University of Groningen The influence of load on tendons and tendinopathy Maciel Rabello, Lucas

University of Groningen

The influence of load on tendons and tendinopathy

Maciel Rabello, Lucas

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patellar tendons using UTC. Rijksuniversiteit Groningen.

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tendons and tendinopathy

Studying Achilles and patellar tendons using UTC

Lucas Maciel Rabello

The influence of load on tendons and tendinopathy

Studying Achilles and patellar tendons using UTC

ISBN

ISBN 978-94-034-1583-3 (printed)

ISBN 978-94-034-1582-6 (PDF without DRM)

Dissertation University of Groningen, the Netherlands

The research in this thesis was fully funded by CNPq – National Council for Scientific and Technological Development, Brazil (grant number 203668/2014-6) awarded to Lucas Maciel Rabello and University Medical Center Groningen (UMCG). The studies presented in this thesis were carried out in the context of research institute SHARE.

Cover & lay-out design

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Print

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© 2019, Lucas Maciel Rabello, Groningen, the Netherlands.

All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without the prior permission of the copyright owner.

to obtain the degree of PhD at the University of Groningen

on the authority of the Rector Magnificus prof. E. Sterken

and in accordance with the decision by the College of Deans. This thesis will be defended in public on

Wednesday 24 April 2019 at 9.00 hours

by

Lucas Maciel Rabello

born on 21 February 1986 in Petrópolis, Brazil

The influence of load on tendons

and tendinopathy

Studying Achilles and patellar tendons using UTC

Prof. R.L. Diercks

Co-supervisors

Dr. I. van den Akker-Scheek Dr. M.S. Brink

Assessment Committee

Prof. K.A.P.M. Lemmink Prof. E.E. Witvrouw Prof. P.U. Dijkstra

11 23 47 59 71 83 99 113 137 151 165 171 177 183 187 191 195

CONTENTS

Chapter 1

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapter 6

Chapter 7

Chapter 8

Chapter 9

Chapter 10

Samenvatting Acknowledgements Curriculum Vitae List of publications

List of (inter)national presentations Research Institute SHARE

Chapter 1

General Introduction

Every day our Achilles and patellar tendons are exposed to loads from daily activities and/ or sport activities. Positive or negative tendon adaptation might occur as a result of those loads. When an adequate load is applied to the tendon with sufficient amount of recovery,

the tendon will show a positive adaptation, increasing load capacity.1 _{However, when}

excessive load is applied with insufficient amount of recovery, a tendon maladaptation occurs.1 _{An example of tendon maladaptation is tendinopathy, a condition that causes pain}

and functional impairment.2 _{This clinical condition not only impairs sport performance,}

but also negatively affects recreational and everyday activities.3,4

The first option of treatment for patients diagnosed with Achilles or patellar tendinopathy is non-surgical treatment, which includes loading exercise, load management and patient education.5_,6 _{Although the effect of load on the Achilles and patellar tendons}

has been previously investigated using conventional imaging tools,7 _{more research is}

needed using new imaging tools such as ultrasound tissue characterisation (UTC). The focus of this dissertation lies in investigating the effect of load on the Achilles and patellar tendons using the UTC imaging tool. The introduction of this thesis starts by explaining tendon structure, including the individual characteristics of the Achilles and patellar tendons. Next, load/overload and its effect on tendon structure is presented, followed by an explanation about Achilles and patellar tendinopathy. A new imaging tool, the UTC, and its use to investigate changes in tendon structure are described. Lastly, the aims of this thesis are presented followed by the thesis outline.

Tendon

Tendons are generally the structures that connect muscle to bones.8 _{Their function is to}

transfer tensile forces generated by muscle cells to bone, resulting in joint movement.9

Tendons also act as shock absorbers and energy storage sites, and help maintain posture

through their proprioceptive properties.10 _{To perform these functions properly, tendons}

have a specialised structure and cellular organisation.11

Tendons are mainly composed of Type I collagen and proteoglycans.12 _{The extracellular} matrix contains 68% water, 30% collagen and 2% elastin.13 _{Between the collagen fibres and} the endotenon are the tenocytes, cells capable of producing component-like type I collagen and ECM molecules during growth and healing.14 _{All tendons have a multi-unit hierarchical} structure (Figure 1): a) fibrils, the smallest tendon structural unit, b) fibres, and c) fascicles. Between fascicles is the interfascicular matrix (IFM), where proteins such as lubricin and elastin are localised.15 _{These substances might facilitate fascicle sliding and recoil.}15 _{A recent} study suggested that alterations in the IFM might be related to tendon injury.16

Despite their similar tendon architecture, different tendons show some unique characteristics. The following sections will present the characteristics of the Achilles and patellar tendons.

Achilles tendon

The Achilles tendon, located in the posterior superficial compartment of the lower leg,18

is the thickest and strongest tendon in the human body.19 _{With an average length of}

10 | Chapter 1

15 cm, the Achilles tendon originates at the fusion of the distal tendon laminae of the

soleus and gastrocnemius muscles20 _{and inserts at the superior, middle and inferior}

facets of the calcaneal tuberosity.21 _{Due to rotation of the limb bud that occurs during}

individual development the Achilles tendon is twisted.22 _{This means that the fibres derived} from the gastrocnemius and the soleus are attached to the lateral and medial part of the calcaneal insertion, respectively.22 _{It is known that different types of tendon torsion alters} biomechanical properties of the tendon, which might be related to tendon injuries such

as Achilles tendinopathy (AT).23 _{Due to the complex anatomy that involves the insertion}

or enthesis, this structure has been described as an ‘enthesis organ’.24 _{This ‘organ’, which} is composed by the enthesis, sesamoid (in the deep part of the tendon) and periosteal (on the opposing superior tuberosity of the calcaneus) fibrocartilages, the retrocalcaneal bursa and a synovial-covered fat pad,25 _{is responsible for the anchorage of soft tissues to bone} and stress dissipation.24

Regarding the blood supply to the Achilles tendon, the paratendon is highly vascularised but it is not clear yet whether the vessels are uniformly distributed throughout the length of the tendon. Two main arteries play an important role in the blood supply: the posterior tibial artery, which supplies mainly the peritendinous tissues, and the peroneal artery.26 The midportion of the tendon shows relative hypovascularity and is where most Achilles tendon injuries occur.26

