Significance of the collagen criss-cross angle distributions in lumbar annuli fibrosi as revealed by finite element simulations

In the human lumbar spine, annulus fibr osus (AF) fibres la rgely contribute to intervertebral disc (IVD) stability, and deta iled annulus models are required to obtain reliable predictions of lumbar spine biom echanics by finite element (FE) modelling. However, different definitions of collagen orientation coexist in the literature for healthy human lumbar AFs and are indiscrimi nately used in mode lling. Therefore, four AF fibre-induced anisotropy models were bu ilt from reported anatomical descriptions and inserted in a L3-L5 lumbar bi-segment FE model. AF models were respectively characterized by radial, tange ntial, radial and tangentia l, and no fibre orientation gradients. IVD local biomechanics was studied under axial rotation and axial compression. A new parameter, i.e. the Fi bre Contribution Qual ity parameter, was computed in the anterior, lateral, postero-l ateral and posterior AFs of each model, in function of fibre stresses, load distributions, and matrix shear strains. Locally, each AF model behaved differently, affecting the IVD biomechanics. The Fibre Contribution Quality (FCQ) parameter established a direct link between local AF fibre organization and loading, while other biomechanical data did not. It was conc luded that local AF fibre orientations should be modelled in rela tion to other segment characteristics. The proposed FCQ parameter could be used to examine such relations, being, therefore particularly relevant to patient-specifi c models or artificial disc designs.Postprint (published version

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

The highly organized collagen network of human lumbar a nnulus fibrosus (AF) is fundamental to preserve the mechanical inte grity of the interverte bral discs. In the healthy AF, fibres are embedded in a hydrated matrix and arranged in a criss-cross fashion, giving an anisotropic structure capab le to undergo large st rains. Quantitative anatomical examinations revealed particular fibre orientation patterns, possibly coming from regional adaptations of the AF mechan ics. Based on such hypothesis, this study aimed to show that the regional differen ces in AF mechanical behaviour can be reproduced by considering only fibre orientatio n changes. Using the finite element (FE) method, AF matrix was modelled as a poro-hy perelastic material, where the porous solid was treated as a comp ressible continuum following a Neo-Hookean constitutive law. Strain-dependent permeability was assumed and all material parameters were taken from the literature. Fibre reinforcement wa s accounted for by adding an extra-term to the porous matrix strain energy density func tion, only active along th e fibre directions. Through such term, fibre orientations were then adjusted, to reproduce AF tensile behaviours measured for four different regi ons: posterior outer (PO), anterior outer (AO), posterior inner (PI) and anterior inne r (AI). Curve calibrations resulted in the following optimal angles, calculated with respect to the circumferential axis: 28º for PO, 23º for AO, 43º for PI and 31º for AI. In average, we obtained fibres 30% more transversal in the inner than in the outer AF against 38% as measured by Cassidy et al. (1989). Fibres more axial in the posterior than in the anterior AF were also measured by Holzapfel et al. (2005), with angle values comparable to our computed average values. Since all the hyperelastic and fluid-phase material parameters remained unchanged throughout the AF, calibration based only on fibre patterns variations may be an effective tool to calibrate the regional AF mechanics in a realistic way.Postprint (published version

A micro-macro evaluation of the vertebral bony endplate permeability based on computational fluid dynamics

The intrinsic permeability is an important parameter that describes the resistance of a porous structure to fluid flo w. It has a key role in poroelastic finite element models of spinal segments, especially at the vertebral endplate, i.e. the interface between intervertebral disc and vertebra. In the understanding of the properties of the complex endplate system, an expli cit evaluation for permeability of subchondral bone is missing. Thus, a new method wa s proposed to evaluate the intrinsic permeability of the bony endplate. CT - based reconstruction s of the bony endplate from a lumbar vertebra were analyzed using computational fluid dynamics , and the i ntrinsic permeability and porosity of the structure were calculated. Results showed that the permeability did not depend on the fluid flow direction, and was statistically similar for both the superior and inferior endplates . Permeability values varied within the range of trabecular bone, while porosity values w ere lower than trabecular bone characteristic values. Finally, i ntrins ic permeability correlated well with porosity through the Kozeny - Karman model, which offer s perspectives for parametric studies involving degenerative or age - related changes at the disc - bone interface.Postprint (published version

