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Orthopaedic Proceedings
Vol. 106-B, Issue SUPP_9 | Pages 11 - 11
16 May 2024
Kendal A Brown R Loizou C Rogers M Sharp R Carr A
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Tendinopathy can commonly occur around the foot and ankle resulting in isolated rupture, debilitating pain and degenerative foot deformity. The pathophysiology and key cells involved are not fully understood. This is partly because the dense collagen matrix that surrounds relatively few resident cells limits the ability of previous techniques to identify and target those cells of interest. In this study, we apply novel single cell RNA sequencing (CITE-Seq) techniques to healthy and tendinopathic foot/ankle tendons. For the first time we have identified multiple sub-populations of cells in human tendons. These findings challenge the view that there is a single principal tendon cell type and open new avenues for further study. Healthy tendon samples were obtained from patients undergoing tendon transfer procedures; including tibialis posterior and FHL. Diseased tendon samples were obtained during debridement of intractable Achilles and peroneal tendinopathy, and during fusion of degenerative joints. Single cell RNA sequencing with surface proteomic analysis identified 10 sub-populations of human tendon derived cells. These included groups expressing genes associated with fibro-adipogenic progenitors (FAPs) as well as ITGA7+VCAM1- recently described in mouse muscle but, as yet, not human tendon. In addition we have identified previously unrecognised sub-classes of collagen type 1 associated tendon cells. Each sub-class expresses a different set of extra-cellular matrix genes suggesting they each play a unique role in maintaining the structural integrity of normal tendon. Diseased tendon harboured a greater proportion of macrophages and cytotoxic lymphocytes than healthy tendon. This inflammatory response is potentially driven by resident tendon fibroblasts which show increased expression of pro-inflammatory cytokines. Finally, identification of a previously unknown sub-population of cells found predominantly in tendinopathic tissue offers new insight into the underlying pathophysiology. Further work aims to identify novel proteins targets for possible therapeutic pathways.


Orthopaedic Proceedings
Vol. 102-B, Issue SUPP_5 | Pages 1 - 1
1 Jul 2020
Fernquest S Palmer A Gimpel M Birchall R Broomfield J Wedatilake T Dijkstra H Lloyd T Pereira C Newman S Carr A Glyn-Jones S
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Background

Cam morphology develops during adolescence and predisposes individuals to future hip pain and osteoarthritis. An improved understanding of cam development is required to determine whether the process is modifiable.

Hypothesis/Purpose

The aim of this study was to characterise the risk factors, timing, and pathogenesis of cam formation.


The Bone & Joint Journal
Vol. 99-B, Issue 1 | Pages 107 - 115
1 Jan 2017
Carr A Cooper C Campbell MK Rees J Moser J Beard DJ Fitzpatrick R Gray A Dawson J Murphy J Bruhn H Cooper D Ramsay C

Aims

The appropriate management for patients with a degenerative tear of the rotator cuff remains controversial, but operative treatment, particularly arthroscopic surgery, is increasingly being used. Our aim in this paper was to compare the effectiveness of arthroscopic with open repair of the rotator cuff.

Patients and Methods

A total of 273 patients were recruited to a randomised comparison trial (136 to arthroscopic surgery and 137 to open surgery) from 19 teaching and general hospitals in the United Kingdom. The surgeons used their usual preferred method of repair. The Oxford Shoulder Score (OSS), two years post-operatively, was the primary outcome measure. Imaging of the shoulder was performed at one year after surgery. The trial is registered with Current Controlled Trials, ISRCTN97804283.


The Bone & Joint Journal
Vol. 98-B, Issue 12 | Pages 1648 - 1655
1 Dec 2016
Murphy J Gray A Cooper C Cooper D Ramsay C Carr A

Aims

A trial-based comparison of the use of resources, costs and quality of life outcomes of arthroscopic and open surgical management for rotator cuff tears in the United Kingdom NHS was performed using data from the United Kingdom Rotator Cuff Study (UKUFF) randomised controlled trial.

Patients and Methods

Using data from 273 patients, healthcare-related use of resources, costs and quality-adjusted life years (QALYs) were estimated at 12 months and 24 months after surgery on an intention-to-treat basis with adjustment for covariates. Uncertainty about the incremental cost-effectiveness ratio for arthroscopic versus open management at 24 months of follow-up was incorporated using bootstrapping. Multiple imputation methods were used to deal with missing data.


Bone & Joint Research
Vol. 5, Issue 6 | Pages 206 - 214
1 Jun 2016
Malak TT Broomfield JAJ Palmer AJR Hopewell S Carr A Brown C Prieto-Alhambra D Glyn-Jones S

Objectives

High failure rates of metal-on-metal hip arthroplasty implants have highlighted the need for more careful introduction and monitoring of new implants and for the evaluation of the safety of medical devices. The National Joint Registry and other regulatory services are unable to detect failing implants at an early enough stage. We aimed to identify validated surrogate markers of long-term outcome in patients undergoing primary total hip arthroplasty (THA).

Methods

We conducted a systematic review of studies evaluating surrogate markers for predicting long-term outcome in primary THA. Long-term outcome was defined as revision rate of an implant at ten years according to National Institute of Health and Care Excellence guidelines. We conducted a search of Medline and Embase (OVID) databases. Separate search strategies were devised for the Cochrane database and Google Scholar. Each search was performed to include articles from the date of their inception to June 8, 2015.


Orthopaedic Proceedings
Vol. 97-B, Issue SUPP_11 | Pages 22 - 22
1 Oct 2015
Morita W Dakin S Snelling S Carr A
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Introduction

Tendon healing begins with inflammation and results in an incomplete repair with fibrosis, culminating in tendon pathology along with tissue degeneration. Inflammatory mediators regulate the expression of growth factors, and members of the TGFβ superfamily including BMPs have been suggested to play a key role in the development of fibrosis. In established tendon diseases where inflammation and reparative processes persists, the cellular phenotype of tendon cells has been implied to undergo a transformation from that of normal tissue. This study investigates the inflammation-driven mechanisms of tendon pathology using an in vitro tendon cell model. We hypothesized that cells from diseased tendons will exhibit dysregulation of TGFβ superfamily members in response to inflammatory mediators when compared to cells derived from healthy tendons.

Materials and Methods

Diseased human tendon cells were isolated from patients with large to massive rotator cuff tears (n=4). Cells isolated from healthy human hamstring tendons served as control tissue (n=5). Cells were treated with human recombinant IL-1β (5ng/ml), oncostatin M (10ng/ml), IL-6 (10ng/ml), IL-10 (10ng/ml) in serum-free medium, or serum-free medium alone (control) for 24 hours. Cell viability was monitored by Alamar Blue assay, and expression of TGFB1, TGFBR1, TGFBR2, CTGF, BMP2 and BMP7 were quantified by quantitative reverse transcription polymerase chain reaction (RT-QPCR).


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 258 - 258
1 Jul 2014
Dean B Lostin E Oakley T Morrey M Carr A
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Summary Statement

The effects of local glucocorticoid on tendon appear broadly negative and this supports the emerging clinical evidence which points toward significant long term harms associated with this treatment modality.

Introduction

The use of locally administered glucocorticoid is widespread in the treatment of painful tendinopathy. Despite evidence of short term benefit, the emerging evidence points toward significant long term harms associated with this method of treatment, including an increased risk of recurrence, rupture and worsened clinical outcomes (1, 2). Our primary purpose was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells.


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 339 - 339
1 Jul 2014
Snelling S Price A Carr A Le L Clark I
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Summary Statement

Dickkopf-3 is upregulated in OA cartilage and synovial tissue. In vitro studies show Dkk3 can prevent cartilage degradation and antagonise Wnt signaling. We hypothesis that Dkk3 can protect against OA-related cartilage destruction.

Introduction

Our group has previously shown that Dkk3, a member of the Dkk family of Wnt antagonists, is upregulated in OA cartilage and synovium. Levels of Dkk3 in synovial fluid are also increased in individuals with tricompartmental OA and after arthroscopy. The role of Dkk3 in cartilage or the factors regulating its expression are not currently understood. Correct regulation of cell signalling pathways is integral to cartilage homeostasis and thus the prevention of OA pathogenesis. Dkk3 is a member of the Dkk family of Wnt antagonists and therefore may impact on chondrocyte biology through interaction with the Wnt pathway. Dkk3 has also been found to influence TGFβ signalling in other cell systems.


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 248 - 248
1 Jul 2014
Hakimi O Mouthuy P Yapp C Wali A Baboldashti NZ Carr A
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Summary Statement

The aim of this study was to compare patterns (aligned, random and grid) of electrospun polydioxanone scaffolds for tendon repair. The aligned design was optimal, directing cell shape, orientation and protein expression. Moreover, it naturally crimped, presenting tendon-like morphology.

Introduction

Nanofibrous electrospun materials have been previously proposed as potential scaffolds for tendon repair, with emphasis on biomimetic design, postulated to encourage tissue regeneration. In this study, we characterised the interaction of primary tendon-derived cells with polydioxanone (PDO) scaffolds. PDO is a polymer with an excellent in vitro and in vivo biocompatibility, and is specifically compatible with tendon-derived cells. Here, we designed electrospun PDO scaffolds with different fibre orientations, namely aligned, random and grid-like patterns. To evaluate their potential as patches for tendon repair, we grew primary tendon derived cells on these scaffolds, and tested different aspects of cell behavior, including cell shape, proliferation and protein expression.


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 98 - 98
1 Jul 2014
Palmer A Fernquest S Hamish L Pollard T McNally E Wilson D Wilson D Madler B Carr A Glyn-Jones S
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Summary

The dGEMRIC index correlates more strongly with the pattern of radiographic joint space narrowing in hip osteoarthritis at five year follow-up than morphological measurements of the proximal femur. It therefore offers potential to refine predictive models of hip osteoarthritis progression.

Introduction

Longitudinal general population studies have shown that femoroacetabular impingement increases the risk of developing hip osteoarthritis, however, morphological parameters have a low positive predictive value. Arthroscopic debridement of impingement lesions has been proposed as a potential strategy for the prevention of osteoarthritis, however, the development of such strategies requires the identification of individuals at high risk of disease progression. We investigated whether delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) predicts disease progression. This imaging modality is an indirect measure of cartilage glycosaminoglycan content.


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 356 - 356
1 Jul 2014
Dean B Murphy R Wheway K Watkins B Franklin S Javaid K Carr A
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Summary Statement

The peripheral neuronal phenotype is significantly altered in rotator cuff tendinopathy (RCT) with a clear upregulation of the Glutaminergic system being present in disease.

Introduction

Shoulder pain is the third most frequent cause of chronic musculoskeletal pain in the community and is usually caused by rotator cuff tendinopathy (RCT). The central and peripheral nervous system play an important role in both tissue homoeostasis and tendon healing. The Glutaminergic system is of key importance in driving the peripheral and central neuronal changes which increase the body's sensitivity to pain (1, 2). No study to date has investigated the role of the glutaminergic system in human RCT. We hypothesised that the peripheral neuronal phenotype would be altered in RCT, and would vary according to disease stage as measured by size of tear. The term ‘peripheral neuronal phenotype’ is used to refer to refer to specific characteristics of the peripheral nervous system, neuronal mediators and the receptors for these mediators in peripheral tissue


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 252 - 252
1 Jul 2014
Mouthuy P Hakimi O Baboldashti NZ Morrey M Lostis E Carr A
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Summary Statement

This study describes the design and preliminary in vitro testing of a novel patch for the repair of rotator cuff tendon tears. The laminated design incorporates woven and electrospun components. The woven element provides the patch with excellent mechanical strength and the electrospun layer improves cell attachment and promotes cell orientation and diferentiation.

Introduction

Aligned nanofibrous electrospun scaffolds have been previously proposed as ideal scaffolds for tendon repair, replicating the anisotropy of tendon and providing a biomimetic design to encourage tissue regeneration (Hakimi et al., 2012). However, such scaffolds are still limited in terms of mechanical properties. This paper presents the design of a novel patch for rotator cuff repair in which the electrospun scaffold is supported by a woven component.


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 24 - 24
1 Jul 2014
Morrey M Lostis E Franklin S Hakimi O Mouthy P Baboldashti NZ Carr A
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Summary Statement

A novel biomimetic polydioxanone tendon patch with woven and electrospun components is biocompatible, recapitulates native tendon architecture and creates a tissue-healing microenvironment directed by a subpopulation of regenerative macrophages. The woven component provides tensile strength while the tendon heals.

Introduction

There is great interest in the use of biomimetic devices to augment tendon repairs. Ideally, implants improve healing without causing adverse local or systemic reactions. Biocompatibility remains a critical issue prior to implantation into humans, as some implants elicit a foreign body response (FBR) involving inflammation, poor wound healing and even fistulae formation. Additionally, the effect on articular cartilage locally or systemically with placement of a juxta-articular implant has not been examined. The purpose of this study is to test the in vivo biocompatibility of a novel hybrid woven and electrospun polydioxanone patch in a rat tendon transection model.


Bone & Joint Research
Vol. 3, Issue 3 | Pages 48 - 50
1 Mar 2014
Lidgren L Gomez-Barrena E N. Duda G Puhl W Carr A


Orthopaedic Proceedings
Vol. 95-B, Issue SUPP_1 | Pages 19 - 19
1 Jan 2013
Thomas G Batra R Kiran A Palmer A Gibbons C Gundle R Hart D Spector T Gill H Javaid M Carr A Arden N Glyn-Jones S
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Introduction

Subtle deformities of the acetabulum and proximal femur are recognised as biomechanical risk factors for the development of hip osteoarthritis (OA) as well as a cause of hip and groin pain. We undertook this study to examine relationships between a number of morphological measurements of the acetabulum and proximal femur and the hip pain in a 20-year longitudinal study.

Methods

In 1989 women of 45–64 years of age were recruited. Each had an AP-Pelvis radiograph at Year-2. These radiographs were analysed using a validated programme for measuring morphology. All morphological measurements were read blinded to outcome. At year 3 all participants were asked whether they experienced hip pain (side specific). This was repeated at visits up to and including 20-years. Logistic regression analysis (with robust standard errors and clustering by subject identifier) was performed using hip pain as a binary outcome. The model adjusted for baseline age, BMI and joint space and included only participants who were pain free on initial questioning.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 417 - 417
1 Sep 2012
Chaudhury S Xia Z Hulley P Carr A
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INTRODUCTION

There is increasing evidence for a multi-stage model of rotator cuff (RC) tendon tears, wherein healing is affected by tear size. The underlying pathophysiology however is not fully understood. Changes in the production and remodeling of the RC extracellular matrix (ECM) are likely to be important determinants of RC tendinopathy as they affect healing and the ability to bear loads. This study aimed to gain greater insight into size related tear pathogenesis by analyzing gene expression profiles from normal, small and massive RC tears.

METHODS

The genetic profiles of 28 human RC tendons were analyzed using microarrays representing the entire genome. 11 massive and 5 small torn RC tendon specimens were obtained from tear edges intraoperatively, and compared to 12 age matched normal controls. Semiquantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemistry were performed for validation.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 420 - 420
1 Sep 2012
Oag H Daines M Nichols A Kiran A Arden N Carr A
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INTRODUCTION

This study describes the prevalence of pain, functional loss and rotator cuff tears (RCTs) in a general population cohort. It is the first multidisciplinary assessment in such a cohort.

METHODS

The Chingford cohort is a 19-year old longitudinal population study comprising 1003 women aged between 44 and 67 at baseline. To date 183 consecutive subjects (366) shoulders have been interviewed about their shoulders. Myometric strength assessment and high-definition ultrasound examination (US) have been performed on all shoulders. Additionally pain thresholds and perceptions of pain have been tested using quantitative sensory testing (QST) and a number of validated questionnaires, including the illness attitudes scale and the pain detect score.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 414 - 414
1 Sep 2012
Chaudhury S Holland C Porter D Vollrath F Carr A
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Introduction

The pathophysiology of high failure rates following rotator cuff tendon repairs, particularly massive tears, is not fully understood. Collagen structural changes have been shown to alter tendon thermal and mechanical properties. Thermal changes in small biopsies, detected by differential scanning calorimetry (DSC) can help to quantify collagen structural differences in torn rotator cuff tendons. This study aimed to form a quantitative rather than qualitative assessment, of whether differences in collagen structure and integrity existed between small biopsies of normal, small and massive rotator cuff tears using DSC.

Methods

Thermal properties were measured for 27 human biopsies taken intra-operatively from normal, small, and massive rotator cuff tendon tears. 3 samples were taken from each patient and subjected to a modulated temperature ramp between 20–80°C at a rate of 2°C per minute with 0.318°C amplitude. The melting temperature (TM) is proposed to represent amide-amide hydrogen bond breakage and resulting protein backbone mobility. Denaturing temperature (TD) reportedly corresponds to the temperature at which the proteins fall out of solution. Denaturation enthalpy (H) should correlate with the amount of triple helical structure. Based upon a pre-study power calculation, this study had 90% power to detect a 10% difference in melting and denaturation temperature between groups with alpha=0.05.

1 specimen per patients was also frozen and cryosectioned and polarised light microscopy was used for quantitative validation. The effect of tear size on heat related parameters were performed using a one-way ANOVA test. A student's unpaired t-test was used to search for differences between individual groups (small tears, massive tears and normal tendons).


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 419 - 419
1 Sep 2012
Chaudhury S Ferguson D Hakimi O Carr A
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INTRODUCTION

In order to address high failure rates following rotator cuff repairs, a greater understanding is required of the underlying structural changes so that treatments can be appropriately targeted and biomarkers of failure can be identified. As collagen is the primary constituent of tendon and determines force transmission, collagen structural changes may affect responses to loading. For example changes in collagen 1 and 5 are associated with the hyperelastic Ehlers-Danlos syndrome, which is diagnosed by looking for pathopneumonic altered collagen fibres or ‘collagen flowers’ in skin using transmission electron microscopy (TEM). To date no study has been performed on the microstructure of torn human rotator cuff tendons using TEM.

It was hypothesized that normal, small and massive human rotator cuff tendons tears will have altered microscopic structures. The unique study aimed to use TEM to compare the ultrastructure of small and massive rotator cuff tears, to normal rotator cuff tendons.

METHODS

Samples from 7 human rotator cuff tendons repairs were obtained, including 4 massive (>5 cm) and 3 small (< 1 cm) tears, and 3 matched normal controls with no history of connective tissue disorders. Specimens were fixed in 4% glutaraldehyde in 0.1M phosphate buffer, processed and examined blind using routine TEM examination.

To assess whether changes in the relative expression of collagen 1 and 5 (COL1A1, COL5A1 and COL5A2) occurred in all tears, qPCR was performed on another 6 phenotypically matched patients.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXIX | Pages 43 - 43
1 Jul 2012
Price A Jackson W Field R Judge A Carr A Arden N Murray D Dawson J Beard D
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Purpose

The Oxford Knee Score (OKS) is a validated and widely used PROM that has been successfully used in assessing the outcome of knee arthroplasty (KA). It has been adopted as the nationally agreed outcome measure for this procedure and is now routinely collected. Increasingly, it is being used on an individual patient basis as a pre-operative measure of osteoarthritis and the need for joint replacement, despite not being validated for this use. The aim of this paper is to present evidence that challenges this new role for the OKS.

Method

We have analysed pre-operative and post-operative OKS data from 3 large cohorts all undergoing KA, totalling over 3000 patients. In addition we have correlated the OKS to patient satisfaction scores. We have validated our findings using data published from the UK NJR.