Microbial resistance to nanotechnologies:An important but understudied consideration using antimicrobial nanotechnologies in orthopaedic implants

Microbial resistance to current antibiotics therapies is a major cause of implant failure and adverse clinical outcomes in orthopaedic surgery.Recent developments in advanced antimicrobial nanotechnologies provide numerous opportunities to effective remove resistant bacteria and prevent resistance from occurring through unique mechanisms.With tunable physicochemical properties,nanomaterials can be designed to be bactericidal,antifouling,immunomodulating,and capable of delivering antibacterial compounds to the infection region with spatiotemporal accuracy.Despite its substantial advancement,an important,but under-explored area,is potential microbial resistance to nanomaterials and how this can impact the clinical use of antimicrobial nanotechnologies.This review aims to provide a better understanding of nanomaterial-associated microbial resistance to accelerate bench-to-bedside translations of emerging nanotechnologies for effective control of implant associated infections.

Advances of biodegradable magnesium-based implants for orthopaedics

Stainless steel,titanium alloys,cobalt-chromium alloys and other metal materials are the most widely used orthopaedic implants.However,there are still some problems in clinical application,including a mechanical mismatch between metal and bone,inflammation and secondary operation.As a new generation of medical metal materials,magnesium(Mg)and its alloys have attracted much attention due to their excellent biodegradability.Biodegradable Mg-based metals have good mechanical and osteogenic properties,and are expected to become implant materials to treat challenging orthopaedic diseases.However,the rapid corrosion rate is still one of the main challenges restricting its clinical application.Alloy and surface modification are effective methods to control the corrosion rate of Mg alloys.This paper reviews the mechanical and biological properties of biodegradable Mg alloys and the problems when they are applied clinically,emphasizing the latest progress of Mg-based metals in alloying and surface modification.The status of the application of Mg-based implants in orthopaedics are also described.

Effect of solution treatment on corrosion characteristics of biodegradable Mg-6Zn alloy

A binary Mg-6Zn biodegradable alloy was solution treated to evaluate the effects of resulting microstructure changes on the alloy＇s degradation rate and mechanisms in-vitro. The treatment was conducted at 350 °C for 6-48 h. Optical and scanning electron microscopy, energy-dispersive X-ray spectroscopy and X-ray diffraction were used to analyze the as-cast and treated samples. Immersion and electrochemical tests were performed in simulated body fluid at 37 °C to assess the samples corrosion resistance. To confirm the results of the corrosion tests, p H measurement was carried out. It is found that over 24 h solution treatment dissolves intermetallic phases in matrix and produces an almost single phase microstructure. Decreasing the intermetallic phases results in lower cathode/anode region ratios and lowers corrosion rates. The results of the electrochemical and mass loss tests reveal that extended solution treatment improves the corrosion resistance of the alloy. The results also show that solution at 350 °C for 24 h enhances the corrosion resistance of the as-cast alloy more than 60%. In addition, decreasing intermetallic phases in the microstructure accompanied a lower p H rise reduced corrosion rate. Solution treatment is suggested as a corrosion improving process for the application of Mg-Zn alloys as biodegradable implant materials.

Additive manufactured metallic implants for orthopaedic applications

Metallic implants are commonly used in various orthopaedic surgeries, like fracture fixation, spinal instrumentation, joint replacement and bone tumour surgery.Patients may need to adapt to the fixed dimensions of the standard implants. It may result in suboptimal fit to the host bones and possible adverse clinical results. The standard traditional implants may not address the reconstructive challenges such as severe bone deformity or bone loss after implant loosening and bone tumour resection. With the advent of digital technologies in medical imaging, computer programming in three-dimensional（3 D） modelling and computer-assisted tools in precise placement of implants, patient-specific implants（PSI） have gained more attention in complex orthopaedic reconstruction. Additive manufacturing technology, in contrast to the conventional subtractive manufacturing, is a flexible process that can fabricate anatomically conforming implants that match the patients’ anatomy and surgical requirements. Complex internal structures with porous scaffold can also be built to enhance osseointegration for better implant longevity. Although basic studies have suggested that additive manufactured（AM） metal structures are good engineered biomaterials for bone replacement, not much peer-reviewed literature is available on the clinical results of the new types of implants. The article gives an overview of the metallic materials commonly used for fabricating orthopaedic implants, describes the metal-based additive manufacturing technology and the processing chain in metallic implants; discusses the features of AM implants;reports the current status in orthopaedic surgical applications and comments on the challenges of AM implants in orthopaedic practice.

Update on the research and development of magnesium-based biodegradable implants and their clinical translation in orthopaedics

Biodegradable magnesium(Mg)or its alloys are desirable materials for development into new-generation internal fixation devices or implants with high biocompatibility,adequate mechanical modulus,and osteopromotive properties,which may overcome some of the drawbacks of the existing permanent orthopaedic implants with regard to stress-shielding of bone and beam-hardening effects on radiographic images.This review summarises the current research status of Mg-based orthopaedic implants in animals and clinical trials.First,detailed information of animal studies including bone fracture repair and anterior cruciate ligament reconstruction with the use of Mg-based orthopaedic devices is introduced.Second,the repair mechanisms of the Mg-based orthopaedic implants are also reviewed.Afterwards,reports of recent clinical cases treated using Mg-based implants in orthopaedics are summarised.Finally,the challenges and the strategies of the use of Mg-based orthopaedic implants are discussed.Taken together,the collected efforts in basic research,translational work,and clinical applications of Mg-based orthopaedic implants over the last decades greatly contribute to the development of a new generation of biodegradable metals used for the design of innovative implants for better treatment of orthopaedic conditions in patients with challenging skeletal disorders or injuries.

Research progress and clinical translation of three-dimensional printed porous tantalum in orthopaedics

With continuous developments in additive manufacturing technology, tantalum (Ta) metal has been manufactured into orthopaedic implants with a variety of forms, properties and uses by three-dimensional printing. Based on extensive research in recent years, the design, processing and performance aspects of this new orthopaedic implant material have been greatly improved. Besides the bionic porous structure and mechanical characteristics that are similar to human bone tissue, porous tantalum is considered to be a viable bone repair material due to its outstanding corrosion resistance, biocompatibility, bone integration and bone conductivity. Numerous in vitro, in vivo, and clinical studies have been carried out in order to analyse the safety and efficacy of these implants in orthopaedic applications. This study reviews the most recent advances in manufacturing, characteristics and clinical application of porous tantalum materials.

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.

Optimising soft tissue in-growth in vivo in additive layer manufactured osseointegrated transcutaneous implants

Osseointegrated transcutaneous implants could provide an alternative and improved means of attaching artificial limbs for amputees,however epithelial down growth,inflammation,and infections are common failure modalities associated with their use.To overcome these problems,a tight seal associated with the epidermal and dermal adhesion to the implant is crucial.This could be achieved with specific biomaterials(that mimic the surrounding tissue),or a tissue-specific design to enhance the proliferation and attachment of dermal fibroblasts and keratinocytes.The intraosseous transcutaneous amputation prosthesis is a new device with a pylon and a flange,which is specifically designed for optimising soft tissue attachment.Previously the flange has been fabricated using traditional machining techniques,however,the advent of additive layer manufacturing(ALM)has enabled 3-dimensional porous flanges with specific pore sizes to be used to optimise soft tissue integration and reduce failure of osseointegrated transcutaneous implants.The study aimed to investigate the effect of ALM-manufactured porous flanges on soft tissue ingrowth and attachment in an in vivo ovine model that replicates an osseointegrated percutaneous implant.At 12 and 24 weeks,epithelial downgrowth,dermal attachment and revascularisation into ALM-manufactured flanges with three different pore sizes were compared with machined controls where the pores were made using conventional drilling.The pore sizes of the ALM flanges were 700,1000 and 1250μm.We hypothesised that ALM porous flanges would reduce downgrowth,improve soft tissue integration and revascularisation compared with machined controls.The results supported our hypothesis with significantly greater soft tissue integration and revascularisation in ALM porous flanges compared with machined controls.

