Tendinopathy, Tendinitis

Current Tendinopathy science  – the emerging role of early inflammation and novel biological therapies.

 

Author: Dr Leon Creaney, Consultant in Sport & Exercise Medicine, Manchester Institute of Health & Performance (MIHP), 299 Alan Turing Way, Manchester, M11 2AZ

 

 

Abstract

 

Tendinopathy is common condition in sport characterised by localised tendon pain and dysfunction. The classic model of exercise-induced tendinopathy describes cycles of microscopic collagen injury and repair without a significant inflammatory component to the process. Increasing evidence suggests a degree of inflammation is present in early tendinopathy and may explain why the condition is painful. An early response to exercise in tendons includes increased proteoglycan content, with Aggrecan in particular linked to painful tendinopathy. Modern imaging techniques such as MRI T2 collagen mapping, sodium mapping and sonoelastography may be able to quantify and monitor stages of healing in tendons and correlate more closely to pain levels than grey-scale ultrasound or standard MRI. With the shifting focus to inflammatory processes attention is again drawn to anti-inflammatory agents such as corticosteroids, but also novel agents Hyaluronic Acid (HA). Potential exists to narrow focus on elements of the inflammatory cascade as therapeutic targets. Loading remains the first line treatment in tendinopathy but novel therapeutic agents such as HA, Platelet-Rich plasma and Autologous Tenocyte Implantation (ATI) have a growing evidence base. ATI brings tendinopathy management into the era of regenerative medicine and presents the possibility of restoring structure and function to degenerative tendons.

 

1.Introduction

 

Tendinopathy (or tendinitis) is a common condition. Up to 30% of presentations in general practice are musculoskeletal-related [1] and these are often tendinopathies. Tendinopathy is particularly common in sport. At the 2016 Olympic games 1,101 athletes reported injuries with 156 (14%) of these being tendon injuries. Track & Field alone accounted for 54 (34.6%) of these injuries with the Achilles being most often affected[2].

 

Tendinopathies are often named after the sport or activity with which they are historically perceived to be most commonly associated with. Examples include:- Shoulder impingement syndromes & Swimmer’s shoulder (Supraspinatus tendinopathy); Tennis Elbow (Common Extensor origin tendinopathy); Golfers Elbow (Common Flexor origin tendinopathy); Greater Trochanteric Pain syndrome (Gluteus Medius or Minimus tendinopathy); Runner’s Bum – (Hamstring origin tendinopathy); Jumper’s Knee (Patella Tendinopathy); Achilles Heel (Achilles tendinopathy); Flat feet (Tibialis Posterior tendinopathy); Ballet dancers (Flexor Hallucis longus tendinopathy). Although nuances exist in the clinical presentation of these conditions, tendinopathy is a broadly similar disease across different anatomical areas with similar pathology and treatment principles. Seemingly any tendon subjected to chronic loading greater than its capacity to regenerate can develop tendinopathy. Optimised loading (work against resistance) is the well-established first line treatment for this condition, but at times is only successful in 55% of patients [3].

 

We present this review summarising the current understanding of tendinopathy in 2018. Included is an overview of normal tendon structure, pathology and the evidence-base for novel treatment methods.

 

2.Normal tendon structure

 

Normal tendon has a high water content, but the dry weight is over 90% Type I collagen which has high tensile strength. Approximately 5% is Type III collagen, which is expressed during the healing phase within damaged tendons, and also some type V collagen. Surrounding the collagen fibrils is a supporting extracellular matrix (ECM) composed of various proteoglycans (versican, decorin, aggrecan).

 

The cellular component of tendons consists of occasional specialist fibroblasts called named tenocytes which reside on the surface of collagen fibrils together with a population of Tendon Stem Cells (TSC). These cells are in many ways analogous to mesenchymal cells of the Osteoblast/Osteocyte/Osteoclast lineage in bone, and are responsible for collagen turnover in tendons.

 

3.Tendinopathy pathophysiology

 

3.1 Eccentric Microtrauma & Collagen turnover

 

Whereas bone is known to be in a constant state of turnover, with remodelling by cells of the Osteoblast-Osteoclast type, there is evidence that tendon collagen has little turnover in adult life in sedentary individuals [4]. This is not the case in habitual exercisers where there is evidence of increased tendon collagen turnover with both adaptive, and maladaptive responses to exercise[4]. Heinemier et al used Carbon-14 dating to demonstrate evidence of increased collagen turnover many years prior to the clinical presentation of tendinopathy.

 

Tenocytes secrete enzymes named Matrix Metalloproteinases (MMP), of which there are at least 18 sub-types. These MMP’s break down (catabolic) damaged collagen and synthesize (anabolic) new collagen fibrils. The balance between these two processes is constantly changing. When tendons are exposed to eccentric exercise (such as running or jumping), there will inevitably be some microtrauma to individual collagen fibres. Collagen has a ‘crimped’ structure when looked at under high-magnification electron microscopy images and has the ability to stretch 4-8% and recoil in a spring-like fashion. The coiled triple helix structure of tropocollagen also contributes to this phenomena. Beyond 8% strain collagen fibres begin to fail [5]. Damaged fibres are actively recycled and replaced with new fibrils. Disruption of this carefully co-ordinated process may lead to tendon disrepair[6]. It is becoming increasingly clear that the proposed model of exercise-induced damage and repair induces the body’s classical response to injury, namely acute inflammation, during the early stages of tendinopathy[7]. As well as damaging collagen, 8% strain has been demonstrated to cause de-differentiation of tendon stem cells (TSC’s) into adipocytes, chondrocytes and osteocytes[8].

 

With accelerated remodelling in tendon, disorganised wavy collagen pattern becomes apparent. Collagen fibrils are less mature, contain more Type III collagen and have reduced collagen cross-links[9] (which contribute to increased tendon strength).

 

3.2 Adaptive tendon responses in athletes

 

There is considerable variation in the normal range of tendon structure in athletes. Hullfish et al 2018 studied 22 competitive middle-distance runners across a competitive season and compared them against non-runner controls [10]. They discovered that asymptomatic tendons (VISA-A 93.8 +/- 8.05) in runners were on average 48% thicker at the Achilles mid-portion, had less organised collagen (40%) and darker, less echogenic appearances on grey-scale ultrasound. Furthermore tendons adapted to become 7% thicker by end of season[11]. They proposed two populations of tendon adaptive response – habituated tendons and symptomatic tendons.

 

3.3 Vascular considerations in tendon pathophysiology

 

Other factors beyond eccentric exercise-induced microtrauma are implicated in the pathogenesis of tendinopathy. Tendons typically have poor blood supply and contain watershed vascular areas that may become ischaemic under tensile strain [12]. Hypoxia, reperfusion injury and generation of oxygen free radicals is a putative mechanism by which tenocytes may be injured leading to signs of tenocyte stress (elongation) and apoptosis. In ruptured degenerative tendons histology confirms evidence of hypoxic-induced injury to tenocytes with increased lipid vacuoles, enlarged lysosomes and degranulated endoplasmic reticulum [13]. Green Tea, a mild anti-oxidant, with some capacity to mitigate against oxygen free radical-mediated damage, has been proposed as a potential protective agent in tendinopathy [14].

 

Wezenbeek et al 2018 studied the blood flow in Achilles tendons in response to exercise, in 351 students at Ghent University [15]. Of the 250 included in final analysis, 11% (n = 27) developed Achilles tendinopathy over a 2-year study period. Female sex was a significant risk factor, however failure to increase blood blow to the tendon post-exercise was an independent risk factor with a predictive accuracy of 81.5%.

This may have implications for post-exercise warm-down protocols. Athletes with a previous history of tendinopathy, female athletes, or otherwise identified ‘at risk’ of tendinopathy may utilise techniques to increase blood flow post-exercise. This may include warm-water immersion (vasodilatation), low intensity lower limb exercise (eg cycling against minimal resistance) or previously studied GTN patches [16].

 

3.4 Changes in Proteoglycan content in pathological tendons

 

Although a lot attention is paid to the quality of collagen in tendons, the extracellular matrix also plays a role in tendon pathology. An early adaptive, potentially maladaptive response occurs in response to exercise. There is an increase in large proteoglycan content (aggrecan/versican) within 1-2 days [17]. This results in an increase in bound water within the ground substance which may lead to collagen matrix disorganisation. Radiological changes parallel to the histological changes have been seen in Ultrasound Tissue Characterisation (UTC) studies in Australian Rules Football [18]. Aggrecan can be upregulated rapidly (<24hr) and can also be degraded with 3 days. UTC echopattern peaks in terms of Type II echos (slight disorganisation) on Day 2 and resolves by Day 4.

