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The COmposite MicroMechanics (COMM) Toolbox is a design tool, developed in MATLAB, which provides efficient pre- and post-processing capabilities for micromechanical analyses of composite materials with finite element analysis. The COMM Toolbox has automated all manual tasks associated with micromechanical analyses of composite materials, providing a simple, convenient environment for creating, submitting, monitoring, and evaluating results from micromechanical analyses. The interactive pre-processing capability currently enables a variety of fiber distributions to be generated, allowing either nonuniform or regular fiber arrangements for both low and high fiber volume fractions to be analyzed under mechanical and/or thermal loading. The functionality of the above features has been demonstrated by carrying out a case study examining the effect of fiber volume fraction on material behavior. Importantly, the COMM Toolbox means that advanced multiscale modeling concepts, which determine material behavior based on the physical interactions of the constituent phases, are likely to gain more widespread exposure from potential academic or industry-based interests. The COMM Toolbox is freely available to the community and can be obtained by contacting the corresponding author. [ABSTRACT FROM PUBLISHER]

This study investigates the biomechanics of type 2 diabetic bone fragility through a multiscale experimental strategy that considers structural, mechanical, and compositional components of ex vivo human trabecular and cortical bone. Human tissue samples were obtained from the femoral heads of patients undergoing total hip replacement. Mechanical testing was carried out on isolated trabecular cores using monotonic and cyclic compression loading and nanoindentation experiments, with bone microdamage analysed using micro-computed tomography (CT) imaging. Bone composition was evaluated using Raman spectroscopy, high-performance liquid chromatography, and fluorometric spectroscopy. It was found that human type 2 diabetic bone had altered mechanical, compositional, and morphological properties compared to non-type 2 diabetic bone. High-resolution micro-CT imaging showed that cores taken from the central trabecular region of the femoral head had higher bone mineral density (BMD), bone volume, trabecular thickness, and reduced trabecular separation. Type 2 diabetic bone also had enhanced macro-mechanical compressive properties under mechanical loading compared to non-diabetic controls, with significantly higher apparent modulus, yield stress, and pre-yield toughness evident, even when properties were normalised against the bone volume. Using nanoindentation, there were no significant differences in the tissue-level mechanical properties of cortical or trabecular bone in type 2 diabetic samples compared to controls. Through compositional analysis, higher levels of furosine were found in type 2 diabetic trabecular bone, and an increase in both furosine and carboxymethyl-lysine (an advanced glycation end-product) was found in cortical bone. Raman spectroscopy showed that type 2 diabetic bone had a higher mineral-to-matrix ratio, carbonate substitution, and reduced crystallinity compared to the controls. Together, this study shows that type 2 diabetes leads to distinct changes in both organic and mineral phases of the bone tissue matrix, but these changes did not coincide with any reduction in the micro- or macro-mechanical properties of the tissue under monotonic or cyclic loading., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides., Methods: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ 42 , the pathogenic self-aggregating species of Aβ., Results: MEDI1814 reduces free Aβ 42 without impacting Aβ 40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n = 57) in single or repeat doses up to 1800 mg intravenously or 200 mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ 42 , increases in total (bound and free) Aβ 42 , but no change in total Aβ 40 in CSF across doses., Discussion: MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ 42 ., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Several peptide dual agonists of the human glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) are in development for the treatment of type 2 diabetes, obesity and their associated complications. Candidates must have high potency at both receptors, but it is unclear whether the limited experimental data available can be used to train models that accurately predict the activity at both receptors of new peptide variants. Here we use peptide sequence data labelled with in vitro potency at human GCGR and GLP-1R to train several models, including a deep multi-task neural-network model using multiple loss optimization. Model-guided sequence optimization was used to design three groups of peptide variants, with distinct ranges of predicted dual activity. We found that three of the model-designed sequences are potent dual agonists with superior biological activity. With our designs we were able to achieve up to sevenfold potency improvement at both receptors simultaneously compared to the best dual-agonist in the training set., (© 2024. The Author(s).)

Purpose: Altered hemodynamics caused by the presence of an endovascular device may undermine the success of peripheral stenting procedures. Flow-enhanced stent designs are under investigation to recover physiological blood flow patterns in the treated artery and reduce long-term complications. However, flow-enhanced designs require the development of customised manufacturing processes that consider the complex behaviour of Nickel-Titanium (Ni-Ti). While the manufacturing routes of traditional self-expanding Ni-Ti stents are well-established, the process to introduce alternative stent designs is rarely reported in the literature, with much of this information (especially related to shape-setting step) being commercially sensitive and not reaching the public domain, as yet., Methods: A reliable manufacturing method was developed and improved to induce a helical ridge onto laser-cut and wire-braided Nickel-Titanium self-expanding stents. The process consisted of fastening the stent into a custom-built fixture that provided the helical shape, which was followed by a shape-setting in air furnace and rapid quenching in cold water. The parameters employed for the shape-setting in air furnace were thoroughly explored, and their effects assessed in terms of the mechanical performance of the device, material transformation temperatures and surface finishing., Results: Both stents were successfully imparted with a helical ridge and the optimal heat treatment parameters combination was found. The settings of 500 °C/30 min provided mechanical properties comparable with the original design, and transformation temperatures suitable for stenting applications (A f  = 23.5 °C). Microscopy analysis confirmed that the manufacturing process did not alter the surface finishing. Deliverability testing showed the helical device could be loaded onto a catheter delivery system and deployed with full recovery of the expanded helical configuration., Conclusion: This demonstrates the feasibility of an additional heat treatment regime to allow for helical shape-setting of laser-cut and wire-braided devices that may be applied to further designs., (© 2024. The Author(s).)

At the tissue-scale and above, there are now well-established structure-property relationships that provide good approximations of the biomechanical performance of bone through, for example, power-law relationships that relate tissue mineral density to elastic properties. However, below the tissue-level, the individual role of the constituents becomes prominent and these simple relationships tend to break down, with more detailed theoretical and computational models are required to describe the mechanical response. In this study, a two-dimensional micromechanics damage-based representative volume element (RVE) of lamellar bone was developed, which included a novel implementation of a phase-field damage model to describe the behaviour of non-collagenous proteins at mineral-mineral and mineral-fibril interface regions. It was found that, while the stiffness of the tissue was governed by the relative proportion of extra-fibrillar mineral and mineralised collagen fibrils, the strength and toughness of the tissue in transverse direction relied on the interactions occurring at mineral-mineral and mineral-fibril interfaces, highlighting the prominence of non-collagenous proteins in determine fracture-based processes at this scale. While fractures tended to initiate in mineral rich areas of the extra-fibrillar mineral matrix, it was found that the presence of mineralised collagen fibrils at low density did not provide a substantial contribution to crack propagation behaviour under transverse loading. However, at physiological volume fraction (Vf MCF =50%), different scenarios could arise depending on the relative strength value of the interphase around the MCFs ( [Formula: see text] ) to the interphase between individual minerals ( [Formula: see text] ): (i) When [Formula: see text] , MCFs appear to facilitate crack propagation with MCF-mineral debonding being the dominant failure mode; (ii) once γ>1, the MCFs hinder the microcracks, leading to inhibition of crack propagation, which can be regarded as an energy dissipation mechanism. The effective fracture properties of the tissue also experience a sudden increase in fracture work density (J-integral) once the crack is arrested by MCFs or severely deflected. Collectively, the predicted behaviour of the model compared well to those reported through experimental and computational methods, highlighting its potential to provide further understanding into the mechanistic response of bone ultrastructure alterations related to the structural and compositional changes resulting from disease and aging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bone is a naturally occurring composite material composed of a stiff mineral phase and a compliant organic matrix of collagen and non-collagenous proteins (NCP). While diverse mineral morphologies such as platelets and grains have been documented, the precise role of individual constituents, and their morphology, remains poorly understood. To understand the role of constituent morphology on the fracture behaviour of lamellar bone, a damage based representative volume element (RVE) was developed, which considered various mineral morphologies and mineralised collagen fibril (MCF) configurations. This model framework incorporated a novel phase-field damage model to predict the onset and evolution of damage at mineral-mineral and mineral-MCF interfaces. It was found that platelet-based mineral morphologies had superior mechanical performance over their granular counterparts, owing to their higher load-bearing capacity, resulting from a higher aspect ratio. It was also found that MCFs had a remarkable capacity for energy dissipation under axial loading, with these fibrillar structures acting as barriers to crack propagation, thereby enhancing overall elongation and toughness. Interestingly, the presence of extrafibrillar platelet-based minerals also provided an additional toughening through a similar mechanism, whereby these structures also inhibited crack propagation. These findings demonstrate that the two primary constituent materials of lamellar bone play a key role in its toughening behaviour, with combined effect by both mineral and MCFs to inhibit crack propagation at this scale. These results have provided novel insight into the fracture behaviour of lamellar bone, enhancing our understanding of microstructure-property relationships at the sub-tissue level., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Simulation of bioresorbable medical devices is hindered by the limitations of current material models. Useful simulations require that both the short- and long-term response must be considered; existing models are not physically-based and provide limited insight to guide performance improvements. This study presents an integrated degradation framework which couples a physically-based degradation model, which predicts changes in both crystallinity (X c ) and molecular weight (M n ), with the results of a micromechanical model, which predicts the effective properties of the semicrystalline polymer. This degradation framework is used to simulate the deployment of a bioresorbable PLLA (Poly (L-lactide) stent into a mock vessel and the subsequent mechanical response during degradation under different diffusion boundary conditions representing neointimal growth. A workflow is established in a commercial finite element code that couples both the immediate and long-term responses. Clinically relevant lumen loss is reported and used to compare different responses and the effect of neo-intimal tissue regrowth post-implantation on degradation and on the mechanical response is assessed. In addition, the effects of possible changes in X c , which could occur during processing and stent deployment, are explored., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Silk is a natural engineering material with a unique set of properties. The major constituent of silk is fibroin, a protein widely used in the biomedical field because of its mechanical strength, toughness and elasticity, as well as its biocompatibility and biodegradability. The domestication of silkworms allows large amounts of fibroin to be extracted inexpensively from silk cocoons. However, the industrial extraction process has drawbacks in terms of sustainability and the quality of the final medical product. The heterologous production of fibroin using recombinant DNA technology is a promising approach to address these issues, but the production of such recombinant proteins is challenging and further optimization is required due to the large size and repetitive structure of fibroin's DNA and amino acid sequence. In this review, we describe the structure-function relationship of fibroin, the current extraction process, and some insights into the sustainability of silk production for biomedical applications. We focus on recent advances in molecular biotechnology underpinning the production of recombinant fibroin, working toward a standardized, successful and sustainable process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The objective of this study is to evaluate the mechanical properties and energy absorption characteristics of the gyroid, dual-lattice and spinodoid structures, as biomimetic lattices, through finite element analysis and experimental characterisation. As part of the study, gyroid and dual-lattice structures at 10% volume fraction were 3D-printed using an elastic resin, and mechanically tested under uniaxial compression. Computational models were calibrated to the observed experimental data and the response of higher volume fraction structures were simulated in an explicit finite element solver. Stress-strain data of groups of lattices at different volume fractions were studied and energy absorption parameters including total energy absorbed per unit volume, energy absorption efficiency and onset of densification strain were calculated. Also, the structures were characterized into bending-dominant and stretch-dominant structures, according to their nodal connectivity and Gibson-and-Ashby's law. The results of the study showed that the dual-lattice is capable of absorbing more energy at each volume fraction cohort. However, gyroid structures showed higher energy absorption efficiency and the onset of densification at higher strains. The spinodoid structure was found to be the poorest structure in terms of energy absorption, specifically at low volume fractions. Also, the results showed that the dual-lattice was a stretch dominated structure, while the gyroid structure was a bending dominated structure, which may be a reason that it is a better candidate for energy absorption applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Bone as a hierarchical composite structure plays a myriad of roles in vertebrate skeletons including providing the structural stability of the body. Despite this critical role, the mechanical behaviour at the sub-micron levels of bone's hierarchy remains poorly understood. At this scale, bone is composed of Mineralised Collagen Fibrils (MCF) embedded within an extra-fibrillar matrix that consists of hydroxyapatite minerals and non-collagenous proteins. Recent experimental studies hint at the significance of the extra-fibrillar matrix in providing the bone with the stiffness and ductility needed to serve its structural roles. However, due to limited resolution of experimental tools, it is not clear how the arrangement of minerals, and in particular their relative distribution between the intra- and extra-fibrillar space contribute to bone's remarkable mechanical properties. In this study, a Coarse Grained Molecular Dynamics (CGMD) framework was developed to study the mechanical properties of MCFs embedded within an extra-fibrillar mineral matrix and the precise roles extra- and intra-fibrillar mineralisation on the load-deformation response was investigated. It was found that the presence of extra-fibrillar mineral resulted in the development of substantial residual stress in the system, by limiting MCF shortening that took place during intra-fibrillar mineralisation, resulting in substantial compressive residual stresses in the extra-fibrillar mineral phase. The simulation results also revealed the crucial role of extra-fibrillar mineralisation in determining the elastic response of the Extrafibrillar mineralised MCF (EFM-MCF) system up to the yield point, while the fibrillar collagen affected the post-yield behaviour. When physiological levels of mineralisation were considered, the mechanical response of the EFM-MCF systems was characterised by high ductility and toughness, with micro-cracks being distributed across the extra-fibrillar matrix, and MCFs effectively bridging these cracks leading to an excellent combination of strength and toughness. Together, these results provide novel insight into the deformation mechanisms of an EFM-MCF system and highlight that this universal building block, which forms the basis for lamellar bone, can provide an excellent balance of stiffness, strength and toughness, achieving mechanical properties that are far beyond the capabilities of the individual constituents acting alone.

