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

Abstract

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.