 

Patella tendon pain has been reported to correlate closely with Glycosaminoglycan (GAG) (Decorin, Versican, Aggrecan) content in the tendon [19]. Attia et al [20] reported falling VISA scores against rising GAG content with a correlation of R2= 0.798. The correlation was most marked in relation to Aggrecan, a molecule with high Chondroitin Sulphate (CS) content. The authors speculated that Aggrecan may more easily diffuse through a disorganised tendon reaching nociceptive targets. Aggrecan itself is hydrophilic and may increase intra-tendinous pressure through increased water content. This potentially explains the typical appearances of tendinopathy on fluid-sensitive MRI sequences. CS is negatively charged and may alter the nociceptor threshold for activation. CS has been implicated in tendon hyperalgesia [21].

 

3.5 Tenocyte changes in tendinopathy

 

There is evidence of cellular hypoxia with lipid vacuoles, enlarged lysosomes, and degranulated endoplasmic retinaculum13 in advanced tendinopathy leading to rupture.

It is also well known that tenocytes change shape from elongated (‘spindle-shaped’) to enlarged & rounded appearances and tend to proliferate in tendinopathy [22]. Tenocytes in this situation have been described as metaplastic with chondroid appearance [23]. Huisman et al (BMC 2014) suggest that mechanical stimulation may induce a more metabolically active tenocyte phenotype with cells that are less elongated and branched [24]. They suggested tenocyte rounding may represent an adaptive response which is not necessarily pathological.

Loading at different intensities has differential effects on tenocytes. At 4-6% optimal strain beneficial effects include type I collagen production and suppression of IL-1b production. However 8% strain can shift gene expression to a pro-inflammatory situation by increasing levels of IL-1b and COX-2 [25]. In addition high-strain mechanical loading has been shown to induce tenocyte apoptosis [26].

 

3.6 Histological correlation to the Cook-Purdham tendon pathology continuum

 

The molecular and histological changes characterised above correlate well to the Cook-Purdam three modelled stages of tendinopathy [27].

 

Reactive tendinopathy is usually completely reversible with a period of offloading. Histologically this is characterised by increased GAG content [20] and minimal collagen disorganisation [18] which reverses rapidly.

 

Later stages of tendinopathy – ‘Tendon dysrepair’ and ‘Degenerative tendinopathy’ are characterised by more permanent changes. Increased collagen disorganisation and replacement with mucoid ground substance and reduced tenocyte capacity. Since tenocytes are vital to maintain tendon homeostasis, any impairment of tenocyte function or numbers represents a more permanent injury to the regenerative capacity of a tendon (‘Hypoxic’ degenerative tendinopathy). These later stages of tendinopathy become progressively less reversible.

 

4.Inflammation & Tendinopathy

 

The maxim that tendinopathy is a purely degenerative process resulting from excessive loading and inability to fully regenerate tendon structure has been challenged in recent literature[28].

Pro-inflammatory cytokines such as IL-1, pro-inflammatory mediators such as Prostaglandin E2 and COX-2, growth factors such as TGF-b1, PDGF and IGF-1 and neurotransmitters such as Substance P are expressed in increased amounts in tendinopathy [29]. In addition ‘Alarmins’ (Heat Shock Proteins, Hypoxia-inducible factor, S100) and IL-6 are released in response to cellular stress [30-31].  Cellular infiltration with classic chronic inflammatory cell types has been demonstrated including cells of macrophage/monocyte type (CD14/CD68) [32], T-Cells and Natural Killer Cells [33].

The presence of chronic inflammation may present putative targets for anti-inflammatoy agents in the future management of tendinopathy [34]. Until now corticosteroids have been viewed as potentially harmful to tendon integrity [35]. However, it has also been hypothesized that unresolved (chronic) inflammation may disturb the remodelling process in tendon injury [36]. In an elaborate experiment published in (Nature) Scientific reports rats had their Achilles tendons transected and were administered systemic Dexamethasone by injection. Rats administered Dexamethasone in Days 0-4 post-injury, the acute inflammatory phase, had structurally poor healing versus Saline treated tendons. Dexamethasone reduced the peak force to failure in these tendons [36].

