Microstructural analysis of skeletal muscle force generation during aging.

Human aging results in a progressive decline in the active force generation capability of skeletal muscle. While many factors related to the changes of morphological and structural properties in muscle fibers and the extracellular matrix (ECM) have been considered as possible reasons for causing age-related force reduction, it is still not fully understood why the decrease in force generation under eccentric contraction (lengthening) is much less than that under concentric contraction (shortening). Biomechanically, it was observed that connective tissues (endomysium) stiffen as ages, and the volume ratio of connective tissues exhibits an age-related increase. However, limited skeletal muscle models take into account the microstructural characteristics as well as the volume fraction of tissue material. This study aims to provide a numerical investigation in which the muscle fibers and the ECM are explicitly represented to allow quantitative assessment of the age-related force reduction mechanism. To this end, a fiber-level honeycomb-like microstructure is constructed and modeled by a pixel-based Reproducing Kernel Particle Method (RKPM), which allows modeling of smooth transition in biomaterial properties across material interfaces. The numerical investigation reveals that the increased stiffness of the passive materials of muscle tissue reduces the force generation capability under concentric contraction while maintains the force generation capability under eccentric contraction. The proposed RKPM microscopic model provides effective means for the cellular-scale numerical investigation of skeletal muscle physiology. NOVELTY STATEMENT: A cellular-scale honeycomb-like microstructural muscle model constructed from a histological cross-sectional image of muscle is employed to study the causal relations between age-associated microstructural changes and age-related force loss using Reproducing Kernel Particle Method (RKPM). The employed RKPM offers an effective means for modeling biological materials based on pixel points in the medical images and allow modeling of smooth transition in the material properties across interfaces. The proposed microstructure-informed muscle model enables quantitative evaluation on how cellular-scale compositions contribute to muscle functionality and explain differences in age-related force changes during concentric, isometric and eccentric contractions

Hierarchical micro-adaptation of biological structures by mechanical stimuli

Remodeling and other evolving processes such as growth or morphogenesis are key factors in the evolution of biological tissue in response to both external and internal epigenetic stimuli. Based on the description of these processes provided by Taber, 1995 and Humphrey et al., 2002 for three important adaptation processes, remodeling, morphogenesis and growth (positive and negative), we shall consider the latter as the increase/decrease of mass via the increase/decrease of the number or size of cells, leading to a change in the volume of the organ. The work of Rodriguez et al. (1994) used the concept of natural configuration previously introduced by Skalak et al. (1982) to formulate volumetric growth. Later, Humphrey et al. (2002) proposed a constrained-mixture theory where changes in the density and mass of different constituents were taken into account. Many other works about biological growth have been presented in recent years, see e.g. Imatani and Maugin, 2002, Garikipati et al., 2004, Gleason and Humphrey, 2004, Menzel, 2004, Amar et al., 2005, Ganghoffer et al., 2005, Ateshian, 2007, Goriely et al., 2007, Kuhl et al., 2007, Ganghoffer, 2010a, Ganghoffer, 2010b and Goktepe et al., 2010. Morphogenesis is associated to changes in the structure shape (Taber, 1995 and Taber, 2009) while remodeling denotes changes in the tissue microstructure via the reorganization of the existing constituents or the synthesis of new ones with negligible volume change. All these processes involve changes in material properties. Although remodeling and growth can, and usually do, occur simultaneously, there are some cases where these processes develop in a decoupled way. For example, Stopak and Harris (1982) reported some experimental results showing remodeling driven by fibroblasts, with no volume growth. We will assume this scenario in this contribution, focusing exclusively on remodeling processes and on the reorientation of fibered biological structures. It is well known that biological tissue remodels itself when driven by a given stimulus, e.g. mechanical loads such as an increase in blood pressure, or changes in the chemical environment that control the signaling processes and the overall evolution of the tissue. Biological remodeling can occur in any kind of biological tissue. In particular, the study of collagen as the most important substance to be remodeled, in all its types (preferentiallyPeer ReviewedPostprint (author's final draft

Modeling of fibrous biological tissues with a general invariant that excludes compressed fibers

