Tibialis Posterior Tendon Transfer for the Management of Foot Drop.

The transfer of a normal tibialis posterior through the interosseous membrane to the dorsum of the foot can restore active ankle dorsiflexion where this has been lost from common peroneal injury, anterior compartment muscle loss, or in some neurological conditions. An appraisal of the indications, planning, and a step-by-step description is provided. How to cite this article: Eisenstein N, Fischer B, Nayagam S. Tibialis Posterior Tendon Transfer for the Management of Foot Drop. Strategies Trauma Limb Reconstr 2023;18(1):56-62.

Triggered metabolism of adenosine triphosphate as an explanation for the chemical heterogeneity of heterotopic ossification.

Heterotopic ossification (HO), the pathological formation of bone in soft tissues, is a debilitating condition, as well as one of the few instances of de novo bone formation in adults. Chemical mapping of HO tissue showed distinct islands of calcium phosphate within phosphate-deficient, calcium-rich regions, suggesting a transition to apatitic bone mineral from a non-phosphatic precursor. The transition of amorphous calcium carbonate (ACC), a generally suggested bone-mineral precursor, in physiological conditions was thus investigated. Here, we show that adenosine triphosphate (ATP), present in high amounts in forming bone, stabilised ACC for weeks in physiological conditions and that enzymatic degradation of ATP triggered rapid crystallisation into apatite, through an amorphous calcium phosphate phase. It is suggested that this localised enzymatic degradation could explain the chemical heterogeneity seen in HO and may also represent a pathway to physiological bone mineralisation.

Bioengineering extracellular vesicles: smart nanomaterials for bone regeneration.

In the past decade, extracellular vesicles (EVs) have emerged as key regulators of bone development, homeostasis and repair. EV-based therapies have the potential to circumnavigate key issues hindering the translation of cell-based therapies including functional tissue engraftment, uncontrolled differentiation and immunogenicity issues. Due to EVs' innate biocompatibility, low immunogenicity, and high physiochemical stability, these naturally-derived nanoparticles have garnered growing interest as potential acellular nanoscale therapeutics for a variety of diseases. Our increasing knowledge of the roles these cell-derived nanoparticles play, has made them an exciting focus in the development of novel pro-regenerative therapies for bone repair. Although these nano-sized vesicles have shown promise, their clinical translation is hindered due to several challenges in the EV supply chain, ultimately impacting therapeutic efficacy and yield. From the biochemical and biophysical stimulation of parental cells to the transition to scalable manufacture or maximising vesicles therapeutic response in vivo, a multitude of techniques have been employed to improve the clinical efficacy of EVs. This review explores state of the art bioengineering strategies to promote the therapeutic utility of vesicles beyond their native capacity, thus maximising the clinical potential of these pro-regenerative nanoscale therapeutics for bone repair.

Space habitats for bioengineering and surgical repair: addressing the requirement for reconstructive and research tissues during deep-space missions.

Numerous technical scenarios have been developed to facilitate a human return to the Moon, and as a testbed for a subsequent mission to Mars. Crews appointed with constructing and establishing planetary bases will require a superior level of physical ability to cope with the operational demands. However, the challenging environments of nearby planets (e.g. geological, atmospheric, gravitational conditions) as well as the lengthy journeys through microgravity, will lead to progressive tissue degradation and an increased susceptibility to injury. The isolation, distance and inability to evacuate in an emergency will require autonomous medical support, as well as a range of facilities and specialised equipment to repair tissue damage on-site. Here, we discuss the design requirements of such a facility, in the form of a habitat that would concomitantly allow tissue substitute production, maintenance and surgical implantation, with an emphasis on connective tissues. The requirements for the individual modules and their operation are identified. Several concepts are assessed, including the presence of adjacent wet lab and medical modules supporting the gradual implementation of regenerative biomaterials and acellular tissue substitutes, leading to eventual tissue grafts and, in subsequent decades, potential tissues/organ-like structures. The latter, currently in early phases of development, are assessed particularly for researching the effects of extreme conditions on representative analogues for astronaut health support. Technical solutions are discussed for bioengineering in an isolated planetary environment with hypogravity, from fluid-gel bath suspended manufacture to cryostorage, cell sourcing and on-site resource utilisation for laboratory infrastructure. Surgical considerations are also discussed.

Spectroscopic detection of traumatic brain injury severity and biochemistry from the retina.

Traumatic brain injury (TBI) is a major burden on healthcare services worldwide, where scientific and clinical innovation is needed to provide better understanding of biochemical damage to improve both pre-hospital assessment and intensive care monitoring. Here, we present an unconventional concept of using Raman spectroscopy to measure the biochemical response to the retina in an ex-vivo murine model of TBI. Through comparison to spectra from the brain and retina following injury, we elicit subtle spectral changes through the use of multivariate analysis, linked to a decrease in cardiolipin and indicating metabolic disruption. The ability to classify injury severity via spectra of the retina is demonstrated for severe TBI (82.0 %), moderate TBI (75.1 %) and sham groups (69.4 %). By showing that optical spectroscopy can be used to explore the eye as the window to the brain, we lay the groundwork for further exploitation of Raman spectroscopy for indirect, non-invasive assessment of brain chemistry.

The Quantification of Injectability by Mechanical Testing.

