Publications by authors named "Damien Lacroix"

55 Publications

A systematic approach to the scale separation problem in the development of multiscale models.

PLoS One 2021 18;16(5):e0251297. Epub 2021 May 18.

Dipartimento di Ingegneria Industriale, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

Throughout engineering there are problems where it is required to predict a quantity based on the measurement of another, but where the two quantities possess characteristic variations over vastly different ranges of time and space. Among the many challenges posed by such 'multiscale' problems, that of defining a 'scale' remains poorly addressed. This fundamental problem has led to much confusion in the field of biomedical engineering in particular. The present study proposes a definition of scale based on measurement limitations of existing instruments, available computational power, and on the ranges of time and space over which quantities of interest vary characteristically. The definition is used to construct a multiscale modelling methodology from start to finish, beginning with a description of the system (portion of reality of interest) and ending with an algorithmic orchestration of mathematical models at different scales within the system. The methodology is illustrated for a specific but well-researched problem. The concept of scale and the multiscale modelling approach introduced are shown to be easily adaptable to other closely related problems. Although out of the scope of this paper, we believe that the proposed methodology can be applied widely throughout engineering.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251297PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130972PMC
May 2021

Bioactive Bromotyrosine Derivatives from the Pacific Marine Sponge (Pulitzer-Finali, 1982).

Mar Drugs 2021 Mar 6;19(3). Epub 2021 Mar 6.

CNRS, Institut de Chimie des Substances Naturelles, Université Paris-Saclay, F-91190 Gif-sur-Yvette, France.

Chemical investigation of the South-Pacific marine sponge led to the isolation of eight new bromotyrosine metabolites named subereins 1-8 (-) along with twelve known co-isolated congeners. The detailed configuration determination of the first representative major compound of this family 11--fistularin-3 (11,17) () is described. Their chemical characterization was achieved by HRMS and integrated 1D and 2D NMR (nuclear magnetic resonance) spectroscopic studies and extensive comparison with literature data. For the first time, a complete assignment of the absolute configurations for stereogenic centers C-11/17 of the known members (11,17) 11--fistularin-3 () and 17-deoxyfistularin-3 () was determined by a combination of chemical modifications, Mosher's technology, and ECD spectroscopy. Consequently, the absolute configurations of all our new isolated compounds - were determined by the combination of NMR, Mosher's method, ECD comparison, and chemical modifications. Interestingly, compounds - were obtained by chemical transformation of the major compound 11--fistularin-3 ( Evaluation for acetylcholinesterase inhibition (AChE), DNA methyltransferase 1 (DNMT1) modulating activity and antifouling activities using marine bacterial strains are also presented.
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http://dx.doi.org/10.3390/md19030143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999702PMC
March 2021

Development of a Computer-Aided Design and Finite Element Analysis Combined Method for Affordable Spine Surgical Navigation With 3D-Printed Customized Template.

Front Surg 2020 25;7:583386. Epub 2021 Jan 25.

National Center for Spinal Disorders, Buda Health Center, Budapest, Hungary.

Revision surgery of a previous lumbosacral non-union is highly challenging, especially in case of complications, such as a broken screw at the first sacral level (S1). Here, we propose the implementation of a new method based on the CT scan of a clinical case using 3D reconstruction, combined with finite element analysis (FEA), computer-assisted design (CAD), and 3D-printing technology to provide accurate surgical navigation to aid the surgeon in performing the optimal surgical technique by inserting a pedicle screw at the S1 level. A step-by-step approach was developed and performed as follows: (1) Quantitative CT based patient-specific FE model of the sacrum was created. (2) The CAD model of the pedicle screw was inserted into the sacrum model in a bicortical convergent and a monocortical divergent position, by overcoming the geometrical difficulty caused by the broken screw. (3) Static FEAs (Abaqus, Dassault Systemes) were performed using 500 N tensile load applied to the screw head. (4) A template with two screw guiding structures for the sacrum was designed and manufactured using CAD design and 3D-printing technologies, and investment casting. (5) The proposed surgical technique was performed on the patient-specific physical model created with the FDM printing technology. The patient-specific model was CT scanned and a comparison with the virtual plan was performed to evaluate the template accuracy FEA results proved that the modified bicortical convergent insertion is stiffer (6,617.23 N/mm) compared to monocortical divergent placement (2,989.07 N/mm). The final template was created via investment casting from cobalt-chrome. The template design concept was shown to be accurate (grade A, Gertzbein-Robbins scale) based on the comparison of the simulated surgery using the patient-specific physical model and the 3D virtual surgical plan. Compared to the conventional surgical navigation techniques, the presented method allows the consideration of the patient-specific biomechanical parameters; is more affordable, and the intraoperative X-ray exposure can be reduced. This new patient- and condition-specific approach may be widely used in revision spine surgeries or in challenging primary cases after its further clinical validation.
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http://dx.doi.org/10.3389/fsurg.2020.583386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873739PMC
January 2021

Analysis of mechanotransduction dynamics during combined mechanical stimulation and modulation of the extracellular-regulated kinase cascade uncovers hidden information within the signalling noise.

Interface Focus 2021 Feb 11;11(1):20190136. Epub 2020 Dec 11.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Osteoporosis is a bone disease characterized by brittle bone and increased fracture incidence. With ageing societies worldwide, the disease presents a high burden on health systems. Furthermore, there are limited treatments for osteoporosis with just two anabolic pharmacological agents approved by the US Food and Drug Administration. Healthy bones are believed to be maintained via an intricate relationship between dual biochemical and mechanical (bio-mechanical) stimulations. It is widely considered that osteoporosis emerges as a result of disturbances to said relationship. The mechanotransduction process is key to this balance, and disruption of its dynamics in bone cells plays a role in osteoporosis development. Nonetheless, the exact details and mechanisms that drive and secure the health of bones are still elusive at the cellular and molecular scales. This study examined the dual modulation of mechanical stimulation and mechanotransduction activation dynamics in an osteoblast (OB). The aim was to find patterns of mechanotransduction dynamics demonstrating a significant change that can be mapped to alterations in the OB responses, specifically at the level of gene expression and osteogenic markers such as alkaline phosphatase. This was achieved using a three-dimensional hybrid multiscale computational model simulating mechanotransduction in the OB and its interaction with the extracellular matrix, combined with a numerical analytical technique. The model and the analysis method predict that within the noise of mechanotransduction, owing to modulation of the bio-mechanical stimulus and consequent gene expression, there are unique events that provide signatures for a shift in the system's dynamics. Furthermore, the study uncovered molecular interactions that can be potential drug targets.
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http://dx.doi.org/10.1098/rsfs.2019.0136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739911PMC
February 2021

[The care process of patient receiving CAR T-cell therapy: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2020 Dec 2;107(12S):S170-S177. Epub 2020 Sep 2.

CHU de Montpellier, service hématologie, 80, avenue Augustin-Fliche, 34295 Montpellier, France.

In Europe, two CAR T-cell products, tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™), were approved in 2018. While these treatments are available for use, allogeneic hematopoietic stem cell transplantation centers still need to set up a dedicated care process inspired by established procedures in the field. In order to determine necessary resources and actors, each step of the CAR T-cell care process must be planned in advance. This process, implemented by the center's coordinating nurse, should be able to be adapted to each center's needs. The purpose of this workshop is to provide the organizational basis for such a process so that each center wishing to set up CAR-T cell activity can do so effectively. After detailing the coordinating nurse's role, we explain each step of the care process and specify essential additional tests.
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http://dx.doi.org/10.1016/j.bulcan.2020.05.014DOI Listing
December 2020

Finite element modelling of hybrid stabilization systems for the human lumbar spine.

Proc Inst Mech Eng H 2020 Dec 18;234(12):1409-1420. Epub 2020 Aug 18.

Mechanical Engineering Department, Faculty of Engineering and Natural Sciences, Ankara Yildirim Beyazit University, Ankara, Turkey.

Intersomatic fusion is a very popular treatment for spinal diseases associated with intervertebral disc degeneration. The effects of three different hybrid stabilization systems on both range of motion and intradiscal pressure were investigated, as there is no consensus in the literature about the efficiency of these systems. Finite element simulations were designed to predict the variations of range of motion and intradiscal pressure from intact to implanted situations. After hybrid stabilization system implantation, L4-L5 level did not lose its motion completely, while L5-S1 had no mobility as a consequence of disc removal and fusion process. BalanC hybrid stabilization system represented higher mobility at the index level, reduced intradiscal pressure of adjacent level, but caused to increment in range of motion by 20% under axial rotation. Higher tendency by 93% to the failure was also detected under axial rotation. Dynesys hybrid stabilization system represented more restricted motion than BalanC, and negligible effects to the adjacent level. B-DYN hybrid stabilization system was the most rigid one among all three systems. It reduced intradiscal pressure and range of motion at the adjacent level except from motion under axial rotation being increased by 13%. Fracture risk of B-DYN and Dynesys Transition Optima components was low when compared with BalanC. Mobility of the adjacent level around axial direction should be taken into account in case of implantation with BalanC and B-DYN systems, as well as on the development of new designs. Having these findings in mind, it is clear that hybrid systems need to be further tested, both clinically and numerically, before being considered for common use.
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http://dx.doi.org/10.1177/0954411920946636DOI Listing
December 2020

Changes in scaffold porosity during bone tissue engineering in perfusion bioreactors considerably affect cellular mechanical stimulation for mineralization.

Bone Rep 2020 Jun 8;12:100265. Epub 2020 Apr 8.

Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB, Eindhoven, the Netherlands.

Bone tissue engineering (BTE) experiments have shown that fluid-induced wall shear stress (WSS) can stimulate cells to produce mineralized extracellular matrix (ECM). The application of WSS on seeded cells can be achieved through bioreactors that perfuse medium through porous scaffolds. In BTE experiments , commonly a constant flow rate is used. Previous studies have found that tissue growth within the scaffold will result in an increase of the WSS over time. To keep the WSS in a reported optimal range of 10-30 mPa, the applied external flow rate can be decreased over time. To investigate what reduction of the external flow rate during culturing is needed to keep the WSS in the optimal range, we here conducted a computational study, which simulated the formation of ECM, and in which we investigated the effect of constant fluid flow and different fluid flow reduction scenarios on the WSS. It was found that for both constant and reduced fluid flow scenarios, the WSS did not exceed a critical value, which was set to 60 mPa. However, the constant flow velocity resulted in a reduction of the cell/ECM surface being exposed to a WSS in the optimal range from 50% at the start of culture to 18.6% at day 21. Reducing the fluid flow over time could avoid much of this effect, leaving the WSS in the optimal range for 40.9% of the surface at 21 days. Therefore, for achieving more mineralized tissue, the conventional manner of loading the perfusion bioreactors ( constant flow rate/velocity) should be changed to a decreasing flow over time in BTE experiments. This study provides an tool for finding the best fluid flow reduction strategy.
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http://dx.doi.org/10.1016/j.bonr.2020.100265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315008PMC
June 2020

Revealing hidden information in osteoblast's mechanotransduction through analysis of time patterns of critical events.

BMC Bioinformatics 2020 Mar 18;21(1):114. Epub 2020 Mar 18.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Background: Mechanotransduction in bone cells plays a pivotal role in osteoblast differentiation and bone remodelling. Mechanotransduction provides the link between modulation of the extracellular matrix by mechanical load and intracellular activity. By controlling the balance between the intracellular and extracellular domains, mechanotransduction determines the optimum functionality of skeletal dynamics. Failure of this relationship was suggested to contribute to bone-related diseases such as osteoporosis.

Results: A hybrid mechanical and agent-based model (Mech-ABM), simulating mechanotransduction in a single osteoblast under external mechanical perturbations, was utilised to simulate and examine modulation of the activation dynamics of molecules within mechanotransduction on the cellular response to mechanical stimulation. The number of molecules and their fluctuations have been analysed in terms of recurrences of critical events. A numerical approach has been developed to invert subordination processes and to extract the direction processes from the molecular signals in order to derive the distribution of recurring events. These predict that there are large fluctuations enclosing information hidden in the noise which is beyond the dynamic variations of molecular baselines. Moreover, studying the system under different mechanical load regimes and altered dynamics of feedback loops, illustrate that the waiting time distributions of each molecule are a signature of the system's state.

Conclusions: The behaviours of the molecular waiting times change with the changing of mechanical load regimes and altered dynamics of feedback loops, presenting the same variation of patterns for similar interacting molecules and identifying specific alterations for key molecules in mechanotransduction. This methodology could be used to provide a new tool to identify potent molecular candidates to modulate mechanotransduction, hence accelerate drug discovery towards therapeutic targets for bone mass upregulation.
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http://dx.doi.org/10.1186/s12859-020-3394-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079370PMC
March 2020

An extended discrete element method for the estimation of contact pressure at the ankle joint during stance phase.

Proc Inst Mech Eng H 2020 May 8;234(5):507-516. Epub 2020 Feb 8.

INSIGNEO Institute for in silico Medicine, The University of Sheffield, Sheffield, UK.

Abnormalities in the ankle contact pressure are related to the onset of osteoarthritis. In vivo measurements are not possible with currently available techniques, so computational methods such as the finite element analysis (FEA) are often used instead. The discrete element method (DEM), a computationally efficient alternative to time-consuming FEA, has also been used to predict the joint contact pressure. It describes the articular cartilage as a bed of independent springs, assuming a linearly elastic behaviour and absence of relative motion between the bones. In this study, we present the extended DEM (EDEM) which is able to track the motion of talus over time. The method was used, with input data from a subject-specific musculoskeletal model, to predict the contact pressure in the ankle joint during gait. Results from EDEM were also compared with outputs from conventional DEM. Predicted values of contact area were larger in EDEM than they were in DEM (4.67 and 4.18 cm, respectively). Peak values of contact pressure, attained at the toe-off, were 7.3 MPa for EDEM and 6.92 MPa for DEM. Values predicted from EDEM fell well within the ranges reported in the literature. Overall, the motion of the talus had more effect on the extension and shape of the pressure distribution than it had on the magnitude of the pressure. The results indicated that EDEM is a valid methodology for the prediction of ankle contact pressure during daily activities.
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http://dx.doi.org/10.1177/0954411920905434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469707PMC
May 2020

A novel algorithm to predict bone changes in the mouse tibia properties under physiological conditions.

Biomech Model Mechanobiol 2020 Jun 30;19(3):985-1001. Epub 2019 Nov 30.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Understanding how bone adapts to mechanical stimuli is fundamental for optimising treatments against musculoskeletal diseases in preclinical studies, but the contribution of physiological loading to bone adaptation in mouse tibia has not been quantified so far. In this study, a novel mechanistic model to predict bone adaptation based on physiological loading was developed and its outputs were compared with longitudinal scans of the mouse tibia. Bone remodelling was driven by the mechanical stimuli estimated from micro-FEA models constructed from micro-CT scans of C57BL/6 female mice (N = 5) from weeks 14 and 20 of age, to predict bone changes in week 16 or 22. Parametric analysis was conducted to evaluate the sensitivity of the models to subject-specific or averaged parameters, parameters from week 14 or week 20, and to strain energy density (SED) or maximum principal strain (ε). The results at week 20 showed no significant difference in bone densitometric properties between experimental and predicted images across the tibia for both stimuli, and 59% and 47% of the predicted voxels matched with the experimental sites in apposition and resorption, respectively. The model was able to reproduce regions of bone apposition in both periosteal and endosteal surfaces (70% and 40% for SED and ε, respectively), but it under-predicted the experimental sites of resorption by over 85%. This study shows for the first time the potential of a subject-specific mechanoregulation algorithm to predict bone changes in a mouse model under physiological loading. Nevertheless, the weak predictions of resorption suggest that a combined stimulus or biological stimuli should be accounted for in the model.
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http://dx.doi.org/10.1007/s10237-019-01266-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203598PMC
June 2020

Heterogeneity in The Mechanical Properties of Integrins Determines Mechanotransduction Dynamics in Bone Osteoblasts.

Sci Rep 2019 09 11;9(1):13113. Epub 2019 Sep 11.

Insigneo Institute for in silico Medicine, University of Sheffield, Sheffield, UK.

Bone cells are exposed to dynamic mechanical stimulation that is transduced into cellular responses by mechanotransduction mechanisms. The extracellular matrix (ECM) provides a physical link between loading and bone cells, where mechanoreceptors, such as integrins, initiate mechanosensation. Though this relationship is well studied, the dynamic interplay between mechanosensation, mechanotransduction and cellular responses is unclear. A hybrid-multiscale model combining molecular, cellular and tissue interactions was developed to examine links between integrins' mechanosensation and effects on mechanotransduction, ECM modulation and cell-ECM interaction. The model shows that altering integrin mechanosensitivity threshold (MT) increases mechanotransduction durations from hours to beyond 4 days, where bone formation starts. This is relevant to bone, where it is known that a brief stimulating period provides persistent influences for over 24 hours. Furthermore, the model forecasts that integrin heterogeneity, with respect to MT, would be able to induce sustained increase in pERK baseline > 15% beyond 4 days. This is analogous to the emergence of molecular mechanical memory signalling dynamics. Therefore, the model can provide a greater understanding of mechanical adaptation to differential mechanical responses at different times. Given reduction of bone sensitivity to mechanical stimulation with age, these findings may lead towards useful therapeutic targets for upregulation of bone mass.
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http://dx.doi.org/10.1038/s41598-019-47958-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739315PMC
September 2019

Effect of cell sample size in atomic force microscopy nanoindentation.

