Muscle Connective Tissue in Limb Development and Disease

The objective of this work is to understand how the disruption of the muscle connective tissue contributes to the limb soft-tissue defects in radial dysplasia. In parallel, the researchers will investigate the role of muscle connective tissue in normal limb development.

Study Overview

• Status: Recruiting
• Conditions: Radial Dysplasia
• Intervention / Treatment: Procedure: Tissue biopsy

Detailed Description

The objective of this work is to understand the origins of the soft tissue defects in a disabling, disfiguring limb anomaly called radial dysplasia, and what mechanisms of normal limb development have been disrupted in these patients to produce their phenotype. The investigators aim to use this knowledge to improve their treatment. Currently, despite sophisticated surgical treatment, the limb malformation the child is born with typically recurs as they grow: it is thus an 'unsolved problem'.

The investigators have previously shown, in an experimental mouse model of radial dysplasia, the underlying soft tissue problem is a change in the muscle connective tissue and its derivatives, causing abnormal soft-tissue patterning. The investigators wish to expand this work into the investigators' patient population by comparing samples of post-natal muscle connective tissue derivatives from radial dysplasia patients with control samples.

The investigators will ask patients undergoing corrective hand surgery to let the investigators take small tissue samples during their planned operations. The investigators will also ask patients having other forms of hand surgery, such as surgery for hand injuries, to let the investigators take similar samples for comparison. In either case, their scar and peri-operative treatment will be unchanged. The investigators will examine the tissue samples in the investigators' laboratory to look for changes in tissue architecture, cellular composition, cell signalling, and how they behave when grown in culture. The investigators will also make attempts to derive cell lines from biopsy samples to use in further studies, exploring cellular phenotype and functional capacity.

Simultaneously, the investigators will look at the long-term surgical outcomes and the range of genetic changes in the investigators' patient population. Eligible patients will be referred for consideration in the (separate) 100,000 genome project; this should further expand the investigators' knowledge of the genetic changes underlying limb anomalies. The ability to combine data on genotype, long-term phenotype and soft tissue changes will give a comprehensive overview of the condition. The investigators expect this to lead to a better understanding of patient subgroups, and to provide a rational basis for improved treatment approaches.

• Study Type: Observational
• Enrollment (Anticipated): 45

Contacts and Locations

• Study Contact: Name: Malcolm Logan, BSc, PhD; Phone Number: 02078486886; Email: malcolm.logan@kcl.ac.uk
• Study Contact Backup: Name: George Murphy; Email: george.murphy@gosh.nhs.uk

Study Locations

• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Recruiting
    • Royal Free Hospital
    • Contact: Bran Sivakumar; Phone Number: 5222 02074059200; Email: branavan.sivakumar@gosh.nhs.uk
    • Principal Investigator: Bran Sivakumar
    • Principal Investigator: George Murphy
  • London, United Kingdom, WC1N 3JH
    • Recruiting
    • Great Ormond Street Hospital for Children NHS Foundation Trust
    • Contact: Bran Sivakumar; Phone Number: 5222 02074059200; Email: branavan.sivakumar@gosh.nhs.uk
    • Principal Investigator: Bran Sivakumar
    • Contact: Gill Smith; Phone Number: 5222 02074059200; Email: gill.smith@gosh.nhs.uk
    • Sub-Investigator: Gill Smith
    • Sub-Investigator: George Murphy
  • London, United Kingdom, SW10 9NH
    • Recruiting
    • Chelsea and Westminster Hospital NHS Foundation Trust
    • Contact: Gill Smith; Email: gill.smith@gosh.nhs.uk
    • Principal Investigator: Gill Smith, FRCS(Plast)
    • Principal Investigator: George Murphy, MA, MRCS
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • Recruiting
      • Oxford University Hospitals
      • Contact: Lucy Cogswell, MA, BMBCh, FRCS Plast; Phone Number: 0300 304 7777
      • Contact: George Murphy, MA, MBBS, MRCS; Email: george.murphy@gosh.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Cases - Any patient attending Great Ormond Street Hospital for reconstructive hand surgery for radial dysplasia.

