Quantifying Age-related Changes in the Mechanical Properties of Tissues

Lead Research Organisation: University of Manchester
Department Name: Materials

Abstract

As people get older the mechanical properties of the body change and many components of the cardiovascular system become stiffer. Stiffening of the arteries has been implicated in increased mortality from heart failure, stroke and aneurysms. Arterial stiffening can also occur through the action of other age-related conditions, e.g. raised blood pressure, diabetes and kidney failure. Collectively, these failures of the cardiovascular system are the most common cause of death in the western world. Other tissues within the body can also deteriorate with time and although not life threatening, can seriously affect the quality of life, e.g. debilitating lower back pain is associated with the mechanical deterioration of the intervertebral disc. Cosmetic changes with age are also important for personal well being and the global market in anti-ageing treatments is forecast to exceed $250 billion by 2015; development of such personal care products is an important part of the British economy. Thus understanding how the ageing process leads to the stiffening of tissue is important in improving life expectancy and importantly, improving the well being of the population as a greater proportion of the population is living longer.
One obstacle to our understanding of how ageing changes the mechanical properties of tissue is the relatively primitive methods currently used to measure them. These were originally developed to measure the properties of engineering materials such as metals and polymers; these are much stiffer than biological materials and are simpler in composition. However, recent developments in mechanical testing methods allow us to now use a technique called nanoindentation that can be used to measure the mechanical properties, not only of tissue but also of the microscopic components that cause the changes in properties with age. By further developing this new technique we will be able to explore how changes in these components that occur during ageing, which can be monitored using microscope observation, degrade the stiffness and other mechanical properties. Because the volumes of material sampled are so small, the technique will allow us to measure the properties of human tissue using a minimally invasive approach. This can then be used to monitor the progress of ageing and chronic disease and any treatment used to alleviate symptoms.

Technical Summary

Age-related changes in the mechanical properties of dynamic tissues within the pulmonary, cardiovascular and musculoskeletal systems profoundly affect human morbidity and mortality. Despite the immense clinical and economic burdens that result from disorders such as hypertension and low back pain, to date attempts to identify and localize the key molecular mechanisms which cause age-related loss of tissue compliance and elastic recoil have been limited by inadequate methods for measuring local mechanical properties of tissue. Therefore, we will develop nanoindentation techniques to map and quantify micrometer-scale changes in tissue mechanical properties to individual tissue components.

Nanoindentation is routinely used in materials science to measure the mechanical properties of small volumes of engineering materials, with micrometre spatial resolution. Using this technique, we will determine how age-related changes in the structure of soft tissue cryo-sections influence local changes in mechanical properties and hence understand the mechanisms that lead to changes in bulk tissue behaviour. To achieve this we have specified a modified commercial nanoindentation platform, to include a high quality optical microscope that utilizes molecular auto-fluorescence and differential interference contrast to identify and then quantify the micromechanical properties of discrete tissue structures. Although we have successfully used nanoindentation to characterize tissue mechanical properties in Manchester, further development of the technique will be undertaken to develop constitutive laws that describe tissue mechanical behaviour and link it to tissue microstructure.

In order to achieve these goals we have assembled a multidisciplinary team of materials scientists, life scientists and clinicians to apply this technique to research projects in three organ system where age-related mechanical change profoundly affect human mortality, morbidity and well-being. These are: 1) the increase in stiffness of the vasculature that occurs during both ageing and age-related disorders such as diabetes; 2) age-related degeneration of the intervertebral disc which is associated with low back pain; and 3) commercially important changes in the mechanical properties of ageing skin. A further advantage of the technology, is that by developing its use with standard histological specimens, we can provide mechanical analysis using very small quantities of tissue samples consistent with minimally invasive biopsies. Once these techniques are established and validated we will disseminate the details via scientific publications and invite the wider research community to utilise the approach.

Publications

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Akhtar R (2016) Frequency-modulated atomic force microscopy localises viscoelastic remodelling in the ageing sheep aorta. in Journal of the mechanical behavior of biomedical materials

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Newton VL (2017) Novel approaches to characterize age-related remodelling of the dermal-epidermal junction in 2D, 3D and in vivo. in Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)

 
Title Nanoindentation of Biological Tissues 
Description This is a method of assaying the mechanical properties of animal tissue using conventional histological slices of the material under study. 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact This has been used for some of the first studies to investigate the stiffening of human cornea as a treatment for Keratokonus 
 
Description Stiffness of Vascular Tissue 
Organisation Manchester Royal Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution Supplying specialist mechanical measurement techniques
Collaborator Contribution Supply of materials, clinical background data
Impact Researcg grant application in preparation
Start Year 2012
 
Description Stiffness of Vascular Tissue 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Supplying specialist mechanical measurement techniques
Collaborator Contribution Supply of materials, clinical background data
Impact Researcg grant application in preparation
Start Year 2012
 
Description Stand at Blue Dot Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Samples being taken from the lab to blue dot.
Year(s) Of Engagement Activity 2017,2018
 
Description Stand at Community Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Stand at the community festival including leapfrog printer, doodle pen Activity and hands on samples.
Year(s) Of Engagement Activity 2017,2018
 
Description Stand at Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Stand at Blue Dot Science and Music Festival. 3D printing demonstration, Hands on demonstration printing conductors, Audience mainly children and young adults, team interacted and fielded questions in 3D printing and printed electronics.
Year(s) Of Engagement Activity 2019
 
Description Stand at Science Festival (Blue Dot festival, July 2019) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Activity was a stand at science festival showing how materials fabrication methods could be used to make biological constructs. Introduced concept of an organ on a chip. Some hands on demonstrations for participants. Audience general public with focus on High school Age children.
Year(s) Of Engagement Activity 2019
 
Description Visit from Altrincham Grammar School for Boys 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 3D printing Workshop
Year(s) Of Engagement Activity 2017