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Manipulating the environment of cultured stem cells to optomise the structure and mechanical properties of cartilaginous tissue constructs


Project Description

Lower back pain (LBP) is a debilitating, age-related, spinal disease which is a major burden on society. Degeneration of the intervertebral disc (IVD) is a key cause of LBP. However, current treatment options are predominantly limited to relieving pain. As a consequence, there is a pressing need to develop tissue engineered IVD replacements and other stem-cell based therapies.

Degeneration of the IVD begins in the inner nucleus pulposus (NP) which is composed primarily of collagen II and the large proteoglycan aggrecan. Current tissue engineering strategies, which concentrate on optimising the ratio of aggrecan to collagen, have failed to replicate NP mechanical properties. We have recently shown that: i) only 0.5% of aggrecan molecules are in the intact form in bovine NP and ii) manipulation of local environmental conditions for cultured NP cells influences aggrecan structure and micromechanical properties. In parallel studies we have shown that micro-computed X-ray tomography (microCT) can be used to visualise and measure the 3D micro-structure and -strain in native IVD. This PhD will bring together these experimental approaches to optimise the molecular structure and micromechanics of mesenchymal stem cell constructs. In order to achieve this aim the student will gain experience in IVD biology, stem cell culture, atomic force microscopy and microCT. There will be opportunity to work with leading experts at the Manchester X-ray Imaging Facility (www.mxif.manchester.ac.uk), Diamond Light Source Synchrotron (www.diamond.ac.uk). Oregon State University (http://oregonstate.edu/) and the Wellcome Trust Centre for Cell Matrix Research (www.wellcome-matrix.org).

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in biochemistry, biophysics, cell biology and related areas. Candidates with experience in stem cell biology, regenerative medicine or cartilage biology are encouraged to apply.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

Walton LA, Bradley RS, Withers PJ, Newton VL, Watson REB, Austin C, Sherratt MJ. 2015. Morphological characterisation of unstained and intact tissue micro-architecture by X-ray computed micro- and nano-tomography. Scientific Reports. 5, 10074.

McConnell JC, O’Connell OV, Brennan K, Weiping L, Howe M, Joseph L, Lim Y, Leek A Waddington R, Rogan J, Astley A, Gandhi A, Kirwan CC, Sherratt MJ, Streuli CH. 2016. Increased peri-ductal collagen micro-organization may contribute to raised mammographic density. Breast Cancer Research. 18, 5.

Clarke LE, McConnell JC, Sherratt MJ, Derby B, Richardson SM, Hoyland JA. 2014. Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs. Arthritis Research and Therapy. 16,R67.

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