 

In contrast, another group of rats were treated with Dexamethasone, during the early remodelling phase, days 5-9, when acute inflammatory processes would be expected to have ceased. In these rats, peak force to failure increased 39% versus Saline. Histologically the Dexamethasone treated tendons had strikingly better looking collagen organisation (parallel, tightly packed and ordered) versus Saline-treated (wavy, increased spacing/extracellular matrix and disordered). As a result the Dexamethasone-treated tendons were able to achieve improved peak force to failure, despite cross-sectional area being 42% less than saline treated tendons. A structurally superior tendon, both stronger and less thickened. Flow cytometry was also performed demonstrating drastically reduced CD8a Cytotoxic T-cells within the tendons. The authors concluded that (chronic) inflammation continuing beyond the initial inflammatory phase of healing disturbs the formation of quality collagen [36].

 

Compressive loads are also implicated in the aetiology of insertional tendinopathies [37]. High compressive loads adjacent to bone may expose tenocytes to excessive cyclic strain leading to maladaptation. Tenocytes exposed to increased cyclic stretch secrete Interleukin-6 (IL-6), a proinflammatory cytokine [7].

 

Thus it can concluded that cellular and humoral inflammatory responses are present in tendinopathy, with inappropriate chronic inflammation being implicated in disease progression. The question arises as to why inflammation might persist inappropriately in the tendons of athletes. Athletes are usually healthy and disease free, with a lower burden of inflammatory disorders, so the cause is unlikely to be systemic. Exercise itself has an inflammatory effect however. Training cycles, characterised by overload stimulus followed by recovery, rely on stimulation of an inflammatory response, to bring about physiological adaptation. Continuing to train on an injured tendon, may well encourage continuing localised inflammation in the tendon. Many tendons remain asymptomatic in early, even late stage disease, so there is often no protective pain signal, alerting an athlete to stop, until tendinopathy is histologically advanced.

 

5.Effects of adiposity and hyperglycaemia on tendons

 

Tendinopathy and Calcific tendinopathy are more common in diabetics. There is evidence of transdifferentiation of fibroblasts into osteoblasts in the aetiogenesis of ectopic calcification in tendons and myositis ossificans in muscle [8]. Furthermore high-glucose treated tenocytes may also differentiate into adipocytes leading to intratendinous lipid deposition38. Mechanical stretch (loading) may suppress this response via activation of ERK.

Adipose tissue, for example Kager’s Fat Pad adjacent to the Achilles tendon has been shown to release pro-inflammatory cytokines which may contribute to a localised and low grade systemic inflammation [39].

 

6.Pain of tendinopathy

 

Pain in tendinopathy is often extreme on palpation, but always remains highly localised to the area of pathology and does not have a tendency to increase in area. Although tendinopathy has been described as a pain syndrome it does not display classical features of central sensitisation in this regard [40]. Tendinopathy pain has a tendency to warm-up  in early stage disease. This means athletes can continue to train, and this characteristic of tendinopathy pain has a permissive effect on disease progression. Tendinopathy pain also warms down upon exercise cessation. Ongoing, disproportionate pain which lingers long after exercise has ceased may imply an inflammatory component to the pain of tendinopathy. It has been demonstrated that the severity of tendinopathy pain is clearly correlated with the Aggrecan content of tendon20. Tendinopathy pain does not seem to relate to collagen structure defined on Grey-scale Ultrasound & MRI [41] or Ultrasound Tissue Characterisation [42].

Aggrecan, a large negatively charged proteoglycan attracts and binds water within tendons causing swelling. This may lead to increased hydrostatic pressure and stimulate local C fibre firing. The negatively charged molecule may also attract K+ and H+. Nociceptive neurons may be sensitised by low pH21.

 

The pain of tendinopathy may be inflammatory in nature, in keeping with the warm-up phenomena and lingering post-exercise pain. As discussed earlier, ongoing exercise stimulus in a diseased tendon may act as the continuing pro-inflammatory signal. Inflammatory cells release plethora of cytokines associated with pain generation. Many tendons are known to degenerate asymptomatically however. Whereas exercise in athletes may encourage a pain signal, via mechanisms described above, in contrast in sedentary individuals, lack of exercise may allow hypoxic tendon degeneration that is less inflammatory in nature with a relative absence of pain. Rupture of previously asymptomatic tendons is well described [13].

