Fabrication of a composite 3D-printed titanium alloy combined with controlled in situ drug release to prevent osteosarcoma recurrence.

Osteosarcoma is a malignant bone tumor occurring in adolescents. Surgery combined with adjuvant or neoadjuvant chemotherapy is the standard treatment. However, systemic chemotherapy is associated with serious side effects and a high risk of postoperative tumor recurrence, leading to a high amputation rate and mortality in cancer patients. Implant materials that can simultaneously repair large bone defects and prevent osteosarcoma recurrence are in urgent need. Herein, an intelligent system comprising 3D-printed titanium scaffold (TS) and pH-responsive PEGylated paclitaxel prodrugs was fabricated for bone defect reconstruction and recurrence prevention following osteosarcoma surgery. The drug-loaded implants exhibited excellent stability and biocompatibility for supporting the activity of bone stem cells under normal body fluid conditions and the rapid release of drugs in response to faintly acidic environments. An in vitro study demonstrated that five human osteosarcoma cell lines could be efficiently eradicated by paclitaxel released in an acidic microenvironment. Using mice models, we demonstrated that the drug-loaded TS can enable a pH-responsive treatment of postoperative tumors and effectively prevent osteosarcoma recurrence. Therefore, local implantation of this composite scaffold may be a promising topical therapeutic method to prevent osteosarcoma recurrence.

Surface treatment of 3D printed porous Ti6Al4V implants by ultraviolet photofunctionalization for improved osseointegration.

Three-dimensional (3D)-printed porous Ti6Al4V implants play an important role in the reconstruction of bone defects. However, its osseointegration capacity needs to be further improved, and related methods are inadequate, especially lacking customized surface treatment technology. Consequently, we aimed to design an omnidirectional radiator based on ultraviolet (UV) photofunctionalization for the surface treatment of 3D-printed porous Ti6Al4V implants, and studied its osseointegration promotion effects in vitro and in vivo, while elucidating related mechanisms. Following UV treatment, the porous Ti6Al4V scaffolds exhibited significantly improved hydrophilicity, cytocompatibility, and alkaline phosphatase activity, while preserving their original mechanical properties. The increased osteointegration strength was further proven using a rabbit condyle defect model in vivo, in which UV treatment exhibited a high efficiency in the osteointegration enhancement of porous Ti6Al4V scaffolds by increasing bone ingrowth (BI), the bone-implant contact ratio (BICR), and the mineralized/osteoid bone ratio. The advantages of UV treatment for 3D-printed porous Ti6Al4V implants using the omnidirectional radiator in the study were as follows: 1) it can significantly improve the osseointegration capacity of porous titanium implants despite the blocking out of UV rays by the porous structure; 2) it can evenly treat the surface of porous implants while preserving their original topography or other morphological features; and 3) it is an easy-to-operate low-cost process, making it worthy of wide clinical application.

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.

Three-dimensional-printed individualized porous implants: A new "implant-bone" interface fusion concept for large bone defect treatment.

Bone defect repairs are based on bone graft fusion or replacement. Current large bone defect treatments are inadequate and lack of reliable technology. Therefore, we aimed to investigate a simple technique using three-dimensional (3D)-printed individualized porous implants without any bone grafts, osteoinductive agents, or surface biofunctionalization to treat large bone defects, and systematically study its long-term therapeutic effects and osseointegration characteristics. Twenty-six patients with large bone defects caused by tumor, infection, or trauma received treatment with individualized porous implants; among them, three typical cases underwent a detailed study. Additionally, a large segmental femur defect sheep model was used to study the osseointegration characteristics. Immediate and long-term biomechanical stability was achieved, and the animal study revealed that the bone grew into the pores with gradual remodeling, resulting in a long-term mechanically stable implant-bone complex. Advantages of 3D-printed microporous implants for the repair of bone defects included 1) that the stabilization devices were immediately designed and constructed to achieve early postoperative mobility, and 2) that osseointegration between the host bone and implants was achieved without bone grafting. Our osseointegration method, in which the "implant-bone" interface fusion concept was used instead of "bone-bone" fusion, subverts the traditional idea of osseointegration.

