Substantial research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, affects fundamental cellular processes, including spreading, growth, proliferation, migration, differentiation and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins are widely used to assess the role of stiffness, and results from such experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo. However, tissues and ECMs are not linearly elastic materials-they exhibit far more complex mechanical behaviours, including viscoelasticity (a time-dependent response to loading or deformation), as well as mechanical plasticity and nonlinear elasticity. Here we review the complex mechanical behaviours of tissues and ECMs, discuss the effect of ECM viscoelasticity on cells, and describe the potential use of viscoelastic biomaterials in regenerative medicine. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and can promote behaviours that are not observed with elastic hydrogels in both two- and three-dimensional culture microenvironments. These findings have provided insights into cell-matrix interactions and how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results suggest design guidelines for the next generation of biomaterials, with the goal of matching tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.

Effects of extracellular matrix viscoelasticity on cellular behaviour.

Traumatic brain injury (TBI) occurs when local mechanical load exceeds certain tolerance levels for brain tissue. Extensive research has been done previously for brain matter experiencing compression at quasistatic loading; however, limited data is available to model TBI under dynamic impact conditions. In this research, an experimental setup was developed to perform unconfined compression tests and stress relaxation tests at strain rates≤90/s. The brain tissue showed a stiffer response with increasing strain rates, showing that hyperelastic models are not adequate. Specifically, the compressive nominal stress at 30% strain was 8.83±1.94, 12.8±3.10 and 16.0±1.41 kPa (mean±SD) at strain rates of 30, 60 and 90/s, respectively. Relaxation tests were also conducted at 10%- 50% strain with the average rise time of 10 ms, which can be used to derive time dependent parameters. Numerical simulations were performed using one-term Ogden model with initial shear modulusµ o =6.06±1.44, 9.44±2.427 and 12.64±1.227 kPa (mean±SD) at strain rates of 30, 60 and 90/s, respectively. A separate set of bonded and lubricated tests were also performed under the same test conditions to estimate the friction coefficient µ, by adopting combined experimental-computational approach. The values ofµwere 0.1±0.03 and 0.15±0.07 (mean±SD) at 30 and 90/s strain rates, respectively, indicating that pure slip conditions cannot be achieved in unconfined compression tests even under fully lubricated test conditions. The material parameters obtained in this study will help to develop biofidelic human brainfinite element models, which can subsequently be used to predict brain injuries under impact conditions. c

http://www.maths.nuigalway.ie/~destrade/Publis/destrade_90.pdf

Mechanical characterization of brain tissue in compression at dynamic strain rates.

The influence of substrate creep on mesenchymal stem cell behaviour and phenotype.

Fifty years of brain tissue mechanical testing: From in vitro to in vivo investigations

The human brain is the continuous subject of extensive investigation aimed at understanding its behavior and function. Despite a clear evidence that mechanical factors play an important role in regulating brain activity, current research efforts focus mainly on the biochemical or electrophysiological activity of the brain. Here, we show that classical mechanical concepts including deformations, stretch, strain, strain rate, pressure, and stress play a crucial role in modulating both brain form and brain function. This opinion piece synthesizes expertise in applied mathematics, solid and fluid mechanics, biomechanics, experimentation, material sciences, neuropathology, and neurosurgery to address today’s open questions at the forefront of neuromechanics. We critically review the current literature and discuss challenges related to neurodevelopment, cerebral edema, lissencephaly, polymicrogyria, hydrocephaly, craniectomy, spinal cord injury, tumor growth, traumatic brain injury, and shaken baby syndrome. The multi-disciplinary analysis of these various phenomena and pathologies presents new opportunities and suggests that mechanical modeling is a central tool to bridge the scales by synthesizing information from the molecular via the cellular and tissue all the way to the organ level.

/pdf/mechanics-of-the-brain-perspectives-challenges-and-3ercw4qnop.pdf

Mechanics of the brain: perspectives, challenges, and opportunities

http://www.mate.tue.nl/mate/pdfs/6852.pdf

The mechanical behaviour of brain tissue: Large strain response and constitutive modelling

The non-linear mechanical behaviour of porcine brain tissue in different deformation modes is determined. An improved method for rotational shear experiments is used, producing an approximately homogeneous strain field and leading to an enhanced accuracy. Results from oscillatory experiments and constant strain rate experiments are presented. Large deformations at the time scale of loading and the material behaviour during complex loading paths (loading-unloading) is investigated. No significant immediate mechanical damage is observed for these shear deformations. A new differential viscoelastic model is used to describe the non-linear mechanical response of brain tissue. This constitutive model is readily applicable in three-dimensional head models in order to predict the mechanical response of the intracranial contents due to an impact. For the covering abstract see ITRD E134311.

The mechanical behaviour of brain tissue: large strain response and constitutive modelling.

The objective of this work was to validate the non-linear viscoelastic constitutive model of brain tissue that was developed in Hrapko et al. (2006) and has shown to provide a good prediction of the shear response. The model predictions were compared to compression relaxation results up to 20% strain of porcine brain tissue samples. Compression and shear results were obtained from the same samples to reduce the effect of inter-sample variation. Compression measurement results with and without initial contact of the sample with the loading plate were compared. The influence of a fluid layer surrounding the sample and the effect of friction were examined and were found to play an important role during compression measurements. The model has been implemented in the explicit Finite Element code MADYMO. Model simulations with varying boundary conditions are used to interpret the compression results. Simulations using the non-linear constitutive model and its linearised version in a 3-D head model showed a difference in the maximum stress and strain responses of 20% and 50%, respectively. For the covering abstract see ITRD E141762.

J. S. H. M. Wismans

Papers

The mechanical behaviour of brain tissue: Large strain response and constitutive modelling

The mechanical behaviour of brain tissue: large strain response and constitutive modelling.

Identifying the mechanical behaviour of brain tissue in both shear and compression

Large strain behaviour of brain tissue in shear and compression