

[38] Volsi AV et al. Near-infrared light responsive folate targeted gold nanorods for combined photothermal-chemotherapy of osteosarcoma. ACS Appl. Mater. Interfaces, 2017, 9: 14453-14469

[39] Yang S, Zhou L, Su Y, Zhang R, Dong C-M. One-pot photoreduction to prepare NIR-absorbing plasmonic gold nanoparticles tethered by amphiphilic polypeptide copolymer for synergistic photothermal-chemotherapy. Chin. Chem. Lett., 2019, 30: 187-191

[40] Liao J et al. Combined cancer photothermal-chemotherapy based on doxorubicin/gold nanorod-loaded polymersomes. Theranostics, 2015, 5: 345-356

[41] Yang X et al. Gold-small interfering RNA as optically responsive nanostructures for cancer theranostics. J. Biomed. Nanotechnol., 2018, 14: 809-828

[42] Li Q et al. Graphene-nanoparticle-based self-healing hydrogel in preventing postoperative recurrence of breast cancer. ACS Biomater. Sci. Eng., 2019, 5: 768-779

[43] Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer, 2017, 17: 20-37

[44] Guo X et al. External magnetic field-enhanced chemo-photothermal combination tumor therapy via iron oxide nanoparticles. ACS Appl. Mater. Interfaces, 2017, 9: 16581-16593

[45] Zhang J et al. Multifunctional ferritin nanoparticles as theranostics for imaging-guided tumor phototherapy. J. Biomed. Nanotechnol., 2019, 15: 1546-1555

[46] Farzin A, Hassan S, Emadi R, Etesami SA, Ai J. Comparative evaluation of magnetic hyperthermia performance and biocompatibility of magnetite and novel Fe-doped hardystonite nanoparticles for potential bone cancer therapy. Mater. Sci. Eng. C., 2019, 98: 930-938

[47] Du Y, Liu X, Liang Q, Liang X-J, Tian J. Optimization and design of magnetic ferrite nanoparticles with uniform tumor distribution for highly sensitive MRI/MPI performance and improved magnetic hyperthermia therapy. Nano Lett., 2019, 19: 3618-3626

[48] Wang K, Yang P, Guo R, Yao X, Yang W. Photothermal performance of MFe₂O₄ nanoparticles. Chin. Chem. Lett., 2019, 30: 2013-2016

[49] Liu Y et al. The combined therapeutic effects of 131iodine-labeled multifunctional copper sulfide-loaded microspheres in treating breast cancer. Atca Pharm. Sin. B, 2018, 8: 371-380

[50] Hu X et al. Multifunctional CuS nanocrystals for inhibiting both osteosarcoma proliferation and bacterial infection by photothermal therapy. J. Nanopart. Res., 2017, 19

[51] Liu RXK et al. An injectable self-assembling collagen-gold hybrid hydrogel for combinatorial antitumor photothermal/photodynamic therapy. Adv. Mater., 2016, 28: 3669-3676

[52] Hou M et al. Responsive agarose hydrogel incorporated with natural humic acid and MnO₂ nanopaticles for effective relief of tumor hypoxia and enhanced photo-induced tumor therapy. Biomater. Sci., 2020, 8: 353-369

[53] Jiang Y-W et al. Palladium nanosheet-knotted injectable hydrogels formed via palladium-sulfur bonding for synergistic chemo-photothermal therapy. Nanoscale, 2020, 12: 210-219

[54] Shan W et al. Improved stable Indocyanine Green (ICG)-mediated cancer optotheranostics with naturalized hepatitis B core particles. Adv. Mater., 2018, 30: 1707567

[55] Pan H, Zhang C, Wang T, Chen J, Sun S-K. In situ fabrication of intelligent photothermal indocyanine green-alginate hydrogel for localized tumor ablation. ACS Appl. Mater. Interfaces, 2019, 11: 2782-2789

[56] Cole JR, Mirin NA, Knight MW, Goodrich GP, Halas NJ. Photothermal efficiencies of nanoshells and nanorods for clinical therapeutic applications. J. Phys. Chem. C., 2009, 113: 12090-12094

[57] Rastinehad AR et al. Gold nanoshell-localized photothermal ablation of prostate tumors in a clinical pilot device study. PNAS, 2019, 116: 18590-18596

[58] Ni PY et al. Injectable thermosensitive PEG-PCL-PEG hydrogel/acellular bone matrix composite for bone regeneration in cranial defects. Biomaterials, 2014, 35: 236-248

[59] Shi R et al. Nano twin-fiber membrane with osteogenic and antibacterial dual functions as artificial periosteum for long bone repairing. J. Biomed. Nanotechnol., 2019, 15: 272-287

[60] Li C et al. Glycosylated superparamagnetic nanoparticle gradients for osteochondral tissue engineering. Biomaterials, 2018, 176: 24-33

[61] Zhang H et al. Magnetic nanoparticle-loaded electrospun polymeric nanofibers for tissue engineering. Mater. Sci. Eng. C., 2017, 73: 537-543

[62] Heo DN et al. Inhibition of osteoclast differentiation by gold nanoparticles functionalized with cyclodextrin curcumin complex. ACS Nano, 2014, 8: 12049-12062

[63] Chen L et al. Drug-loaded calcium alginate hydrogel system for use in oral bone tissue repair. Int. J. Mol. Sci., 2017, 18: 989

[64] Li A, Xie J, Li J. Recent advances in functional nanostructured materials for bone-related diseases. J. Mater. Chem. B, 2019, 7: 509-527

[65] Lin Y, Xiao Y, Liu C. The horizon of materiobiology: a perspective on material-guided cell-behavior and tissue engineering. Chem. Rev., 2017, 117: 4376-4421

[66] Yang D et al. The immune reaction and degradation fate of scaffold in cartilage/bone tissue engineering. Mater. Sci. Eng. C., 2019, 104: 109927

[67] Kossover O et al. Growth factor delivery for the repair of critical size tibia defect using an acellular, biodegradable polyethylene glycol-albumin, hydrogel implant. ACS Biomater. Sci. Eng., 2020, 6: 100-111

[68] Ji X et al. Mesenchymal stem cell-loaded thermosensitive hydroxypropyl chitin hydrogel combined with a three-dimensional-printed poly(Ɛ-caprolactone)/nano-hydroxyapatite scaffold to repair bone defects via osteogenesis, angiogenesis and immunomodulation. Theranostics, 2020, 10: 725-740

[69] Lee TT et al. Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials. Nat. Mater., 2015, 14: 352-360

[70] Hou S et al. Simultaneous nano- and microscale structural control of injectable hydrogel via assembly of nanofibrous protein microparticles for tissue regeneration. Biomaterials, 2019, 223: 119458

[71] Huang D et al. Viscoelasticity in natural tissues and engineered scaffolds for tissue reconstruction. Acta Biomater., 2019, 97: 74-92

[72] Zhang K et al. Advanced smart biomaterials and constructs for hard tissue engineering and regeneration. Bone Res., 2018, 6: 31

[73] Wu J et al. Functionalization of silk fibroin electrospun scaffolds via BMSC affinity peptide grafting through oxidative self-polymerization of dopamine for bone regeneration. ACS Appl. Mater. Interfaces, 2019, 11: 8878-8895

[74] Wang Q, Huang Y, Qian Z. Nanostructured surface modification to bone implants for bone regeneration. J. Biomed. Nanotechnol., 2018, 14: 628-648

[75] Hu Q, Liu M, Chen G, Xu Z, Lv Y. Demineralized bone scaffolds with tunable matrix stiffness for efficient bone integration. ACS Appl. Mater. Interfaces, 2018, 10: 27669-27680

[76] Xie J et al. Substrate elasticity regulates adipose-derived stromal cell differentiation towards osteogenesis and adipogenesis through β-catenin transduction. Acta Biomater., 2018, 79: 83-95

[77] Sadtler K et al. Design, clinical translation and javascript:__doPostBack('UCCKEditor$Pane7_content$ctl18','')immunological response of biomaterials in regenerative medicine. Nat. Rev., 2016, 1: 16040

[78] Gu Z et al. Double network hydrogel for tissue engineering. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2018, 10

[79] Brokesh AM, Gaharwar AK. Inorganic biomaterials for regenerative medicine. ACS Appl. Mater. Interfaces, 2020, 12: 5319-5344

[80] Yao Q et al. 3D interpenetrated graphene foam/58 S bioactive glass scaffolds for electrical-stimulation-assisted differentiation of rabbit mesenchymal stem cells to enhance bone regeneration. J. Biomed. Nanotechnol., 2019, 15: 602-611

[81] Farokhi M et al. Importance of dual delivery systems for bone tissue engineering. J. Control. Release, 2016, 225: 152-169

[82] Wang W et al. Local delivery of BMP-2 from poly(lactic-co-glycolic acid) microspheres incorporated into porous nanofibrous scaffold for bone tissue regeneration. J. Biomed. Nanotechnol., 2017, 13: 1446-1456

[83] Ma H, Feng C, Chang J, Wu C. 3D-printed bioceramic scaffolds: from bone tissue engineering to tumor therapy. Acta Biomater., 2018, 79: 37-59

[84] Liu W et al. Application and performance of 3D printing in nanobiomaterials. J. Nanomater., 2013, 2: 1-7

[85] Matai I, Kaur G, Seyedsalehi A, McClinton A, Laurencin CT. Progress in 3D bioprinting technology for tissue/organ regenerative engineering. Biomaterials, 2020, 226: 119536

[86] Choe G, Oh S, Seok JM, Park SA, Lee JY. Graphene oxide/alginate composites as novel bioinks for three-dimensional mesenchymal stem cell printing and bone regeneration applications. Nanoscale, 2019, 11: 23275-23285

[87] Yang C, Huan Z, Wang X, Wu C, Chang J. 3D printed Fe scaffold with HA nanocoating for bone regeneration. ACS Biomater. Sci. Eng., 2018, 4: 608-616

[88] Yang WF et al. Surface-modified hydroxyapatite nanoparticle-reinforced polylactides for three-dimensional printed bone tissue engineering scaffolds. J. Biomed. Nanotechnol., 2018, 14: 294-303

[89] Liu Y et al. 3D-printed scaffolds with bioactive elements-induced photothermal effect for bone tumor therapy. Acta Biomater., 2018, 73: 531-546

[90] Wang X et al. A 3D-printed scaffold with MoS₂ nanosheets for tumor therapy and tissue regeneration. NPG Asia Mater., 2017, 9

[91] Wang Y et al. Selenite-releasing bone mineral nanoparticles retard bone tumor growth and improve healthy tissue functions in vivo. Adv. Health Mater., 2015, 4: 1813-1818

[92] Pan S et al. 2D MXene-integrated 3D-printing scaffolds for augmented osteosarcoma phototherapy and accelerated tissue reconstruction. Adv. Sci., 2020, 7: 1901511

[93] Zheng Y, Yang Y, Deng Y. Dual therapeutic cobalt-incorporated bioceramics accelerate bone tissue regeneration. Mater. Sci. Eng. C., 2019, 90: 770-782

[94] Zhuang H et al. Three-dimensional-printed bioceramic scaffolds with osteogenic activity for simulataneous photo/magnetothermal therapy of bone tumors. ACS Biomater. Sci. Eng., 2019, 5: 6725-6734

[95] Liu G et al. Modulating the cobalt dose range to manipulate multisystem cooperation in bone environment: a strategy to resolve the controversies about cobalt use for orthopedic application. Theranostics, 2020, 10: 1074-1089

[96] Ma H et al. A bifunctional biomaterial with photothermal effect for tumor therapy and bone regeneration. Adv. Funct. Mater., 2016, 26: 1197-1208

[97] Dang W et al. A bifunctional scaffold with CuFeSe₂ nanocrystals for tumor therapy and bone reconstrcution. Biomaterials, 2018, 160: 92-106

[98] Ma H et al. 3D printing of biomaterials with mussel-inspired nanostructures for tumor therapy and tissue regeneration. Biomaterials, 2016, 111: 138-148