Patellar tendon

The patellar tendon connects the quadriceps muscle complex to the tibia. The structure is frequently referred to as a ligament because the patella, a sesamoid bone, is situated within the tendon. This anatomical characteristic could be interpreted as a

bone-to-bone attachment.27 _{However, a previous study observed that the patellar tendon is}

similar to other tendons and demonstrates that tendons have different characteristics Figure 1. The hierarchical structure of a tendon (reproduced from Journal of Orthopaedic Research, Screen et al, 33,

793-799, 2015 with permission from PMC Copyright).17

Tropocollagen

1.5 nm 50-500 nm 10-50 µm 50-400 µm 500-2000 µm

Fibril Fibre _Fascile

Interfascicular Matrix Interfascicular Tenocyte Cell General introduction | 11

than ligaments.27 _{The patellar tendon extends from the inferior pole of the patella to the} anterior tibial tubercle.28 _{Blood is supplied to the patellar tendon by three main sources:} the lateral inferior genicular artery (ILGA), the anterior tibial recurrent artery (ATRA) and the medial inferior genicular artery (IMGA).29

Both the Achilles and patellar tendons are subjected to load every day – during activities of daily living, work, and physical/sport activities. For that reason, it is necessary to better understand load definition and its influence on the Achilles and patellar tendons.

Load/Overload

Load is generally defined as the force (produced by skeletal muscles) a structure is subjected to due to superposed weight.30 _{In sport science literature load, consisting of volume and} intensity, is defined as the stimulus caused by a sport or non-sport burden that is applied

to the human biological system.1 _{Load is necessary to maintain the normal function of}

tendons and homeostasis of their micro-environment.31 _{The effectiveness of training load}

depends on the total load performed and the total amount of recovery between sessions.32

An adequate load together with sufficient recovery promotes biological adaptation of the tissue, causing an improvement in tendon characteristics with a subsequent increased capacity to withstand tendon load (Figure 2).33

When the tendon is submitted to mechanical loads, tenocytes are stimulated to produce

cytokines that alter the components of extracellular matrix.31 _{This alteration occurs to}

promote tendon homeostasis, remodelling and repair by producing matrix components

such as collagens.34 _{The process of converting mechanical load into cellular responses}

resulting in structural changes is called mechanotransduction.35 _{When an excessive or}

repetitive load is applied to the tendon (overload), there will be a discontinuation of the tenocyte-tenocyte attachment and communication, causing detrimental effects that may lead to injury (tendinopathy) (Figure 3).31,34

Load Recovery Load Recovery

Increeased capacity Reduced capacity Base Level Time Capacity

Figure 2. Biological adaptation through cycles of loading and recovery (adapted from Soligard T et al, 2016.1₎

Tendinopathy

Tendinopathy is an umbrella term indicating a non-rupture injury in the tendon or paratendon that is exacerbated by mechanical loading.36 _{It is clinically characterised by a}

localised, painful and swollen tendon, accompanied by impaired performance.37

To better understand the tendon’s pathological process caused by load, Cook & Purdam

(2009) described the ‘continuum model’.38 _{This model differentiates tendon pathology}

into three different stages: reactive tendinopathy, tendon disrepair (failed healing) and degenerative tendinopathy. Although there are three distinct stages, there is continuity between them.38 _{According to the authors the reactive stage, an acute response to load, is} reversible. If the tendon is given enough rest the structure returns to normal, showing an adaptation of the tendon to the load. If however the balance between load and amount of rest is disrupted, a matrix disorganisation (disrepair stage) is observed with possible progression to the degenerative stage, with unlikely reversibility of pathology.38 _{It is important to observe} that factors other than load management might influence the changes in tendon structure, including recovery period and psychological factors.

The changes in the structure of tendinopathic tendons include: disorganisation of collagen fibres, increased number of vessels and sensory nerves, increase in hydrated components of the extracellular matrix, breakdown of tissue (tendon/endotendon/ paratendon) organisation, and haphazardly arranged proliferation of smaller, type III collagen fibres.36

Below follows a detailed description of Achilles and patellar tendinopathy.

Midportion and insertional Achilles tendinopathy

AT is one of the causes of posterior heel pain, a common problem for middle-aged overweight patients not involved in sports as well as in the sport-active population,

Figure 3. Biological maladaptation through cycles of excessive loading and/or inadequate recovery (adapted from Soligard T et al, 2016).1

Base Level

Time

Capacity Reduced ability to accept load

Increased susceptibility to injury

14 | Chapter 1

especially runners.39,40 _{The incidence of AT in the adult population is reported to be 2.35} per 1000.4 _{Among those patients who visited a general practitioner, 35% of cases are linked} to sports participation.4

The dysfunctions caused by AT, such as pain and reduced function during and after activities, can have a severe impact on a patient’s ability to be physically active and even on activities of daily living (ADL). This might affect the social aspect, as it can cause estrangement from friends and family, and a decrease in the patient’s mental well-being (e.g. feelings of depression) and overall quality-of-life is often seen.41 _{AT can also affect a} patient’s ability to work, which next to healthcare costs has a financial impact on society.42 Furthermore, in the athletic population this condition affects the ability to participate in

training and perform optimally, in severe cases leading to missed games.43

The aetiology of AT is still unclear. Age, sex, obesity, overload, footwear and genetics are some of the risks factors identified by previous authors.44 _{Both female sex and blood} flow response after running were recently identified as significant predictors for the

development of AT.45 _{However, more research is needed to understand the several causes}

of the injury.

Conservative (or non-surgical) treatment is normally the first choice for rehabilitation

of these patients.46 _{Load management, which includes patient education, load monitoring}

and rehabilitation based on progressive load training, is frequently used in daily practice.47 Of the rehabilitation exercises suggested, eccentric exercises (ECC) and heavy slow-resistance exercises (HSR) are the most frequently used. Previous authors showed patient-reported improvement after 12 weeks of rehabilitation following an exercise programme

based on the ECC or HSR.48 _{No significantly different results were found when comparing}

the two exercise forms. Several other non-evidence-based treatment options, including extracorporeal shockwave therapy (ESWT), stretching and night splints are available, but

load management is the cornerstone of treatment.46

Patellar tendinopathy

Patellar tendinopathy (PT) is the term to describe the pain in the proximal portion of

the patellar tendon49 _{and is frequently observed in athletes involved in jumping sports}

who complain of pain during jumping and landing.50 _{The prevalence of PT among elite}

basketball and volleyball players is 31.9% and 45%, respectively.3,51 _{In recreational athletes}

the incidence is 11.8%-14.4% among volleyball and basketball players, respectively.3 _A

retrospective study found that out of 100 subjects, 71% developed symptoms before the age of 23.52 _{Disruption of activities of daily living, reduced physical activity and early} cessation of athletic careers are frequently observed as a result of this injury.53

As described previously, it is known that PT occurs frequently in athletes, but the exact causes of the pathology remain unclear.54 _{Factors such as gender, weight}55,56 _{and training} load57 _{are described as being influential to the development of patellar tendinopathy.} Similar to the treatment described for patients diagnosed with AT, conservative treatment based on load management is the first choice,58 _{but for the 10% of patients who} are refractory to conservative treatment there can be an indication for surgery.59 _Surgical

treatment seems to yield significant improvement in symptoms and function.60,61 _However,

more research is needed to investigate the effects of such treatment.

