Fibres formed from collagen occur in a diverse range of tissues in the body (e.g. cartilage, bone, tendons, ligaments, cornea, blood vessels, and skin) and are the main providers of tensile strength. Changes in the organisation of collagen fibrils that occur after injury (e.g. burns, lacerations, or substance abuse) and disease (e.g. fibrosis, osteoarthritis, cancer) result in tissue failure and loss of biological function.
The aim of this PhD project is to understand the formation of the structural tissues and higher order assemblies of collagen fibres and fibrils, and how mechanical strength and other properties are generated and regulated.
This will be achieved by using a combination high-end electron microscopy and biomechanics to understand the structure and biomechanics of single fibrils and fibrillar assemblies.
Mechanical properties and 3D ultrastructure will be related at different stages in development. The collagen fibril has a hierarchical structure, consisting of fibrils and micro-fibrils. It is known that the size and packing density of sub-filaments changes during development, but no correlated study of mechanical and structural properties has been done before.
Collagen fibrils in tendons and in tendon-like constructs will be imaged using cryoTEM and serial block-face SEM imaging (Gatan-3view). The sub-structure of individual filaments and small fragments of higher order material will be determined by cryoTEM tomography (FEI Polara TEM), on frozen fragmented material. New visualisation techniques will be developed in order to track filaments within fibrils in 3D volumes determined. State-of-the-art mechanical rigs developed in the Kader lab will be used to measure mechanical and viscoelastic properties of the fibres.
Attempts in academia and industry to make replacement tissues from animal-derived collagen have been disappointing. Research on how the fibril is constructed will help towards development of synthetic materials that can replace the use of collagen in biomedical applications.
This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.
Kalson, N. S., Holmes, D. F., Herchenhan, A., Lu, Y, Starborg, T. and Kadler, K. E. (2011) Slow stretching that mimics embryonic growth rate stimulates structural and mechanical development of tendon-like tissue in vitro. Developmental Dynamics, in press.
Kalson, N. S., Holmes, D. F., Kapacee, Z., Otermin, I., Lu, Y., Ennos, R. Elizabeth G. Canty-Laird and Kadler, K. E. (2010) An experimental model for studying the biomechanics of embryonic tendon: Evidence that the development of mechanical properties depends on the actinomyosin machinery. Matrix Biology 29: 678-689.
Holmes, D. F. and Kadler, K. E. (2006) The 10+4 microfibril structure of thin cartilage fibrils. Proceedings of the National Academy of Sciences U. S. A. 103(46): 17249-17254
Holmes, D. F., Gilpin, C. J., Baldock, C., Ziesa, U., Koster, A. and Kadler, K. E. (2001) Corneal collagen fibril structure in three dimensions: structural insights into fibril assembly, mechanical properties and tissue organisation. Proceedings of the National Academy of Sciences U. S. A. 98: 7307-7312
Beecher N, Roseman, AM, Jowitt TA, Berry R, Troilo H, Kammerer RA, Shuttleworth CA, Kielty CM, Baldock C. Collagen VI conformation of A-domain arrays and microfibril architecture. J Biol Chem (2011) PMID: 21908605.