Simvastatin/hydrogel-loaded 3D-printed titanium alloy scaffolds suppress osteosarcoma via TF/NOX2-associated ferroptosis while repairing bone defects

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Simvastatin/hydrogel-loaded 3D-printed titanium alloy scaffolds suppress osteosarcoma via TF/NOX2-associated ferroptosis while repairing bone defects

Postoperative anatomical reconstruction and prevention of local recurrence after tumor resection are two vital clinical challenges in osteosarcoma treatment.A three-dimensional(3D)-printed porous Ti6Al4V scaffold(3DTi)is an ideal material for reconstructing critical bone defects with numerous advantages over traditional implants,including a lower elasticity modulus,stronger bone-implant interlock,and larger drug-loading space.Simvastatin is a multitarget drug with anti-tumor and osteogenic potential;however,its efficiency is unsatisfactory when delivered systematically.Here,simvastatin was loaded into a 3DTi using a thermosensitive poly(lactic-co-gly-colic)acid(PLGA)-polyethylene glycol(PEG)-PLGA hydrogel as a carrier to exert anti-osteosarcoma and oste-ogenic effects.Newly constructed simvastatin/hydrogel-loaded 3DTi(Sim-3DTi)was comprehensively appraised,and its newfound anti-osteosarcoma mechanism was explained.Specifically,in a bone defect model of rabbit condyles,Sim-3DTi exhibited enhanced osteogenesis,bone in-growth,and osseointegration compared with 3DTi alone,with greater bone morphogenetic protein 2 expression.In our nude mice model,simvastatin loading reduced tumor volume by 59%-77%without organic damage,implying good anti-osteosarcoma activity and biosafety.Furthermore,Sim-3DTi induced ferroptosis by upregulating transferrin and nicotinamide adenine dinucleotide phosphate oxidase 2 levels in osteosarcoma both in vivo and in vitro.Sim-3DTi is a promising osteogenic bone substitute for osteosarcoma-related bone defects,with a ferroptosis-mediated anti-osteosarcoma effect.

Practical strategy to construct anti-osteosarcoma bone substitutes by loading cisplatin into 3D-printed titanium alloy implants using a thermosensitive hydrogel

Surgical resection and perioperative adjuvant chemotherapy-based therapies have improved the prognosis of patients with osteosarcoma;however,intraoperative bone defects,local tumour recurrence,and chemotherapy-induced adverse effects still affect the quality of life of patients.Emerging 3D-printed titanium alloy(Ti6Al4V)implants have advantages over traditional implants in bone repair,including lower elastic modulus,lower stiffness,better bone conduction,more bone in-growth,stronger mechanical interlocking,and lager drug-loading capacity by their inherent porous structure.Here,cisplatin,a clinical first-line anti-osteosarcoma drug,was loaded into Ti6Al4V implants,within a PLGA-PEG-PLGA thermo-sensitive hydrogel,to construct bone substitutes with both anti-osteosarcoma and bone-repair functions.The optimal concentrations of cisplatin(0.8 and 1.6 mg/mL)were first determined in vitro.Thereafter,the anti-tumour effect and biosafety of the cisplatin/hydrogel-loaded implants,as well as their bone-repair potential were evaluated in vivo in tumour-bearing mouse,and bone defect rabbit models,respectively.The loading of cisplatin reduced tumour volume by more than two-thirds(from 641.1 to 201.4 mm3)with negligible organ damage,achieving better anti-tumour effects while avoiding the adverse effects of systemic cisplatin delivery.Although bone repair was hindered by cisplatin loading at 4 weeks,no difference was observed at 8 weeks in the context of implants with versus without cisplatin,indicating acceptable long-term stability of all implants(with 8.48%-10.04%bone in-growth and 16.94%-20.53%osseointegration).Overall,cisplatin/hydrogel-loaded 3D-printed Ti6Al4V implants are safe and effective for treating osteosarcoma-caused bone defects,and should be considered for clinical use.