General introduction | 15

Imaging

Conventional imaging tools such as Magnetic Resonance Imaging (MRI) and ultrasound (US) might be used to diagnose, predict and monitor changes in tendon structure. The benefits of using imaging tests in tendinopathy are still unclear though.62 _{When used} for diagnosis, US and MRI can give a good anatomical view of the structure and are helpful towards excluding other conditions in the differential diagnosis.6,63 _{Their role in}

tendinopathy is however still being debated.64,65 _{It is known that conventional imaging}

tools should be used to predict tendinopathy, since it was previously observed that the

presence of imaging abnormalities was considered a risk factor for developing symptoms.66

As previously stated, the use of imaging to monitor changes in tendon structure is not clear yet. A systematic review showed that the relation between clinical and imaging outcomes

of treatment is unclear.67 _{Both US and MRI have advantages and disadvantages when}

it comes to their use in investigating tendon structure. In addition, these conventional imaging tools focus on subjective measures (presence or absence of tendon abnormalities)

and/or on the measurement of tendon dimensions (e.g. tendon volume and thickness).62 _A

relatively new imaging technique, ultrasound tissue characterisation (UTC), might play an important role in addressing the limitations of conventional imaging tools.

UTC uses conventional ultrasound techniques to construct a three-dimensional image of the tendon. The structural integrity of the tendon can be made visible and is defined by four echo types: echo type I: intact and aligned tendon bundles; echo type II: less integer and waving tendon bundles; echo type III: mainly fibrillar tissue; echo type IV: a mainly amorphous matrix with loose fibrils, cells or fluid.68 _{To acquire UTC images,} the examiner uses a 7 MHz to 10 MHz linear ultrasound transducer (SmartProbe 12L5-V, Terason 2000+; Teratech; Burlington, MD, USA) positioned in a tracking device (UTC Tracker, UTC Imaging, Stein, The Netherlands) that moves automatically along the tendon long axis over a distance of 12 cm recording regular images at intervals of 0.2 mm. One of the advantages of this equipment, compared to conventional US, is that transducer tilt, angle, gain, focus and depth are standardised using the tracking device. Moreover, one single scan creates a 3D view of the tendon (sagittal, coronal and transverse planes). The imaging analyses are performed using a specific software, the UTC analyser. Contours, known as regions of interest (ROI), are drawn manually in the transverse plane with a distance not exceeding 5 mm. The outcomes are presented in percentages of echo types I-IV.69

A previous study investigating the Achilles tendon using UTC showed excellent interobserver reliability,69 _{yet there is no information on reliability of the UTC when used} to assess the structure of the patellar tendon. The growing number of studies using UTC stress the importance of investigating the benefits of using this technique. For monitoring purposes, previous studies showed that, based on UTC analysis, tendons show a positive

or negative adaptation or no changes as a response to load.70–72 _{Factors like amount of}

load performed, population investigated and methods used might influence the results. There is however a lack of evidence on the association between amount of load performed and changes in tendon structure. Previous authors observed that outcomes measured with conventional imaging tools (US and MRI) are not associated with changes in clinical outcomes after treatment.73 _{Similar findings were observed for UTC,}74,75 _{yet the number of} studies published is limited and factors like UTC methodology used should be taken into consideration. In conclusion, the use of UTC needs more investigation.

Aims of this thesis

The general objective of this thesis is to investigate the effect of load on healthy and pathological Achilles and patellar tendons using UTC, a new ultrasound-based imaging technique. The specific aims were to investigate:

1 - the use of UTC to characterise and quantify tendon structure;

2 - the influence of load on the Achilles and patellar tendon structure of healthy subjects; 3 - the relation between changes in tendon structure and changes in clinical outcome

after conservative treatment of patients diagnosed with Achilles or patellar tendinopathy.

Outline of the thesis

Aim 1 was investigated in Chapters 2 and 3. Chapter 2 presents a review of the use of the

UTC imaging technique to investigate tendon structure. Chapter 3 describes a study that

investigated UTC reliability for the patellar tendon.

Chapters 4, 5 and 6 refer to aim 2 of this thesis. Chapter 4 presents the results of a

cross-sectional study that investigated the effect of two different loads (low and high) on

the Achilles tendon structure of novice runners. Chapter 5 describes a study monitoring

the changes in Achilles tendon structure of recreational athletes after running a marathon.

Chapter 6 describes a study investigating the relation between load and changes in

patellar tendon structure in male elite volleyball players during the preseason.

The third aim of this thesis is investigated in Chapters 7, 8 and 9. The study in

Chapter 7 compared the tendon structure of the asymptomatic and symptomatic

tendons of patients with unilateral tendinopathy (insertional AT, midportion AT and

PT) with controls. Chapter 8 presents a review of the association between clinical and

imaging outcomes after therapeutic loading exercises in patients diagnosed with AT and PT. Chapter 9 presents the clinical results of a longitudinal cohort study in AT and PT

patients, comparing imaging outcomes to clinical outcomes at baseline and at short-term follow-up. In the final chapter of this thesis, Chapter 10, the results of the studies are

discussed and clinical implications and future recommendations are presented.

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General introduction | 19

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55. de Vries AJ, van der Worp H, Diercks RL, van den Akker-Scheek I, Zwerver J. Risk factors for patellar tendinopathy in volleyball and basketball players: A survey-based prospective cohort study. Scand J Med Sci Sport 2015;25:678–684.

56. van der Worp H, van Ark M, Roerink S, Pepping GJ, van den Akker-Scheek I, Zwerver J. Risk factors for patellar tendinopathy: a systematic review of the literature. Br J Sports Med 2011;45:446–452. 57. Visnes H, Bahr R. Training volume and body composition as risk factors for developing jumper’s

knee among young elite volleyball players. Scand J Med Sci Sport 2013;

58. Reinking MF. Current concepts in the treatment of patellar tendinopathy. Int J Sports Phys Ther 2016;11:854–866.

59. Panni a S, Tartarone M, Maffulli N. Patellar tendinopathy in athletes. Outcome of nonoperative and operative management. Am J Sports Med 2000;28:392–397.

60. Alaseirlis DA, Konstantinidis GA, Malliaropoulos N, Nakou LS, Korompilias A, Maffulli N. Arthroscopic treatment of chronic patellar tendinopathy in high-level athletes. Muscles Ligaments Tendons 2012;2:267–72.

61. Pascarella A, Alam M, Pascarella F, Latte C, Di Salvatore MG, Maffulli N. Arthroscopic Management of Chronic Patellar Tendinopathy. Am J Sports Med 2011;39:1975–1983.

62. Docking SI, Ooi CC, Connell D. Tendinopathy: Is Imaging Telling Us the Entire Story? J Orthop Sport Phys Ther 2015;45:842–852.

63. Malliaras P, Cook J, Purdam C, Rio E. Patellar Tendinopathy: Clinical Diagnosis, Load Management, and Advice for Challenging Case Presentations. J Orthop Sport Phys Ther 2015;45:887–898. 64. Peers KH LR. Patellar tendinopathy in athletes: current diagnostic and therapeutic

recommendations. Sport Med 2005;35:71–87.

65. Longo UG, Ronga M, Maffulli N. Achilles Tendinopathy. Sport Med Arthrosc Rev 2009;17:112–26. 66. McAuliffe S, McCreesh K, Culloty F, Purtill H, O’Sullivan K. Can ultrasound imaging predict the

development of Achilles and patellar tendinopathy? A systematic review and meta-analysis. Br J Sports Med 2016;50:1516–1523.

67. Drew BT, Smith TO, Littlewood C, Sturrock B. Do structural changes (eg, collagen/matrix) explain the response to therapeutic exercises in tendinopathy: a systematic review. Br J Sports Med 2014;48:966–972.

68. van Schie HTM, de Vos RJ, de Jonge S, Bakker EM, Heijboer MP, Verhaar JAN, Tol JL, Weinans H. Ultrasonographic tissue characterisation of human Achilles tendons: quantification of tendon structure through a novel non-invasive approach. Br J Sports Med 2010;44:1153–1159.

69. Van Schie HTM, De Vos RJ, De Jonge S, Bakker EM, Heijboer MP, Verhaar JAN, Tol JL, Weinans H. Ultrasonographic tissue characterisation of human Achilles tendons: Quantification of tendon structure through a novel non-invasive approach. Br J Sports Med 2010;44:1153–1159.

70. Docking SI, Rosengarten SD, Cook J. Achilles tendon structure improves on UTC imaging over a 5-month pre-season in elite Australian football players. Scand J Med Sci Sport 2016;26:557–563. 71. Rosengarten SD, Cook JL, Bryant AL, Cordy JT, Daffy J, Docking SI. Australian football players’

Achilles tendons respond to game loads within 2 days: an ultrasound tissue characterisation (UTC) study. Br J Sport Med 2015;49:183–187.

72. van Ark M, Docking SI, van den Akker-Scheek I, Rudavsky A, Rio E, Zwerver J, Cook JL. Does the adolescent patellar tendon respond to 5 days of cumulative load during a volleyball tournament? Scand J Med Sci Sport 2016;26:189–196.

73. Drew BT, Smith TO, Littlewood C, Sturrock B. Do structural changes (eg, collagen/matrix) explain the response to therapeutic exercises in tendinopathy: a systematic review. Br J Sports Med 2014;48:966–972.

74. van Ark M, Rio E, Cook J, van den Akker-Scheek I, Gaida JE, Zwerver J, Docking S. Clinical improvements are not explained by changes in tendon structure on UTC following an exercise program for patellar tendinopathy. Am J Phys Med Rehabil 2018;1.

75. de Vos RJ, Heijboer MP, Weinans H, Verhaar JAN, van Schie HTM. Tendon Structure’s Lack of Relation to Clinical Outcome after Eccentric Exercises in Chronic Midportion Achilles Tendinopathy. J Sport Rehabil 2012;21:34–43.

Chapter 2

Substantiating the use of ultrasound tissue characterization in the

analysis of tendon structure - A systematic review

Lucas Maciel Rabello Olivier C Dams

Inge van den Akker-Scheek Johannes Zwerver

Seth O’Neill

Clinical Journal of Sport Medicine (In press)

Abstract

Objective: To determine the role of UTC in predicting, diagnosing and monitoring tendon

injuries. Additionally, this study aims to provide recommendations for standardized methodology of UTC administration and analysis.

Data source: The PubMed, Embase and Web of Science databases were searched (up to

September 2018). All scientific literature concerning the use of UTC in assessing tendons was collected. The initial search resulted in a total of 1972 hits and, after screening by eligibility criteria, 27 articles were included.

Results: In total, 18 investigating the Achilles tendon, 5 the patellar tendon and 4

both Achilles and patellar tendons were included. The methods of UTC administration and analysis differed and were not uniform. The studies showed that the use of UTC to predict Achilles tendinopathy (AT) is inconclusive, but that a higher amount of tendon disorganization increases the risk of developing patellar tendinopathy (PT). In terms of diagnosis, UTC might provide additional information in AT cases. Additionally, promising results were found for the use of UTC in both AT and PT in monitoring the effect of load or treatment on tendon structure.

Conclusion: More research regarding the use of UTC in predicting tendon pathology

is required. UTC seems useful as an adjunct diagnostic modality since it can be used to differentiate symptomatic from asymptomatic tendons. Additionally, UTC is a promising device to be used to monitor changes in tendon structure in response to load or treatment. Moreover, we provide recommendations of a standardized protocol concerning the methods of UTC measurement and analysis.

Key words: tendinopathy, ultrasound, Achilles tendon, patellar tendon

Introduction

The Achilles and the patellar tendons are two of the strongest tendons in the human body

and thus subjected to large and frequent weight-bearing forces.27,28 _{As a result of this}

loading, these tendons are prone to overuse injuries such as tendinopathy, occurring in both (recreational) athletes44 _{and sedentary individuals.}18 _{The prevalence of Achilles and} patellar tendinopathy is estimated at approximately 2.35 and 1.60 per 1000 in the general population,1 _{and even higher in competitive athletes,}17 _{and these numbers are expected to} rise due to increasing (recreational) sport participation, especially in the middle-aged.25 Tendinopathy causes significant (functional) impairment and may be career ending for athletes.37 _{Additionally, the injury is difficult to treat and many patients fail to respond}

to treatment.28 _{It has been proposed that tendinopathy can eventually lead to rupture}

of the tendon,21,22,26 _{further worsening the prognosis with regard to tendon function and} participation in sporting activities.