J Mech Behav Biomed Mater 2019 06 18;94:259-266. Epub 2019 Mar 18.

Insigneo Institute for in silico Medicine, University of Sheffield, Mappin Street, Sheffield S1 3JD, UK; Department of Mechanical Engineering, University of Sheffield, Western Bank, Sheffield S10 2TN, UK. Electronic address:

Single-cell technologies are powerful tools to evaluate cell characteristics. In particular, Atomic Force Microscopy (AFM) nanoindentation experiments have been widely used to study single cell mechanical properties. One important aspect related to single cell techniques is the need for sufficient statistical power to obtain reliable results. This aspect is often overlooked in AFM experiments were sample sizes are arbitrarily set. The aim of the present work was to propose a tool for sample size estimation in the context of AFM nanoindentation experiments of single cell. To this aim, a retrospective approach was used by acquiring a large dataset of experimental measurements on four bone cell types and by building saturation curves for increasing sample sizes with a bootstrap resampling method. It was observed that the coefficient of variation (CV) decayed with a function of the form y = ax with similar parameters for all samples tested and that sample sizes of 21 and 83 cells were needed for the specific cells and protocol employed if setting a maximum threshold on CV of 10% or 5%, respectively. The developed tool is made available as an open-source repository and guidelines are provided for its use for AFM nanoindentation experimental design.
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http://dx.doi.org/10.1016/j.jmbbm.2019.03.018DOI Listing
June 2019

Poroelastic Modeling of Highly Hydrated Collagen Hydrogels: Experimental Results vs. Numerical Simulation With Custom and Commercial Finite Element Solvers.

Front Bioeng Biotechnol 2018 23;6:142. Epub 2018 Oct 23.

Department of Mechanical Engineering, Insigneo Institute for in silico Medicine, University of Sheffield, Sheffield, United Kingdom.

This study presents a comparison between the performances of two Finite Element (FE) solvers for the modeling of the poroelastic behavior of highly hydrated collagen hydrogels. Characterization of collagen hydrogels has been a widespread challenge since this is one of the most used natural biomaterials for Tissue Engineering (TE) applications. V-Biomech® is a free custom FE solver oriented to soft tissue modeling, while Abaqus® is a general-purpose commercial FE package which is widely used for biomechanics computational modeling. Poroelastic simulations with both solvers were compared to two experimental protocols performed by Busby et al. (2013) and Chandran and Barocas (2004), also using different implementations of the frequently used Neo-Hookean hyperelastic model. The average differences between solvers outputs were under 5% throughout the different tests and hydrogel properties. Thus, differences were small enough to be considered negligible and within the variability found experimentally from one sample to another. This work demonstrates that constitutive modeling of soft tissues, such as collagen hydrogels can be achieved with either V-Biomech or Abaqus standard options (without user-subroutine), which is important for the biomechanics and biomaterials research community. V-Biomech has shown its potential for the validation of biomechanical characterization of soft tissues, while Abaqus' versatility is useful for the modeling and analysis of TE applications where other complex phenomena may also need to be captured.
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http://dx.doi.org/10.3389/fbioe.2018.00142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205953PMC
October 2018

Hyaluronic acid selective anchoring to the cytoskeleton: An atomic force microscopy study.

PLoS One 2018 25;13(10):e0206056. Epub 2018 Oct 25.

Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

The hyaluronic acid component of the glycocalyx plays a role in cell mechanotransduction by selectively transmitting mechanical signals to the cell cytoskeleton or to the cell membrane. The aim of this study was to evaluate the mechanical link between the hyaluronic acid molecule and the cell cytoskeleton by means of atomic force microscopy single molecule force spectroscopy. Hyaluronic acid molecules on live cells were targeted with probes coated with hyaluronic acid binding protein. Two different types of events were observed when the detachment of the target molecule from the probe occurred, suggesting the presence of cytoskeleton- and membrane-anchored molecules. Membrane-anchored molecules facilitated the formation of tethers when pulled. About 15% of the tested hyaluronic acid molecules were shown to be anchored to the cytoskeleton. When multiple molecules bonded to the probe, specific detachment patterns were observed, suggesting that a cytoskeletal bond needed to be broken to improve the ability to pull tethers from the cell membrane. This likely resulted in the formation of tethering structures maintaining a cytoskeletal core similar to the ones observed for cells over-expressing HA synthases. The different observed rupture events were associated with separate mechanotransductive mechanisms in an analogous manner to that previously proposed for the endothelial glycocalyx. Single cytoskeleton anchored rupture events represent HA molecules linked to the cytoskeleton and therefore transmitting mechanical stimuli into the inner cell compartments. Single membrane tethers would conversely represent the glycocalyx molecules connected to areas of the membrane where an abundance of signalling molecules reside.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206056PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201909PMC
April 2019

Comparison of patient-specific computational models vs. clinical follow-up, for adjacent segment disc degeneration and bone remodelling after spinal fusion.

PLoS One 2018 30;13(8):e0200899. Epub 2018 Aug 30.

Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.

Spinal fusion is a standard surgical treatment for patients suffering from low back pain attributed to disc degeneration. However, results are somewhat variable and unpredictable. With fusion the kinematic behaviour of the spine is altered. Fusion and/or stabilizing implants carrying considerable load and prevent rotation of the fused segments. Associated with these changes, a risk for accelerated disc degeneration at the adjacent levels to fusion has been demonstrated. However, there is yet no method to predict the effect of fusion surgery on the adjacent tissue levels, i.e. bone and disc. The aim of this study was to develop a coupled and patient-specific mechanoregulated model to predict disc generation and changes in bone density after spinal fusion and to validate the results relative to patient follow-up data. To do so, a multiscale disc mechanoregulation adaptation framework was developed and coupled with a previously developed bone remodelling algorithm. This made it possible to determine extra cellular matrix changes in the intervertebral disc and bone density changes simultaneously based on changes in loading due to fusion surgery. It was shown that for 10 cases the predicted change in bone density and degeneration grade conforms reasonable well to clinical follow-up data. This approach helps us to understand the effect of surgical intervention on the adjacent tissue remodelling. Thereby, providing the first insight for a spine surgeon as to which patient could potentially be treated successfully by spinal fusion and in which patient has a high risk for adjacent tissue changes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200899PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116979PMC
January 2019

Early life vitamin D depletion alters the postnatal response to skeletal loading in growing and mature bone.

