A B S T R A C TFor over ten years, metallic skeletal endoprostheses have been produced in select cases by additive manufacturing (AM) and increasing awareness is driving demand for wider access to the technology. This review brings together key stakeholder perspectives on the translation of AM research; clinical application, ongoing research in the field of powder bed fusion, and the current regulatory framework. The current clinical use of AM is assessed, both on a mass-manufactured scale and bespoke application for patient specific implants. To illuminate the benefits to clinicians, a case study on the provision of custom cranioplasty is provided based on prosthetist testimony. Current progress in research is discussed, with immediate gains to be made through increased design freedom described at both meso-and macro-scale, as well as long-term goals in alloy development including bioactive materials. In all cases, focus is given to specific clinical challenges such as stress shielding and osseointegration. Outstanding challenges in industrialisation of AM are openly raised, with possible solutions assessed. Finally, overarching context is given with a review of the regulatory framework involved in translating AM implants, with particular emphasis placed on customisation within an orthopaedic remit. A viable future for AM of metal implants is presented, and it is suggested that continuing collaboration between all stakeholders will enable acceleration of the translation process. fection or surgical complications [11][12][13].Currently, the majority of skeletal endoprostheses are produced from titanium (Ti) or cobalt chromium (CoCr) based alloys, which meet the criteria of durability, strength, corrosion resistance and a low immune response [14,15]. These characteristics however come at the cost of the high stiffness of these alloys in comparison to bone. Mismatch between the mechanical properties of bone and orthopaedic materials

Additive manufacturing technologies have been utilised in healthcare to create patient-specific implants. This study demonstrates the potential to add new implant functionality by further exploiting the design flexibility of these technologies. Selective laser melting was used to manufacture titanium-based (Ti-6Al-4V) implants containing a reservoir. Pore channels, connecting the implant surface to the reservoir, were incorporated to facilitate antibiotic delivery. An injectable brushite, calciumphosphate cement, was formulated as a carrier vehicle for gentamicin. Incorporation of the antibiotic significantly (p=0.01) improved the compressive strength (5.8± 0.7 MPa) of the cement compared to non-antibiotic samples. The controlled release of gentamicin sulphate from the calcium phosphate cement injected into the implant reservoir was demonstrated in short term elution studies using ultraviolet visible spectroscopy. Orientation of the implant pore channels were shown, using micro-computed tomography, to impact design reproducibility and the back-pressure generated during cement injection which ultimately altered porosity. The amount of antibiotic released from all implant designs over a 6 hour period (b28% of the total amount) were found to exceed the minimum inhibitory concentrations of Staphylococcus aureus (16 μg/mL) and Staphylococcus epidermidis (1 μg/mL); two bacterial species commonly associated with periprosthetic infections. Antibacterial efficacy was confirmed against both bacterial cultures using an agar diffusion assay. Interestingly, pore channel orientation was shown to influence the directionality of inhibition zones. Promisingly, this work demonstrates the potential to additively manufacture a titanium-based antibiotic eluting implant, which is an attractive alternative to current treatment strategies of periprosthetic infections.

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Heterotopic ossification (HO) is the formation of pathological bone in ectopic sites and it can have serious consequences for functional outcomes. For many years, its main clinical relevance was as a rare complication of elective joint arthroplasty or CNS injury and a number of prophylaxes were developed to mitigate against it in these settings. As a consequence of changes in patterns of wounding and survival in conflicts since the turn of the century, post-traumatic HO has become much more common and case severity has increased. It represents one of the main barriers to rehabilitation in a large cohort of combat-injured patients. However, extant prophylaxes have not been shown to be effective or appropriate in this patient cohort. In addition, the lack of reliable early detection or means of predicting which patients will develop HO is another barrier to effective prevention. This review examines the current state of understanding of post-traumatic HO including the historical context, epidemiology, pathophysiology, clinical issues, currently prophylaxis and detection, management, and potential future approaches. Our aims are to highlight the current lack of effective means of early detection and prevention of HO after major trauma and to stimulate research into novel solutions to this challenging problem. ß

Raman spectroscopy shows promise as a tool for timely diagnostics via in-vivo spectroscopy of the eye, for a number of ophthalmic diseases. By measuring the inelastic scattering of light, Raman spectroscopy is able to reveal detailed chemical characteristics, but is an inherently weak effect resulting in noisy complex signal, which is often difficult to analyse. Here, we embraced that noise to develop the self-optimising Kohonen index network (SKiNET), and provide a generic framework for multivariate analysis that simultaneously provides dimensionality reduction, feature extraction and multi-class classification as part of a seamless interface. The method was tested by classification of anatomical ex-vivo eye tissue segments from porcine eyes, yielding an accuracy >93% across 5 tissue types. Unlike traditional packages, the method performs data analysis directly in the web browser through modern web and cloud technologies as an open source extendable web app. The unprecedented accuracy and clarity of the SKiNET methodology has the potential to revolutionise the use of Raman spectroscopy for in-vivo applications.