[99] Ma H et al. 3D printing of high-strength bioscaffolds for the synergistic treatment of bone cancer. NPG Asia Mater., 2018, 10: 31-44

[100] Dang W et al. LaB₆ surface chemistry-reinforced scaffolds for treating bone tumors and bone defects. Appl. Mater. Today, 2019, 16: 42-55

[101] Fu S, Hu H, Chen J, Zhu Y, Zhao S. Silicone resin derived larnite/C scaffolds via 3D printing for potential tumor therapy and bone regeneration. Chem. Eng. J., 2019, 382: 122928

[102] Dong S, Chen Y, Yu L, Lin K, Wang X. Magnetic hyperthermia-synergistic H₂O₂ self-sufficient catalytic suppression of osteosarcoma with enhanced bone-regeneration bioactivity by 3D-printing composite scaffolds. Adv. Funct. Mater., 2019, 30: 1907071

[103] Xu M et al. Custom-made locked plating for acetabular fracture: a pilot study in 24 consecutive cases. Orthopedics, 2014, 37: 660-670

[104] Ma L et al. 3D printed personalized titanium plates improve clinical outcome in microwave ablation of bone tumors around the knee. Sci. Rep., 2017, 7

[105] Li D et al. Self-assembled hydroxyapatite-graphene scaffold for photothermal cancer therapy and bone regeneration. J. Biomed. Nanotechnol., 2018, 14: 2003-2017

[106] Saber-Samandari S, Mohammadi-Aghdam M, Saber-Samandari S. A novel magnetic bifunctional nanocomposite scaffold for photothermal therapy and tissue engineering. Inter. J. Bio. Macromol., 2019, 13: 810-818

[107] Wang G et al. A bifunctional scaffold for tissue regeneration and photothermal therapy. J. Biomed. Nanotechnol., 2018, 14: 698-706

[108] Zhou Z-F et al. Calcium phosphate-phosphorylated adenosine hybrid microspheres for anti-osteosarcoma drug delivery and osteogenic differentiation. Biomaterials, 2017, 121: 1-14

[109] Yang F et al. Magnetic mesoporous calcium sillicate/chitosan porous scafflods for enhanced bone regeneration and photothermal-chemotherapy of osteosarcoma. Sci. Rep., 2018, 8

[110] Lu JW, Yang F, Ke QF, Xie XT, Guo YP. Magnetic nanoparticles modified-porous scaffolds for bone regeneration and photothermal therapy against tumors. Nanomedicine, 2018, 14: 811-822

[111] Dong S et al. A novel multifunctional carbon aerogel-coated platform for osteosarcoma therapy and enhanced bone regeneration. J. Mater. Chem. B, 2020, 8: 368-379

[112] Zhao PP et al. Ordered arrangement of hydrated GdPO₄ nanorods in magnetic chitosan matrix promotes tumor photothermal therapy and bone regeneration against breast cancer bone metastases. Chem. Eng. J., 2020, 381: 122694

[113] Yu K et al. PMMA-Fe₃O₄ for internal mechanical support and magnetic ablation of bone tumors. Theranostics, 2019, 14: 4192-4207

[114] Wang L et al. Multi-functional bismuth-doped bioglasses: combining bioactivity and photothermal response for bone tumor treatment and tissue repair. Light. Sci. Appl., 2018, 7: 1

[115] Zhang W et al. A hydrogenated black TiO₂ coating with excellent effect for photothermal therapy of bone tumor and bone regeneration. Mater. Sci. Eng. C., 2019, 102: 458-470

[116] Li Q et al. The design, mechanism and biomedical application of self-healing hydrogels. Chin. Chem. Lett., 2017, 28: 1857-1874

[117] Zhang K et al. Adaptable hydrogels mediate cofactor-assisted activation of biomarker-responsive drug delivery via positive feedback for enhanced tissue regeneration. Adv. Sci., 2018, 5: 1800875

