Osteogenic-angiogenic coupling in fracture repair - Why do some patients fail to heal?

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.

Although bone is commonly thought to heal well following fracture, failure to repair can still occur and is hard to treat. Scaphoid fracture is the most common type of wrist fracture and is often affected by failure to heal. 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 osteoarthritis 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, alongside osteogenic cells and angiogenic (blood vessel) cells. 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 (osteogenic) to the fracture site. The interaction between angiogenic and osteogenic cells is likely important to fracture repair, but we don’t know how this communication breaks down when repair fails. 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 between osteogenic and angiogenic cells 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.

For students interested in pursuing an MSc by Research, a project addressing a subset of the aims above will be considered.

REFERENCES 

1. Dean BJF. The management of suspected scaphoid fractures in the UK: a national cross-sectional study. Bone Jt Open. 2021;2(11):997-1003. https://doi.org/10.1302/2633-1462.211.bjo-2021-0146
2. A. Iordachescu, H. D. Amin, S. M. Rankin, R. L. Williams, C. Yapp, A. Bannerman, A. Pacureanu, O. Addison, P. A. Hulley, L. M. Grover, Adv. Biosys. 2018, 2, 1700156. https://doi.org/10.1002/adbi.201700156
3. Baldwin M, Buckley CD, Guilak F, Hulley P, Cribbs AP, Snelling S. A roadmap for delivering a human musculoskeletal cell atlas. Nat Rev Rheumatol. 2023 Nov;19(11):738-752. https://doi.org/10.1038/s41584-023-01031-2

Key Words

Fracture, Bone, Single-Cell Sequencing, Angiogenesis, Immune

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

SUPERVISORY TEAM AND RESEARCH GROUP

The supervisor team are Associate Professor Sarah Snelling, Dr Benjamin Dean, Dr Mathew Baldwin and Associate Professor Philippa Hulley.  They will provide you with essential oversight and support for the clinical, laboratory and computational aspects of your DPhil.

You will join out interdisciplinary and collaborative research teams. You will be based primarily in Associate Professor Snelling’s team of laboratory and computational postdoctoral scientists, clinical academics, research assistants and DPhil students. This will be enriched by regular supervisory team meetings and weekly joint lab meetings wth other supervisory team members.

TRAINING

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

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 2025.  Applications should be made to the following programme, using the specified course code:

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

Further information can be found here.

The Botnar Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body. The Botnar and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).