Background and Objectives: Bioresorbable braided stents, typically made of bioresorbable polymers such as poly-l-lactide (PLLA), have great potential in the treatment of critical limb ischemia, particularly in cases of long-segment occlusions and lesions with high angulation. However, the successful adoption of these devices is limited by their low radial stiffness and reduced elastic modulus of bioresorbable polymers. This study proposes a computational optimization procedure to enhance the mechanical performance of bioresorbable braided stents and consequently improve the treatment of critical limb ischemia., Methods: Finite element analyses were performed to replicate the radial crimping test and investigate the implantation procedure of PLLA braided stents. The stent geometry was characterized by four design parameters: number of wires, wire diameter, initial stent diameter, and braiding angle. Manufacturing constraints were considered to establish the design space. The mechanical performance of the stent was evaluated by defining the radial force, foreshortening, and peak maximum principal stress of the stent as objectives and constraint functions in the optimization problem. An approximate relationship between the objectives, constraint, and the design parameters was defined using design of experiment coupled with surrogate modelling. Surrogate models were then interrogated within the design space, and a multi-objective design optimization was conducted., Results: The simulation of radial crimping was successfully validated against experimental data. The radial force was found to be primarily influenced by the number of wires, wire diameter, and braiding angle, with the wire diameter having the most significant impact. Foreshortening was predominantly affected by the braiding angle. The peak maximum principal stress exhibited contrasting behaviour compared to the radial force for all parameters, with the exception of the number of wires. Among the Pareto-optimal design candidates, feasible peak maximum principal stress values were observed, with the braiding angle identified as the differentiating factor among these candidates., Conclusions: The exploration of the design space enabled both the understanding of the impact of design parameters on the mechanical performance of bioresorbable braided stents and the successful identification of optimal design candidates. The optimization framework contributes to the advancement of innovative bioresorbable braided stents for the effective treatment of critical limb ischemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

The objective of this study is to present a credibility assessment of finite element modelling of self-expanding nickel-titanium (Ni-Ti) stents through verification and validation (VV) activities, as set out in the ASME VV-40 standard. As part of the study, the role of calculation verification, model input sensitivity, and model validation is examined across three different application contexts (radial compression, stent deployment in a vessel, fatigue estimation). A commercially available self-expanding Ni-Ti stent was modelled, and calculation verification activities addressed the effects of mesh density, element integration and stable time increment on different quantities of interests, for each context of use considered. Sensitivity analysis of the geometrical and material input parameters and validation of deployment configuration with in vitro comparators were investigated. Results showed similar trends for global and local outputs across the contexts of use in response to the selection of discretization parameters, although with varying sensitivities. Mesh discretisation showed substantial variability for less than 4 × 4 element density across the strut cross-section in radial compression and deployment cases, while a finer grid was deemed necessary in fatigue estimation for reliable predictions of strain/stress. Element formulation also led to substantial variation depending on the chosen integration options. Furthermore, for explicit analyses, model results were highly sensitive to the chosen target time increment (e.g., mass scaling parameters), irrespective of whether quasistatic conditions were ensured (ratios of kinetic and internal energies below 5%). The higher variability was found for fatigue life simulation, with the estimation of fatigue safety factor varying up to an order of magnitude depending on the selection of discretization parameters. Model input sensitivity analysis highlighted that the predictions of outputs such as radial force and stresses showed relatively low sensitivity to Ni-Ti material parameters, which suggests that the calibration approaches used in the literature to date appear reasonable, but a higher sensitivity to stent geometry, namely strut thickness and width, was found. In contrast, the prediction of vessel diameter following deployment was least sensitive to numerical parameters, and its validation with in vitro comparators offered a simple and accurate (error ~ 1-2%) method when predicting diameter gain, and lumen area, provided that the material of the vessel is appropriately characterized and modelled., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bernini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

No-show patient visits should be considered risk events. No-shows impact the quality and continuity of patient care. Missed visits increase health care risks by deferred or missed diagnosis and treatment, and increases costs of care. This performance improvement project proactively implemented a telemedicine system of care during a public health emergency (PHE). The goal was to improve health care access and decrease health care disparities despite emergency management changes in organizational staffing and federal stay-at-home orders. Telemedicine visits also addressed known causes of historically high in-person no-show office rates-lack of transportation, childcare issues, mobility issues, and adverse weather conditions. Despite location in a Hospital Census Tract where 50% of our population is below the Federal Poverty Level, with less access to technology, telemedicine proved to be successful. The Revised Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0) guidelines were the planning framework. The Model for Healthcare Improvement including Part 1 (AIM) and Part 2 (Plan-Do-Study-Act) was used to develop interventions, outcomes, and rationale for use. Data was collected from January 2020 thru March 2022, with 22,831 total scheduled visits (15,837 in-person, 6994 telemedicine). The average monthly no-show rate for in-person visits was 35% compared to 9% for telemedicine visits., (© 2023 American Society for Healthcare Risk Management of the American Hospital Association.)

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33 red ) and oxidized IL-33 (IL-33 ox ) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 10 7  M -1  s -1 , to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33 red and a fast association rate (8.5 × 10 7  M -1  s -1 ), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33 red and IL-33 ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease., (© 2023. The Author(s).)

Individuals with Type-2 Diabetes (T2D) have an increased risk of bone fracture, without a reduction in bone mineral density. It is hypothesised that the hyperglycaemic state caused by T2D forms an excess of Advanced Glycated End-products (AGEs) in the organic matrix of bone, which are thought to stiffen the collagen network and lead to impaired mechanical properties. However, the mechanisms are not well understood. This study aimed to investigate the geometrical, structural and material properties of diabetic cortical bone during the development and progression of T2D in ZDF (fa/fa) rats at 12-, 26- and 46-weeks of age. Longitudinal bone growth was impaired as early as 12-weeks of age and by 46-weeks bone size was significantly reduced in ZDF (fa/fa) rats versus controls (fa/+). Diabetic rats had significant structural deficits, such as bending rigidity, ultimate moment and energy-to-failure measured via three-point bend testing. Tissue material properties, measured by taking bone geometry into account, were altered as the disease progressed, with significant reductions in yield and ultimate strength for ZDF (fa/fa) rats at 46-weeks. FTIR analysis on cortical bone powder demonstrated that the tissue material deficits coincided with changes in tissue composition, in ZDF (fa/fa) rats with long-term diabetes having a reduced carbonate:phosphate ratio and increased acid phosphate content when compared to age-matched controls, indicative of an altered bone turnover process. AGE accumulation, measured via fluorescent assays, was higher in the skin of ZDF (fa/fa) rats with long-term T2D, bone AGEs did not differ between strains and neither AGEs correlated with bone strength. In conclusion, bone fragility in the diabetic ZDF (fa/fa) rats likely occurs through a multifactorial mechanism influenced initially by impaired bone growth and development and proceeding to an altered bone turnover process that reduces bone quality and impairs biomechanical properties as the disease progresses., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, the influence of a plasma electrolytic oxidation (PEO) surface treatment on a medical-grade WE43-based magnesium alloy is examined through an experimental and computational framework that considers the effects of localised corrosion features and mechanical properties throughout the corrosion process. First, a comprehensive in-vitro immersion study was performed on WE43-based tensile specimens with and without PEO surface modification, which included fully automated spatial reconstruction of the phenomenological features of corrosion through micro-CT scanning, followed by uniaxial tensile testing. Then the experimental data of both unmodified and PEO-modified groups were used to calibrate parameters of a finite element-based surface corrosion model. In-vitro, it was found that the WE43-PEO modified group had a significantly lower corrosion rate and maintained significantly higher mechanical properties than the unmodified. While corrosion rates were ∼50% lower in the WE43-PEO modified specimens, the local geometric features of corroding surfaces remained similar to the unmodified WE43 group, however evolving after almost the double amount of time. We were also able to quantitatively demonstrate that the PEO surface treatment on magnesium continued to protect samples from corrosion throughout the entire period tested, and not just in the early stages of corrosion. Using the results from the testing framework, the model parameters of the surface-based corrosion model were identified for both groups. This enabled, for the first time, in-silico prediction of the physical features of corrosion and the mechanical performance of both unmodified and PEO modified magnesium specimens. This simulation framework can enable future in-silico design and optimisation of bioabsorbable magnesium devices for load-bearing medical applications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

