Scaphoid fractures: Identifying the cellular targets and key molecular pathways for improved repair outcomes

This full-time DPhil post at the Botnar Institute will use cutting edge laboratory and computational methods to interrogate the mechanisms underlying failed repair following scaphoid fracture. This work will contribute substantially to an unmet clinical need, and deliver critical next-generation reference datasets of healthy and diseased wrist bones to the Human Cell Atlas. You will work as part of a dynamic, interdisciplinary team who will provide an exciting range of training opportunities.

Scaphoid fracture is the most common type of wrist fracture. It affects young active individuals, and unfortunately of those who present early with relatively undisplaced fractures around 5 to 10% of fractures do not unite.¹ Of those who present with significant displacement or in a delayed fashion, the rate of failure to heal is even higher.  This means that patients often need surgery, but these are also increasingly prone to failure with greater delays from the original injury. Patients with failed repairs are more likely to suffer arthritis and disability, given the age of patients with fractures this is a significant individual and societal burden.

Our bones are composed of a wealth of different cell types that maintain bone health and drive repair following fracture. In the long bones, immune cells are particularly important at all stages of fracture repair. The scaphoid has a reduced blood supply and it is hypothesised that this may limit repair, particulary limiting the influx of immune and stem cells to the fracture site. We also do not know the critical immune and non-immune cells and molecules that drive scaphoid bone repair.

As part of this DPhil you will process bone samples collected from the clinical team. You will use these samples for next-generation sequencing, imaging, computational analysis and to study molecular dynamics in  novel multi-lineage 3D organotypic models^2,3. Ultimately this suite of methods and skills will allow you to identify new treatment strategies to improve outcomes for scaphoid fracture patients. The DPhil will include:

1. A systematic review of the histopathological and molecular changes in scaphoid non-union.
2. A critical literature review on current understanding of the cellular and molecular drivers of scaphoid repair and non-union, and comparison with knowledge on bone generally.
3. Delivery of a temporal cellular atlas (bulk and single-nuclei RNAseq) of human scaphoid bone in health, following fracture and following failed repair. This will include computational analysis to identify critical changes in immune- and non-immune cell subset abundance, cell-cell interactions and differentially regulated pathways that may drive or inhibit repair.
4. Imaging validation of critical cell types, pathways and interactions to build a spatial atlas of scaphoid bone in health, fracture and repair failure.
5. Using in-house multi-lineage in vitro models, you will enrich and deplete identified cell subsets and pathways you hypothesise are vital for scaphoid repair and repair failure . You will use functional assays, imaging and sequencing methods to assess impact of these changes in cells and pathways in driving or inhibiting successful bone formation.

References

1. https://doi.org/10.1302/2633-1462.211.bjo-2021-0146
2. https://doi.org/10.1002/adbi.201700156
3. https://doi.org/10.1038/s41584-021-00600-7

SELECTION CRITERIA

Essential

A degree in a biomedical, medical or related subject 

Excellent communication skills

Experience of writing scientific essays, documents or dissertations

Experience of working or studying within a research environment

Willingness to learn computational and sequencing methods

Desirable

Experience of processing human tissue samples

Laboratory and/or computational analysis experience of sequencing methods

Imaging experience

BENEFITS

The Botnar Research Centre – part of Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS) - plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which  leads research and education into the causes of musculoskeletal diseases and their treatments.

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 and translational immunology. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and participate at regular seminars/workshops within the Department/their research team. Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments.

We will ensure hands-on laboratory and computational training and embedding within our international Tendon Seed Network and Ancestry Network. This will provide the candidate with laboratory and computational guidance and support both locally and internationally. Qualitative work will be supported through our long-standing population health and clinical trial unit collaborators.

Finally, the student will be expected to regularly present data in Departmental seminars, the Soft Tissue Repair group & multi-team computational meetings. Attendance at National and International meetings will also be encouraged, for which financial support is available.

HOW TO APPLY AND APPLICATION REQUIREMENTS

You should contact Associate Professor Sarah Snelling or NDORMS Graduate Studies (graduate.studies@ndorms.ox.ac.uk).  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 2024.  Applications should be made to the following programme using the specified course code (for online application):

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

Further information can be found here.