Neil M. Eisenstein

Adding functionality with additive manufacturing: Fabrication of titanium-based antibiotic eluting implants.

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, calcium phosphate cement, was formulated as a carrier vehicle for gentamicin. Incorporation of the antibiotic significantly (p=0.01) improved the compressive strength (5.8±0.7MPa) 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 6hour period (<28% of the total amount) were found to exceed the minimum inhibitory concentrations of Staphylococcus aureus (16μg/mL) and Staphylococcus epidermidis (1μg/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.

Identifying the cellular mechanisms leading to heterotopic ossification

Heterotopic ossification (HO) is a debilitating condition defined by the de novo development of bone within non-osseous soft tissues, and can be either hereditary or acquired. The hereditary condition, fibrodysplasia ossificans progressiva is rare but life threatening. Acquired HO is more common and results from a severe trauma that produces an environment conducive for the formation of ectopic endochondral bone. Despite continued efforts to identify the cellular and molecular events that lead to HO, the mechanisms of pathogenesis remain elusive. It has been proposed that the formation of ectopic bone requires an osteochondrogenic cell type, the presence of inductive agent(s) and a permissive local environment. To date several lineage-tracing studies have identified potential contributory populations. However, difficulties identifying cells in vivo based on the limitations of phenotypic markers, along with the absence of established in vitro HO models have made the results difficult to interpret. The purpose of this review is to critically evaluate current literature within the field in an attempt identify the cellular mechanisms required for ectopic bone formation. The major aim is to collate all current data on cell populations that have been shown to possess an osteochondrogenic potential and identify environmental conditions that may contribute to a permissive local environment. This review outlines the pathology of endochondral ossification, which is important for the development of potential HO therapies and to further our understanding of the mechanisms governing bone formation.

Left Of Bang Interventions in Trauma: ethical implications for military medical prophylaxis

Advances in medical capability should be accompanied by discussion of their ethical implications. In the military medical context there is a growing interest in developing prophylactic interventions that will mitigate the effects of trauma and improve survival. The ethics of this novel capability are currently unexplored. This paper describes the concept of trauma prophylaxis (Left Of Bang Interventions in Trauma) and outlines some of the ethical issues that need to be considered, including within concept development, research and implementation. Trauma prophylaxis can be divided into interventions that do not (type 1) and those that do (type 2) have medical enhancement as an unintended side effect of their prophylactic action. We conclude that type 1 interventions have much in common with established military medical prophylaxis, and the potentially enhancing qualities of type 2 interventions raise different issues. We welcome further debate on both interventions.

Post-Traumatic Heterotopic Ossification: An Old Problem in Need of New Solutions: POST-TRAUMATIC HETEROTOPIC OSSIFICATION

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.

Bedside, Benchtop, and Bioengineering: Physicochemical Imaging Techniques in Biomineralization

The need to quantify physicochemical properties of mineralization spans many fields. Clinicians, mineralization researchers, and bone tissue bioengineers need to be able to measure the distribution, quantity, and the mechanical and chemical properties of mineralization within a wide variety of substrates from injured muscle to electrospun polymer scaffolds and everything in between. The techniques available to measure these properties are highly diverse in terms of their complexity and utility. Therefore it is of the utmost importance that those who intend to use them have a clear understanding of the advantages and disadvantages of each technique and its appropriateness to their specific application. This review provides all of this information for each technique and uses heterotopic ossification and engineered bone substitutes as examples to illustrate how these techniques have been applied. In addition, we provide novel data using advanced techniques to analyze human samples of combat related heterotopic ossification.

The design of additively manufactured lattices to increase the functionality of medical implants

The rise of antibiotic resistant bacterial species is driving the requirement for medical devices that minimise infection risks. Antimicrobial functionality may be achieved by modifying the implant design to incorporate a reservoir that locally releases a therapeutic. For this approach to be successful it is critical that mechanical functionality of the implant is maintained. This study explores the opportunity to exploit the design flexibilities possible using additive manufacturing to develop porous lattices that maximise the volume available for drug loading while maintaining load-bearing capacity of a hip implant. Eight unit cell types were initially investigated and a volume fraction of 30% was identified as the lowest level at which all lattices met the design criteria in ISO 13314. Finite element analysis (FEA) identified three lattice types that exhibited significantly lower displacement (10-fold) compared with other designs; Schwartz primitive, Schwartz primitive pinched and cylinder grid. These lattices were additively manufactured in Ti-6Al-4V using selective laser melting. Each design exceeded the minimum strength requirements for orthopaedic hip implants according to ISO 7206-4. The Schwartz primitive (Pinched) lattice geometry, with 10% volume fill and a cubic unit cell period of 10, allowed the greatest void volume of all lattice designs whilst meeting the fatigue requirements for use in an orthopaedic implant (ISO 7206-4). This paper demonstrates an example of how additive manufacture may be exploited to add additional functionality to medical implants.

Towards research combat readiness: prepared, prospective and preapproved

Research drives the advancement of medical knowledge during war, but planning and execution are too slow to enable early data acquisition. Future conflicts are likely to be shorter and more dispersed, requiring innovation to avoid missing out on the crucial early stages. To seize the initiative, we suggest that a collection of preapproved research studies be designed, stored and maintained within the medical command structure so that they are ready for immediate implementation at the onset of future conflicts, even during the most kinetic early phases of deployment.

Enzymatically regulated demineralisation of pathological bone using sodium hexametaphosphate

The pathological formation of bone in soft tissue can result in significant disability, prevent prosthetic limbs from fitting, and limit joint movement. A range of conditions exist, which are characterised by this local tissue ossification. The awareness of one such condition, heterotopic ossification, has increased recently due to the extraordinarily high incidence of the condition in military amputees (64.6%). Although the process of formation is biologically mediated through a massive inflammatory response, there is currently no adequate treatment or prophylaxis for the condition. This study investigates the use of hexametaphosphate (HMP) as a demineralising agent for the treatment of pathological ossification. Other demineralising agents exist but their application is limited due to unwanted effects on biological processes such as blood clotting and an inability to control their activity. This study demonstrates, for the first time, that the demineralising effect of HMP can be modified by local pH and is controlled through the activity of alkaline phosphatase, an enzyme that is found throughout the body. HMP was shown, using micro computed tomography, to cause large scale demineralisation of samples of pathological bone and was able to inhibit hydroxyapatite precipitation in a supersaturated solution. Stiffness and maximum force to failure of rat tibiae incubated in HMP were 49% (p = 0.001) and 41% (p = 0.03) lower, respectively, than controls. In contrast, no significant difference was observed in yield force, demonstrating specificity of action of HMP against hydroxyapatite, with no unwanted effect on collagen. Contrary to established understanding of the mechanism of its dissolution of calcium phosphate salts, micro X-ray fluorescence measurements of the hydroxyapatite surfaces suggested that the demineralising effect was mediated in the solution rather than surface binding of HMP. These findings suggest that HMP is effective at dissolving hydroxyapatite and, as such, is a promising a candidate for the treatment of a range of pathological ossifications.