Dispersed collagen fibers in fibrous soft biological tissues have a significant effect on the overall mechanical behavior of the tissues. Constitutive modeling of the detailed structure obtained by using advanced imaging modalities has been investigated extensively in the last decade. In particular, our group has previously proposed a fiber dispersion model based on a generalized structure tensor. However, the fiber tension–compression switch described in that study is unable to exclude compressed fibers within a dispersion and the model requires modification so as to avoid some unphysical effects. In a recent paper we have proposed a method which avoids such problems, but in this present study we introduce an alternative approach by using a new general invariant that only depends on the fibers under tension so that compressed fibers within a dispersion do not contribute to the strain-energy function. We then provide expressions for the associated Cauchy stress and elasticity tensors in a decoupled form. We have also implemented the proposed model in a finite element analysis program and illustrated the implementation with three representative examples: simple tension and compression, simple shear, and unconfined compression on articular cartilage. We have obtained very good agreement with the analytical solutions that are available for the first two examples. The third example shows the efficacy of the fibrous tissue model in a larger scale simulation. For comparison we also provide results for the three examples with the compressed fibers included, and the results are completely different. If the distribution of collagen fibers is such that it is appropriate to exclude compressed fibers then such a model should be adopted

Regional diversity in the murine cortical vascular network is revealed by synchrotron X-ray tomography and is amplified with age

Cortical bone is permeated by a system of pores, occupied by the blood supply and osteocytes. With ageing, bone mass reduction and disruption of the microstructure are associated with reduced vascular supply. Insight into the regulation of the blood supply to the bone could enhance the understanding of bone strength determinants and fracture healing. Using synchrotron radiation-based computed tomography, the distribution of vascular canals and osteocyte lacunae was assessed in murine cortical bone and the influence of age on these parameters was investigated. The tibiofibular junction from 15-week- and 10-month-old female C57BL/6J mice were imaged post-mortem. Vascular canals and three-dimensional spatial relationships between osteocyte lacunae and bone surfaces were computed for both age groups. At 15 weeks, the posterior region of the tibiofibular junction had a higher vascular canal volume density than the anterior, lateral and medial regions. Intracortical vascular networks in anterior and posterior regions were also different, with connectedness in the posterior higher than the anterior at 15 weeks. By 10 months, cortices were thinner, with cortical area fraction and vascular density reduced, but only in the posterior cortex. This provided the first evidence of age-related effects on murine bone porosity due to the location of the intracortical vasculature. Targeting the vasculature to modulate bone porosity could provide an effective way to treat degenerative bone diseases, such as osteoporosis

Governing equations of tissue modelling and remodelling: A unified generalised description of surface and bulk balance

Several biological tissues undergo changes in their geometry and in their bulk material properties by modelling and remodelling processes. Modelling synthesises tissue in some regions and removes tissue in others. Remodelling overwrites old tissue material properties with newly formed, immature tissue properties. As a result, tissues are made up of different "patches", i.e., adjacent tissue regions of different ages and different material properties, within evolving boundaries. In this paper, generalised equations governing the spatio-temporal evolution of such tissues are developed within the continuum model. These equations take into account nonconservative, discontinuous surface mass balance due to creation and destruction of material at moving interfaces, and bulk balance due to tissue maturation. These equations make it possible to model patchy tissue states and their evolution without explicitly maintaining a record of when/where resorption and formation processes occurred. The time evolution of spatially averaged tissue properties is derived systematically by integration. These spatially-averaged equations cannot be written in closed form as they retain traces that tissue destruction is localised at tissue boundaries. The formalism developed in this paper is applied to bone tissues, which exhibit strong material heterogeneities due to their slow mineralisation and remodelling processes. Evolution equations are proposed in particular for osteocyte density and bone mineral density. Effective average equations for bone mineral density (BMD) and tissue mineral density (TMD) are derived using a mean-field approximation. The error made by this approximation when remodelling patchy tissue is investigated. The specific time signatures of BMD or TMD during remodelling events may provide a way to detect these events occurring at lower, unseen spatial resolutions from microCT scans.Comment: 14 pages, 8 figures. V2: minor stylistic changes, more detailed derivation of Eqs (30)-(31), additional comments on implication of BMD and TMD signatures for microCT scan

Dynamic problems for metamaterials: Review of existing models and ideas for further research

Metamaterials are materials especially engineered to have a peculiar physical behaviour, to be exploited for some well-specified technological application. In this context we focus on the conception of general micro-structured continua, with particular attention to piezoelectromechanical structures, having a strong coupling between macroscopic motion and some internal degrees of freedom, which may be electric or, more generally, related to some micro-motion. An interesting class of problems in this context regards the design of wave-guides aimed to control wave propagation. The description of the state of the art is followed by some hints addressed to describe some possible research developments and in particular to design optimal design techniques for bone reconstruction or systems which may block wave propagation in some frequency ranges, in both linear and non-linear fields. (C) 2014 Elsevier Ltd. All rights reserved

Structural characterization and statistical-mechanical model of epidermal patterns

In proliferating epithelia of mammalian skin, cells of irregular polygonal-like shapes pack into complex nearly flat two-dimensional structures that are pliable to deformations. In this work, we employ various sensitive correlation functions to quantitatively characterize structural features of evolving packings of epithelial cells across length scales in mouse skin. We find that the pair statistics in direct and Fourier spaces of the cell centroids in the early stages of embryonic development show structural directional dependence, while in the late stages the patterns tend towards statistically isotropic states. We construct a minimalist four-component statistical-mechanical model involving effective isotropic pair interactions consisting of hard-core repulsion and extra short-ranged soft-core repulsion beyond the hard core, whose length scale is roughly the same as the hard core. The model parameters are optimized to match the sample pair statistics in both direct and Fourier spaces. By doing this, the parameters are biologically constrained. Our model predicts essentially the same polygonal shape distribution and size disparity of cells found in experiments as measured by Voronoi statistics. Moreover, our simulated equilibrium liquid-like configurations are able to match other nontrivial unconstrained statistics, which is a testament to the power and novelty of the model. We discuss ways in which our model might be extended so as to better understand morphogenesis (in particular the emergence of planar cell polarity), wound-healing, and disease progression processes in skin, and how it could be applied to the design of synthetic tissues

Continuum Modeling and Simulation in Bone Tissue Engineering

Bone tissue engineering is currently a mature methodology from a research perspective. Moreover, modeling and simulation of involved processes and phenomena in BTE have been proved in a number of papers to be an excellent assessment tool in the stages of design and proof of concept through in-vivo or in-vitro experimentation. In this paper, a review of the most relevant contributions in modeling and simulation, in silico, in BTE applications is conducted. The most popular in silico simulations in BTE are classified into: (i) Mechanics modeling and sca old design, (ii) transport and flow modeling, and (iii) modeling of physical phenomena. The paper is restricted to the review of the numerical implementation and simulation of continuum theories applied to di erent processes in BTE, such that molecular dynamics or discrete approaches are out of the scope of the paper. Two main conclusions are drawn at the end of the paper: First, the great potential and advantages that in silico simulation o ers in BTE, and second, the need for interdisciplinary collaboration to further validate numerical models developed in BTE.Ministerio de Economía y Competitividad del Gobierno España DPI2017-82501-

Constitutive Models for Tumour Classification

The aim of this paper is to formulate new mathematical models that will be able to differentiate not only between normal and abnormal tissues, but, more importantly, between benign and malignant tumours. We present preliminary results of a tri-phasic model and numerical simulations of the effect of cellular adhesion forces on the mechanical properties of biological tissues. We pursued the following three approaches: (i) the simulation of the time-harmonic linear elastic models to examine coarse scale effects and adhesion properties, (ii) the investigation of a tri-phasic model, with the intent of upscaling this model to determine effects of electro-mechanical coupling between cells, and (iii) the upscaling of a simple cell model as a framework for studying interface conditions at malignant cells. Each of these approaches has opened exciting new directions of research that we plan to study in the future

Computational modelling of void growth in swelled hydrogels

The nature and the large notable distinguishing features of polymeric gels explain their pervasive use as biomaterials in both regenerative medicine and tissue engineering. With regard to their biocompatibility, their ability to withstand large deformation and their significant capacity of solvent absorption, these biomaterials are often selected owing to their versatile mechanical properties and especially the closeness to soft biological tissues, amongst others. A finite-strain theory for the study of the overall behaviour of a porous polymeric gel where microvoids are present is presented. The swollen polymeric gel is modeled as a two-component body composed of two incompressible components, namely, an elastic porous polymer imbibed with a solvant. The chemical equilibrium is assumed to be preponderate at the interface between the porous polymer and the environment where the chemical potential of the solvent is fixed. The initially dry porous polymer undergoes large deformation induced by absorption of a solvent from the environment and mechanical loading. In this paper an attempt is made towards obtaining an estimation of the macroscopic responses of the swollen porous polymer to prescribed proportional loadings. To this end, a two-level representation of the material at hand for which the Representative Volume Element (RVE) imbibed with a solvent is a simple axisymmetric cylinder composed of a homogeneous matrix surrounding a spherical void, is considered. The computational study addresses the situation where the RVE is subjected to prescribed axial and lateral overall stresses under conditions of constant overall stress triaxiality. For fixed values of the Flory-Huggins parameter and the nominal concentration of the solvent, the overall stress-strain behaviour of the RVE model, the influence of the initial porosity, and the prescribed stress triaxiality ratio have been outlined