Addressing Shoulder Pain: Single-cell led repurposing of injectables for subacromial impingement syndrome

RESEARCH OUTLINE

This full-time DPhil post at the Botnar Institute will use cutting edge laboratory and computational methods to interrogate the mechanisms underlying shoulder pain. You will work as part of a collaborative, interdisciplinary team who will provide an exciting range of training opportunities.

Shoulder pain is common with a reported prevalence of 6% in the general population rising to 21% in those over the age of 70 years of age. It accounts for 2.4% of all primary care consultations in the UK with a mean annual cost of €4139, which is before any additional costs from sick leave or secondary care are considered. Irrespective of the underlying aetiology around 10% of all patients with shoulder pain will have either a subacromial or glenohumeral corticosteroid injection and, in many cases, receive repeated injections.

Subacromial pain

Subacromial impingement accounts for 70% of all shoulder-pain. The pain originates from the subacromial space, an area consisting of the rotator cuff tendons and overlying subacromial bursa. The intrinsic theory of subacromial pain holds that pathological inflammation within these structures is the underlying cause. Histological studies of the subacromial bursa have demonstrated T-cell, B-cell and macrophages infiltration in impingement syndrome.  However, to date, there has been no detailed assessment of the cellular constituents and phenotypes of the subacromial bursa in health and disease.

Glenohumeral pain

Glenohumeral osteoarthritis is a common cause of shoulder-pain in those over 60 years-of-age and the third most common large joint affected by degenerative joint disease. Synovial inflammation, macrophage infiltration and fibrosis have been implicated in the pathogenesis, and is the basis for initial non-operative treatment with corticosteroid injections. However, the systematic molecular profiling of glenohumeral synovium is also notably absent.

Clinical need

Current national guidelines recommend anti-inflammatory corticosteroid injections, as first line for subacromial impingement and glenohumeral arthritis.  However, corticosteroid injections offer only a marginal, and short-term, benefit over local anaesthetic alone. Current guidance also limits the number of subacromial bursal injections, due to concerns that corticosteroids may cause long-term tendon damage. Multiple small trials have investigated novel injectables; including: high-volume corticosteroid, hyaluronic acid and platelet-rich plasma but without any demonstrable benefit, and none with any supporting laboratory data. There is a clear clinical need to identify new injectables, robustly supported by early phase data, for the treatment of subacromial and glenohumeral shoulder pain.

Aims of this DPhil

The focus of this project is to improve understanding of the underlying biological processes occurring in patients with impingement syndrome and glenohumeral osteoarthritis. The project will involve collection of subacromial bursa and glenohumeral synovium from patients undergoing planned shoulder procedures as part of their routine clinical care pathway. This tissue will then be studied using cutting edge laboratory techniques, including single-cell sequencing, imaging, machine learning and in vitro assays to further our understanding of the underlying pathological processes, including inflammation. Key questions asked will be:

1. What are the distinct cellular types and states present in bursa and synovium from impingement syndrome compared to healthy controls?

2. What are the distinct cellular types and states in healthy compared to osteoarthritic glenohumeral bursa and synovium?

3. Are there unique or unifying cell types or pathways active in impingement syndrome compared to glenohumeral osteoarthritis? Does this provide insights to how recurrent trauma affects healthy shoulder synovium?

4. Which existing therapeutics could be repurposed to revert cell types within bursa from glenohumeral osteoarthritic or impingement syndrome patients towards a healthy phenotype?

We aim to characterise the distinct cellular populations and phenotypes present in bursal and synovial tissue from the shoulder. Diseased bursal tissue from impingement syndrome will be compared with healthy shoulder bursal tissues from patients undergoing surgical procedures for shoulder instability. A further comparison will be made for osteoarthritic glenohumeral synovium, against healthy synovial tissue from patients undergoing surgical procedures for impingement syndrome and also for shoulder instability. We have elected to have a second control group to strengthen our scientific comparison with osteoarthritis synovium and enable a secondary exploration of how recurrent trauma effects healthy shoulder synovium. 

An in-silico analysis will then permit a phenotypic screen of existing therapeutics, capable of reversing the phenotype of single or multiple cell types towards a healthy phenotype. In-vitro characterisation of putative candidates will then enable initial validation. While our data will also facilitate a concurrent ‘target based’ approach, our focus is on a phenotype driven drug repurposing approach to shorten the lead time to potential clinical adoption.

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

KEY REFERENCES

1. Klatte-Schulz F, Thiele K, Scheibel M, Duda GN, Wildemann B. Subacromial Bursa: A Neglected Tissue Is Gaining More and More Attention in Clinical and Experimental Research. Cells. 2022 Feb 14;11(4):663. https://doi.org/10.1038/s41584-021-00600-7
2. 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

KEYWORDS

Osteoarthritis, Single-Cell Sequencing, Therapeutic, Pain

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 Mathew Baldwin and Associate Professor Steve Gwilym.  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 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 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.

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