[118] Niu Y, Yang T, Ke R, Wang C. Preparation and characterization of pH-responsive sodium alginate/humic acid/konjac hydrogel for L-ascorbic acid controlled release. Mater. Express, 2019, 9: 563-569

[119] Wang X et al. Near-infrared light-triggered drug delivery system based on black phosphorus for in vivo bone regeneration. Biomaterials, 2018, 179: 164-174

[120] Wu D, Xie X, Kadi AA, Zhang Y. Photosensitive peptide hydrogels as smart materials for applications. Chin. Chem. Lett., 2018, 29: 1098-1104

[121] Yang Z, Liu J, Lu Y. Doxorubicin and CD-CUR inclusion complex co-loaded in thermosensitive hydrogel PLGA-PEG-PLGA localized administration for osteosarcoma. Int. J. Oncol., 2020, 57: 433-444

[122] Li Q et al. Granphene nanoparticles-based self-healing hydrogel in preventing post-operative recurrence of breast cancer. ACS Biomater. Sci. Eng., 2019, 5: 768-779

[123] Liu Q, Wang H, Li G, Liu M, Wu H. A photocleavable low molecular weight hydrogel for light-triggered drug delivery. Chin. Chem. Lett., 2019, 30: 485-488

[124] Gumustas SA et al. Systematic evaluation of drug-loaded hydrogels for application in osteosarcoma treatment. Curr. Pharm. Biotechnol., 2016, 17: 866-872

[125] Hu Y, Chen X, Li Z, Zheng S, Cheng Y. Thermosensitive in situ gel containing luteolin micelles is a promising efficient agent for colorectal cancer peritoneal metastasis treatment. J. Biomed. Nanotechnol., 2020, 16: 54-64

[126] Zhao H et al. Dual-functional guanosine-based hydrogel integrating localized delivery and anticancer activities for cancer therapy. Biomaterials, 2020, 230: 119598

[127] Yang Z et al. The effect of PLGA-based hydrogel scaffold for improving the drug maximum-tolerated dose for in situ osteosarcoma treatment. Colloids Surf. B Biointerfaces, 2018, 172: 387-394

[128] Ma H et al. PLK1 sh RNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for osteosarcoma treatment. Biomaterials, 2014, 35: 8723-8734

[129] Chen Y et al. An injectable, near-infrared light-responsive click cross-linked azobenzene hydrogel for breast cancer chemotherapy. J. Biomed. Nanotechnol., 2019, 15: 1923-1936

[130] Zheng Y et al. Injectable hydrogel-microsphere construct with sequential degradable for locally synergistic chemotherapy. ACS Appl. Mater. Interfaces, 2017, 9: 3487-3496

[131] Yu L, Ding J. Injectable hydrogels as unique biomedical materials. Chem. Soc. Rev., 2008, 37: 1473-1481

[132] Park MH, Joo MK, Choi GG, Jeong B. Biodegradable thermogels. Acc. Chem. Res., 2012, 45: 424-433

[133] Wasupalli GK, Verma D. Injectable and thermosensitive nanofibrous hydrogel for bone tissue engineering. Mater. Sci. Eng. C., 2020, 107: 110343

[134] Dimatteo R, Darling NJ, Segura T. In situ forming injectable hydrogels for drug delivery and wound repair. Adv. Drug Deliv. Rev., 2018, 127: 167-184

[135] Sun Y, Nan D, Jin H, Qu X. Recent advances of injectable hydrogels for drug delivery and tissue engineering applications. Polym. Test., 2020, 81: 106283

[136] Luo S et al. An injectable, bifunctional hydrogel with photothermal effects for tumor therapy and bone regeneration. Macromol. Biosci., 2019, 19

[137] Wu W et al. Local release of gemcitabine via in situ UV-crosslinked lipid-strengthened hydrogel for inhibiting osteosarcoma. Drug Deliv., 2018, 25: 1642-1651

[138] Ma H et al. Localized co-delivery of doxorubicin, cisplatin, and methotrexate by thermosensitive hydrogels for enhanced osteosarcoma treatment. ACS Appl. Mater. Interfaces, 2015, 7: 27040-27048

[139] Roodman GD. Mechanism of bone metastasis. N. Engl. J. Med., 2004, 350: 1655-1664

[140] Yang Y-S et al. Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis. Nat. Commun., 2019, 10

[141] Hirabayashi H et al. Bone-specific delivery and sustained release of diclofenac, a non-steroidal anti-inflammatory drug, via bisphosphonic prodrug based on the osteotropic drug delivery system (ODDS). J. Control. Release, 2001, 70: 183-191

[142] Chong CR, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med., 2013, 19: 1389-1400

[143] David E et al. 12b80-hydroxybisphosphonate linked doxorubcin: bone targeted strategy for treatment of osteosarcoma. Bioconjug. Chem., 2019, 30: 1665-1676

[144] Thamake SI, Raut SL, Gryczynski Z, Ranjan AP, Vishwanatha JK. Alendronte coated poly-lactic-co-glycolic acid (PLGA) nanoparticles targeting of metastatic breast cancer. Biomaterials, 2012, 33: 7164-7173

[145] He Y et al. Bisphosphonate-functionalized coordination polymer nanoparticles for the treatment of bone metastatic breast cancer. J. Control. Release, 2017, 264: 76-88

[146] Ravanbakhsh M et al. Mesoporous bioactive glasses for the combined application of osteosarcoma treatment and bone regeneration. Mater. Sci. Eng. C., 2019, 104: 109994

[147] Cole LE, Vargo-Gogola T, Roeder RK. Targeted delivery to bone and mineral deposits using bisphosphonate ligands. Adv. Drug Deliv. Rev., 2016, 99: 12-27

[148] Low SA, Kopeček J. Targeting polymer therapeutics to bone. Adv. Drug Deliv. Rev., 2012, 64: 1189-1204

[149] Hatami E et al. Development of zoledronic acid-based nanoassemblies for bone-targetd anticancer therapy. ACS Biomater. Sci. Eng., 2019, 5: 2343-2354

[150] Yamashita S et al. Development of PEGylated aspartic acid-modified liposomes as a bone-targeting carrier for the delivery of paclitaxel and treatment of bone metastasis. Biomaterials, 2018, 154: 74-85

[151] Poznak CHV et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J. Clin. Oncol., 2011, 29: 1221-1227

[152] Liang C et al. Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA interference-based bone anabolic strategy. Nat. Med., 2015, 21: 288-296

[153] Wang Y et al. Osteotropic peptide-mediated bone targeting for photothermal treatment of bone tumors. Biomaterials, 2017, 114: 97-105

[154] Feng S et al. Engineering of bone- and CD44-dual-targeting redox-sensitive liposomes for treatment of orthotopic osteosarcoma. ACS Appl. Mater. Interfaces, 2019, 11: 7357-7368

[155] Yang L, Webster TJ. Nanotechnology controlled drug delivery for treating bone disease. Expert Opin. Drug Deliv., 2009, 6: 851-864

[156] Raucci MG et al. Exfoliated black phosphorus promotes in vitro bone regeneration and suppresses osteosarcoma progression through cancer-related inflammation inhibition. ACS Appl. Mater. Interfaces, 2019, 11: 9333-9342

[157] Li K et al. Calcium-mineralized polypeptide nanoparticle for intracellular drug delivery in osteosarcoma chemotherapy. Bioact. Mater., 2020, 5: 721-731

[158] Zhang M et al. Fabrication of curcumin-modified TiO₂ nanoarrays via cyclodextrin based polymer functional coatings for osteosarcoma therapy. Adv. Health Mater., 2019, 8: 1901031

[159] Cheng H et al. Development of nanomaterials for bone-targeted drug delivery. Drug Discov. Today, 2017, 22: 1336-1350

[160] Song H et al. Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett., 2019, 19: 3040-3048

[161] Rotman SG et al. Drug delivery systems functionalized with bone mineral seeking agents for bone targeted therapeutics. J. Control. Release, 2018, 269: 88-99

[162] Carbone EJ et al. Osteotropic nanoscale drug delivery systems based on small molecule bone-targeting moieties. Nanomedicine, 2017, 13: 37-47