Injectable biomaterials are becoming increasingly popular for the minimally invasive delivery of drugs and cells. These materials are typically more viscous than traditional aqueous injections and may be semi-solid, therefore, their injectability cannot be assumed. This protocol describes a method to objectively assess the injectability of these materials using a standard mechanical tester. The syringe plunger is compressed by the crosshead at a set rate, and the force is measured. The maximum or plateau force value can then be used for comparison between samples, or to an absolute force limit. This protocol can be used with any material, and any syringe and needle size or geometry. The results obtained may be used to make decisions about formulations, syringe and needle sizes early in the translational process. Further, the effects of altering formulations on injectability may be quantified, and the optimum time to inject temporally changing materials determined. This method is also suitable as a reproducible way to examine the effects of injection on a material, to study phenomena such as self-healing and filter pressing or study the effects of injection on cells. This protocol is faster and more directly applicable to injectability than rotational rheology, and requires minimal post processing to obtain key values for direct comparisons.

Filling the Gap: A Correlation between Objective and Subjective Measures of Injectability.

Various injectable biomaterials are developed for the minimally invasive delivery of therapeutics. Typically, a mechanical tester is used to ascertain the force required to inject these biomaterials through a given syringe-needle system. However, currently there is no method to correlate the force measured in the laboratory to the perceived effort required to perform that injection by the end user. In this article, the injection force (F) for a variety of biomaterials, displaying a range of rheological properties, is compared with the effort scores from a 50 person panel study. The maximum injection force measured at crosshead speed 1 mm s-1 is a good proxy for injection effort, with an R2 of 0.89. This correlation leads to the following conclusions: participants can easily inject 5 mL of substance for F < 12 N; considerable effort is required to inject 5 mL for 12 N < F < 38 N; great effort is required and <5 mL can be injected for 38 N < F < 64 N; and materials are entirely non-injectable for F > 64 N. These values may be used by developers of injectable biomaterials to make decisions about formulations and needle sizes early in the translational process.

Development of the Self Optimising Kohonen Index Network (SKiNET) for Raman Spectroscopy Based Detection of Anatomical Eye Tissue.

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.

Physical Structuring of Injectable Polymeric Systems to Controllably Deliver Nanosized Extracellular Vesicles.

Extracellular vesicles (EVs) are emerging as a promising alternative approach to cell-therapies. However, to realize the potential of these nanoparticles as new regenerative tools, healthcare materials that address the current limitations of systemic administration need to be developed. Here, two technologies for controlling the structure of alginate based microgel suspensions are used to develop sustained local release of EVs, in vitro. Microparticles formed using a shearing technique are compared to those manufactured using vibrational technology, resulting in either anisotropic sheet-like or spheroid particles, respectively. EVs harvested from preosteoblasts are isolated using differential ultracentrifugation and successfully loaded into the two systems, while maintaining their structures. Promisingly, in addition to exhibiting even EV distribution and high stability, controlled release of vesicles from both structures is exhibited, in vitro, over the 12 days studied. Interestingly, a significantly greater number of EVs are released from the suspensions formed by shearing (69.9 ± 10.5%), compared to the spheroids (35.1 ± 7.6%). Ultimately, alterations to the hydrogel physical structures have shown to tailor nanoparticle release while simultaneously providing ideal material characteristics for clinical injection. Thus, the sustained release mechanisms achieved through manipulating the formation of such biomaterials provide a key to unlocking the therapeutic potential held within EVs.

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.

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.

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. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1061-1068, 2018.

Incidence and medical management of bisphosphonate-associated atypical femoral fractures in a major trauma centre: a retrospective observational study.

BACKGROUND: Atypical femoral fractures (AFFs) are rare events associated with increased duration of bisphosphonate exposure. Recommended management of AFFs include cessation of bisphosphonates and imaging of the contralateral femur. The aims of this study were to identify the local incidence of AFFs in bisphosphonate users and to audit the medical management of AFFs against published recommendations. METHODS: A retrospective analysis of the admissions database for a major trauma centre identified all femoral fractures (3150) in a five-year period (July 2009 to June 2014). Electronic health records and radiographs were reviewed using the 2013 American Society for Bone and Mineral Research (ASBMR) diagnostic criteria for AFF to establish the number of cases. To estimate incidence, the total number of bisphosphonate users was derived from primary care prescription and secondary care day-case records. Medical management of cases with AFF on bisphosphonates was audited against guidance from ASBMR and Medicines & Healthcare Products Regulatory Agency. RESULTS: 10 out of 3150 femoral fractures met criteria for AFF; 7 of these patients had a history of exposure to bisphosphonates (6 oral, 1 intravenous). There were 19.1 AFFs per 100,000 years of bisphosphonate use in our region. Bisphosphonates were stopped and the contralateral femur imaged in only 2 of the 7 patients treated with bisphosphonates. CONCLUSION: Our local incidence is in line with published figures; however, this is the first published evidence suggesting that medical management and identification of AFF may be suboptimal. Managing these patients remains challenging due to their rarity and possible lack of awareness.

Surface Finish has a Critical Influence on Biofilm Formation and Mammalian Cell Attachment to Additively Manufactured Prosthetics.

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.

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.

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.

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.

Disassociation at the head-trunnion interface: an unseen complication of modular hip hemiarthroplasty.

A woman in her mid-90s underwent a left uncemented bipolar hemiarthroplasty for an intracapsular femoral neck fracture. Postoperative radiographs at 48h showed a disassociation of the left femoral prosthesis at the head-trunnion interface, with the bipolar head remaining in the acetabulum. There was no preceding trauma and the patient had mobilised postoperatively. The hip was revised to a monopolar head, and the patient's hip was protected postoperatively in a brace limiting flexion and external rotation. At 30 days following revision she was mobilising pain-free with a stable hip. Disassociation at the head-trunnion interface has never been reported in hip hemiarthroplasty, and is only described in relation to primary or revision total hip replacements (THR) following dislocation or trauma to the THR. This demonstrates a potential complication of modular prostheses for trauma.