PLoS One 2018 25;13(1):e0190675. Epub 2018 Jan 25.

Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield; Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.

There is increasing evidence of persistent effects of early life vitamin D exposure on later skeletal health; linking low levels in early life to smaller bone size in childhood as well as increased fracture risk later in adulthood, independently of later vitamin D status. A major determinant of bone mass acquisition across all ages is mechanical loading. We tested the hypothesis in an animal model system that early life vitamin D depletion results in abrogation of the response to mechanical loading, with consequent reduction in bone size, mass and strength during both childhood and adulthood. A murine model was created in which pregnant dams were either vitamin D deficient or replete, and their offspring moved to a vitamin D replete diet at weaning. Tibias of the offspring were mechanically loaded and bone structure, extrinsic strength and growth measured both during growth and after skeletal maturity. Offspring of vitamin D deplete mice demonstrated lower bone mass in the non loaded limb and reduced bone mass accrual in response to loading in both the growing skeleton and after skeletal maturity. Early life vitamin D depletion led to reduced bone strength and altered bone biomechanical properties. These findings suggest early life vitamin D status may, in part, determine the propensity to osteoporosis and fracture that blights later life in many individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190675PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784894PMC
February 2018

Local displacement and strain uncertainties in different bone types by digital volume correlation of synchrotron microtomograms.

J Biomech 2017 06 20;58:27-36. Epub 2017 Apr 20.

Department of Oncology and Metabolism and INSIGNEO Institute for In Silico Medicine, University of Sheffield, Sir Frederick Mappin Building, Pam Liversidge Building, Sheffield S1 3JD, UK. Electronic address:

Understanding bone mechanics at different hierarchical levels is fundamental to improve preclinical and clinical assessments of bone strength. Digital Volume Correlation (DVC) is the only experimental measurement technique used for measuring local displacements and calculating local strains within bones. To date, its combination with laboratory source micro-computed tomography (LS-microCT) data typically leads to high uncertainties, which limit its application. Here, the benefits of synchrotron radiation micro-computed tomography (SR-microCT) for DVC are reported. Specimens of cortical and trabecular bovine bone and murine tibiae, were each scanned under zero-strain conditions with an effective voxel size of 1.6μm. In order to consider the effect of the voxel size, analyses were also performed on downsampled images with voxel size of 8μm. To evaluate displacement and strain uncertainties, each pair of tomograms was correlated using a global DVC algorithm (ShIRT-FE). Displacement random errors for original SR-microCT ranged from 0.024 to 0.226μm, depending on DVC nodal spacing. Standard deviation of strain errors was below 200 microstrain (ca. 1/10 of the strain associated with physiological loads) for correlations performed with a measurement spatial resolution better than 40μm for cortical bovine bone (240μm for downsampled images), 80μm for trabecular bovine bone (320μm for downsampled images) and murine tibiae (120μm for downsampled images). This study shows that the uncertainties of SR-microCT-based DVC, estimated from repeated scans, are lower than those obtained from LS-microCT-based DVC on similar specimens and low enough to measure accurately the local deformation at the tissue level.
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http://dx.doi.org/10.1016/j.jbiomech.2017.04.007DOI Listing
June 2017

Bone Cell Models: Impact of Fluid Shear Stress on Bone Formation.

Front Bioeng Biotechnol 2016 15;4:87. Epub 2016 Nov 15.

Department of Mechanical Engineering, University of Sheffield, Sheffield, UK; INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK.

This review describes the role of bone cells and their surrounding matrix in maintaining bone strength through the process of bone remodeling. Subsequently, this work focusses on how bone formation is guided by mechanical forces and fluid shear stress in particular. It has been demonstrated that mechanical stimulation is an important regulator of bone metabolism. Shear stress generated by interstitial fluid flow in the lacunar-canalicular network influences maintenance and healing of bone tissue. Fluid flow is primarily caused by compressive loading of bone as a result of physical activity. Changes in loading, e.g., due to extended periods of bed rest or microgravity in space are associated with altered bone remodeling and formation . , it has been reported that bone cells respond to fluid shear stress by releasing osteogenic signaling factors, such as nitric oxide, and prostaglandins. This work focusses on the application of models to study the effects of fluid flow on bone cell signaling, collagen deposition, and matrix mineralization. Particular attention is given to set-ups, which allow long-term cell culture and the application of low fluid shear stress. In addition, this review explores what mechanisms influence the orientation of collagen fibers, which determine the anisotropic properties of bone. A better understanding of these mechanisms could facilitate the design of improved tissue-engineered bone implants or more effective bone disease models.
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http://dx.doi.org/10.3389/fbioe.2016.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108781PMC
November 2016

In silico bone mechanobiology: modeling a multifaceted biological system.

Wiley Interdiscip Rev Syst Biol Med 2016 11 7;8(6):485-505. Epub 2016 Sep 7.

INSIGNEO Institute for In Silico Medicine, Department of Mechanical Engineering, University of Sheffield, Sheffield, UK.

Mechanobiology, the study of the influence of mechanical loads on biological processes through signaling to cells, is fundamental to the inherent ability of bone tissue to adapt its structure in response to mechanical stimulation. The immense contribution of computational modeling to the nascent field of bone mechanobiology is indisputable, having aided in the interpretation of experimental findings and identified new avenues of inquiry. Indeed, advances in computational modeling have spurred the development of this field, shedding new light on problems ranging from the mechanical response to loading by individual cells to tissue differentiation during events such as fracture healing. To date, in silico bone mechanobiology has generally taken a reductive approach in attempting to answer discrete biological research questions, with research in the field broadly separated into two streams: (1) mechanoregulation algorithms for predicting mechanobiological changes to bone tissue and (2) models investigating cell mechanobiology. Future models will likely take advantage of advances in computational power and techniques, allowing multiscale and multiphysics modeling to tie the many separate but related biological responses to loading together as part of a larger systems biology approach to shed further light on bone mechanobiology. Finally, although the ever-increasing complexity of computational mechanobiology models will inevitably move the field toward patient-specific models in the clinic, the determination of the context in which they can be used safely for clinical purpose will still require an extensive combination of computational and experimental techniques applied to in vitro and in vivo applications. WIREs Syst Biol Med 2016, 8:485-505. doi: 10.1002/wsbm.1356 For further resources related to this article, please visit the WIREs website.
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http://dx.doi.org/10.1002/wsbm.1356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082538PMC
November 2016

Effects of oxidative stress-induced changes in the actin cytoskeletal structure on myoblast damage under compressive stress: confocal-based cell-specific finite element analysis.

Biomech Model Mechanobiol 2016 12 19;15(6):1495-1508. Epub 2016 Mar 19.

Division of Biomedical Engineering, The Chinese University of Hong Kong, Rm. 429, Ho Sin Hang Engineering Building, Shatin, N.T. Hong Kong SAR, China.

Muscle cells are frequently subjected to both mechanical and oxidative stresses in various physiological and pathological situations. To explore the mechanical mechanism of muscle cell damage under loading and oxidative stresses, we experimentally studied the effects of extrinsic hydrogen peroxides on the actin cytoskeletal structure in C2C12 myoblasts and presented a finite element (FE) analysis of how such changes in the actin cytoskeletal structure affected a myoblast's capability to resist damage under compression. A confocal-based cell-specific FE model was built to parametrically study the effects of stress fiber density, fiber cross-sectional area, fiber tensile prestrain, as well as the elastic moduli of the stress fibers, actin cortex, nucleus and cytoplasm. The results showed that a decrease in the elastic moduli of both the stress fibers and actin cortex could increase the average tensile strain on the actin cortex-membrane structure and reduce the apparent cell elastic modulus. Assuming the cell would die when a certain percentage of membrane elements were strained beyond a threshold, a lower elastic modulus of actin cytoskeleton would compromise the compressive resistance of a myoblast and lead to cell death more readily. This model was used with a Weibull distribution function to successfully describe the extent of myoblasts damaged in a monolayer under compression.
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http://dx.doi.org/10.1007/s10237-016-0779-0DOI Listing
December 2016

Traction Forces of Endothelial Cells under Slow Shear Flow.

Biophys J 2015 Oct;109(8):1533-6

Institute for Bioengineering of Catalonia, Barcelona, Spain; Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.

Endothelial cells are constantly exposed to fluid shear stresses that regulate vascular morphogenesis, homeostasis, and disease. The mechanical responses of endothelial cells to relatively high shear flow such as that characteristic of arterial circulation has been extensively studied. Much less is known about the responses of endothelial cells to slow shear flow such as that characteristic of venous circulation, early angiogenesis, atherosclerosis, intracranial aneurysm, or interstitial flow. Here we used a novel, to our knowledge, microfluidic technique to measure traction forces exerted by confluent vascular endothelial cell monolayers under slow shear flow. We found that cells respond to flow with rapid and pronounced increases in traction forces and cell-cell stresses. These responses are reversible in time and do not involve reorientation of the cell body. Traction maps reveal that local cell responses to slow shear flow are highly heterogeneous in magnitude and sign. Our findings unveil a low-flow regime in which endothelial cell mechanics is acutely responsive to shear stress.
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http://dx.doi.org/10.1016/j.bpj.2015.08.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624165PMC
October 2015

Primary cilia mechanics affects cell mechanosensation: A computational study.

J Theor Biol 2015 Aug 5;379:38-46. Epub 2015 May 5.

INSIGNEO - Institute for in silico medicine, Department of Mechanical Engineering, The University of Sheffield, Sir Frederick Mappin Building, Mappin Street, Sheffield S1 3JD, United Kingdom. Electronic address:

Primary cilia (PC) are mechanical cell structures linked to the cytoskeleton and are central to how cells sense biomechanical signals from their environment. However, it is unclear exactly how PC mechanics influences cell mechanosensation. In this study we investigate how the PC mechanical characteristics are involved in the mechanotransduction process whereby cilium deflection under fluid flow induces strains on the internal cell components that regulate the cell׳s mechanosensitive response. Our investigation employs a computational approach in which a finite element model of a cell consisting of a nucleus, cytoplasm, cortex, microtubules, actin bundles and a primary cilium was used together with a finite element representation of a flow chamber. Fluid-structure interaction analysis was performed by simulating perfusion flow of 1mm/s on the cell model. Simulations of cells with different PC mechanical characteristics, showed that the length and the stiffness of PC are responsible for the transmission of mechanical stimuli to the cytoskeleton. Fluid flow deflects the cilium, with the highest strains found at the base of the PC and in the cytoplasm. The PC deflection created further strains on the cell nucleus but did not influence microtubules and actin bundles significantly. Our results indicate that PC deflection under fluid flow stimulation transmits mechanical strain primarily to other essential organelles in the cytoplasm, such as the Golgi complex, that regulate cells' mechanoresponse. The simulations further suggest that cell mechanosensitivity can be altered by targeting PC length and rigidity.
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http://dx.doi.org/10.1016/j.jtbi.2015.04.034DOI Listing
August 2015

Computational techniques for the assessment of fracture repair.