Functionalization of 3D-printed titanium alloy orthopedic implants: a literature review.

Titanium alloy orthopedic implants produced by 3D printing combine the dual advantages of having a complex structure that cannot be manufactured by traditional techniques and the excellent physical and chemical properties of titanium and its alloys; they have been widely used in the field of orthopedics in recent years. The inherent porous structure of 3D-printed implants and the original modification processes for titanium alloys provide conditions for the functionalization of implants. To meet the needs of orthopedic surgeons and patients, functionalized implants with long-term stability and anti-infection or anti-tumor properties have been developed. The various methods of functionalization deserve to be summarized, compared and analyzed. Therefore, in this review, we will collect and discuss existing knowledge on the functionalization of 3D-printed titanium alloy orthopedic implants.

Sustainable release of vancomycin from micro-arc oxidised 3D-printed porous Ti6Al4V for treating methicillin-resistant Staphylococcus aureus bone infection and enhancing osteogenesis in a rabbit tibia osteomyelitis model.

Elimination of infection and enhancement of osteogenesis by orthopaedic implants are two critical factors in the treatment of complex bone infections. A prolonged and expensive procedure requiring two surgical steps and a 6-8-week period of joint immobilisation is utilised as a primary treatment for revision arthroplasty of an infected prosthesis, greatly affecting long-term patient care for the ageing population. Here, we evaluated the effects of vancomycin-loaded in micro-arc oxidised (MAO) three-dimensional (3D) printed porous Ti6Al4V scaffolds on osteogenesis. This system showed a high loading capacity and sustained vancomycin release kinetics, as demonstrated using high-performance liquid chromatography. In vivo, 0.1 mL of 108 colony forming units (CFU) methicillin-resistant Staphylococcus aureus was injected into the tibias of rabbits to induce severe osteomyelitis. Physical, haematological, radiographic, microbiological, and histopathological analyses were performed to evaluate the effects of treatment. Rabbits with vancomycin-loaded in MAO scaffolds showed the inhibition of bone infection and enhancement of osteogenesis, resulting in better outcomes than in the other groups. Overall, these findings demonstrated the potential of this 3D printed porous Ti6Al4V, with good osteogenesis and sustained vancomycin release properties, for application in the treatment of complex bone infections.

Improved osseointegration with rhBMP-2 intraoperatively loaded in a specifically designed 3D-printed porous Ti6Al4V vertebral implant.

Three-dimensional (3D)-printed porous Ti6Al4V implants are commonly used for reconstructing bone defects in the treatment of orthopaedic diseases owing to their excellent osteoconduction. However, to achieve improved therapeutic outcomes, the osteoinduction of these implants requires further improvement. The aim of this study was to investigate the combined use of recombinant human BMP-2 (rhBMP-2) with a 3D-printed artificial vertebral implant (3D-AVI) to improve the osteoinduction. Eight male Small Tail Han sheep underwent cervical corpectomy, and 3D-AVIs with or without loaded rhBMP-2 in cavities designed at the center were implanted to treat the cervical defect. Radiographic, micro-computed tomography, fluorescence labelling, and histological examination revealed that the osseointegration efficiency of the rhBMP-2 group was significantly higher than that of the blank control group. The biomechanical test results suggested that rhBMP-2 reduced the range of motion of the cervical spine and provided a more stable implant. Fluorescence observations revealed that the bone tissue grew from the periphery to the center of the 3D-AVIs, first growing into the pore space and then interlocking with the Ti6Al4V implant surface. Therefore, we successfully improved osseointegration of the 3D-AVI by loading rhBMP-2 into the cavity designed at the center of the Ti6Al4V implant, realizing earlier and more stable fixation of implants postoperatively in a simple manner. These benefits of rhBMP-2 are expected to expand the application range and reliability of 3D-printed porous Ti6Al4V implants and improve their therapeutic efficacy.