This study developed an enhanced phenomenological model for the predictions of surface-based localised corrosion of magnesium alloys for use in medical applications. The modelling framework extended previous surface-based approaches by considering the role of β-phase components throughout the material volume to better predict spatial and temporal aspects of surface-based corrosion in magnesium alloys. This enhanced surface-based corrosion model offers many advantages as it (i) captures multi-directional pitting, (ii) captures various pit morphologies, (iii) eliminates mesh sizing effects, (iv) reduces computational cost through custom time controls (v) offers control of pit sizing and (vi) produces corrosion rates that are independent of pitting parameter values. The model was fully implemented in three dimensions within the finite element framework and shows excellent potential to enable robust predictions of the long-term performance of magnesium-based implants undergoing corrosion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

It has been suggested that adverse changes in bone quality due to the accumulation of advanced glycation end-products (AGEs) may play a role in the increased skeletal fragility. These non-enzymatic glycation mediated crosslinks are caused due to the presence of sugars in the extracellular space and can be induced in-vitro. AGEs exist naturally in bone, but with diseases such as type-2 diabetes, they are found at higher levels. While previous studies have examined the relationships between AGE accumulation and some mechanical properties, there is a lack of understanding of how AGE accumulation affects the fracture mechanics behaviour of bone tissue at fall-related loading rates. The objective of this study was to investigate the relationship between AGE accumulation and the fracture mechanics of cortical bone tissue. An in vitro glycation model was used to simulate diabetic conditions in twenty anatomically adjacent pairs of bone from a single bovine femur, which reduced the possibility of inter-specimen variability. Mechanical characterisation was carried out using 3-point bend, fracture toughness and nanoindentation testing, while bone composition was analysed by quantifying the accumulation of fluorescent AGEs. Under three-point bend testing, it was found that the yield stress, ultimate flexural strength, and secant modulus of the glycated samples were significantly higher than the controls. Furthermore, fracture toughness testing showed that the critical fracture toughness was increased by 16% in glycated samples compared to controls. These results provide no evidence that AGEs alone play a role in bone fragility at fall-related loading rates, with AGE accumulation actually found to enhance several pre- and post-yield properties of the tissue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In this study, we evaluate the performance of three algorithms as computational models of trabecular bone architecture, through systematic evaluation of morphometric, topological, and mechanical properties. Here, we consider the widely-used gyroid lattice structure, the recently-developed spinodoid structure and a structure similar to Voronoi lattices introduced here as the dual-lattice. While all computational models were calibrated to recreate the trabecular tissue volume (e.g. BV/TV), it was found that both the gyroid- and spinodoid-based structures showed substantial differences in many other morphometric and topological parameters and, in turn, showed lower effective mechanical properties compared to trabecular bone. The newly-developed dual-lattice structures better captured both morphometric parameters and mechanical properties, despite certain differences being evident their topological configuration compared to trabecular bone. Still, these computational algorithms provide useful platforms to investigate trabecular bone mechanics and for designing biomimetic structures, which could be produced through additive manufacturing for applications that include bone substitutes, scaffolds and porous implants. Furthermore, the software for the creation of the structures has been added to the open source toolbox GIBBON and is therefore freely available to the community., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Much of our current understanding of the performance of self-expanding wire-braided stents is based on mechanical testing of Nitinol-based or polymeric non-bioresorbable (e.g. PET, PP etc.) devices. The small amount of data present for bioresorbable devices characterizes stents with big nominal diameters (D>6mm), with a distinct lack of data describing the mechanical performance of small-diameter wire-braided bioresorbable devices (D≤5mm). This study presents a systematic investigation of the mechanical performance of wire-braided bioresorbable Poly-L-Lactic Acid (PLLA) stents having different braiding angles (α=45° , α=30°, and α=20°), wire diameters (d=100μm, and d=150μm), wire count (n=24 and n=48), braiding patterns (1:1-1, 2:2-1 and 1:1-2) and stent diameters (D=5mm, D=4mm, and D=2.5mm). Mechanical characterisation was carried out by evaluating the radial, longitudinal and bending response of the devices. Our results showed that smaller braid angles, larger wire diameters, higher number of wires and smaller stent diameter led to an increase in the stent mechanical properties across each of the three mechanical tests performed. It was found that geometrical features of a polymeric braided stent could be adapted to achieve a similar performance to the one of a metallic device. In particular, substantial increases in stent mechanical properties were found for a low braiding angle and when the braiding pattern followed a one-over-one-under configuration with two wires in parallel (1:1-2). Finally, it was shown that a mathematical model proposed in literature for metal braided stents can provide reasonable predictions also of polymeric stent performance but just in circumstances where wire friction does not have a dominant role. This study presents a wide range of experimental data that can provide an important reference for further development of wire-braided bioresorbable devices., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ted J. Vaughan reports financial support was provided by EU Framework Programme for Research and Innovation Marie Sklodowska-Curie Actions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Mineralized collagen fibrils (MCFs) comprise collagen molecules and hydroxyapatite (HAp) crystals and are considered universal building blocks of bone tissue, across different bone types and species. In this study, we developed a coarse-grained molecular dynamics (CGMD) framework to investigate the role of mineral arrangement on the load-deformation behaviour of MCFs. Despite the common belief that the collagen molecules are responsible for flexibility and HAp minerals are responsible for stiffness, our results showed that the mineral phase was responsible for limiting collagen sliding in the large deformation regime, which helped the collagen molecules themselves undergo high tensile loading, providing a substantial contribution to the ultimate tensile strength of MCFs. This study also highlights different roles for the mineralized and non-mineralized protofibrils within the MCF, with the mineralized groups being primarily responsible for load carrying due to the presence of the mineral phase, while the non-mineralized groups are responsible for crack deflection. These results provide novel insight into the load-deformation behaviour of MCFs and highlight the intricate role that both collagen and mineral components have in dictating higher scale bone biomechanics.

In craniofacial bone defects, the promotion of bone volume augmentation remains a challenge. Finding strategies for bone regeneration such as combining resorbable minerals with organic polymers would contribute to solving the bone volume roadblock. Here, dicalcium phosphate dihydrate, chitosan and hyaluronic acid were used to functionalize a bone-side collagen membrane. Despite an increase in the release of inflammatory mediators by human circulating monocytes, the in vivo implantation of the functionalized membrane allowed the repair of a critical-sized defect in a calvaria rat model with de novo bone exhibiting physiological matrix composition and structural organization. Microtomography, histological and Raman analysis combined with nanoindentation testing revealed an increase in bone volume in the presence of the functionalized membrane and the formation of woven bone after eight weeks of implantation; these data showed the potential of dicalcium phosphate dihydrate, chitosan and hyaluronic acid to induce an efficient repair of critical-sized bone defects and establish the importance of thorough multi-scale characterization in assessing biomaterial outcomes in animal models.