The diagnosis of tendinopathy is usually clinical, but it can be confirmed with imaging, such as ultrasound (US) or magnetic resonance imaging (MRI). However, there seems to be a poor correlation between imaging results and patient-reported symptoms.13,23 This makes it difficult for clinicians to monitor treatment and to predict athlete’s (future) risk for injury. A systematic review by McAuliffe et al. concluded that US may be useful

in predicting future tendinopathy,32 _{though US poses problems such as inter-operator}

variance, variations in transducer positioning and lack of standardization.

Van Schie et al.,42 _{attempted to address these issues by introducing the imaging modality} ultrasound tissue characterisation (UTC). UTC is an ultrasonographic imaging modality that consists of a 10 MHz linear array transducer fitted to a tracking device that automatically takes 600 images in transverse, sagittal and coronal planes at intervals of 0.2 mm along

the tendon.42 _{These recordings can be analyzed by quantification and calculation of the}

percentage of echo types of a specific portion of the tendon tissue. These echo types (I-IV) represent tendon integrity and fibrillar disorganization: (I) highly stable, (II) medium stable, (III) highly variable and (IV) constantly low intensity and variable distribution.42 This imaging tool is only validated in equine tendon however, since 2010, the UTC has

been widely used in the investigation of humans tendon.41

UTC can discriminate symptomatic from asymptomatic tendons.42 _{However, the}

role of UTC in diagnosing, predicting and monitoring tendon injuries is still relatively unknown. Additionally, despite the potential UTC has in quantifying tendon structure, no conclusive guidelines exist for either the scanning of tendons or analyzing of the images. This has led to large variations in scanning and reporting of UTC imaging. There are currently several variations of scanning methods using different patient, ankle/knee and tracker positions, as well as scanning directions that may impact reliability and/or validity of reported findings. In addition to the methods of scanning, there are large variations in the methodology employed for the image analysis: the main variations appear to be the window size (number of frames the pixel brightness and stability pattern are based on, variations in this impact the percentage of the different echo types) and the length of tissue the quantification is based on, entire tendon or small section. Because UTC is not yet standard clinical practice it is hypothesized that the methods of administration vary and lack uniformity and this impacts the research conclusions.

26 | Chapter 2

This study aims to determine the role of UTC in predicting, diagnosing and (treatment-progress) monitoring tendon injuries by systematically reviewing all available literature relating to UTC administration and/or analysis of tendons. Additionally, this study aims to provide recommendations for standardized methodology of UTC administration and analysis.

Methods

This systematic review was conducted according to the PRISMA-Protocol for Systematic reviews.33 Search strategy and criteria

A systematic electronic search using the databases PubMed, Embase and Web of Science was performed in September 2018. All scientific literature concerning the use of UTC in human tendon (injuries) was collected. Implementation and validation of the search terms and search methods was attained from a Medical Librarian at the University of Groningen. Search strategy is listed in Table 1.

Study Selection

Inclusion criteria were: studies using UTC to assess tendon structure. There was no language restriction. Reviews, case-studies and animal-studies were excluded.

Data Extraction and Analysis

Two reviewers were involved in the study selection process. Two reviewers (LMR and OCD) independently selected the studies by applying the inclusion and exclusion criteria in three successive rounds. In the first round reviewers screened the titles followed by the abstracts selection. In the third round the full text was screened. In case of disagreement between the two reviewers in any of the rounds, a third opinion (IvdAS) was requested. The following data was extracted from the full texts of the included articles:

• Study information: author(s), year, design;

• Subject information: characteristics, injury, follow-up;

• UTC scanning methodology: patient position (prone, supine, sitting or standing), direction of the scan (proximal or distal), window size (9, 17 or 25) and area of the tendon analyzed;

Table 1. Search strings by database.

Database Search string

PubMed (“Achilles Tendon”[Mesh] OR achilles tend*[tw] OR ((achill*[tw] OR patella*[tw]) AND

(“Tendinopathy”[Mesh] OR tendonit*[tw] OR tendinit*[tw] OR tendinos*[tw] OR rupture [tw] OR tear [tw] OR tendinopath*[tw] OR tendon*[tw]))) AND (UTC [tw] OR echotype* [tw] OR (tissue[tw] AND characteri*[tw]) OR (ultraso*[tw] AND characteri*[tw])) NOT (“Animals”[Mesh] NOT “Humans”[Mesh])

Embase (‘achilles tendon’/exp OR ‘achilles tendinitis’/exp OR achillodyn*:ab,ti,de OR ((achill* OR

patella*) NEAR/3 (tendino* OR tendini* OR tendon* OR rupture OR tear)):ti,ab,de) AND (UTC OR echotype* OR (tissue AND characteri*) OR (ultraso* AND characteri*)):ab,ti,de NOT (‘animal’/exp NOT ‘human’/exp)

• UTC’s clinical role in predicting, diagnosing and monitoring tendon injuries, UTC results, practical recommendations for UTC application. The following were the definitions employed: Predicting: UTC use prior to or until the development of symptomatic injury

Diagnosis: UTC use to show structure and pathology; cross-sectional design

Monitoring: UTC use longitudinally to assess tendon structure in response to a stimulus (treatment, load e.g.).

Results

Search Results

The applied search yielded 1351 articles (See Fig. 1). Of these articles, 27 met our inclusion criteria. The methods of UTC administration are presented in Table 2. The other extracted data are presented in Table 3. Eighteen studies performed a scan of the Achilles tendon,4,11,42,43,46–51,12,16,19,20,30,31,36,40 _{five of the patellar tendon}2,3,15,38,39 _{and four studies} assessed both.8–10,14 _{No publications regarding the use of UTC in other tendons were found.} Most studies concerned patients with (a history of) Achilles midportion tendinopathy.

Substantiating the use of ultrasound tissue characterization in the analysis of tendon structure - A systematic review | 27

Identification

Screening

Eligibility

Included

Records identified through database searching (n = 1952) PubMed (n = 430); Embase (n = 773); Web of Science (n = 749)

Records after duplicates removed (n = 1351)

Records screened (n = 210)

Full-text articles assessed for eligibility (n = 36) Records excluded (n = 174) Studies included in qualitative synthesis (n = 27)

Full-text articles excluded (n = 9), reason: - UTC was not applied

Author Patient position Direction of Side Window Interval between the scan size Area analyzed contours Table 2

. Methods of UTC administration

Docking et al.,

2018b

Docking et al.,

2018a

de Sá et al., 2018 Rudavsky et al.,

2018

V

an Ark et _al., 2018 _Waugh et _al., 2018

A

chilles: prone with their feet off the _{edge of a plinth in 90 degrees of ankle dorsiflexion Patellar: supine with their knee at ;120 degrees flexion A}chilles: prone with their feet off the _{edge of a plinth in 90 degrees of ankle dorsiflexion Patellar: supine with their knee at ;120 degrees flexion Prone on an examination bed with their feet placed on a foot and ankle stabilizer to stabilize and position the A}

chilles

tendon Supine position with the left knee flexed to 90° Supine position with the left knee flexed to 100° Prone position with foot placed in stabilizer used achieves perpendicular alignment.

UTC transducer placed at

5/10 degree dorsiflexion.

From proximal to distal From proximal to distal Not described From proximal to distal From proximal to distal Not described Unilateral or Bilateral Unilateral Bilateral Unilateral Unilateral Bilateral 25 25 25 25 25 25

A

chilles: from the disappearance of the calcaneus _{to the appearance of the musculotendinous junction Patellar: from the disappearance of the inferior patella pole to 3 cm distally A}chilles: from the disappearance of the calcaneus _{to the appearance of the musculotendinous junction Patellar: from the disappearance of the inferior patella pole to 3 cm distally The examiner determined the landmark (2cm from the calcaneal insertion) in the sagittal plane.}

Contours were drawn at 2mm proximal

and distal to the landmark (4 mm total) From the disappearance of the inferior pole of the patella,

extending one centimeters distally

From the disappearance of the inferior pole of the patella,

extending three centimeters distally

A scan 2.5 cm proximal of the insertion of the Achilles tendon was located.

The A

chilles tendon

border was outlines 2 mm either side of this slice location in the sagittal plane and the two contours interpolated to create a 20 scans x 0.2 mm region of interest. Not described Not described 4 mm No more than 4 mm No greater than 5 mm 4 mm

Area of interest (R OI) Heyward et al., 2018 Rudavsky et al., 2017 Esmaeili et al., 2017 Stanley et al., 2017 Hernández G et al,. 2016

Bedi et al., 2016 Docking et al.,

2016a

Prone position with maximum ankle dorsiflexion Supine position with the left knee flexed to 90° Achilles: Standing on a raised level surface with the great toe and knee touching the wall in a standardized lunge position Patellar: Supine position,

knee flexed

at ~60º. Standing on a raised level surface with the great toe and knee touching the wall in a standardized lunge position Sitting position with foot placed in a high surface and knee flexed 90º Standing on a raised level surface with the great toe and knee touching the wall in a standardized lunge position Achilles: Standing on a raised level surface with the great toe and knee touching the wall in a standardized lunge position Patellar tendon: Supine position,

knee

flexed at ~60º.

Distal to proximal From proximal to distal Distal to proximal Distal to proximal Distal to proximal Distal to proximal Achilles tendon: Distal

to

proximal

Patellar tendon: Proximal to distal Unilateral Unilateral Bilateral Unilateral Bilateral Uni/ Bilateral Uni/ Bilateral No greater than 5 mm No more than 4 mm No greater than 5 mm 0.5 mm (if necessary

,

more frequent contours were added) Not consistent No greater than 5 mm No greater than 5 mm

25 25 25 17 Not descrbed 25 25

A

chilles midportion (from 2 cm proximal to the _{upper border of the calcaneus in a proximal direction) from the disappearance of the inferior pole of the patella,}

extending two centimeters distally

A

chilles: Multiple contours (from the _{disappearance of the calcaneus to the musculotendinous junction Patella: over a distance of 3 cm starting from the disappearance of the inferior pole of the patella. 0.5 cm proximal to the insertion of the A}chilles to the calcaneus,

continuing to the

30 | Chapter 2

Standing on a raised level surface with the great toe and knee touching the wall in a standardized lunge position Prone position with ankle in approximately 5-10º of dorsiflexion Prone position with maximal ankle dorsiflexion Supine position with ~100º of knee flexion Prone position with maximal ankle dorsiflexion Standing on a raised level surface with the great toe and knee touching the wall in a standardized lunge position Prone position with feet hanging over the edge and with ankle in approximately 5-10º of dorsiflexion Prone position with ankle dorsiflexion of 15º Participants stood on an elevated platform,

with their toes and knee

against a wall.

From disappearance of the calcaneus to the musculotendinous junction Achilles Insertion: 5 contours (from the disappearance of the calcaneus to 2 cm proximal) Midportion: 9 contours (from 2 to 6 cm proximal to the upper border of the calcaneus in a proximal direction) Not described From the apex of the patella to 2 cm distally Not described From 2 to 4 cm proximal to the upper border of the calcaneus in a proximal direction From 3 to 5 cm proximal to the calcaneal insertion 5 contours: maximum thickness and 1.5 cm proximal and distal from the segment of maximum thickness From the point that the calcaneus disappeared to the musculotendinous junction

Distal to proximal Not described Distal to proximal Proximal to distal Distal to proximal Distal to proximal Not described Proximal to distal Distal to proximal Unilateral Bilateral Unilateral Unilateral Unilateral Unilateral Unilateral Unilateral Uni/ Bilateral No greater than 5 mm 5 mm No greater than 5 mm 5 mm 5 mm 7.5 mm Not described

Docking et al., 2016b W ezenbeek et al., 2016

and 2018 Masci et al., 2016 Van Ark et al.,

2016

Masci el al., 2015 Rosengarten et al.,

2015 de Jonge et al., 2015a de Jonge et al., 2015b Docking et al., 2015 25 17 25 25 25 25 9 9 25

Substantiating the use of ultrasound tissue characterization in the analysis of tendon structure - A systematic review | 31

Standing on a raised level surface with the great toe and knee touching the wall Prone position with feet hanging over the edge,

with dorsiflexio

Prone position with ankle dorsiflexion of 15º Prone position with maximal ankle dorsiflexion From the disappearance of the calcaneus to the musculotendinous junction 5 contours: 1.5 cm proximal and distal from the thickest segment (total 3 cm) 5 contours: 1.5 cm proximal and distal from the thickest segment (total 3 cm) Mean of the thickest part of the tendon and 2 mm proximal and distal

Distal to proximal Not described Not described Proximal to distal Unilateral Unilateral Unilateral Unilateral 6 mm 6 mm W ong et al., 2015 de V os et al., 2012 De V os et al., 2011 Van Schie et al., 2010 25 9 9 9

Table 3

. Characteristics and results of the included articles.

Docking et al.,

2018b

Docking et al.,

2018a

de Sá et al., 2018 Rudavsky et al.,

2018

Prospective cohort Prospective Cohort Cross- sectional Prospective cohort

A percentage of DIS above ≈2.5%

was a significant risk factor for the presence of symptoms at baseline Percentage of DIS showed a weak relationship with severity of symptoms at baseline Abnormal tendons contained greater mCSA of AFS compared with normal tendons. Patellar tendon showed significant difference between players with and without a history of symptoms,

and

players with and without current symptoms. The proportion of echo type I patterns [ST 70 (10)%,

CG 74

(13)%] were equivalent in the two groups Nine percentage of adolescent dancers developed pathology during this study

. Only 2 of 5

participants who developed pathology reported pain associated with their tendon Quantification of tendon structure using UTC did not enhance the ability to identify athletes who developed symptoms The extent of disorganization in A

chilles and patellar

tendons does not impact on the presence or severity of clinical symptoms There is no evidence of a negative statin influence on Achilles tendon structure Pathology in the proximal patellar tendon can develop during adolescence

Subject Characteristics

A

chilles _{tendon: 23.9 Patella tendon: 23.8 A}chilles _{tendon: 23.9 Patella tendon: 23.9 Statin users: 66 Controls: 63 Range from 11 - 18}

A

chilles ten

-don: 163 _{Patella ten}

-don: 171

A

chilles ten

-don: 149 _{Patella ten}

-don: 152

Statin users: 33 (29:4) Controls: 33 (29:4) 57 (34:23) YES (elite) YES (elite) YES (recrea

-tional) YES (recrea

-tional)

YES and NO YES and NO NO NO Predicting Diagnosis Diagnosis/ Predicting _Monitoring Single scan Single scan Single scan 2 years

Author/Y ear Design Mean age Number Sports Injury Clinical Follow-up Results Injury (Y ears) (male: (A chilles/patellar application female) tendinopathy)

Outcomes of treatments for patellar tendinopathy need to be based on clinical findings rather than imaging UTC evaluation should not be the sole basis in predicting the development of tendinopathy UTC can be used to assess tendon response to loading; should preferably be used in combination with other analyses.

Low to moderate loads may be beneficial in the treatment,

management or

rehabilitation of A

chilles

tendinopathy Presence of tendon structure abnormalities was not related to pain,

which suggests that

development of symptoms involves a complex interplay between a number of factors. Regular UTC assessment could find maladaptation to increased training load.

No significant changes on tendon structure were observed after exercise program Structural parameters (echo- types) did not predict A

chilles

tendinopathy Decrease in echo type I seen after longer rest training compared to shorter rest training.

The change in echo

type was not related to the change in young’

s modulus.

No significant changes on echo types (I-IV) over the period. Significant effects of time were found for echo types III and IV (decrease) Tendon disorganization (echo types III + IV) increased; there was a greater increase in the group with abnormalities. Both limbs and tendons showed increased echo type I. Training load had inconsistent effects on changes in tendon structure.

van Ark et a;l.,

2018 W ezenbeek et al., 2018 W aught et al., 2018 Heyward et al., 2017 Rudavsky et al., 2017 Esmaeili et al., 2017

Randomized clinical trial Prospective cohort Prospective Randomised crossover Prospective cohort Prospective cohort 22,7 18.03 30.1 22 Ballet dancers from 11 and 18 Control from 21-40 23.7 18 (16:2) 250 (113:137) 18 (8:10) 21 (12:9) _{60 (25:35)} 26 (26:0) Yes (recrea

-tional) YES (recrea

-tional) YES (recrea

-tional) YES (recrea

-tional) YES (recrea

-tional) YES (Profes

-sional)

YES NO NO NO NO NO Monitoring Predicting Monitoring Monitoring Predicting Monitoring 4 weeks 2 years _{12 weeks} 2,7 days 2 years _{18 weeks}

34 | Chapter 2

Outcomes of treatments for patellar tendinopathy need to be based on clinical findings rather than imaging UTC evaluation should not be the sole basis in predicting the development of tendinopathy UTC can be used to assess tendon response to loading; should preferably be used in combination with other analyses.

Low to moderate loads may be beneficial in the treatment,

management or

rehabilitation of A

chilles

tendinopathy Presence of tendon structure abnormalities was not related to pain,

which suggests that

development of symptoms involves a complex interplay between a number of factors. Regular UTC assessment could find maladaptation to increased training load.

No significant changes on tendon structure were observed after exercise program Structural parameters (echo- types) did not predict A

chilles

tendinopathy Decrease in echo type I seen after longer rest training compared to shorter rest training.

The change in echo

type was not related to the change in young’

s modulus.

No significant changes on echo types (I-IV) over the period. Significant effects of time were found for echo types III and IV (decrease) Tendon disorganization (echo types III + IV) increased; there was a greater increase in the group with abnormalities. Both limbs and tendons showed increased echo type I. Training load had inconsistent effects on changes in tendon structure.

van Ark et a;l.,

2018 W ezenbeek et al., 2018 W aught et al., 2018 Heyward et al., 2017 Rudavsky et al., 2017 Esmaeili et al., 2017

Randomized clinical trial Prospective cohort Prospective Randomised crossover Prospective cohort Prospective cohort 22,7 18.03 30.1 22 Ballet dancers from 11 and 18 Control from 21-40 23.7 18 (16:2) 250 (113:137) 18 (8:10) 21 (12:9) _{60 (25:35)} 26 (26:0) Yes (recrea

-tional) YES (recrea

-tional) YES (recrea

-tional) YES (recrea

-tional) YES (recrea

-tional) YES (Profes

-sional)

YES NO NO NO NO NO Monitoring Predicting Monitoring Monitoring Predicting Monitoring 4 weeks 2 years _{12 weeks} 2,7 days 2 years _{18 weeks}

Increase in echo type I.

Overall

positive adaptation (shift from type II to type I) in tendon structure during season. No significant difference between professional and young players tendon structure. No significant differences on tendon structure of symptomatic compared to asymptomatic side. Decrease in echo types III and IV; increase in echo types I and II. Echo types I and II were signi

ficantly lower in the

pathological tendon in comparison to normal tendons and echo types III and IV

were

significantly increased. Echo type I increased and echo types II-IV

decreased,

suggesting a tendon improved at the end of the pre-season. UTC detects tendon disorganization in the medial part of the A

chilles tendon.

UTC can detect changes in tendon structure over a season. UTC cannot differentiate symptomatic and asymptomatic cases UTC offers an objective method to evaluate healing of Achilles tendons. UTC can possibly detect ‘pathological’

tendons,

inconclusive is if this results in tendon symptoms. UTC can detect changes in tendon in response to load. UTC can complement US and colour Doppler by demonstrating disorganized focal medical A

chilles tendon

structure indicative of plantaris tendon involvement in tendinopathy

.

Stanley et al.,

2017

Hernández G et al,. 2016 Bedi et al., 2016 Docking et al.,

2016a

Docking et al.,

2016b

Masci et al.,

2016

Prospective cohort Cohort Prospective Prospective Prospective Prospective cohort 19.76 22.6 32 Achilles tendon: 28.17 Patella tendon: 24.04 23.8 40 21 (9:12) 20 (20:0) 15 (13:2) Achilles _tendon:66 (63:3) Patella

tendon: 50 (49:1) 18 (18:0) 18 (14:4) YES (semi

-profes

-sional) YES (Profes

-sional/ recrea

-tional) YES (Prof. semip

ro

f.)

NO/YES (Seden

-tary/ elite athletes) YES (Pro

-fe ss io na l) YES (Recrea -tional/ profes -sional) NO NO YES NO specific injury , ‘patholog -ical’ and

‘healthy’ tendons NO YES

Monitoring Diagnosis Monitoring Diagnosis Monitoring Diagnosis Baseline, 1,

2,

3

months Single scan ₂₅ months Single scan _{5 months} Single scan

No significant changes in tendon structure (echo types I-IV) over the tournament period Tendon structure: 54,6% echo type I,

42.8% echo type II,

2.2%

echo type III,

and 0.3% echo

type IV

.

More echo type II at insertion than midportion. Female tendons contained more echo type II (in insertion and midportion than male). Increase in echo types I + II and decrease in III + IV

at 6 months.

Difference in UTC results between groups.

There

was a transient change (day 2) in tendon structure (disorganization) in those with normal tendons that returned to baseline at day 4. UTC shows definite abnormali

-ties in type 2 Diabetes patients (possibly also type 1) possibly predictive of tendinopathy

.

Either structure is stable enough,

UTC is useless or

tournament/time insufficient to bring about change? UTC assesses tendon structure and should be interpreted different depending on location (insertion or midportion) of tendon or gender of participant. UTC can assess structural response to treatment UTC may be able to detect changes in tendon structure in response to load. Screening for high risk of development

van Ark et al.,

2016 W ezenbeek et al., 2017 Masci et al ., 2015 Rosengarten et al., 2015 de Jonge et al., 2015a

Prospective Cross- sectional Prospective case-series Prospective Case- control

17 .2 17 .9 39 23.8 Type 1 dia

-betics: 23 Type 2 dia

-betics: 49.6 Controls for type 1: 24.2 Controls for type 2: 46.6 41 (30:11) 70 (29:41) 8 (7:1) 21 (21:0) Type 1: 24 (9:15) _{Control type 1: 20 (9:11)} Type 2:24 (15:9) _{Control type 2: 24 (13:11)} YES (recrea

-tional) YES (recrea

-tional) YES(rec

-reational) YES (Profes

-sional) NO/YES (Sed

-entary/ recrea

-tional)

NO NO YES YES NO Monitoring Diagnosis Monitoring Monitoring Predicting Each day of a 5-day volleyball tournament Single

scan

6 months Baseline, 1, 2 and 4 days Single scan

Difference in echo types between symptomatic and asymptomatic groups. Tendon structure returns to values of asymptomatic within 24 weeks

.

No relationship however between UTC tendon structure and symptoms.

No

correlation

between

Visa-A

and UTC. Significant difference in tendon structure between symptomatic,

asymptomatic

and control group. Asymptomatic tendon is structurally compromised Baseline structure was similar between groups,

no

structural response to load in either group over 4 days post exercise. No correlation between

Visa-A and UTC.

An improve

-ment on echo types I and II was observed without corre

-lation to symptom severity

.

Improvement in tendon structure after 24 weeks. No difference in change of echo type between treatment groups.

Prospec -tive Prospec -tive Pro -spective case-con -trol Prospec -tive clini

-cal trial Rand

-omized clinical trial

Symp

-tomatic group: 49.7 Asymp

-tomatic group: 51.4 Tendinop

-athy group: 30.3 Healthy group: 26.8 Diabetic patient: 37

.9

Control: 32.9 46 PRP group: 49 (8.1) Saline group: 50 (9.4)

Symptomat

-ic group: 54(26:28)

Asymptomat

-ic group: 26 (18:8) _Tendinopathy group: 21 (20:1) Healthy _{group: 6 (5:1)} Diabetic _{group:7 ( 5:2) Control group:} 10 (4:6) 25 (10:15) _{PRP group: 27} (13:14) _{Saline group:} 27 (13:14) NO/YES (Seden

-tary/rec

-reational) YES (rec

-reational/ profes

-sional) YES (rec

-reational) NO/YES (Seden

-tary/rec

-reational) NO/YES (Seden

-tary/rec

-reational)

YES YES NO YES YES Monitoring Diagnosis Monitoring Monitoring Monitoring

6,

12,

24

and 52 weeks.

Single scan Baseline,

2

and 4 days _{after the run.} Baseline,

2,

8,

16 and 24 weeks. _{Baseline 6, 12,} and 24 weeks

de Jonge et al., 2015b Docking et al., 2015 W ong et al., 2015 de V os et al., 2012 de V os et al., 2011

UTC has no correlation with clinical measure (VISA

-A

score) UTC might be useful to differentiate between symptomatic and asymptomatic patients and “healthy “

subjects.

No significant difference in UTC results between diabetics and controls.

No transient

response to load. UTC assesses tendon structure,

though this seems

unrelated to symptoms. UTC assesses tendon structure response to treatment(s)

Symptomatic tendons showed less echo types I + II than asymptomatic.

Case-con -trol Sympto -matic: 44.9 Asympto -matic: 43.6 Symptomatic group: 26 (12:14) Asymptomat -ic: 26 (16:10) Not de -scribed YES Diagnosis Single scan

van Schie et al.,

2010