Project title:

dentification and validation of tissue-resident human Skeletal Stem Cells (hSSC) in the 1^st Carpo-metacarpal Joint (CMCJ) of osteoarthritic (OA) patients.

Grant Holder: MATTHEW P MURPHY

Position: Academic Clinical Fellow in Plastic Surgery,

North West (East) Deanery, University of Manchester, United Kingdom.

Date of award

15/11/2021

Start date for research

04/01/2022

Date of report

15/02/2024

Grant Awarded (i.e. £10,000)

10000

Is this an interim, or final, report

FINAL REPORT

FINAL REPORT

A sincere thanks to BSSH for allowing the extension of my Grant.

As part of the original team at Stanford who discovered the human skeletal stem cell (SSC), I have been fortunate to return to Stanford to continue my research during my ACF 6 month research block. During this time I have been involved in establishing a research project to identify the presence of tissue-resident SCC in the trapezium of human subjects who suffer from 1^st CMCJ OA.

By using Fluorescence-Activated Cell Sorting (FACS), I have successfully isolated human SSC from osteoarthritic trapezium. The tissue components where, by FACS, SSC appear to exist are the bone, cartilage and soft tissues (periosteum, ligament, tendon insertion). The SSC isolated from each tissue component have shown the ability to differentiate into bone, cartilage in vitro with an inability to differentiate into fat (Figure 1). These data suggest that these SSC behave in a similar fashion to the SSC isolated from other specimens previously investigated (femoral heads, foetal long bones, fracture samples etc).

While at Stanford I established a large animal porcine study investigating the key growth factors applied locally to cartilage defects that allow for robust regeneration of cartilage. Through Growth factor Enhanced Micro-fracturing (G.E.M) I have been able to regenerate cartilage in a large animal model defect model (Figure 2 and Figure 3).

The ability to repeatedly regenerate hyaline-like cartilage in a large animal model utilising FDA-Approved factors is a huge step forward in the goal of beginning first-in-human trials.

What is the relevance/value of this research to hand surgery:

By determining that osteoarthritic trapezium specimens do have a population of tissue-resident SSC, theoretically one should be able to activate the tissue-resident SSC population and encourage regeneration of cartilage through niche augmentation. The ability to regenerate cartilage will provide an additional tool in the hand surgeons armamentarium in treating 1^st CMCJ OA.

If final report, please provide bullet point list of conclusions/important findings

• Human SCC (hSSC) exist in the Trapezium of OA patients.
• The hSSC have the ability to differentiate into bone cartilage and stromal tissue in vitro and in vivo.
• Since beginning the project, we have also begun a large-animal study which confirms the ability to regenerate hyaline-like cartilage in porcine critical-size cartilage defects by augmenting the stem cell niche with BMP2 and inhibiting VEGF signalling through Cabozantinib.

Please list presentations based on work performed in this study

             IAPS 2022, TERMIS March 2023, RCSEng HUNTERIAN LECTURE 2023.

Please list publications based on work performed in this study

Main manuscript in progress (utilised as part of a large project). Chosen journal would be Nature Medicine or Cell Stem Cell. BSSH will be credited for their contribution.

The technique and factors have been fully patented and will be utilised for the development of an independent start-up company developing a product that can be used by surgeons performing MF/Joint resurfacing procedures.

Other publications during grant not utilising the BSSH funding.

Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration

PMID: 37232969, PMCID: PMC10217467 DOI: 10.3390/gels9050377.

Please state what additional research this study has/is leading to

• A large animal study preclinical translational study at Stanford.
• Pre-clinical work at Stanford in conjunction with University of Manchester.

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

• N/A

How has this grant awards helped your career development?

• YES
• This grant has provided me with the opportunity to continue my research in conjunction with Stanford. While at Stanford I was fortunate to utilise many of their reagents for experiments however with this grant I was able to replace some of those components utilised as well as ensuring that UoM have key reagents that can be utilised for future experiments in the UK.