Clavos intramedulares vs. placas de osteosíntesis para fracturas de fémur. Análisis por elementos finitos

La estabilización interna de fracturas de la diáfisis femoral se realiza mediante la implantación de clavos intramedulares o placas de osteosíntesis. El objetivo de este estudio es realizar una comparación biomecánica por elementos finitos de ambos implantes y así desarrollar una herramienta preclínica para guiar a los cirujanos en la elección del método de estabilización más adecuado para cada fractura. Se malló un fémur entero en el cual se practicó una fractura de 1mm ó 3mm en la diáfisis. Los modelos de placa y clavo se mallaron a partir de la geometría de los implantes, para el clavo se realizaron dos modelos con diámetros distintos (11 y 13 mm). El estudio incluye simulaciones en dos etapas de regeneración de la fractura (con modulo de elasticidad en la fractura de 1 MPa ó 10 MPa), con implantes de acero inoxidable y titanio. Las cargas aplicadas simulan el apoyo monopodal e incluyen la actuación de la cadera, y los músculos abductores, psoas ilíaco e iliotibial. Los resultados muestran que la tensión en los implantes aumenta con el tamaño de la fractura y disminuye con su módulo. Los clavos tienden a inducir más deformación en la fractura que las placas. El diámetro de los clavos influye en la tensión inducida en el hueso y en la deformación en la fractura, los resultados de los clavos más anchos tienden a los resultados de las placas

Clavos intramedulares vs. placas de osteosíntesis para fracturas de fémur: Análisis por elementos finitos.

La estabilización interna de fracturas de la diáfisis femoral se realiza mediante la implantación de clavos intramedulares o placas de osteosíntesis. El objetivo de este estudio es realizar una comparación biomecánica por elementos finitos de ambos implantes y así desarrollar una herramienta preclínica para guiar a los cirujanos en la elección del método de estabilización más adecuado para cada fractura. Se malló un fémur entero en el cual se practicó una fractura de 1mm ó 3mm en la diáfisis. Los modelos de placa y clavo se mallaron a partir de la geometría de los implantes, para el clavo se realizaron dos modelos con diámetros distintos (11 y 13 mm). El estudio incluye simulaciones en dos etapas de regeneración de la fractura (con modulo de elasticidad en la fractura de 1 MPa ó 10 MPa), con implantes de acero inoxidable y titanio. Las cargas aplicadas simulan el apoyo monopodal e incluyen la actuación de la cadera, y los músculos abductores, psoas ilíaco e iliotibial. Los resultados muestran que la tensión en los implantes aumenta con el tamaño de la fractura y disminuye con su módulo. Los clavos tienden a inducir más deformación en la fractura que las placas. El diámetro de los clavos influye en la tensión inducida en el hueso y en la deformación en la fractura, los resultados de los clavos más anchos tienden a los resultados de las placas

Nanotechnology in regenerative medicine: the materials side

Regenerative medicine is an emerging multidisciplinary field that aims to restore, maintain or enhance tissues and hence organ functions. Regeneration of tissues can be achieved by the combination of living cells, which will provide biological functionality, and materials, which act as scaffolds to support cell proliferation. Mammalian cells behave in vivo in response to the biological signals they receive from the surrounding environment, which is structured by nanometre-scaled components. Therefore, materials used in repairing the human body have to reproduce the correct signals that guide the cellstowards a desirable behaviour. Nanotechnology is not only an excellent tool to produce material structures that mimic the biological ones but also holds the promise of providing efficient delivery systems. The application of nanotechnology to regenerative medicine is a wide issue and this short review will only focus on aspects of nanotechnology relevant to biomaterials science. Specifically, the fabrication of materials, such as nanoparticles and scaffolds for tissue engineering, and the nanopatterning of surfaces aimed at eliciting specific biological responses from the host tissue will be addressed.Postprint (published version

Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer

The importance of integrating biomarkers into the TNM staging has been emphasized in the 8 th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8 th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.Peer reviewe

Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers

PURPOSE: The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC). METHODS: Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors. RESULTS: We collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio \u3c72, 48.9 iDFS; P < .001; \u3c72, 55.8 D-DFS; P < .001; \u3c72, 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs 65 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%). CONCLUSION: This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls