The mechanics of the collagen fibrillar network in ageing cartilage

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The connective tissues in our bodies are made up of both cells as well as a fibrous matrix around the cells. The fibrous matrix plays the major role in giving the tissue its mechanical properties needed for function. Despite having very different functions, the fibrous matrices of different soft tissues are at the molecular level made up of similar building blocks: collagen molecules, long sugar chains linked by protein (proteoglycans), and water. In particular, collagen molecules form long thin fibrils, which assemble into a network along with the gel-like material of proteoglycans and water. To achieve a range of diverse functions from the same building blocks, different soft tissues often vary the relative proportion of fibrils to the proteoglycan gel, or their orientation or interconnection to form complex composite materials at very small scales, below the thickness of a human hair. When we age, the properties of our connective tissues tend to deteriorate: e.g. skin becomes stiffer, and cartilage breaks down in osteoarthritis. These adverse changes arise from changes in either the intrinsic properties of the building blocks, or in their architecture. Because these changes occur at very small (nanometre) length scales, it is challenging to find out both the change and its effect on mechanics. To address this, our group has developed a high resolution X-ray imaging technique which works like a diffraction grating for collagen: it picks up regularities in the arrangement of the nanoscale collagen fibril networks in tissues, and when used with a very bright X-ray source like a synchrotron, can track how the fibrils stretch, reorient or otherwise respond to loads. In this project, we will apply this method to understand how the nanoscale mechanics of the collagen fibrillar network in cartilage changes in ageing. Articular cartilage serves as a frictionless bearing surface in joints, and cushions the load transfer between bones. If overloaded, the fibrous matrix breaks down and leads to osteoarthritis, joint pain and immobility. We aim to understand how the compositional changes in collagen link to the alterations in its nanoscale mechanics - and eventually to joint breakdown. We will combine the X-ray technique with high-level characterisation of the protein composition and structure in the tissue as it ages. Such a combination is completely novel: the X-ray technique has not been applied to cartilage before, and its combination with proteomics enables a clear link between structural change and mechanical function.In cartilage, the collagen fibrillar network resists the swelling pressure of the proteoglycan gel. We first aim to understand how this load-balance changes in ageing, and by varying the chemical structure and relative proportion of different components in cartilage, to understand the mechanisms linking changes at the molecular level to disruption of mechanical equilibrium. Secondly, we will study real-time deformation of collagen fibrils as they are subjected to the types of load observed in real life and how ageing affects these dynamics. This is especially relevant because ageing leads to fibrillated and disrupted cartilage, but the mechanism by which collagen fibrils fail to resist loading is not understood. We will then focus on two types of relevant biomechanics: repeated loading or local traumatic impact. First, we will investigate whether the fibrillar response to repetitive loading is altered in ageing. Then, we will map, with micron-resolution, how collagen fibrils around the site of a local injury deform, testing the hypothesis that compositional change in ageing enables the damage to spread across the joint. To achieve these aims, we have brought together complementary expertise in X-ray nanomechanics (Gupta), cartilage mechanics (Knight), proteomics of ageing tissues (Swift) and synchrotron technology (Terrill), all of whom are internationally leading in their fields.