This study presents a computational framework that investigates the effect of localised surface-based corrosion on the mechanical performance of a magnesium-based alloy. A finite element-based phenomenological corrosion model was used to generate a wide range of corrosion profiles, with subsequent uniaxial tensile test simulations to predict the mechanical response to failure. The python-based detection framework PitScan provides detailed quantification of the spatial phenomenological features of corrosion, including a full geometric tracking of corroding surface. Through this approach, this study is the first to quantitatively demonstrate that a surface-based non-uniform corrosion model can capture both the geometrical and mechanical features of a magnesium alloy undergoing corrosion by comparing to experimental data. Using this verified corrosion modelling approach, a wide range of corrosion scenarios was evaluated and enabled quantitative relationships to be established between the mechanical integrity and key phenomenological corrosion features. In particular, we demonstrated that the minimal cross-sectional area parameter was the strongest predictor of the remaining mechanical strength (R 2  = 0.98), with this relationship being independent of the severity or spatial features of localised surface corrosion. Interestingly, our analysis demonstrated that parameters described in ASTM G46-94 showed weaker correlations to the mechanical integrity of corroding specimens, compared to parameters determined by Pitscan . This study establishes new mechanistic insight into the performance of the magnesium-based materials undergoing corrosion., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Despite being commonly employed to treat peripheral artery disease, self-expanding Nitinol stents are still associated with relatively high incidence of failure in the mid- and long-term due to in-stent restenosis or fatigue fracture. The practice of stent oversizing is necessary to obtain suitable lumen gain and apposition to the vessel wall, though it is regarded as a potential cause of negative clinical outcomes when mis-sizing occurs. The objective of this study was to develop a computational model to provide a better understanding of the structural effects of stent sizing in a patient-specific scenario, considering oversizing ratio OS, defined as the stent nominal diameter to the average vessel diameter, between 1.0 and 1.8. It was found that OS < 1.2 resulted in problematic short-term outcomes, with poor lumen gain and significant strut malapposition. Oversizing ratios that were in the range 1.2 ≤ OS ≤ 1.4 provided the optimum biomechanical performance following implantation, with improved lumen gain, reduced incomplete stent apposition and favourable predicted long-term fatigue performance. Excessive oversizing, OS > 1.4, did not provide any further benefit in outcomes, showing limited increases in lumen gain and unfavourable long-term performance, with higher mean strain values predicted from the fatigue analysis. Therefore, our findings predict that the optimal oversizing ratio for self-expanding Nitinol stents is in the range of 1.2 ≤ OS ≤ 1.4, which is similar to clinical observations, with this study providing detailed insight into the biomechanical basis for this., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this study, a coupled computational modelling framework for bone fracture repair is presented that enables predictions of both healing and remodelling phases of the fracture region and is used to investigate the role of an internal fixation plate on the long-term healing performance of a fracture tibia under a range of different conditions. It was found that introduction of a titanium plate allowed the tibia to undergo successful healing at higher loading conditions and fracture gaps, compared with the non-plated versions. While these plated cases showed faster rates of repair in the healing phase, their performance was substantially different once they entered the remodelling phase, with substantial regions of stress shielding predicted. This framework is one of the few implementations of both fracture healing and remodelling phases of bone repair and includes several innovative approaches to smoothing, time-averaging and time incrementation in its implementation, thereby avoiding any unwanted abrupt changes between tissue phenotypes. This provides a better representation of tissue development in the fracture site when compared with fracture healing models alone and provides a suitable platform to investigate the long-term performance of orthopaedic fixation devices. This would enable the more effective design of permanent fixation devices and optimisation of the spatial and temporal performance of bioabsorbable implants., (© 2022 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

Endovascular stenting presents a promising approach to treat peripheral artery stenosis. However, a significant proportion of patients require secondary interventions due to complications such as in-stent restenosis and late stent thrombosis. Clinical failure of stents is not only attributed to patient factors but also on endothelial cell (EC) injury response, stent deployment techniques, and stent design. Three-dimensional in vitro bioreactor systems provide a valuable testbed for endovascular device assessment in a controlled environment replicating hemodynamic flow conditions found in vivo . To date, very few studies have verified the design of bioreactors based on applied flow conditions and their impact on wall shear stress, which plays a key role in the development of vascular pathologies. In this study, we develop a computationally informed bioreactor capable of capturing responses of human umbilical vein endothelial cells seeded on silicone tubes subjected to hemodynamic flow conditions and deployment of a self-expanding nitinol stents. Verification of bioreactor design through computational fluid dynamics analysis confirmed the application of pulsatile flow with minimum oscillations. EC responses based on morphology, nitric oxide (NO) release, metabolic activity, and cell count on day 1 and day 4 verified the presence of hemodynamic flow conditions. For the first time, it is also demonstrated that the designed bioreactor is capable of capturing EC responses to stent deployment beyond a 24-hour period with this testbed. A temporal investigation of EC responses to stent implantation from day 1 to day 4 showed significantly lower metabolic activity, EC proliferation, no significant changes to NO levels and EC's aligning locally to edges of stent struts, and random orientation in between the struts. These EC responses were indicative of stent-induced disturbances to local hemodynamics and sustained EC injury response contributing to neointimal growth and development of in-stent restenosis. This study presents a novel computationally informed 3D in vitro testbed to evaluate stent performance in presence of hemodynamic flow conditions found in native peripheral arteries and could help to bridge the gap between the current capabilities of 2D in vitro cell culture models and expensive pre-clinical in vivo models., Competing Interests: SN is on her secondment at Vascular Flow Technologies Dundee, United Kingdom. RH and CD are employed by Vascular Flow Technologies Dundee, United Kingdom. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nandan, Schiavi-Tritz, Hellmuth, Dunlop, Vaughan and Dolan.)

Purpose: Polymer covered stents have demonstrated promising clinical outcomes with improved patency rates compared to traditional bare-metal stents. However, little is known on the mechanical implication of stent covering. This study aims to provide insight into the role of a polymeric cover on the biomechanical performance of self-expanding laser-cut stents through a combined experimental-computational approach., Methods: Experimental bench top tests were conducted on bare and covered versions of a commercial stent to evaluate the radial, axial and bending response. In parallel, a computational framework with a novel covering strategy was developed that accurately predicts stent mechanical performance. Different stent geometries and polymer materials were also considered to further improve understanding on covered stent mechanics., Results: Results show that stent covering causes increased initial axial stiffness and up to 60% greater radial resistive force at small crimp diameters as the cover folds and self-contacts. The incorporation of a cover allows stent designs without interconnecting struts, thereby providing improved flexibility without compromising radial force. It was also shown that use of a stiffer PET polymeric covering material caused significant alterations to the radial and axial response, with the initial axial stiffness increasing six-fold and the maximum radial resistive force increasing four-fold compared to a PTFE-PU covered stent., Conclusion: This study demonstrates that stent covering has a substantial effect on the overall stent mechanical performance and highlights the importance of considering the mechanical properties of the combined cover and stent., (© 2021. Biomedical Engineering Society.)

Lamellar bone is one of the fundamental structural units of bone tissue and it consists of mineralised collagen fibrils (MCFs) embedded within an extra-fibrillar matrix comprised of hydroxyapatite minerals distributed throughout a matrix of non-collagenous proteins (NCPs). While both intra- and extra-fibrillar phases provide a critical contribution to tissue-level behaviour, the mechanical implications of their structural arrangement, and in particular the relative distribution of HA minerals between both phases, remains poorly understood. This study presents a multiscale finite element framework to investigate the role of intra- and extra-fibrillar mineralisation on the elastic properties of bone tissue by considering two levels of structural hierarchy. At the nanoscale, representative volume elements (RVEs) of both MCFs and the extra-fibrillar matrix were developed, and a homogenisation strategy was used to determine the effective elastic properties of each phase. At the sub-micron level, an RVE of lamellar bone that accounted for newly reported patterns of mineral platelets encircling collagen fibrils was used to predict the effective response of lamellar bone tissue, with material properties established from the previous length scale. The results demonstrated that the overall mineral content in the tissue is the biggest contributor to the effective elastic properties of lamellar bone. While this is perhaps unsurprising, importantly, it was demonstrated that the extra-fibrillar matrix (and mineral therein) is the phase that makes the primary contribution to the elastic response of the tissue. The two main reasons that the extra-fibrillar matrix dominated the load-bearing response are (i) the greater proportion of mineral content compared to the intra-fibrillar regions and (ii) the highly ordered arrangement of mineral platelets that are aligned to the longitudinal axis of MCFs. Both of these features resulted in extra-fibrillar mineral strain ratios that were consistently higher than intra-fibrillar mineral strain ratios under axial loading. As a result, the predicted elastic properties of MCFs were much lower than the extra-fibrillar matrix, indicating that intra-fibrillar mineralisation only provided a modest contribution to the stiffness of bone tissue. Collectively, the predicted results of the multiscale approach compared well to the range properties measured through various experimental testing methods, highlighting its potential to provide further insight into the role of sub-tissue features of tissue biomechanics., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The competing structural and hemodynamic considerations in valve design generally require a large amount of in vitro hydrodynamic and durability testing during development, often resulting in inefficient "trial-and-error" prototyping. While in silico modelling through finite element analysis (FEA) has been widely used to inform valve design by optimising structural performance, few studies have exploited the potential insight FEA could provide into critical hemodynamic performance characteristics of the valve. The objective of this study is to demonstrate the potential of FEA to predict the hydrodynamic performance of tri-leaflet aortic valve implants obtained during development through in vitro testing. Several variations of tri-leaflet aortic valves were designed and manufactured using a synthetic polymer and hydrodynamic testing carried out using a pulsatile flow rig according to ISO 5840, with bulk hydrodynamic parameters measured. In silico models were developed in tandem and suitable surrogate measures were investigated as predictors of the hydrodynamic parameters. Through regression analysis, the in silico parameters of leaflet coaptation area, geometric orifice area and opening pressure were found to be suitable indicators of experimental in vitro hydrodynamic parameters: regurgitant fraction, effective orifice area and transvalvular pressure drop performance, respectively.

Osteopontin (OPN) is a one of the most abundant non-collagenous proteins in the bone's organic matrix. OPN is responsible for mediating bonding at mineral interfaces in the extrafibrillar space and recent evidence shows that it is a major contributor to bone's fracture resistance. While several experimental studies have identified an important role for calcium ions in mediating energy dissipation in OPN protein networks, the underlying molecular mechanisms remain largely unknown. In the current study, the role of calcium ions on energy dissipation at OPN interface with hydroxyapatite (HAp) as the main bone mineral was investigated. For the first time, the three-dimensional structure of OPN proteins were predicted, and it was found that calcium ions greatly influenced the final protein configuration and energy dissipation performance. Under small deformation, the compact cOPN structure, resulting from calcium ions presence, facilitated greater energy dissipation through sacrificial bond breaking and mechanisms mediated by the surface-bound calcium. At larger deformation, the compact structure also enabled cOPN to dissipate higher energy. Moreover, it was found that phosphorylation of OPN played an important role in energy dissipation. While previous studies have shown that OPN dissipated energy by forming aggregate networks, this study also showed that network formation is not necessary and that individual OPN proteins can dissipate large amounts of energy at HAp interfaces., (Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

This study presents a comprehensive evaluation of the mechanical, micro-mechanical and physical properties of Reva Medical Fantom Encore Bioresorbable Scaffolds (BRS) subjected to a thermally-accelerated degradation protocol. The Fantom Encore BRS were immersed in phosphate buffered saline solution at 50 °C for 112 days with radial compression testing, nanoindentation, differential scanning calorimetry, gel permeation chromatography and mass loss characterisation performed at consecutive time points. In the initial stages of degradation (Days 0-21), the Fantom Encore BRS showed increases in radial strength and stiffness, despite a substantial reduction in in molecular weight, with a slight increase in the melt temperature also observed. In the second phase (Days 35-54), the radial strength of the BRS samples were maintained despite a continued loss in molecular weight. However, during this phase, the ductility of the stent showed a reduction, with stent fracture occurring earlier in the crimp process and with lower amounts of plastic deformation evident under visual examination post-fracture. In the final phase (Days 63-112), the load-bearing capacity of the Fantom Encore BRS showed continued reduction, with decreases in radial stiffness and strength, and drastic reduction in the work-to-fracture of the devices. Throughout each phase, there was a steady increase in the relative crystallinity, with limited mass loss until day 112 and only minor changes in glass transition and melt temperatures. Limited changes were observed in nano-mechanical properties, with measured local elastic moduli and hardness values remaining largely similar throughout degradation. Given that the thermally-accelerated in vitro conditions represented a four-fold acceleration of physiological conditions, these results suggest that the BRS scaffolds could exhibit substantially brittle behaviour after ∼ one year of implantation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This study aims at proposing and discussing useful indications to all those who need to validate a numerical model of coronary stent deployment. The proof of the reliability of a numerical model is becoming of paramount importance in the era of in silico trials. Recently, the ASME V&V Standard Committee for medical devices prepared the V&V 40 standard document that provides a framework that guides users in establishing and assessing the relevance and adequacy of verification and validation activities performed for proving the credibility of models. To the knowledge of the authors, only a few examples of the application of the V&V 40 framework to medical devices are available in the literature, but none about stents. Specifically, in this study, the authors wish to emphasize the choice of a relevant set of experimental activities to provide data for the validation of computational models aiming to predict coronary stent deployment. Attention is focused on the use of ad hoc 3D-printed mock vessels in the validation plan, which could allow evaluating aspects of clinical relevance in a representative but controlled environment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Berti, Antonini, Poletti, Fiuza, Vaughan, Migliavacca, Petrini and Pennati.)

This study develops a three-dimensional automated detection framework ( PitScan ) that systematically evaluates the severity and phenomenology of pitting corrosion. This framework uses a python-based algorithm to analyse microcomputer-tomography scans (μCT) of cylindrical specimens undergoing corrosion. The approach systematically identifies several surface-based corrosion features, enabling full spatial characterisation of pitting parameters, including pit density, pit size, pit depth as well as pitting factor according to ASTM G46-94. Furthermore, it is used to evaluate pitting formation in tensile specimens of a Rare Earth Magnesium alloy undergoing corrosion, and relationships between key pitting parameters and mechanical performance are established. Results demonstrated that several of the parameters described in ASTM G46-94, including pit number, pit density and pitting factor, showed little correlation to mechanical performance. However, this study did identify that other parameters showed strong correlations with the ultimate tensile strength and these tended to be directly linked to the reduction of the cross-sectional area of the specimen. Specifically, our results indicate, that parameters directly linked to the loss of the cross-sectional area (e.g. minimum material width), are parameters that are most suited to provide an indication of a specimen's mechanical performance. The automated detection framework developed in this study has the potential to provide a basis to standardise measurements of pitting corrosion across a range of metals and future prediction of mechanical strength over degradation time., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

This study presents a systematic evaluation of the physical, thermal and mechanical performance of medical-grade semi-crystalline PLLA undergoing thermally-accelerated degradation. Samples were immersed in phosphate-buffered saline solution at 50 °C for 112 days and mass loss, molecular weight, thermal properties, degree of crystallinity, FTIR and Raman spectra, tensile elastic modulus, yield stress and failure stress/strain were evaluated at consecutive time points. Samples showed a consistent reduction in molecular weight and melting temperature, a consistent increase in percent crystallinity and limited changes in glass transition temperature and mass loss. At day 49, a drastic reduction in tensile failure strain was observed, despite the fact that elastic modulus, yield and tensile strength of samples were maintained. Brittleness increase was followed by rapid increase in degradation rate. Beyond day 70, samples became too brittle to test indicating substantial deterioration of their load-bearing capacity. This study also presents a computational micromechanics framework that demonstrates that the elastic modulus of a semi-crystalline polymer undergoing degradation can be maintained, despite a reducing molecular weight through compensatory increases in percent crystallinity. This study presents novel insight into the relationship between physical properties and mechanical performance of medical-grade PLLA during degradation and could have important implications for design and development of bioresorbable stents for vascular applications., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The further development of future Magnesium based biodegradable implants must consider not only the freedom of design, but also comprise implant volume reduction, as both aspects are crucial for the development of higher functionalised implants, such as plate systems or scaffold grafts in bone replacement therapy. As conventional manufacturing methods such as turning and milling are often accompanied by limitations concerning implant design and functionality, the process of laser powder bed fusion (LPBF) specifically for Magnesium alloys was recently introduced. In addition, the control of the degradation rate remains a key aspect regarding biodegradable implants. Recent studies focusing on the degradation behaviour of additively manufactured Magnesium scaffolds disclosed additional intricacies when compared to conventionally manufactured Magnesium parts, as a notably larger surface area was exposed to the immersion medium and scaffold struts degraded non-uniformly. Moreover, chemical etching as post processing technique is applied to remove sintered powder particles from the surface, altering surface chemistry. In this study, cylindrical Magnesium specimens were manufactured by LPBF and surfaces were consecutively modified by phosphoric etching and machining. Degradation behaviour and biocompatibility were then investigated, revealing that etched samples exhibited the overall lowest degradation rates, but experienced large pit formation, while the reduction of surface roughness resulted in a delay of degradation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Self-expanding covered braided stents are routinely used across a diverse range of clinical applications, but few computational studies have attempted to replicate their complex behaviour. In this study, a computational framework was developed to predict the functional performance of bare and covered self-expanding wire braided stents, with a systematic evaluation on the effect of various braid and cover parameters presented. Simulated radial force and kink deformation tests show good agreement to experimental data for covered braided stents across a range of braid angles and cover thicknesses. Our results demonstrate that braid angle is a key governing parameter that dictates the radial and kink performance of both bare-metal and covered wire braided stents. It was also demonstrated that addition of a polymeric cover to a wire braided stent causes a stiffer radial response across all braid angles, particularly when thicker and/or stiffer covering systems were considered. This study represents the first experimentally-validated computational model for covered wire braided stent systems and has excellent potential to be used in future design of these devices for a range of applications., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study presents an investigation into the role of Osteocalcin (OC) on bone biomechanics, with the results demonstrating that the protein's α-helix structures play a critical role in energy dissipation behavior in healthy conditions. In the first instance, α-helix structures have high affinity with the Hydroxyapatite (HAp) mineral surface and provide favorable conditions for adsorption of OC proteins onto the mineral surface. Using steered molecular dynamics simulation, several key energy dissipation mechanisms associated with α-helix structures were observed, which included stick-slip behavior, a sacrificial bond mechanism and a favorable binding feature provided by the Ca 2+ motif on the OC protein. In the case of Type-2 Diabetes, this study demonstrated that possible glycation of the OC protein can occur through covalent crosslinking between Arginine and N-terminus regions, causing disruption of α-helices leading to a lower protein affinity to the HAp surface. Furthermore, the loss of α-helix structures allowed protein deformation to occur more easily during pulling and key energy dissipation mechanisms observed in the healthy configuration were no longer present. This study has significant implications for our understanding of bone biomechanics, revealing several novel mechanisms in OC's involvement in energy dissipation. Furthermore, these mechanisms can be disrupted following the onset of Type-2 Diabetes, implying that glycation of OC could have a substantial contribution to the increased bone fragility observed during this disease state.

Affinity maturation is a powerful technique in antibody engineering for the in vitro evolution of antigen binding interactions. Key to the success of this process is the expansion of sequence and combinatorial diversity to increase the structural repertoire from which superior binding variants may be selected. However, conventional strategies are often restrictive and only focus on small regions of the antibody at a time. In this study, we used a method that combined antibody chain shuffling and a staggered-extension process to produce unbiased libraries, which recombined beneficial mutations from all six complementarity-determining regions (CDRs) in the affinity maturation of an inhibitory antibody to Arginase 2 (ARG2). We made use of the vast display capacity of ribosome display to accommodate the sequence space required for the diverse library builds. Further diversity was introduced through pool maturation to optimize seven leads of interest simultaneously. This resulted in antibodies with substantial improvements in binding properties and inhibition potency. The extensive sequence changes resulting from this approach were translated into striking structural changes for parent and affinity-matured antibodies bound to ARG2, with a large reorientation of the binding paratope facilitating increases in contact surface and shape complementarity to the antigen. The considerable gains in therapeutic properties seen from extensive sequence and structural evolution of the parent ARG2 inhibitory antibody clearly illustrate the advantages of the unbiased approach developed, which was key to the identification of high-affinity antibodies with the desired inhibitory potency and specificity., Competing Interests: Competing interest statement: A patent application has been filed on antibodies related to this work (UK Patent Application No. GB1912030.2 filed on 21 August 2019: Binding Molecules [ARG2]).The authors declare no competing interest.

The US Supreme Court has required that death penalty schemes narrow the class of persons eligible for a death sentence. Through the selection requirement, juries must use mitigating and aggravating evidence jointly to select the offenders engaged in the worst of the worst crimes. This study utilized between-subjects experimental design to test juror's ability to narrow directly. Utilizing the vignette approach, with brief descriptions of capital trials nested in self-administered questionnaires, we experimentally manipulated aggravating and mitigating evidence presented to mock jurors and examined their sentencing decisions in two independent samples. While mock jurors were able to identify offenders they considered to be engaged in serious crimes and offenders with diminished culpability, mitigating evidence and aggravating evidence did not interact and there was considerable inconsistency in the effects of mitigating evidence within and between samples. Implications for the constitutionality of the death penalty are considered., (© 2020 John Wiley & Sons, Ltd.)

Filopodia are finger-like actin-rich protrusions that extend from the cell surface and are important for cell-cell communication and pathogen internalization. The small size and transient nature of filopodia combined with shared usage of actin regulators within cells confounds attempts to identify filopodial proteins. Here, we used phage display phenotypic screening to isolate antibodies that alter the actin morphology of filopodia-like structures (FLS) in vitro. We found that all of the antibodies that cause shorter FLS interact with SNX9, an actin regulator that binds phosphoinositides during endocytosis and at invadopodia. In cells, we discover SNX9 at specialized filopodia in Xenopus development and that SNX9 is an endogenous component of filopodia that are hijacked by Chlamydia entry. We show the use of antibody technology to identify proteins used in filopodia-like structures, and a role for SNX9 in filopodia., (© 2020 Jarsch et al.)

Persistent pathogens have evolved to avoid elimination by the mammalian immune system including mechanisms to evade complement. Infections with African trypanosomes can persist for years and cause human and animal disease throughout sub-Saharan Africa. It is not known how trypanosomes limit the action of the alternative complement pathway. Here we identify an African trypanosome receptor for mammalian factor H, a negative regulator of the alternative pathway. Structural studies show how the receptor binds ligand, leaving inhibitory domains of factor H free to inactivate complement C3b deposited on the trypanosome surface. Receptor expression is highest in developmental stages transmitted to the tsetse fly vector and those exposed to blood meals in the tsetse gut. Receptor gene deletion reduced tsetse infection, identifying this receptor as a virulence factor for transmission. This demonstrates how a pathogen evolved a molecular mechanism to increase transmission to an insect vector by exploitation of a mammalian complement regulator.

Self-expanding wire braided stents have been used in a wide-range of medical implant applications due to the distinct flexibility offered by the wide-range of tunable design parameters, which includes braid angle, wire diameter and braid pattern. Recently, there has been increasing attention on developing covered stent systems in endovascular repair, whereby the stent frame is wrapped with a graft or textile material, typically made from expanded polytetrafluoroethylene (ePTFE) or polyester (PET, Dacron). However, the addition of a polymeric cover to a wire braided stent fundamentally changes its mechanism(s) of deformation and there is distinct lack of understanding how the functional performance of these systems compares to their bare-metal counterparts. This paper presents the first systematic evaluation of the effect of a polymeric cover on braided stent mechanics using radial compression, axial compression and tension, kink deformation and stent elongation testing. Nitinol wire braided stents were manufactured with braid angles of α = 30°, α = 45°, and α = 60°, and subsequently covered with a polyurethane-silicone composite polymer with cover thicknesses of t = 25 μm and t = 100 μm. Results demonstrate that the response of both bare-metal and covered wire braided stents is heavily influenced by braid angle across all loading regimes. In particular, it was shown that the bare-metal stents exhibited higher stiffness under radial and axial loading when the direction of loading was closer aligned to the orientation of the wires. It was shown that covering stents with a polymeric cover led to a stiffer response across all braid angles and, in some cases, this could be up to two orders of magnitude greater when thicker covering systems were considered (t = 100 μm). Covered wire braided stents with braid angles of α = 30° and α = 45° show excellent potential for use in femoropopliteal applications, where the addition of 25 μm cover increased the radial resistive force but did not have any negative effects in terms of flexibility. The current analysis shows that use of a cover in braided stent mechanics is another variable parameter which can be used to produce optimum stent properties tailored to an application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor 'invisible' to the host's immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to suppression of anti-tumor T-cell-mediated immune responses. Here we describe the isolation and characterization of a high affinity antibody (C0021158) that inhibits ARG2 enzymatic function completely, effectively restoring T-cell proliferation in vitro . Enzyme kinetic studies confirmed that C0021158 exhibits a noncompetitive mechanism of action, inhibiting ARG2 independently of L-arginine concentrations. To elucidate C0021158's inhibitory mechanism at a structural level, the co-crystal structure of the Fab in complex with trimeric ARG2 was solved. C0021158's epitope was consequently mapped to an area some distance from the enzyme's substrate binding cleft, indicating an allosteric mechanism was being employed. Following C0021158 binding, distinct regions of ARG2 undergo major conformational changes. Notably, the backbone structure of a surface-exposed loop is completely rearranged, leading to the formation of a new short helix structure at the Fab-ARG2 interface. Moreover, this large-scale structural remodeling at ARG2's epitope translates into more subtle changes within the enzyme's active site. An arginine residue at position 39 is reoriented inwards, sterically impeding the binding of L-arginine. Arg39 is also predicted to alter the p K A of a key catalytic histidine residue at position 160, further attenuating ARG2's enzymatic function. In silico molecular docking simulations predict that L-arginine is unable to bind effectively when antibody is bound, a prediction supported by isothermal calorimetry experiments using an L-arginine mimetic. Specifically, targeting ARG2 in the tumor microenvironment through the application of C0021158, potentially in combination with standard chemotherapy regimens or alternate immunotherapies, represents a potential new strategy to target immune cold tumors.

Osteoporosis is associated with systemic bone loss, leading to a significant deterioration of bone microarchitecture and an increased fracture risk. Although recent studies have shown that the distribution of bone mineral becomes more heterogeneous because of estrogen deficiency in animal models of osteoporosis, it is not known whether osteoporosis alters mineral distribution in human bone. Type 2 diabetes mellitus (T2DM) can also increase bone fracture risk and is associated with impaired bone cell function, compromised collagen structure, and reduced mechanical properties. However, it is not known whether alterations in mineral distribution arise in diabetic (DB) patients' bone. In this study, we quantify mineral content distribution and tissue microarchitecture (by μCT) and mechanical properties (by compression testing) of cancellous bone from femoral heads of osteoporotic (OP; n = 10), DB ( n = 7), and osteoarthritic (OA; n = 7) patients. We report that though OP cancellous bone has significantly deteriorated compressive mechanical properties and significantly compromised microarchitecture compared with OA controls, there is also a significant increase in the mean mineral content. Moreover, the heterogeneity of the mineral content in OP bone is significantly higher than controls (+25%) and is explained by a significant increase in bone volume at high mineral levels. We propose that these mineral alterations act to exacerbate the already reduced bone quality caused by reduced cancellous bone volume during osteoporosis. We show for the first time that cancellous bone mineralization is significantly more heterogeneous (+26%) in patients presenting with T2DM compared with OA (non-DB) controls, and that this heterogeneity is characterized by a significant increase in bone volume at low mineral levels. Despite these mineralization changes, bone microarchitecture and mechanical properties are not significantly different between OA groups with and without T2DM. Nonetheless, the observed alterations in mineral heterogeneity may play an important tissue-level role in bone fragility associated with OP and DB bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research., (© 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.)

To maintain prolonged infection of mammals, African trypanosomes have evolved remarkable surface coats and a system of antigenic variation 1 . Within these coats are receptors for macromolecular nutrients such as transferrin 2,3 . These must be accessible to their ligands but must not confer susceptibility to immunoglobulin-mediated attack. Trypanosomes have a wide host range and their receptors must also bind ligands from diverse species. To understand how these requirements are achieved, in the context of transferrin uptake, we determined the structure of a Trypanosoma brucei transferrin receptor in complex with human transferrin, showing how this heterodimeric receptor presents a large asymmetric ligand-binding platform. The trypanosome genome contains a family of around 14 transferrin receptors 4 , which has been proposed to allow binding to transferrin from different mammalian hosts 5,6 . However, we find that a single receptor can bind transferrin from a broad range of mammals, indicating that receptor variation is unlikely to be necessary for promiscuity of host infection. In contrast, polymorphic sites and N-linked glycans are preferentially found in exposed positions on the receptor surface, not contacting transferrin, suggesting that transferrin receptor diversification is driven by a need for antigenic variation in the receptor to prolong survival in a host.

P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely because of the difficulty in engineering specificity and selectivity. Here, we describe for the first time the generation of a panel of diverse monoclonal antibodies (mAbs) to human and mouse P2X4, capable of both positive and negative modulation of channel function. The affinity-optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity for human P2X4 and induced potent and complete block of P2X4 currents. Site-directed mutagenesis of P2X4 revealed the head domain as a key interaction site for inhibitory mAbs. Inhibition of spinal P2X4 either by intrathecal delivery of an anti-P2X4 mAb or by systemic delivery of an anti-P2X4 bispecific mAb with enhanced blood-spinal cord barrier permeability produced long-lasting (>7 days) analgesia in a mouse model of neuropathic pain. We therefore propose that inhibitory mAbs binding the head domain of P2X4 have therapeutic potential for the treatment of neuropathic pain.