 

It is worthwhile remembering at this juncture that not all painful tendons are tendinopathic. Inflammatory arthropathy & enthesopathy are prevalent in society and must not be missed, but other pathologies such as partial tears and intra-tendinous tears may also present with similar symptoms. Chan et al reported a series of 740 patients with achilles tendon pain [43]. Intra-tendinous tears (ITT) are defined as clearly visualised echopoor areas (USS) situated centrally and extending towards but not reaching the tendon edge. There is pain on direct palpation. 5% of patients in this cohort had ITT as opposed to tendinopathy. The history is often more acute, less insidious with highly localised pain and the ability to continue training at low levels but not maximally i.e. high impact. It occurs in a younger cohort of patients, more commonly male, and more elite than the usual tendinopathy population. The maxim the eyes only see what the mind knows applies here. It is an important differential diagnosis to consider in athletes presenting with apparent tendinopathy.

 

7.Imaging in tendinopathy

 

Grey scale ultrasound [44] and MRI are common imaging modalities used to verify the diagnosis of tendinopathy and exclude other differential diagnoses. Recent attention has focused on functional imaging of tendons with novel modalities including UTC – Ultrasound Tissue Characterisation, MRI Collagen mapping and Elastography.

 

7.1 Ultrasound Tissue Characterisation

UTC [45] represents an enhancement of grey scale ultrasound. Whereas larger well ordered (parallel) collagen bundles generate clear echos (appearing white), smaller fibrils and cells however do not reflect sound directly back to the transducer and will produce a reduced echo pattern (grey-black). UTC utilises a motorised device to drive an ultrasound probe along the tendon. This collects standardised, reproducible ultrasound images which a far less reliant on the skill of the ultrasonographer. Computer software is able to compound the images to produce images in any plane, including the coronal plane, which conventional ultrasound cannot. False-colour mapping then assigns a coloured pixel according to the quality of the tendon at each location:-

 

·      Green – intact and aligned tendon bundles (size > 0.38mm)

·      Blue – discontinuous, waving bundles (size > 0.38mm)

·      Red – main fibrillar (size << 0.38mm)

·      Black – mainly amorphous matrix with loose fibrils, cells or matrix

 

As such UTC provides objective measurement of tendon integrity, relating to tensile strength. UTC has been used to guide rehabilitation in patellar tendinopathy in Volleyball & Basketball players. Van Ark et al subjected 29 players to a 4-week isometric or isotonic loading programme [46]. Whilst symptoms improved over this time period, UTC echo structure did not change significantly, leading the authors to conclude that structural change is not required to improve symptoms. Similar results were found in the Achilles tendon by de Jonge et al. 54 patients engaged in a loading programme lasting 12 weeks[42]. At 24 weeks a significant improvement in UTC tendon structure could be demonstrated with Echo types I & II increasing from 74.6% to 85.6%, at which point these tendons did not differ significantly in structure from an asymptomatic control group. Again no correlation between Echo types I & II and VISA-A score could be demonstrated. Whereas tendon structure improved rapidly, VISA-A score improved slowly over 52 weeks. These two studies challenge the utility of UTC in tendon rehabilitation given that tendon structure does not need to normalise in order to have symptom resolution. UTC can however be used to classify tendinopathy into different types which exhibit different severity. Bee et al [47] again were unable to demonstrate correlation between percentage of Echo types I & II to either VAS or VISA-A, but when classifying disease as either predominantly ventral or dorsal, the dorsal group had clearly higher VAS and lower VISA-A scores.

 

7.2 Magnetic resonance T2 mapping

T2 mapping is commonly used to assess articular cartilage healing, but a similar technique can be used to assess tendons [48]. T2 relaxation time is proportionate to collagen fibre orientation (shorter for parallel collagen bundles) and water concentration in tissue. Fukawa et al demonstrated in a rabbit Achilles tendon model injury that MRI T2 relaxation times in injured tendon correlated well with histological healing. Again using a false-colour scale (red for long T2 values, increasing to blue for short T2 values), healing tendons were seen to change from red to blue when evaluated at 2, 4, 8 and 12-weeks post-injury. At 12 weeks T2 appearances were comparable to control tendons. Such imaging could conceivably be used to facilitate return to play (RTP) decisions.

In this study the rabbit tendons were separated into a control group treated with saline and a group with Platelet-rich plasma. Over the 12 week period, the PRP treated group demonstrated a clear trend of superior Bonar grade scores for histological healing and MRI T2 relaxation times, though not reaching statistical significance.