Controls - Any patient attending Oxford University Hospitals, Chelsea and Westminster or the Royal Free Hospital for reconstructive hand surgery.

Description

Cases

Inclusion Criteria:

• Patients with a clinical diagnosis of radial dysplasia, requiring reconstructive surgery
• Either sex
• Informed (parental) consent to participate

Exclusion Criteria:

• Patients with a clinical diagnosis of radial dysplasia, but not requiring reconstructive surgery
• Patients with a diagnosis other than radial dysplasia
• Patients with extensive previous scarring to their forearm and hand.
• Patients with a significant pathological skin or soft tissue lesion at the donor site.

Controls

Inclusion Criteria:

• Patients with an injury requiring reconstructive surgery
• Either sex
• Informed (parental) consent to participate

Exclusion Criteria:

• Patients with extensive previous scarring to their forearm and hand.
• Patients with a significant pathological skin or soft tissue lesion at the donor site.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Radial dysplasia patients; Recruited participants will have 2-3 small tissue biopsy samples taken during 1-2 of their planned reconstructive surgical procedures for radial dysplasia, whilst under general anaesthesia in the operating theatre. Samples will be taken by scalpel or scissors, by the operating surgeon, from within the surgical site in the forearm and hand. The skin incision and deep dissection will have to be made as part of the normal course of reconstructive surgery, regardless of participation in this study.	Procedure: Tissue biopsy; Sampling of tissue as described.
Control patients; Recruited participants will have 2-3 small tissue biopsy samples taken during their planned reconstructive surgery for hand trauma, whilst under general anaesthesia in the operating theatre. Samples will be taken by scalpel or scissors, by the operating surgeon, from within the surgical site in the forearm and hand. The skin incision and deep dissection will have to be made as part of the normal course of reconstructive surgery, regardless of participation in this study.	Procedure: Tissue biopsy; Sampling of tissue as described.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterisation of muscle connective tissue derivatives - structure	The characterization of any structural difference in tissue organisation within muscle connective tissue derivatives, comparing normal control patients to patients with radial dysplasia.	3 years
Characterisation of muscle connective tissue derivatives - function	The characterization of any functional difference in gene expression within muscle connective tissue derivatives, comparing normal control patients to patients with radial dysplasia.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of biomarker(s).	The identification of a novel biomarker (or biomarkers) for human muscle connective tissue derivatives, which may potentially serve as a diagnostic or prognostic tool	3 years
Identification of muscle connective tissue progenitor-cell pool.	The potential identification of a stem-cell-like or progenitor-cell pool for muscle connective tissue derivatives in mature soft tissue.	3 years

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Royal Free Hospital NHS Foundation Trust; Chelsea and Westminster NHS Foundation Trust; Great Ormond Street Hospital for Children NHS Foundation Trust
• Investigators: Study Chair: Malcolm Logan, PhD, King's College London; Principal Investigator: Bran Sivakumar, FRCS(Plast), Great Ormond Street Hospital for Children NHS Foundation Trust; Principal Investigator: Gill Smith, FRCS(Plast), Great Ormond Street Hospital for Children NHS Foundation Trust; Principal Investigator: George Murphy, MA, MRCS, Great Ormond Street Hospital for Children NHS Foundation Trust; Principal Investigator: Lucy Cogswell, MA, BMBCh, FRCS Plast, Oxford University Hospitals

Publications and helpful links

Helpful Links

• Study website - for version control & distribution of patient information leaflets / consent forms.

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2016
• Primary Completion (Anticipated): February 1, 2026
• Study Completion (Anticipated): August 1, 2036

Study Registration Dates

• First Submitted: November 16, 2015
• First Submitted That Met QC Criteria: November 19, 2015
• First Posted (Estimate): November 20, 2015

Study Record Updates

• Last Update Posted (Actual): April 21, 2022
• Last Update Submitted That Met QC Criteria: April 13, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Muscle connective tissue; Small leucine-rich proteoglycans; Limb development
• Other Study ID Numbers: 14SG01; 15/LO/2085 (Other Identifier: London Hampstead REC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO