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Orthopaedic Proceedings
Vol. 106-B, Issue SUPP_12 | Pages 3 - 3
10 Jun 2024
Alsousou J Keene D Harrison P O'Connor H Wagland S Dutton S Hulley P Lamb S Willett K
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Background

The PATH-2 trial found no evidence of a benefit of Platelet Rich Plasma (PRP) injection versus a placebo after Achilles tendon rupture (ATR) at six-months. ATR often leave longer-term functional deficiencies beyond six-months. This study aim is to determine if PRP affect tendon functional outcomes at two-years after rupture.

Study design

Randomised multi-centre two-arm parallel-group, participant- and assessor-blinded, superiority trial.


Orthopaedic Proceedings
Vol. 106-B, Issue SUPP_7 | Pages 18 - 18
8 May 2024
Keene D Alsousou J Harrison P Hulley P Wagland S Parsons S Thompson J O'Connor H Schlüssel M Dutton S Lamb S Willett K
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Background

Disability and slow return to sport and work after tendon rupture are major challenges. Platelet Rich Plasma (PRP) is an autologous supraphysiological concentration of platelets from whole blood that has demonstrated positive cellular and physiological effects on healing in laboratory conditions but evidence from adequately powered robust clinical trials is lacking. We aimed to determine the clinical efficacy of PRP for treatment of acute Achilles tendon rupture.

Methods

In a placebo-controlled, participant- and assessor-blinded, trial at 19 NHS hospitals we randomly assigned 230 adults starting acute Achilles rupture non-surgical management to PRP injection or dry-needle insertion (placebo) to the rupture gap under local anaesthetic. Patients with confounding or contraindicated concurrent medical conditions were excluded. The primary outcome was muscle-tendon function, assessed by the limb symmetry index (LSI, uninjured limb/injured limb × 100, higher scores better) of the work (Joules) performed during the heel-rise endurance test at 24 weeks. Secondary outcomes were: Achilles Tendon Rupture Score (ATRS, 0–100, higher scores better), quality of life (SF-12), pain, and goal attainment. Trial registration: ISRCTN54992179


The Bone & Joint Journal
Vol. 104-B, Issue 11 | Pages 1256 - 1265
1 Nov 2022
Keene DJ Alsousou J Harrison P O’Connor HM Wagland S Dutton SJ Hulley P Lamb SE Willett K

Aims

To determine whether platelet-rich plasma (PRP) injection improves outcomes two years after acute Achilles tendon rupture.

Methods

A randomized multicentre two-arm parallel-group, participant- and assessor-blinded superiority trial was undertaken. Recruitment commenced on 28 July 2015 and two-year follow-up was completed in 21 October 2019. Participants were 230 adults aged 18 years and over, with acute Achilles tendon rupture managed with non-surgical treatment from 19 UK hospitals. Exclusions were insertion or musculotendinous junction injuries, major leg injury or deformity, diabetes, platelet or haematological disorder, medication with systemic corticosteroids, anticoagulation therapy treatment, and other contraindicating conditions. Participants were randomized via a central online system 1:1 to PRP or placebo injection. The main outcome measure was Achilles Tendon Rupture Score (ATRS) at two years via postal questionnaire. Other outcomes were pain, recovery goal attainment, and quality of life. Analysis was by intention-to-treat.


Bone & Joint Research
Vol. 9, Issue 9 | Pages 623 - 632
5 Sep 2020
Jayadev C Hulley P Swales C Snelling S Collins G Taylor P Price A

Aims

The lack of disease-modifying treatments for osteoarthritis (OA) is linked to a shortage of suitable biomarkers. This study combines multi-molecule synovial fluid analysis with machine learning to produce an accurate diagnostic biomarker model for end-stage knee OA (esOA).

Methods

Synovial fluid (SF) from patients with esOA, non-OA knee injury, and inflammatory knee arthritis were analyzed for 35 potential markers using immunoassays. Partial least square discriminant analysis (PLS-DA) was used to derive a biomarker model for cohort classification. The ability of the biomarker model to diagnose esOA was validated by identical wide-spectrum SF analysis of a test cohort of ten patients with esOA.


Orthopaedic Proceedings
Vol. 97-B, Issue SUPP_11 | Pages 2 - 2
1 Oct 2015
Mansel C Gardiner N Kuzma-Kuzniarska M Hulley P Thompson M
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Introduction

Tendon disease and rupture are common in patients with diabetes and these are exacerbated by poor healing. although nanoscale changes in diabetic tendon are linked to increased strength and stiffness. The resistance to mechanical damage of a tissue may be measured using fatigue testing but this has not been carried out in diabetic tendon, although the toughness of diabetic bone is known to be reduced. The aim of this study was to measure the static fatigue behaviour of tendons from a streptozotocin (STZ)-induced rat model of diabetes, hypothesising that diabetes causes tendon to show lower resistance to mechanical damage than healthy tendon.

Materials and Methods

Diabetic (n=3, 12 weeks post-STZ) and age-matched control (n=3) adult male Sprague Dawley rats were culled, tails harvested and stored at −80ºC. Following defrosting, fascicles (5 per animal) were carefully dissected, mean diameter measured using an optical micrometer and mounted in a Bose Biodynamics test machine using custom grips in a PBS bath. Static fatigue testing at 30 MPa to failure enabled both elastic modulus (initial ramp) and steady state creep rate (gradient at creep curve inflexion) to be measured. Data are reported as median ± interquartile range and pw0.05 using a Mann-Whitney U test was taken as significant.


Orthopaedic Proceedings
Vol. 96-B, Issue SUPP_11 | Pages 344 - 344
1 Jul 2014
Armengol M Brown C Hulley P Price A Gill H
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Summary

The mechanical properties of porcine tibial plateau (TP) cartilage are shown to vary topographically. Low Elastic moduli (Em) were found in the positions where unicompartimental knee osteoarthritis (OA) lesions are typically expected to develop. These results suggest that there is a different response to load in these areas.

Introduction

OA is one of the ten most disabling diseases in developed countries. OA of the knee, in particular, is a major cause of mobility impairment; up to 40% of the population over the age of 70 suffers from OA of the knee. It has been observed that unicompartmental knee OA occurs with very distinct and repeatable lesion patterns. It is hypothesised that these patterns are the result of differences in the material properties throughout articular cartilage. The aim of this study was to measure the mechanical properties of porcine cartilage in a whole undamaged TP.


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_XXXVI | Pages 6 - 6
1 Aug 2012
Alsousou J Handley R Hulley P Thompson M McNally E Harrison P Willett K
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Purpose

Platelet Rich Plasma (PRP) has been shown to have positive effect in tendon regeneration in in-vitro and limited in-vivo animal studies. We aim to study PRP use in acute Achilles tendon rupture (ATR) regeneration in a purposely designed clinical trial.

Methods

This is a prospective double-arm patient-blinded randomized controlled trial. ATR patients were randomized into PRP treatment or control groups. Non-operatively treated patients received PRP or control injection in clinic. In operatively treated patients, PRP gel was applied in the ruptured gap during percutaneous repair. Standard rehabilitation protocol was used and patients were followed up for 24 weeks. ATR, VISA-A and FAOS scores were used as subjective outcome measures. Functional ultrasound Elastography (FUSE) was performed at each follow-up to assess the mechanical properties of tendons. PRP analysis and tendon needle-biopsy were performed to study the histological differences during healing in both groups.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XVIII | Pages 6 - 6
1 May 2012
Franklin S Zargar N Willett K Hulley P Thompson M
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Introduction

The use of platelet-rich concentrate (PRC) to enhance the healing response in tendon repair is currently an area of considerable interest. Activated platelets release a cocktail of growth factors and ECM regulating molecules. Previous work suggests that tenocytes are activated by contact with these clot-derived molecules. Our studies on tenocytes and PRC aim to establish the direct molecular and functional effects of PRC on tenocytes and to support the clinical research on Achilles tendon repair taking place within our group. We hypothesise that applying PRC to human tenocytes in culture will increase proliferation rate and survival by activating relevant signalling pathways.

Materials and Methods

Using a centrifugation method, PRC was extracted from fresh human whole blood. The PRC was immediately clotted and left in medium overnight to release biological factors (at least 95% of presynthesized growth factors are secreted in the first hour of activation)1. Human tenocytes derived from explanted healthy hamstring were used for up to three passages. Cells were treated with varying concentrations of PRC-conditioned medium and assessed for viable cell number (Alamar Blue™ fluorescence) and proliferation (Ziva™ Ultrasensitive BrdU assay) after 72hrs. For western blotting, cells were treated with 10% PRC for 5 or 30 minutes. Antibodies to P-ERK and P-Akt detected the active protein state on the blot, followed by membrane stripping and re-probing with pan antibodies. Quantification was achieved by densitometry using Visionworks software v. 6.7.1.


Bone & Joint Research
Vol. 1, Issue 3 | Pages 36 - 41
1 Mar 2012
Franklin SL Jayadev C Poulsen R Hulley P Price A

Objectives

Surgical marking during tendon surgery is often used for technical and teaching purposes. This study investigates the effect of a gentian violet ink marker pen, a common surgical marker, on the viability of the tissue and cells of tendon.

Methods

In vitro cell and tissue methods were used to test the viability of human hamstring explants and the migrating tenocytes in the presence of the gentian violet ink.


Orthopaedic Proceedings
Vol. 93-B, Issue SUPP_I | Pages 30 - 30
1 Jan 2011
Rout R McDonnell S Hollander A Davidson R Clark I Murray D Gill H Hulley P Price A
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Our aim was to investigate the molecular features of progressive severities of cartilage damage, within the phenotype of Anteromedial Gonarthrosis (AMG).

Ten medial tibial plateau specimens were collected from patients undergoing unicompartmental knee replacements. The cartilage within the area of macroscopic damage was divided into equal thirds: T1(most damaged), to T3 (least damaged). The area of macroscopically undamaged cartilage was taken as a 4th sample, N. The specimens were prepared for histological (Safranin-O and H& E staining) and immunohistochemical analysis (Type I and II Collagen, proliferation and apoptosis). Immunoassays were undertaken for Collagens I and II and GAG content. Real time PCR compared gene expression between areas T and N.

There was a decrease in OARSI grade across the four areas, with progressively less fibrillation between areas T1, T2 and T3. Area N had an OARSI grade of 0 (normal). The GAG immunoassay showed decreased levels with increasing severity of cartilage damage (p< 0.0001). There was no significant difference in the Collagen II content or gene expression between areas. The Collagen I immunohistochemistry showed increased staining within chondrocyte pericellular areas in the undamaged region (N) and immunoassays showed that the Collagen I content of this macroscopically and histologically normal cartilage, was significantly higher than the damaged areas (p< 0.0001). Furthermore, real time PCR showed a significant increase in Collagen I expression in the macroscopically normal areas compared to the damaged areas (p=0.04).

In AMG there are distinct areas, demonstrating progressive cartilage loss. We conclude that in this phenotype the Collagen I increase, in areas of macroscopically and histologically normal cartilage, may represent very early changes of the cartilage matrix within the osteoarthritic disease process. This may be able to be used as an assay of early disease and as a therapeutic target for disease modification or treatment.


Orthopaedic Proceedings
Vol. 93-B, Issue SUPP_I | Pages 70 - 70
1 Jan 2011
Rout R Mcdonnell S Snelling S Xia X Bottomley N Hulley P Price A
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Introduction: Anteromedial gonarthrosis (AMG) is a distinct phenotype of osteoarthritis (OA), with a specific pattern of disease. There is full thickness cartilage loss anteromedially, progressing to an area of damaged cartilage, and then to an area of macroscopically and histologically normal cartilage posteriorly. It can be considered to be a spatial model of OA progression. Apoptosis, or chondrocyte cell death, has been shown to be a feature of OA cartilage, however the triggers are poorly understood; similarly, reactive oxygen species (ROS) have been implicated in OA. They have never been studied in a replicable topographical model of OA. This study characterises the regional levels of cell death and implicated ROS in AMG using a number of immunohistochemical studies.

Method: Ten tibial resection specimens were obtained from patients undergoing unicompartmental knee arthroplasty. Eight above knee amputations (from patients with peripheral vascular disease) were used as age matched controls. Cross sections taken through all regions were paraffin embedded. Routine histology was performed and immunohistochemical studies were conducted for Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Active Caspase 3, Cytochrome C, Active Bax, Bim, 3-Nitrotyrosine and Forkhead Box O3A (FOXO 3A).

Results: Cell death, as detected by TUNEL appeared predominantly in the surface layer of chondrocytes of damaged cartilage (p< 0.001). Median values were 23% in superficial cartilage (range 0 – 51) compared to 0% in deeper cartilage (range 0 – 15). There was a significant difference in TUNEL staining between regions (p=0.001). This ranged from 26% (most damaged) to 4% (undamaged). There was a good correlation with degree of cartilage damage (ρ=0.66, p< 0.001) asdefined by histological grade and TUNEL was significantly higher (p< 0.001) in AMG compared to the control samples which showed an average of 2% TUNEL overall. Upstream markers of apoptosis (Active Caspase 3, Cytochrome C, Active Bax), assessed qualitatively, were present in a similar distribution to that of TUNEL staining. 3-Nitrotyrosine was also shown to be a predominantly surface phenomenon. There was a significant difference (p< 0.001) between regions, ranging from 58% (most damaged) to 10% (undamaged). Again, this was significantly higher that the control samples (p< 0.001). In line with indicators of ROS mediated damage, Bim and FOXO3A were also detected.

Discussion: The mechanism of apoptosis in OA cartilage has not been studied in depth, and understanding the biochemical and molecular responses of ‘stressed’ chondrocytes may provide invaluable information about the specific causes of cell death. Such cellular responses may provide targets for disease modification, thus delaying or preventing the need for joint arthroplasty. We conclude that AMG is a phenotype demonstrating cartilage at progressive stages of disease. Apoptosis involves the intrinsic mitochondrial pathway and ROS appear to be implicated. Further work is needed to provide evidence of what lies further upstream of markers demonstrated in this study.


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_IV | Pages 570 - 570
1 Oct 2010
Benson R Carr A Hulley P Mcdonnell S Rees J
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The aim of this study was to find evidence of tissue hypoxia and apoptosis (programmed cell death) have on a human model of rotator cuff failure.

We studied twenty seven patients with no tear mild impingment (3), no tear moderate impingment (3), no tear severe impingment (3), partial tear (3), small tear (3), moderate tear (3), large tear (3), massive tear (3) and control (3) who were undergoing shoulder arthroscopy, subacromial decompression and potential rotator cuff repair. A supraspinatus tendon biopsy was taken during debridement/repair on all cases (ethics number C01.071). Control tendon was obtained from the subscapularis tendon of patients undergoing stabilization surgery.

Biopsies were analysed using two immunocytological techniques. A monoclonal antibody against BNIP-3 (a pro-apoptotic marker of hypoxia) and TUNEL (an apoptotic marker). An immunofluorescent nuclear counterstain DAPI (4 6-Diamidino-2-phenylindole dihy-drochloride) was used to stain all cells. Positive cells and total cell number were then counted in 10 high powered fields per section.

The results showed a significant increase in BNIP-3 expression in the cuff tears compared with intact tendons. This increase was least in the massive tears. Apoptosis increases from mild impingement to massive cuff tears (mean 7.3% to 21%)


Orthopaedic Proceedings
Vol. 91-B, Issue SUPP_III | Pages 468 - 469
1 Sep 2009
Rout R Mcdonnell S Hollander A Clark I Simms T Davidson R Dickinson S Waters J Gill H Murray D Hulley P Price A
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The aim of this study was to investigate the molecular features of progressive severities of cartilage damage, within the phenotype of Anteromedial Osteoarthritis of the Knee (AMOA).

Ten medial tibial plateau specimens were collected from patients undergoing unicompartmental knee replacements. The cartilage within the area of macroscopic damage was divided into equal thirds: T1(most damaged), to T3 (least damaged). The area of macroscopically undamaged cartilage was taken as a 4th sample, N. The specimens were prepared for histological (Safranin-O and H& E staining) and immunohistochemical analysis (Type I and II Collagen). Immunoassays were undertaken for Collagens I and II and GAG content. Real time PCR compared gene expression between areas T and N.

There was a decrease in OARSI grade across the four areas, with progressively less fibrillation between areas T1, T2 and T3. Area N had an OARSI grade of 0 (normal).

The GAG immunoassay showed decreased levels with increasing severity of cartilage damage (ANOVA P< 0.0001). There was no significant difference in the Collagen II content or gene expression between areas. The Collagen I immunohistochemistry showed increased staining within chondrocyte territorial areas in the undamaged region (N) and immunoassays showed that the Collagen I content of this macroscopically and histologically normal cartilage, was significantly higher than the damaged areas (ANOVA P< 0.0001). Furthermore, real time PCR showed that there was a significant increase in Collagen I expression in the macroscopically normal areas (p=0.04).

In AMOA there are distinct areas, demonstrating progressive cartilage loss. We conclude that in this phenotype the Collagen I increase, in areas of macroscopically and histologically normal cartilage, may represent very early changes of the cartilage matrix within the osteoarthritic disease process. This may be able to be used as an assay of early disease and as a therapeutic target for disease modification or treatment.


Orthopaedic Proceedings
Vol. 91-B, Issue SUPP_II | Pages 259 - 259
1 May 2009
Benson R Rees J Hulley P Carr A
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The aim of this study was to understand the role tissue hypoxia and apoptosis have on a human model of rotator cuff failure. We studied twenty seven patients with no tear mild impingment (3), no tear moderate impingment (3), no tear severe impingment (3), partial tear (3), small tear (3), moderate tear (3), large tear (3), massive tear (3) and control (3). A supraspinatus tendon biopsy was taken during debridement/repair in all cases (ethics no. C01.071). Control tendon was obtained from the subscapularis tendon of patients undergoing stabilization surgery. Biopsies were analysed using two immunocytological techniques. A monoclonal antibody against BNIP-III (a marker of hypoxia) and TUNEL (Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling – an apoptotic detection process). An immunoflorescent counterstain DAPI (4′,6-diamidino-2-phenylindol) was used to stain all cells. Positive cells and total cell number were then counted in 10 high powered fields. The results showed a significant increase in BNIP-III expression in the cuff tears compared with intact tendons. This increase was least in the massive tears. Apoptosis increases from mild impingment to massive cuff tears (mean 7.3% to 21%) In conclusion, as tear size increases, the viability of the tendon reduces with increasing hypoxia and apoptosis.


Orthopaedic Proceedings
Vol. 90-B, Issue SUPP_III | Pages 578 - 578
1 Aug 2008
Price A Xia Z Hulley P Murray D Triffitt J
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Aim: The aim of this study was to investigate whether viable chondrocytes can be isolated and subsequently expanded in culture, from cryopreserved intact human articular cartilage.

Method: Human articular cartilage samples, retrieved from patient undergoing total knee replacement, were cored as 5 mm diameter discs then minced to approximately 0.1 mm3 size pieces. Samples were cryopreserved at the following stages; intact cartilage discs, minced cartilage and chondrocytes immediately after enzymatic isolation. After completing of isolation, cell viability was examined using LIVE/DEAD fluorescent staining. Isolated chondrocytes were then cultured and a cell proliferation assay was performed at day 4, 7, 14, 21 and 28 days.

Results: The results showed that the viability of isolated chondrocytes from control, cryopreserved intact AC discs, minced AC and isolated then frozen samples were 71.84 ± 2.63%, 25.61 ± 2.41%, 31.32 ± 2.47 % and 42.53 ± 4.66% respectively. Isolated chondrocytes from all groups were expanded by following degrees after 28 days of culture; Group A: 10 times, Group B: 18 times, Group C: 106 times, and Group D: 154 times.

Conclusion: We conclude that viable chondrocytes can be isolated from cryopreserved intact human AC and then cultured to expand their number. This method could be employed to patients benefit undergoing autologous chondrocyte implantation.


Orthopaedic Proceedings
Vol. 90-B, Issue SUPP_II | Pages 391 - 391
1 Jul 2008
McDonnell S Benson R Hulley P Athanasou N Carr A Price A
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Antero-medial osteoarthritis of the knee displays a well recognised pattern of cartilage damage on the medial tibial plateau. Anteriorly there is a full thickness cartilage defect, with transition to a partial thickness defect, becoming full thickness in the posterior third of the plateau. The retained posterior cartilage is macroscopically normal, but no previous study has assessed its histo-logical features. This study characterises the histological changes, to examine if antero-medial OA of the knee represents a model of progressive osteoarthritic cartilage damage.

Five unicompartmental resection specimens of patients with idiopathic single compartment antero-medial osteoarthritis were assessed. The samples were stained with H& E and Saffinin-O stains and reviewed using the Mankin system, an established method for scoring osteoarthritic changes in cartilage (range 0 [normal] to 14 [grossly osteoarthritic]) Digital images of the histology were reviewed by two observers to exclude inter and intra observer error. Each specimen was assessed at 4 interval points (A,B,C,D) along the A-P axis starting from the most posterior aspect of the exposed bone to the area of macroscopically normal cartilage. Three repeat measurements were taken from the macroscopically normal region (D1,D2,D3). The scores were compared to historical age matched controls of non-osteoarthritic cartilage, where a Mankin grade of < 3 suggests normal cartilage.

From anterior to posterior the H& E staining showed a consistent decrease in structural integrity and cellularity of the cartilage, matched by a qualitative decrease in GAG content (Saffinin-O staining). Mean Mankin scores showed a progressive decrease in score; A = 14.0 (95% CI 0), B = 5.8 (95%CI 2.4), C = 4.4 (95%CI 2.5), D = 1.0 (95%CI 0.9) {p=0.04 ANOVA}. Repeated measurements at the macroscopically normal area showed the Mankin grade was maintained; D1= 1.0 (95%CI 0.9), D2 = 0.6 (95%CI 0.5), D3 = 0.6 (95%CI 0.6).

The results show that the retained posterior cartilage in antero-medial arthritis has a consistently normal Mankin grade. We suggest the defect represents a model of progressive cartilage damage from near normal (posterior) to the grossly osteoarthritic state (anterior).