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.

With recent advancement in nanotechnology and materials science, we have been able to fabricate electronics on flexible, stretchable and 3D substrates to cover electrical functional units on soft and non-planar surfaces for monitoring, control and making smart systems New requirements have been raised that electronics need to be implemented into objects with a minimal invasiveness followed by a 3D distribution of nano- and micro-scale sensor units in a large volume while maintaining mechanical ultra-flexibility

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Syringe Injectable Electronics

The mammalian brain is composed of an outer layer of gray matter, consisting of cell bodies, dendrites, and unmyelinated axons, and an inner core of white matter, consisting primarily of myelinated axons Recent evidence suggests that microstructural differences between gray and white matter play an important role during neurodevelopment While brain tissue as a whole is rheologically well characterized, the individual features of gray and white matter remain poorly understood Here we quantify the mechanical properties of gray and white matter using a robust, reliable, and repeatable method, flat-punch indentation To systematically characterize gray and white matter moduli for varying indenter diameters, loading rates, holding times, post-mortem times, and locations we performed a series of n = 192 indentation tests We found that indenting thick, intact coronal slices eliminates the common challenges associated with small specimens: it naturally minimizes boundary effects, dehydration, swelling, and structural degradation When kept intact and hydrated, brain slices maintained their mechanical characteristics with standard deviations as low as 5% throughout the entire testing period of five days post mortem White matter, with an average modulus of 1895 kPa±0592 kPa, was on average 39% stiffer than gray matter, p 001 , with an average modulus of 1389 kPa±0289 kPa, and displayed larger regional variations It was also more viscous than gray matter and responded less rapidly to mechanical loading Understanding the rheological differences between gray and white matter may have direct implications on diagnosing and understanding the mechanical environment in neurodevelopment and neurological disorders

Mechanical properties of gray and white matter brain tissue by indentation.

Mechanical characterization of human brain tissue.

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.

Although many studies on the mechanical properties of brain tissue exist, some controversy concerning the possible differences in mechanical properties of white and gray matter tissues remains. Indentation experiments are conducted on white and gray matter tissues of various regions of the cerebrum and on tissue from the thalamus and the midbrain to study interregional differences. An advantage of indentation, when compared to standard rheological tests as often used for the characterization of brain tissue, is that it is a local test, requiring only a small volume of tissue to be homogeneous. Indentation tests are performed at different speeds and the force relaxation after a step indent is measured as well. White matter tissue is found to be stiffer than gray matter and to show more variation in response between different samples which is consistent with structural differences between white matter and gray matter. In addition to differences between white matter and gray matter, also different regions of brain tissue are compared.

http://www.mate.tue.nl/mate/pdfs/10923.pdf

Mechanical properties of brain tissue by indentation : interregional variation

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

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

To understand brain injuries better, the mechanical properties of brain tissue have been studied for 50 years; however, no universally accepted data set exists. The variation in material properties reported may be caused by differences in testing methods and protocols used. An overview of studies on the mechanical properties of brain tissue is given, focusing on testing methods. Moreover, the influence of important test conditions, such as temperature, anisotropy, and precompression was experimentally determined for shear deformation. The results measured at room temperature show a stiffer response than those measured at body temperature. By applying the time-temperature superposition, a horizontal shift factor a T =8.5-11 was found, which is in agreement with the values found in literature. Anisotropy of samples from the corona radiata was investigated by measuring the shear resistance for different directions in the sagittal, the coronal, and the transverse plane. The results measured in the coronal and the transverse plane were 1.3 and 1.25 times stiffer than the results obtained from the sagittal plane. The variation caused by anisotropy within the same plane of individual samples was found to range from 25% to 54%. The effect of precompression on shear results was investigated and was found to stiffen the sample response. Combinations of these and other factors (postmortem time, donor age, donor type, etc.) lead to large differences among different studies, depending on the different test conditions.

http://www.mate.tue.nl/~peters/Papers/2008/HrapkoEA_BrainTestCond_2008.pdf

The Influence of Test Conditions on Characterization of the Mechanical Properties of Brain Tissue

Towards a reliable characterisation of the mechanical behaviour of brain tissue: The effects of post-mortem time and sample preparation

http://www.mate.tue.nl/mate/pdfs/9418.pdf

M Matej Hrapko

Papers

Mechanical properties of brain tissue by indentation : interregional variation

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

The Influence of Test Conditions on Characterization of the Mechanical Properties of Brain Tissue

Towards a reliable characterisation of the mechanical behaviour of brain tissue: The effects of post-mortem time and sample preparation

Characterisation of the mechanical behaviour of brain tissue in compression and shear.