Injury 2014 Jun;45 Suppl 2:S23-31

INSIGNEO Institute for in Silico Medicine, Department of Mechanical Engineering, University of Sheffield, United Kingdom.

The combination of high-resolution three-dimensional medical imaging, increased computing power, and modern computational methods provide unprecedented capabilities for assessing the repair and healing of fractured bone. Fracture healing is a natural process that restores the mechanical integrity of bone and is greatly influenced by the prevailing mechanical environment. Mechanobiological theories have been proposed to provide greater insight into the relationships between mechanics (stress and strain) and biology. Computational approaches for modelling these relationships have evolved from simple tools to analyze fracture healing at a single point in time to current models that capture complex biological events such as angiogenesis, stochasticity in cellular activities, and cell-phenotype specific activities. The predictive capacity of these models has been established using corroborating physical experiments. For clinical application, mechanobiological models accounting for patient-to-patient variability hold the potential to predict fracture healing and thereby help clinicians to customize treatment. Advanced imaging tools permit patient-specific geometries to be used in such models. Refining the models to study the strain fields within a fracture gap and adapting the models for case-specific simulation may provide more accurate examination of the relationship between strain and fracture healing in actual patients. Medical imaging systems have significantly advanced the capability for less invasive visualization of injured musculoskeletal tissues, but all too often the consideration of these rich datasets has stopped at the level of subjective observation. Computational image analysis methods have not yet been applied to study fracture healing, but two comparable challenges which have been addressed in this general area are the evaluation of fracture severity and of fracture-associated soft tissue injury. CT-based methodologies developed to assess and quantify these factors are described and results presented to show the potential of these analysis methods.
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http://dx.doi.org/10.1016/j.injury.2014.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078600PMC
June 2014

Numerical exploration of the combined effect of nutrient supply, tissue condition and deformation in the intervertebral disc.

J Biomech 2014 Apr 15;47(6):1520-5. Epub 2014 Feb 15.

INSIGNEO Institute for in silico medicine, Department of Mechanical Engineering, University of Sheffield, Sir Frederick Mappin Building, Mappin Street, Sheffield S1 3JD UK. Electronic address:

Novel strategies to heal discogenic low back pain could highly benefit from comprehensive biophysical studies that consider both mechanical and biological factors involved in intervertebral disc degeneration. A decrease in nutrient availability at the bone-disc interface has been indicated as a relevant risk factor and as a possible initiator of cell death processes. Mechanical behaviour of both healthy and degenerated discs could highly interact with cell death in these compromised situations. In the present study, a mechano-transport finite element model was used to investigate the nature of mechanical effects on cell death processes via load-induced metabolic transport variations. Cycles of static sustained compression were chosen to simulate daily human activity. Healthy and degenerated cases were simulated as well as a reduced supply of solutes and an increase in solute exchange area at the bone-disc interface. Results showed that a reduction in metabolite concentrations at the bone-disc boundaries induced cell death, even when the increased exchange area was simulated. Slight local mechanical enhancements of glucose in the disc centre were capable of decelerating cell death but occurred only with healthy mechanical properties. However, mechanical deformations were responsible for a worsening in terms of cell death in the inner annulus, a disadvantaged zone far from the boundary supply with both an increased cell demand and a strain-dependent decrease of diffusivity. Such adverse mechanical effects were more accentuated when degenerative properties were simulated. Overall, this study paves the way for the use of biophysical models for a more integrated understanding of intervertebral disc pathophysiology.
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http://dx.doi.org/10.1016/j.jbiomech.2014.02.004DOI Listing
April 2014

Impact of hip anatomical variations on the cartilage stress: a finite element analysis towards the biomechanical exploration of the factors that may explain primary hip arthritis in morphologically normal subjects.

Clin Biomech (Bristol, Avon) 2014 Apr 17;29(4):444-50. Epub 2014 Jan 17.

Biomechanics and Mechanobiology, Institute for Bioengineering of Catalonia, Spain; INSIGNEO Institute for in silico Medicine, Department of Mechanical Engineering, University of Sheffield, United Kingdom. Electronic address:

Background: Hip arthritis is a pathology linked to hip-cartilage degeneration. Although the etiology of this disease is not well defined, it is known that age is a determinant risk factor. However, hip arthritis in young patients could be largely promoted by biomechanical factors. The objective of this paper is to analyze the impact of some normal anatomical variations on the cartilage stress distributions numerically predicted at the hip joint during walking.

Methods: A three-dimensional finite element model of the femur and the pelvis with the most relevant axial components of muscle forces was used to simulate normal walking activity. The hip anatomical condition was defined by: neck shaft angle, femoral anteversion angle, and acetabular anteversion angle with a range of 110-130°, 0-20°, and 0-20°, respectively. The direct boundary method was used to simulate the hip contact.

Findings: The hydrostatic stress found at the cartilage and labrum showed that a ±10° variation with respect to the reference brings significant differences between the anatomic models. Acetabular anteversion angle of 0° and femoral anteversion angle of 0° were the most affected anatomical conditions with values of hydrostatic stress in the cartilage near 5MPa under compression.

Interpretation: Cartilage stresses and contact areas were equivalent to the results found in literature and the most critical anatomical regions in terms of tissue loads were in a good accordance with clinical evidence. Altogether, results showed that decreasing femoral or acetabular anteversion angles isolatedly causes a dramatic increase in cartilage loads.
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http://dx.doi.org/10.1016/j.clinbiomech.2014.01.004DOI Listing
April 2014

Structural finite element analysis to explain cell mechanics variability.

J Mech Behav Biomed Mater 2014 Oct 17;38:219-31. Epub 2013 Dec 17.

INSIGNEO Institute for In Silico Medicine, Department of Mechanical Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD, United Kingdom. Electronic address:

The ability to model the mechanical responses of different cell types presents many opportunities to tissue engineering research to further identify changes from physiological conditions to disease. Using a previously validated finite element cell model we aim to show how variation of the material properties of the intracellular components affects cell response after compression and shearing. A parametric study was performed to understand the key mechanical features from different cell types, focussing on specific cytoskeleton components and prestress. Results show that actin cortex does not have a mechanical role in resisting shearing loading conditions. The sensitivity analysis predicted that cell force to compression and shearing is highly affected by changes in cortex thickness, cortex Young's modulus and rigidity of the remaining cytoplasm. Variation of prestress affects mainly the response of cells under shear loads and the model defines a relationship between cell force and prestress depending on the specific loading conditions, which is in good agreement with in vitro experiments. The results are used to make predictions that can relate mechanical properties with cell phenotype to be used as guidelines for individual cytoskeletal structures for future modelling efforts of the structure-function relationships of living cells.
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http://dx.doi.org/10.1016/j.jmbbm.2013.11.022DOI Listing
October 2014

A multi-structural single cell model of force-induced interactions of cytoskeletal components.

Biomaterials 2013 Aug 21;34(26):6119-26. Epub 2013 May 21.

Department of Mechanical Engineering, University of Sheffield, Sheffield, United Kingdom.

Several computational models based on experimental techniques and theories have been proposed to describe cytoskeleton (CSK) mechanics. Tensegrity is a prominent model for force generation, but it cannot predict mechanics of individual CSK components, nor explain the discrepancies from the different single cell stimulating techniques studies combined with cytoskeleton-disruptors. A new numerical concept that defines a multi-structural 3D finite element (FE) model of a single-adherent cell is proposed to investigate the biophysical and biochemical differences of the mechanical role of each cytoskeleton component under loading. The model includes prestressed actin bundles and microtubule within cytoplasm and nucleus surrounded by the actin cortex. We performed numerical simulations of atomic force microscopy (AFM) experiments by subjecting the cell model to compressive loads. The numerical role of the CSK components was corroborated with AFM force measurements on U2OS-osteosarcoma cells and NIH-3T3 fibroblasts exposed to different cytoskeleton-disrupting drugs. Computational simulation showed that actin cortex and microtubules are the major components targeted in resisting compression. This is a new numerical tool that explains the specific role of the cortex and overcomes the difficulty of isolating this component from other networks in vitro. This illustrates that a combination of cytoskeletal structures with their own properties is necessary for a complete description of cellular mechanics.
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http://dx.doi.org/10.1016/j.biomaterials.2013.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513724PMC
August 2013

Simulation of cell seeding within a three-dimensional porous scaffold: a fluid-particle analysis.

Tissue Eng Part C Methods 2012 Aug 2;18(8):624-31. Epub 2012 Apr 2.

Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain.

Cell seeding is a critical step in tissue engineering. A high number of cells evenly distributed in scaffolds after seeding are associated with a more functional tissue culture. Furthermore, high cell densities have shown the possibility to reduce culture time or increase the formation of tissue. Experimentally, it is difficult to predict the cell-seeding process. In this study, a new methodology to simulate the cell-seeding process under perfusion conditions is proposed. The cells are treated as spherical particles dragged by the fluid media, where the physical parameters are computed through a Lagrangian formulation. The methodology proposed enables to define the kinetics of cell seeding continuously over time. An exponential relationship was found to optimize the seeding time and the number of cells seeded in the scaffold. The cell distribution and cell efficiency predicted using this methodology were similar to the experimental results of Melchels et al. One of the main advantages of this method is to be able to determine the three-dimensional position of all the seeded cells and to, therefore, better know the initial conditions for further cell proliferation and differentiation studies. This study opens up the field of numerical predictions related to the interactions between biomaterials, cells, and dynamics media.
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http://dx.doi.org/10.1089/ten.TEC.2011.0660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401387PMC
August 2012

Regional annulus fibre orientations used as a tool for the calibration of lumbar intervertebral disc finite element models.

Comput Methods Biomech Biomed Engin 2013 6;16(9):923-8. Epub 2012 Jan 6.

a Institute for Bioengineering of Catalonia , Barcelona , Spain.

The collagen network of the annulus fibrosus largely controls the functional biomechanics of the lumbar intervertebral discs (IVDs). Quantitative anatomical examinations have shown bundle orientation patterns, possibly coming from regional adaptations of the annulus mechanics. This study aimed to show that the regional differences in annulus mechanical behaviour could be reproduced by considering only fibre orientation changes. Using the finite element method, a lumbar annulus was modelled as a poro-hyperelastic material in which fibres were represented by a direction-dependent strain energy density term. Fibre orientations were calibrated to reproduce the annulus tensile behaviours measured for four different regions: posterior outer, anterior outer, posterior inner and anterior inner. The back-calculated fibre angles and regional patterns as well as the global disc behaviour were comparable with anatomical descriptions reported in the literature. It was concluded that annulus fibre variations might be an effective tool to calibrate lumbar spine IVD and segment models.
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http://dx.doi.org/10.1080/10255842.2011.644539DOI Listing
May 2014

Unprecedented occurrence of isoaspartic acid in a plant cyclopeptide.

Org Lett 2012 Jan 5;14(2):576-9. Epub 2012 Jan 5.

Molécules de Communication et Adaptation des Micro-Organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 63 rue Buffon 75005 Paris, France.

Three structurally related cycloheptapeptides, cyclocitropsides A-C, have been isolated from a MeOH extract of the root bark of Citropsis articulata, a medicinal plant in Uganda. Their sequences were elucidated on the basis of their MS/MS fragmentation, extensive 2D-NMR, chemical degradation, and biochemical modifications. Surprisingly, the sequence of cyclocitropside C differed from that of cyclocitropside B only by an Asp(5)/isoAsp(5) substitution. This is the first report of an isoAsp residue in a plant cyclic peptide.
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http://dx.doi.org/10.1021/ol203190fDOI Listing
January 2012
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