[163] Farrell KB, Karpeisky A, Thamm DH, Zinnen S. Bisphosphonate conjugation for bone specific drug targeting. Bone Rep., 2018, 9: 47-60

[164] Chu W et al. Calcium phosphate nanoparticles functionalized with alendronate-conjugated polyethlene glycol (PEG) for the treatment of bone metastasis. Int. J. Pharm., 2017, 516: 352-363

[165] Wang Y et al. Multifunctional melanin-like nanoparticles for bone-targeted chemo-photothermal therapy of malignant bone tumors and osteolysis. Biomaterials, 2018, 183: 10-19

[166] Lee KK et al. Bone-targeting carbon dots: effect of nitrogen-doping on binding affinity. RSC Adv., 2019, 9: 2708-2717

[167] Sun W et al. Bone-targeted nanoplatform combining zoledronate and photothermal therapy to treat breast cancer bone metastasis. ACS Nano, 2019, 13: 7556-7567

[168] McClung M et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am. J. Med., 2013, 126: 13-20

[169] Zhou Z et al. One stone with two birds: phytic acid-capped platinum nanoparticles for targeted combination therapy of bone tumors. Biomaterials, 2019, 194: 130-138

[170] Lu Y et al. High-activity chitosan/nanohydroxyapatite/zoledronic acid scaffolds for simultaneous tumor inbibition, bone repair and infection eradication. Mater. Sci. Eng. C., 2018, 82: 225-233

[171] Cojocaru FD et al. Magnetic composite scaffolds for potential applications in radiochemotherapy of malignant bone tumors. Medicina, 2019, 55: 153

[172] Yang Q et al. Engineering 2D mesoporous silica@MXene-integrated 3D-printing scaffolds for combinatory osteosarcoma therapy and NO-augmented bone regeneration. Small, 2020, 16

[173] Yu Q et al. Copper silicate hollow microspheres incorporated scaffolds for chemo-photothermal therapy of melanoma and tissue engineering. ACS Nano, 2018, 12: 2695-2707

[174] Zhou L et al. Injectable self-healing antibacterial bioactive polypeptide-based hybrid nanosystems for efficiently treating multidrug resistant infection, skin-tumor therapy, and enhancing wound healing. Adv. Funct. Mater., 2019, 29: 1806883

[175] Li J et al. Lysozyme-assisted photothermal eradiction of methicillin-resistant Staphylococcus aureus infection and acceletated tissue repair with natural melanosome nanostructures. ACS Nano, 2019, 13: 11153-11167

[176] Yanagi T, Kajiya H, Kawaguchi M, Kido H, Fukushima T. Photothermal stress triggered by near infrared-irradiated carbon nanotubes promotes bone deposition in rat calvarial defects. J. Biomater. Appl., 2015, 29: 1109-1118

[177] Lu Y et al. High-activity chitosan/nanohydroxyapatite/zoledronic acid scaffolds for simultaneous tumor inhibition, bone repair and infection eradication. Mater. Sci. Eng. C., 2018, 82: 225-233

[178] Lu Y et al. Zero-dimensional carbon dots enhance bone regeneration, osterosarcoma ablation, and clinical bacterial eradication. Bioconjug. Chem., 2018, 29: 2982-2993

[179] Ma L et al. A novel photothermally controlled multifunctional scaffold for clinical treatment of osteosarcoma and tissue regeneration. Mater. Today, 2020, 36: 48-62

[180] Wang X et al. Bifunctional scaffolds for the photothermal therapy of breast tumor cells and adipose tissue regeneration. J. Mater. Chem. B, 2018, 6: 7728-7736

Funding

The National Key Research and Development Program of China (2017YFC1103500, 2017YFC1103502), NSFC 31771096, NSFC 31930067, #x00A0;NSFC 31525009, 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18002)

the National Natural Science Foundation (31972925), Sichuan Science and Technology Program (2020YJ0065), Sichuan University Spark Project (2018SCUH0029), State Key Laboratory of Oral Diseases Foundation (SKLOD202016)