Development and Optimisation of Hydrogel Scaffolds for Microvascular Network Formation.

Traumatic injuries are a major cause of morbidity and mortality worldwide; however, there is limited research on microvascular traumatic injuries. To address this gap, this research aims to develop and optimise an in vitro construct for traumatic injury research at the microvascular level. Tissue engineering constructs were created using a range of polymers (collagen, fibrin, and gelatine), solvents (PBS, serum-free endothelial media, and MES/NaCl buffer), and concentrations (1-5% w/v). Constructs created from these hydrogels and HUVECs were evaluated to identify the optimal composition in terms of cell proliferation, adhesion, migration rate, viability, hydrogel consistency and shape retention, and tube formation. Gelatine hydrogels were associated with a lower cell adhesion, whereas fibrin and collagen ones displayed similar or better results than the control, and collagen hydrogels exhibited poor shape retention; fibrin scaffolds, particularly at high concentrations, displayed good hydrogel consistency. Based on the multipronged evaluation, fibrin hydrogels in serum-free media at 3 and 5% w/v were selected for further experimental work and enabled the formation of interconnected capillary-like networks. The networks formed in both hydrogels displayed a similar architecture in terms of the number of segments (10.3 ± 3.21 vs. 9.6 ± 3.51) and diameter (8.6446 ± 3.0792 µm vs. 7.8599 ± 2.3794 µm).

Comparison of a Scaled Cadaver-Based Musculoskeletal Model With a Clinical Upper Extremity Model.

Reliably and accurately estimating joint/segmental kinematics from optical motion capture data has remained challenging. Studies objectively characterizing human movement patterns have typically involved inverse kinematics and inverse dynamics techniques. Subsequent research has included scaled cadaver-based musculoskeletal (MSK) modeling for noninvasively estimating joint and muscle loads. As one of the ways to enhance confidence in the validity of MSK model predictions, the kinematics from the preceding step that drives such a model needs to be checked for agreement or compared with established/widely used models. This study rigorously compares the upper extremity (UE) joint kinematics calculated by the Dutch Shoulder Model implemented in the AnyBody Managed Model Repository (involving multibody kinematics optimization (MKO)) with those estimated by the Vicon Plug-in Gait model (involving single-body kinematics optimization (SKO)). Ten subjects performed three trials of (different types of) reaching tasks in a three-dimensional marker-based optical motion capture laboratory setting. Joint angles, processed marker trajectories, and reconstruction residuals corresponding to both models were compared. Scatter plots and Bland-Altman plots were used to assess the agreement between the two model outputs. Results showed the largest differences between the two models for shoulder, followed by elbow and wrist, with all root-mean-squared differences less than 10 deg (although this limit might be unacceptable for clinical use). Strong-to-excellent Spearman's rank correlation coefficients were found between the two model outputs. The Bland-Altman plots showed a good agreement between most of the outputs. In conclusion, results indicate that these two models with different kinematic algorithms broadly agree with each other, albeit with few key differences.

Effectiveness of Influenza Vaccines in the HIVE Household Cohort Over 8 Years: Is There Evidence of Indirect Protection?

BACKGROUND: The evidence that influenza vaccination programs regularly provide protection to unvaccinated individuals (ie, indirect effects) of a community is lacking. We sought to determine the direct, indirect, and total effects of influenza vaccine in the Household Influenza Vaccine Evaluation (HIVE) cohort. METHODS: Using longitudinal data from the HIVE cohort from 2010-11 through 2017-18, we estimated direct, indirect, and total influenza vaccine effectiveness (VE) and the incidence rate ratio of influenza virus infection using adjusted mixed-effect Poisson regression models. Total effectiveness was determined through comparison of vaccinated members of full or partially vaccinated households to unvaccinated individuals in completely unvaccinated households. RESULTS: The pooled, direct VE against any influenza was 30.2% (14.0-43.4). Direct VE was higher for influenza A/H1N1 43.9% (3.9 to 63.5) and B 46.7% (17.2 to 57.5) than A/H3N2 31.7% (10.5 to 47.8) and was higher for young children 42.4% (10.1 to 63.0) than adults 18.6% (-6.3 to 37.7). Influenza incidence was highest in completely unvaccinated households (10.6 per 100 person-seasons) and lower at all other levels of household vaccination coverage. We found little evidence of indirect VE after adjusting for potential confounders. Total VE was 56.4% (30.1-72.9) in low coverage, 43.2% (19.5-59.9) in moderate coverage, and 33.0% (12.1 to 49.0) in fully vaccinated households. CONCLUSIONS: Influenza vaccines may have a benefit above and beyond the direct effect but that effect in this study was small. Although there may be exceptions, the goal of global vaccine recommendations should remain focused on provision of documented, direct protection to those vaccinated.

Comparing thermal discomfort with skin temperature response of lower-limb prosthesis users during exercise.

BACKGROUND: Thermal discomfort is prevalent among prosthesis users. This observational study of thirty unilateral lower-limb prosthesis users compared their skin temperatures and the thermal discomfort experienced during exercise between their residual and contralateral limbs. METHODS: Participants performed a 2-minute interval cycling exercise test. Skin temperature was measured at matched locations on each leg during the 1-minute rest intervals. Average rate-of-change in skin temperature was compared between legs using a repeated measures analysis of variance. Participants rated thermal discomfort on each leg before and after exercise, and a Wilcoxon signed-rank test was used to compare legs. Ordinal regression evaluated the relationship between the rate-of-change in temperature on the residual limb and the perceived thermal discomfort. FINDINGS: After exercise, thermal discomfort ranked higher on the amputated side (P = 0.007). On average, both legs cooled during exercise (P = 0.002), but the difference between legs was not significant. The rate-of change in skin temperature on the residual limb during exercise did not relate to the thermal discomfort experienced (odds ratio of 0.357). INTERPRETATION: These findings indicate that in this patient population, skin temperature does not explain the thermal discomfort experienced, and subjective thermal discomfort is inadequate for detecting thermoregulatory issues, with potential implications for long-term tissue health.

Ion current and action potential alterations in peripheral neurons subject to uniaxial strain.

Peripheral nerves, subject to continuous elongation and compression during everyday movement, contain neuron fibers vital for movement and sensation. At supraphysiological strains resulting from trauma, chronic conditions, aberrant limb positioning, or surgery, conduction blocks occur which may result in chronic or temporary loss of function. Previous in vitro stretch models, mainly focused on traumatic brain injury modelling, have demonstrated altered electrophysiological behavior during localized deformation applied by pipette suction. Our aim was to evaluate the changes in voltage-activated ion channel function during uniaxial straining of neurons applied by whole-cell deformation, more physiologically relevant model of peripheral nerve trauma. Here, we quantified experimentally the changes in inwards and outwards ion currents and action potential (AP) firing in dorsal root ganglion-derived neurons subject to uniaxial strains, using a custom-built device allowing simultaneous cell deformation and patch clamp recording. Peak inwards sodium currents and rectifying potassium current magnitudes were found to decrease in cells under stretch, channel reversal potentials were found to be left-shifted, and half-maximum activation potentials right-shifted. The threshold for AP firing was increased in stretched cells, although neurons retained the ability to fire induced APs. Overall, these results point to ion channels being damaged directly and immediately by uniaxial strain, affecting cell electrophysiological activity, and can help develop prevention and treatment strategies for peripheral neuropathies caused by mechanical trauma.

Engineering a uniaxial substrate-stretching device for simultaneous electrophysiological measurements and imaging of strained peripheral neurons.

Peripheral nerves are continuously subjected to mechanical strain during everyday movements, but excessive stretch can lead to damage and neuronal cell functionality can also be impaired. To better understand cellular processes triggered by stretch, it is necessary to develop in vitro experimental methods that allow multiple concurrent measurements and replicate in vivo mechanical conditions. Current commercially available cell stretching devices do not allow flexible experimental design, restricting the range of possible multi-physics measurements. Here, we describe and characterise a custom-built uniaxial substrate-straining device, with which neurons cultured on aligned patterned surfaces (50 µm wide grooves) can be strained up to 70% and simultaneously imaged with widefield and confocal imaging (up to 100x magnification). Furthermore, direct and indirect electrophysiological measurements by patch clamping and calcium imaging can be made during strain application. We characterise the strain applied to cells cultured in deformable wells by using finite element method simulations and experimental data, showing local surface strains of up to 60% with applied strains of up to 25%. We also show how patterned substrates do not alter the mechanical properties of the system compared to unpatterned surfaces whilst still inducing a homogeneous cell response to strain. The characterisation of this device will be useful for research into investigating the effect of whole-cell mechanical stretch on neurons at both single cell and network scales, with applications found in peripheral neuropathy modelling and in platforms for preventive and regenerative studies.

Membrane Mechanical Properties Regulate the Effect of Strain on Spontaneous Electrophysiology in Human iPSC-Derived Neurons.

Peripheral nerves contain neuron fibers vital for movement and sensation and are subject to continuous elongation and compression during everyday movement. At supraphysiological strains conduction blocks occur, resulting in permanent or temporary loss of function. The mechanisms underpinning these alterations in electrophysiological activity remain unclear; however, there is evidence that both ion channels and network synapses may be affected through cell membrane transmitted strain. The aim of this work was to quantify the changes in spontaneous activity resulting from application of uniaxial strain in a human iPS-derived motor neuron culture model, and to investigate the role of cell membrane mechanical properties during cell straining. Increasing strain in a custom-built cell-stretching device caused a linear decrease in spontaneous activity, and no immediate recovery of activity was observed after strain release. Imaging neuronal membranes with c-Laurdan showed changes to the lipid order in neural membranes during deformation with a decrease in lipid packing. Neural cell membrane stiffness can be modulated by increasing cholesterol content, resulting in reduced stretch-induced decrease of membrane lipid packing and in a reduced decrease in spontaneous activity caused by mechanical strain. Together these results indicate that the mechanism whereby cell injury causes impaired transmission of neural impulses may be governed by the mechanical state of the cell membrane, and contribute to establishing a direct relationship between neural uniaxial straining and loss of spontaneous neural activity.

Rapid and efficient differentiation of functional motor neurons from human iPSC for neural injury modelling.

Primary rodent neurons and immortalised cell lines have overwhelmingly been used for in vitro studies of traumatic injury to peripheral and central neurons, but have some limitations of physiological accuracy. Motor neurons (MN) derived from human induced pluripotent stem cells (iPSCs) enable the generation of cell models with features relevant to human physiology. To facilitate this, it is desirable that MN protocols both rapidly and efficiently differentiate human iPSCs into electrophysiologically active MNs. In this study, we present a simple, rapid protocol for differentiation of human iPSCs into functional spinal (lower) MNs, involving only adherent culture and use of small molecules for directed differentiation, with the ultimate aim of rapid production of electrophysiologically functional cells for short-term neural injury experiments. We show successful differentiation in two unrelated iPSC lines, by quantifying neural-specific marker expression, and by evaluating cell functionality at different maturation stages by calcium imaging and patch clamping. Differentiated neurons were shown to be electrophysiologically altered by uniaxial mechanical deformation. Spontaneous network activity decreased with applied stretch, indicating aberrant network connectivity. These results demonstrate the feasibility of this rapid, simple protocol for differentiating iPSC-derived MNs, suitable for in vitro neural injury studies focussing on electrophysiological alterations caused by mechanical deformation or trauma.

Strain partitioning between nerves and axons: Estimating axonal strain using sodium channel staining in intact peripheral nerves.

BACKGROUND: Peripheral nerves carry afferent and efferent signals between the central nervous system and the periphery of the body. When nerves are strained above physiological levels, conduction blocks occur, resulting in debilitating loss of motor and sensory function. Understanding the effects of strain on nerve function requires knowledge of the multi-scale mechanical behaviour of the tissue, and how this is transferred to the cellular environment. NEW METHOD: The aim of this work was to establish a technique to measure the partitioning of strain between tissue and axons in axially loaded peripheral nerves. This was achieved by staining extracellular domains of sodium channels clustered at nodes of Ranvier, without altering tissue mechanical properties by fixation or permeabilisation. RESULTS: Stained nerves were imaged by multi-photon microscopy during in situ tensile straining, and digital image correlation was used to measure axonal strain with increasing tissue strain. Strain was partitioned between tissue and axon scales by an average factor of 0.55. COMPARISONS WITH EXISTING METHODS: This technique allows non-invasive probing of cell-level strain within the physiological tissue environment. CONCLUSIONS: This technique can help understand the mechanisms behind the onset of conduction blocks in injured peripheral nerves, as well as to evaluate changes in multi-scale mechanical properties in diseased nerves.

Probing multi-scale mechanics of peripheral nerve collagen and myelin by X-ray diffraction.

Peripheral nerves are continuously subjected to mechanical forces, both during everyday movement and as a result of traumatic events. Current mechanical models focus on explaining the macroscopic behaviour of the tissue, but do not investigate how tissue strain translates to deformations at the microstructural level. Predicting the effect of macro-scale loading can help explain changes in nerve function and suggest new strategies for prevention and therapy. The aim of this study was to determine the relationship between macroscopic tensile loading and micro scale deformation in structures thought to be mechanically active in peripheral nerves: the myelin sheath enveloping axons, and axially aligned epineurial collagen fibrils. The microstructure was probed using X-ray diffraction during in situ tensile loading, measuring the micro-scale deformation in collagen and myelin, combined with high definition macroscopic video extensiometry. At a tissue level, tensile loading elongates nerves axially, whilst simultaneously compressing circumferentially. The non-linear behaviour observed in both directions is evidence, circumferentially, that the nerve core components have the ability to rearrange before bearing load and axially, of a recruitment process in epineurial collagen. At the molecular level, axially aligned epineurial collagen fibrils are strained, whilst the myelin sheath enveloping axons is compressed circumferentially. During induced compression, the myelin sheath shows high circumferential stiffness, indicating a possible role in mechanical protection of axons. The myelin sheath is deformed from low loads, despite the non-linearity of whole tissue compression, indicating more than one mechanism contributing to myelin compression. Epineurial collagen shows similar load-bearing characteristics to those of other collagenous connective tissues. This new microstructural knowledge is key to understand peripheral nerve mechanical behaviour, and will support new regenerative strategies for traumatic and repetitive injury.

A biomechanical model for fibril recruitment: Evaluation in tendons and arteries.

Simulations of soft tissue mechanobiological behaviour are increasingly important for clinical prediction of aneurysm, tendinopathy and other disorders. Mechanical behaviour at low stretches is governed by fibril straightening, transitioning into load-bearing at recruitment stretch, resulting in a tissue stiffening effect. Previous investigations have suggested theoretical relationships between stress-stretch measurements and recruitment probability density function (PDF) but not derived these rigorously nor evaluated these experimentally. Other work has proposed image-based methods for measurement of recruitment but made use of arbitrary fibril critical straightness parameters. The aim of this work was to provide a sound theoretical basis for estimating recruitment PDF from stress-stretch measurements and to evaluate this relationship using image-based methods, clearly motivating the choice of fibril critical straightness parameter in rat tail tendon and porcine artery. Rigorous derivation showed that the recruitment PDF may be estimated from the second stretch derivative of the first Piola-Kirchoff tissue stress. Image-based fibril recruitment identified the fibril straightness parameter that maximised Pearson correlation coefficients (PCC) with estimated PDFs. Using these critical straightness parameters the new method for estimating recruitment PDF showed a PCC with image-based measures of 0.915 and 0.933 for tendons and arteries respectively. This method may be used for accurate estimation of fibril recruitment PDF in mechanobiological simulation where fibril-level mechanical parameters are important for predicting cell behaviour.

Three-dimensional printed upper-limb prostheses lack randomised controlled trials: A systematic review.

BACKGROUND: Three-dimensional printing provides an exciting opportunity to customise upper-limb prostheses. OBJECTIVE: This review summarises the research that assesses the efficacy and effectiveness of three-dimensional printed upper-limb prostheses. STUDY DESIGN: Systematic review. METHODS: PubMed, Web of Science and OVID were systematically searched for studies that reported human trials of three-dimensional printed upper-limb prostheses. The studies matching the language, peer-review and relevance criteria were ranked by level of evidence and critically appraised using the Downs and Black Quality Index. RESULTS: After removing duplicates, 321 records were identified. Eight papers met the inclusion criteria. No studies used controls; five were case studies and three were small case-series studies. All studies showed promising results, but none demonstrated external validity, avoidance of bias or statistically significant improvements over conventional prostheses. The studies demonstrated proof-of-concept rather than assessing efficacy, and the devices were designed to prioritise reduction of manufacturing costs, not customisability for comfort and function. CONCLUSION: The potential of three-dimensional printing for individual customisation has yet to be fully realised, and the efficacy and effectiveness to be rigorously assessed. Until randomised controlled trials with follow-up are performed, the comfort, functionality, durability and long-term effects on quality of life remain unknown. Clinical relevance Initial studies suggest that three-dimensional printing shows promise for customising low-cost upper-limb prosthetics. However, the efficacy and effectiveness of these devices have yet to be rigorously assessed. Until randomised controlled trials with follow-up are performed, the comfort, functionality, durability and long-term effects on patient quality of life remain unknown.