Functionalized TiCu/TiCuN coating promotes osteoporotic fracture healing by upregulating the Wnt/β-catenin pathway

Osteoporosis results in decreased bone mass and insufficient osteogenic function.Existing titanium alloy implants have insufficient osteoinductivity and delayed/incomplete fracture union can occur when used to treat osteoporotic fractures.Copper ions have good osteogenic activity,but their dose-dependent cytotoxicity limits their clinical use for bone implants.In this study,titanium alloy implants functionalized with a TiCu/TiCuN coating by arc ion plating achieved a controlled release of copper ions in vitro for 28 days.The coated alloy was co-cultured with bone marrow mesenchymal stem cells and showed excellent biocompatibility and osteoinductivity in vitro.A further exploration of the underlying mechanism by quantitative real-time polymerase chain reaction and western blotting revealed that the enhancement effects are related to the upregulation of genes and proteins(such as axin2,β-catenin,GSK-3β,p-GSK-3β,LEF1 and TCF1/TCF7)involved in the Wnt/β-catenin pathway.In vivo experiments showed that the TiCu/TiCuN coating significantly promoted osteoporotic fracture healing in a rat femur fracture model,and has good in vivo biocompatibility based on various staining results.Our study confirmed that TiCu/TiCuN-coated Ti promotes osteoporotic fracture healing associated with the Wnt pathway.Because the coating effectively accelerates the healing of osteoporotic fractures and improves bone quality,it has significant clinical application prospects.

Opportunities and challenges for the biodegradable magnesium alloys as next-generation biomaterials

In recent years,biodegradable magnesium alloys emerge as a new class of biomaterials for tissue engineering and medical devices.Deploying biodegradable magnesium-based materials not only avoids a second surgical intervention for implant removal but also circumvents the long-term foreign body effect of permanent implants.However,these materials are often subjected to an uncontrolled and fast degradation,acute toxic responses and rapid structural failure presumably due to a localized,too rapid corrosion process.The patented Mg-Nd-Zn-based alloys(JiaoDa BioMg[JDBM])have been developed in Shanghai Jiao Tong University in recent years.The alloy series exhibit lower biodegradation rate and homogeneous nanophasic degradation patterns as compared with other biodegradable Mg alloys.The in vitro cytotoxicity tests using various types of cells indicate excellent biocompatibility of JDBM.Finally,bone implants using JDBM-1 alloy and cardiovascular stents using JDBM-2 alloy have been successfully fabricated and in vivo long-term assessment via implantation in animal model have been performed.The results confirmed the reduced degradation rate in vivo,excellent tissue compatibility and long-term structural and mechanical durability.Thus,this novel Mg-alloy series with highly uniform nanophasic biodegradation represent a major breakthrough in the field and a promising candidate for manufacturing the next generation biodegradable implants.

Optimization of mechanical and antibacterial properties of Ti-3wt%Cu alloy through cold rolling and annealing

In this work,a process of cold rolling with 70%thickness reduction and different annealing temperatures was selected to regulate the microstructure of Ti-3wt%Cu alloy.Microstructural evolution,mechanical properties and antibacterial properties of the Ti-3wt%Cu alloy under different conditions were systematically investigated in terms of X-ray diffraction(XRD),scanning electron microscope(SEM),transmission electron microscope(TEM),tensile and antibacterial test.The results indicated that cold rolling could dramatically increase the ultimate tensile stress(UTS)from 520 to 928 MPa,but reduce the fracture strain from 15.3%to 3.8%.With the annealing temperature increasing from 400 to 800C for 1 h,the UTS decreased from 744 to 506 MPa and the fracture strain increased from12.7%to 24.4%.Moreover,the antibacterial properties of the Ti-3wt%Cu alloy under different conditions showed excellent antibacterial rate(>96.69%).The results also indicated that the excellent combination of strength and ductility of the Ti-3wt%Cu alloy with cold rolling and following annealing could be achieved in a trade-off by tuning the size and distribution of Ti2Cu phase,which could increase the applicability of the alloy in clinical practice.More importantly,the antibacterial properties maintained a good stability for the Ti-3wt%Cu alloy under different conditions.The excellent combination of mechanical properties and antibacterial properties could make the Ti-3wt%Cu alloy a good candidate for long-term orthopaedic implant application.