Additive manufacturing (AM) technologies enable greater geometrical design freedom compared with subtractive processes. This flexibility has been used to manufacture patient-matched implants. Although the advantages of AM are clear, the optimization at each process stage is often understated. Here we demonstrate that surface finishing of selective laser melted (SLM) implants significantly alters topography, which has implications for cellular and biofilm adhesion. Hot isostatic pressing of as-fabricated Ti-6Al-4V implants was shown to reduce porosity (1.04 to 0.02%) and surface roughness (34 ± 8 to 22 ± 3 μm). Despite these surface changes, preosteoblasts exhibited a similar viability and proliferation after 7 days of culture. Contrastingly, sandblasting and polishing significantly reduced cellular activity and increased cytotoxicity. Bacterial specimens (Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa) adhered more homogeneously to sandblasted implants compared with other treatments. This suggests that sandblasting may place the implant at risk of infection and reduce the strength of interaction with the surrounding soft tissues. The ability to tune the adhesion of cells to additively manufactured Ti-6Al-4V implants using postprocessing methods was demonstrated. Because the degree of tissue integration required of implants is application specific, these methods may be useful to tailor osseointegration. However, surface competition between mammalian and bacterial cells remains a challenge.

SummaryObjectiveViscoelastic properties of articular cartilage have been characterised at physiological frequencies. However, studies investigating the interaction between cartilage and subchondral bone and the influence of underlying bone histomorphometry on the viscoelasticity of cartilage are lacking.MethodDynamic Mechanical Analysis (DMA) has been used to quantify the dynamic viscoelasticity of bovine tibial plateau osteochondral cores, over a frequency sweep from 1 to 88 Hz. Specimens (approximately aged between 18 and 30 months) were neither osteoarthritic nor otherwise compromised. A maximum nominal stress of 1.7 MPa was induced. Viscoelastic properties of cores have been compared with that of its components (cartilage and bone) in terms of the elastic and viscous components of both structural stiffness and material modulus. Micro-computed tomography scans were used to quantify the histomorphological properties of the subchondral bone.ResultsOpposing frequency-dependent loss stiffness, and modulus, trends were witnessed for osteochondral tissues: for cartilage it increased logarithmically (P < 0.05); for bone it decreased logarithmically (P < 0.05). The storage stiffness of osteochondral cores was logarithmically frequency-dependent (P < 0.05), however, the loss stiffness was typically frequency-independent (P > 0.05). A linear relationship between the subchondral bone plate (SBP) thickness and cartilage thickness (P < 0.001) was identified. Cartilage loss modulus was linearly correlated to bone mineral density (BMD) (P < 0.05) and bone volume (P < 0.05).ConclusionThe relationship between the subchondral bone histomorphometry and cartilage viscoelasticity (namely loss modulus) and thickness, have implications for the initiation and progression of osteoarthritis (OA) through an altered ability of cartilage to dissipate energy.

Titanium‐based orthopedic implants are increasingly being fabricated using additive manufacturing (AM) processes such as selective laser melting (SLM), direct laser deposition (DLD), and electron beam melting (EBM). These techniques have the potential to not only produce implants with properties comparable to conventionally manufactured implants, but also improve on standard implant models. These models can be customized for individual patients using medical data, and design features, such as latticing, hierarchical scaffolds, or features to complement patient anatomy, can be added using AM to produce highly functional patient‐anatomy‐specific implants. Alloying prospects made possible through AM allow for the production of Ti‐based parts with compositions designed to reduce modulus and stress shielding while improving bone fixation and formation. The design‐to‐process lead time can be drastically shortened using AM and associated post‐processing, making possible the production of tailored implants for individual patients. This review examines the process and product characteristics of the three major metallic AM techniques and assesses the potential for these in the increased global uptake of AM in orthopedic implant fabrication.