Clinical efficacy and effectiveness of 3D printing: a systematic review.

OBJECTIVE: To evaluate the clinical efficacy and effectiveness of using 3D printing to develop medical devices across all medical fields. DESIGN: Systematic review compliant with Preferred Reporting Items for Systematic Reviews and Meta-Analyses. DATA SOURCES: PubMed, Web of Science, OVID, IEEE Xplore and Google Scholar. METHODS: A double-blinded review method was used to select all abstracts up to January 2017 that reported on clinical trials of a three-dimensional (3D)-printed medical device. The studies were ranked according to their level of evidence, divided into medical fields based on the International Classification of Diseases chapter divisions and categorised into whether they were used for preoperative planning, aiding surgery or therapy. The Downs and Black Quality Index critical appraisal tool was used to assess the quality of reporting, external validity, risk of bias, risk of confounding and power of each study. RESULTS: Of the 3084 abstracts screened, 350 studies met the inclusion criteria. Oral and maxillofacial surgery contained 58.3% of studies, and 23.7% covered the musculoskeletal system. Only 21 studies were randomised controlled trials (RCTs), and all fitted within these two fields. The majority of RCTs were 3D-printed anatomical models for preoperative planning and guides for aiding surgery. The main benefits of these devices were decreased surgical operation times and increased surgical accuracy. CONCLUSIONS: All medical fields that assessed 3D-printed devices concluded that they were clinically effective. The fields that most rigorously assessed 3D-printed devices were oral and maxillofacial surgery and the musculoskeletal system, both of which concluded that the 3D-printed devices outperformed their conventional comparators. However, the efficacy and effectiveness of 3D-printed devices remain undetermined for the majority of medical fields. 3D-printed devices can play an important role in healthcare, but more rigorous and long-term assessments are needed to determine if 3D-printed devices are clinically relevant before they become part of standard clinical practice.

Quantitative multiphoton microscopy of murine urinary bladder morphology during in situ uniaxial loading.

Urodynamic tests are the gold standard for the diagnosis of bladder dysfunction, and the mechanical compliance of the bladder is an important parameter in these tests. The bladder wall has a layered structure, differentially affected by pathology, so knowledge of the contribution and role of these layers and their constituents to overall bladder compliance will enhance interpretation of these clinical tests. In this study we document the functional morphology of the detrusor and lamina propria of the murine bladder wall using a custom in-situ tensile loading system under multiphoton microscopy (MPM) observation in unloaded state and under incremental uniaxial stretch. Features in the stress-stretch curves of bladder samples were then directly related to corresponding MPM images. Collagen organisation across wall depth was quantified using image analysis techniques. The hypothesis that the lamina propria deformed at low strain by unfolding of the rugae and rearranging collagen fibrils was confirmed. A novel 'pocket' feature in the detrusor was observed along with extensive rearrangement of fibrils in two families at different depths, providing higher stiffness at high stretches in the detrusor. The very different deformations of detrusor and lamina propria were accommodated by the highly coiled structure of collagen in the lamina propria. Imaging and mechanical studies presented here allow gross mechanical response to be attributed to specific components of the bladder wall and further, may be used to investigate the impact of microstructural changes due to pathology or aging, and how they impair tissue functionality. STATEMENT OF SIGNIFICANCE: This article reports the first in-situ multiphoton microscopy observations of microstructural deformation under uniaxial tensile loading of ex vivo bladder. We describe collagen rearrangement through the tissue thickness and relate this directly to the stress-stretch behaviour. We confirm for the first time the unfolding of rugae and realignment of fibrils in the lamina propria during extension and the rapid stiffening as two fibril families in the detrusor are engaged. This technique provides new insight into microstructure function and will enhance understanding of the impact of changes due to pathology or aging.

Mechanobiological modelling of tendons: Review and future opportunities.

Tendons are adapted to carry large, repeated loads and are clinically important for the maintenance of musculoskeletal health in an increasing, actively ageing population, as well as in elite athletes. Tendons are known to adapt to mechanical loading. Also, their healing and disease processes are highly sensitive to mechanical load. Computational modelling approaches developed to capture this mechanobiological adaptation in tendons and other tissues have successfully addressed many important scientific and clinical issues. The aim of this review is to identify techniques and approaches that could be further developed to address tendon-related problems. Biomechanical models are identified that capture the multi-level aspects of tendon mechanics. Continuum whole tendon models, both phenomenological and microstructurally motivated, are important to estimate forces during locomotion activities. Fibril-level microstructural models are documented that can use these estimated forces to detail local mechanical parameters relevant to cell mechanotransduction. Cell-level models able to predict the response to such parameters are also described. A selection of updatable mechanobiological models is presented. These use mechanical signals, often continuum tissue level, along with rules for tissue change and have been applied successfully in many tissues to predict in vivo and in vitro outcomes. Signals may include scalars derived from the stress or strain tensors, or in poroelasticity also fluid velocity, while adaptation may be represented by changes to elastic modulus, permeability, fibril density or orientation. So far, only simple analytical approaches have been applied to tendon mechanobiology. With the development of sophisticated computational mechanobiological models in parallel with reporting more quantitative data from in vivo or clinical mechanobiological studies, for example, appropriate imaging, biochemical and histological data, this field offers huge potential for future development towards clinical applications.

Probing multi-scale mechanical damage in connective tissues using X-ray diffraction.

The accumulation of microstructural collagen damage following repetitive loading is linked to painful and debilitating tendon injuries. As a hierarchical, semi-crystalline material, collagen mechanics can be studied using X-ray diffraction. The aim of the study was to describe multi-structural changes in tendon collagen following controlled plastic damage (5% permanent strain). We used small angle X-ray scattering (SAXS) to interrogate the spacing of collagen molecules within a fibril, and wide angle X-ray scattering (WAXS) to measure molecular strains under macroscopic loading. Simultaneous recordings of SAXS and WAXS patterns, together with whole-tissue strain in physiologically hydrated rat-tail tendons were made during increments of in situ tensile loading. Results showed that while tissue level modulus was unchanged, fibril modulus decreased significantly, and molecular modulus significantly increased. Further, analysis of higher order SAXS peaks suggested structural changes in the gap and overlap regions, possibly localising the damage to molecular cross-links. Our results provide new insight into the fundamental damage processes at work in collagenous tissues and point to new directions for their mitigation and repair. STATEMENT OF SIGNIFICANCE: This article reports the first in situ loading synchrotron studies on mechanical damage in collagenous tissues. We provide new insight into the nano- and micro-structural mechanisms of damage processes. Pre-damaged tendons showed differential alteration of moduli at macro, micro and nano-scales as measured using X-ray scattering techniques. Detailed analysis of higher order diffraction peaks suggested damage is localised to molecular cross-links. The results are consistent with previous X-ray scattering studies of tendons and also with recent thermal stability studies on damaged material. Detailed understanding of damage mechanisms is essential in the development of new therapies promoting tissue repair.

A novel chemo-mechano-biological model of arterial tissue growth and remodelling.

Arterial growth and remodelling (G&R) is mediated by vascular cells in response to their chemical and mechanical environment. To date, mechanical and biochemical stimuli tend to be modelled separately, however this ignores their complex interplay. Here, we present a novel mathematical model of arterial chemo-mechano-biology. We illustrate its application to the development of an inflammatory aneurysm in the descending human aorta. The arterial wall is modelled as a bilayer cylindrical non-linear elastic membrane, which is internally pressurised and axially stretched. The medial degradation that accompanies aneurysm development is driven by an inflammatory response. Collagen remodelling is simulated by adaption of the natural reference configuration of constituents; growth is simulated by changes in normalised mass-densities. We account for the distribution of attachment stretches that collagen fibres are configured to the matrix and, innovatively, allow this distribution to remodel. This enables the changing functional role of the adventitia to be simulated. Fibroblast-mediated collagen growth is represented using a biochemical pathway model: a system of coupled non-linear ODEs governs the evolution of fibroblast properties and levels of key biomolecules under the regulation of Transforming Growth Factor (TGF)-ß, a key promoter of matrix deposition. Given physiologically realistic targets, different modes of aneurysm development can be captured, while the predicted evolution of biochemical variables is qualitatively consistent with trends observed experimentally. Interestingly, we observe that increasing the levels of collagen-promoting TGF-ß results in arrest of aneurysm growth, which seems to be consistent with experimental evidence. We conclude that this novel Chemo-Mechano-Biological (CMB) mathematical model has the potential to provide new mechanobiological insight into vascular disease progression and therapy.

