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Arthrofibrosis: a comparative study of persistent and resolving disease at single cell resolution (NDORMS 2023/4)


   Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences

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  Prof Stephanie Dakin, Prof Christopher Buckley, Prof Andrew Price  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Arthrofibrosis is the pathologic stiffening of a joint due to an exaggerated inflammatory fibrotic response leading to the development of non-compliant scar tissue1. As a common complication following total knee arthroplasty, arthrofibrosis is a significant cause of pain and disability for patients, with up to 25% of patients requiring additional surgery to restore adequate joint motion2. Conversely, frozen shoulder affecting the shoulder joint capsule is an example of an inflammatory fibrotic joint disease that is uniquely self-limiting. By studying frozen shoulder patient tissues and cells, we identified distinct populations of tissue resident cells provide a resolving fibrotic niche conducive to restoring homeostasis in the shoulder capsule.

The precise cellular and molecular cues that determine whether inflammatory fibrosis persists or resolves remain to be identified. Knowledge from how fibrosis can resolve in the shoulder joint capsule can inform the biological cues to push persistent fibrotic diseases like knee arthrofibrosis towards a resolving pathway. This project will create a cellular and spatial atlas of the human knee capsule during development, health and fibrotic disease such that the cell populations can be directly compared with those in the shoulder joint capsule where fibrosis resolves. The project will also utilise established tissue culture models as functional assays to identify the cell types and molecules causal to fibrosis and resolution. Findings from this research will identify new therapeutic strategies to promote resolution of knee arthrofibrosis, addressing an unmet clinical patient requirement, and help resolve persistent inflammatory fibrotic pathologies in other tissues.

Training

The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. Training will be provided in techniques including scRNAseq, histology, multiplex immunohistochemistry and tissue culture utilising 2D & 3D models.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will also be required to attend regular seminars within the Department and those relevant in the wider University.

Students will be expected to present data regularly in Departmental seminars, the Dakin Soft Tissue Joint Disease Group and to attend external conferences to present their research globally, with limited financial support from the Department.

Students will also have the opportunity to work closely with the Buckley & Price Research Groups.

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

How to Apply

The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Graduate Studies Office ([Email Address Removed]) who will be able to advise you of the essential requirements. Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable).

The application guide and form is found online and the DPhil will commence in October 2023. Applications should be made to one of the following programmes using the specified course code:

D.Phil in Musculoskeletal Sciences (course code: RD_ML2)

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford


References

1. Thompson, R., et al. Arthrofibrosis After Total Knee Arthroplasty: Pathophysiology, Diagnosis, and Management. Orthop Clin North Am 50, 269-279 (2019).
2. Stephenson, J.J., Quimbo, R.A. & Gu, T. Knee-attributable medical costs and risk of re-surgery among patients utilizing non-surgical treatment options for knee arthrofibrosis in a managed care population. Curr Med Res Opin 26, 1109-1118 (2010).
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