A hyperelastic fibre-reinforced continuum model of healing tendons with distributed collagen fibre orientations.

The healing process of ruptured tendons is problematic due to scar tissue formation and deteriorated material properties, and in some cases, it may take nearly a year to complete. Mechanical loading has been shown to positively influence tendon healing; however, the mechanisms remain unclear. Computational mechanobiology methods employed extensively to model bone healing have achieved high fidelity. This study aimed to investigate whether an established hyperelastic fibre-reinforced continuum model introduced by Gasser, Ogden and Holzapfel (GOH) can be used to capture the mechanical behaviour of the Achilles tendon under loading during discrete timepoints of the healing process and to assess the model's sensitivity to its microstructural parameters. Curve fitting of the GOH model against experimental tensile testing data of rat Achilles tendons at four timepoints during the tendon repair was used and achieved excellent fits ([Formula: see text]). A parametric sensitivity study using a three-level central composite design, which is a fractional factorial design method, showed that the collagen-fibre-related parameters in the GOH model-[Formula: see text] and [Formula: see text]-had almost equal influence on the fitting. This study demonstrates that the GOH hyperelastic fibre-reinforced model is capable of describing the mechanical behaviour of healing tendons and that further experiments should focus on establishing the structural and material parameters of collagen fibres in the healing tissue.

Tribological changes in the articular cartilage of a human femoral head with avascular necrosis.

The present study evaluated the tribological properties of the articular cartilage surface of the human femoral head with postcollapse stage avascular necrosis (AVN) using atomic force microscopy. The cartilage surface in the postcollapse stage AVN of the femoral head was reported to resemble those of disuse conditions, which suggests that the damage could be reversible and offers the possibilities of success of head-sparing surgeries. By comparing the tribological properties of articular cartilage in AVN with that of osteoarthritis, the authors intended to understand the cartilage degeneration mechanism and reversibility of AVN. Human femoral heads with AVN were explanted from the hip replacement surgery of four patients (60-83 years old). Nine cylindrical cartilage samples (diameter, 5 mm and height, 0.5 mm) were sectioned from the weight-bearing areas of the femoral head with AVN, and the cartilage surface was classified according to the Outerbridge Classification System (AVN0, normal; AVN1, softening and swelling; and AVN2, partial thickness defect and fissuring). Tribological properties including surface roughness and frictional coefficients and histochemistry including Safranin O and lubricin staining were compared among the three groups. The mean surface roughness Rq values of AVN cartilage increased significantly with increasing Outerbridge stages: Rq = 137 ± 26 nm in AVN0, Rq = 274 ± 49 nm in AVN1, and Rq = 452 ± 77 nm in AVN2. Significant differences in Rq were observed among different Outerbridge stages in all cases (p < 0.0001). The frictional coefficients (µ) also increased with increasing Outerbridge stages. The frictional coefficient values were µ = 0.115 ± 0.034 in AVN0, µ = 0.143 ± 0.025 in AVN1, and µ = 0.171 ± 0.039 in AVN2. Similarly to the statistical analysis of surface roughness, significant statistical differences were detected between different Outerbridge stages in all cases (p < 0.05). Both surface roughness and frictional coefficient of cartilage, which were linearly correlated, increased with increasing Outerbridge stages in postcollapse AVN. The underlying mechanism of these results can be related to proteoglycan loss within the articular cartilage that is also observed in osteoarthritis. With regard to the tribological properties, the cartilage degeneration mechanism in AVN was similar to that of osteoarthritis without reversibility.

The Mechanical, Structural, and Compositional Changes of Tendon Exposed to Elastase.

The mechanical response of tendon is dependent on the interaction of structural molecules that constitute the extracellular matrix. However, little is known about the role of elastic fibers that are present in this structure. Elastase treatments have been used to elucidate the mechanical role of elastic fibers in numerous tissues. Here, we show that a standard elastase treatment affects the mechanical properties of tendon, including the ultimate tensile strength and failure strain. Moreover, elastase-treated specimens exhibit significant structural and compositional changes including crimp undulation and release of glycosaminoglycans. These data demonstrate that a common elastase treatment has a complex digestion profile that influences the structure-function relationship of tendon. Thus, defining the mechanical role of elastic fibers in tendon using this technique is challenging. This introduces new and exciting questions regarding the function of elastic fibers in tendon, which may not be as well understood as previously thought.