 

Further biochemical assessment of tendon structure is possible using 7T Sodium imaging which relates to Glycosaminoglycan (GAG) content [49]. As previously discussed GAG content within tendons correlates more closely to symptoms than tendon collagen structure. Juras et al demonstrated sodium SNR (signal to noise ratio) of 4.9 in healthy controls versus 9.3 in patients with Achilles tendinopathy. Correlation between sodium SNR and cadaver GAG content was high with a Pearson coefficient of 0.71. This data further corroborates previous findings that tendon pain relates to increased GAG content and potential exists to track this in real time in human patients. Further research may elicit how loading regimes can be optimised to both improve collagen structure and reduce GAG content concurrently.

 

7.3 Tendon elastography (Sonoelastography SE)

This modified ultrasound technique is able to quantify tendon hardness, or stiffness. De Zordo et al assigned three grades: grade 1 (blue) hardest tissue, grade 2 (green) hard tissue, grade 3 (red) soft tissue [50]. In healthy tendons a stiff pattern (blue-green) was observed in 86.7% of tendons. There is a tendency for long term exercise [51] and eccentric loading [52] to increase tendon stiffness. In symptomatic Achilles tendinopathy SE is able to detect early tendon softening, before conventional ultrasound changes are apparent [50]. Perhaps most importantly Gatz et al found SE more sensitive than conventional US in the monitoring of tendon healing with a positive correlation with symptoms, suggesting SE may have future application in monitoring treatment [53].  

 

8. Tendinopathy Management

8.1 Loading

Heavy tendon loading is long established [54] and remains the Gold standard in tendinopathy management [55]. Whilst the emphasis originally sat with eccentric loading [54], further studies established also the efficacy and role of concentric [56] and isometric contractions [57].

 

Mechanotransduction [58] refers to the conversion of a mechanical signal (i.e. loading) into an adaptive biological response, and is seen throughout musculoskeletal tissues. Overload leads to skeletal muscle hypertrophy in response to resistance training, tendon regeneration in tendon loading, and increased bone mineral density as a response to load-bearing exercise. There are various molecular pathways via which the effect is mediated [59] including stretch-activated ion channels, G-Protein coupled receptors, integrins, and growth factors such as MGF (Mechano growth factor, IGF-1Ec, TGF-b1) are released in response to exercise [60]. Growth factor binding on the cell surface leads to activation of a signalling cascade ending in the nucleus. Binding of transcription factors such as scleraxis activates COL1A1 gene transcription and type I collagen formation1. Further elucidation of these mechanism may allow further refinement of loading regimes and identify novel therapeutic targets.

 

Time under tension is a key concept in loading regimes, though little is understood regarding the biological basis for this principal. Burd et al compared 6-second versus 1-second contractions in knee extension exercises [61]. Biopsy of vastus lateralis revealed increased myofibrillar protein synthetic rate in the Slow contraction group compared to controls. Presumably exercises performed slowly also create less stretch-shortening cycle (eccentric) induced trauma to the tendon microstructure.

 

Tenocytes seem to respond better to cyclical strain (with periods of rest) than continuous loading [24], and there is some suggestion that a larger number of cycles (1,000 v 100) has a greater stimulatory effect on TGF-b1 and Collagen Type I production[24]. There is suggestion of a ceiling effect on number of contractions [62] with 10,000 contractions having not much greater effect on fibroblast collagen production than 1,000 contractions.

 

Exercise also induces microscopic tendon injury. In the first 24 hours after exercise fibroblasts must clear damaged collagen fibres with MMP’s & TIMP’s being the effector enzymes of this process [63]. Protein degradation predominates in this process prior to net protein synthesis for approximately the first 36 hours [62]. The need for rest periods in between bouts of therapeutic exercise needs to be considered when designing loading regimes.

 

In terms of contraction type, Heinemeier et al found no difference in Collagen Type I production between eccentric, concentric and isometric training in Sprague-Dawley rats [64], in keeping with similar findings in human clinical trials [56]. Thus it appears that any form of load that induces fibroblast strain will induce protein synthesis.

 

In terms of tenocyte strain, 4-8% has been consistently shown to induce optimal response. Lower magnitude strain has minimal effect, whereas > 8% strain may lead to tropocollagen fibre rupture. Translation research needs to elicit what degree of loading in a clinical setting correlates to 4-8% tenocyte strain in vitro.

 

8.2 Tendon nutrition

 

Very little research has been published regarding optimising nutrition for tendons. Shaw & Baar 2016 investigated the effects of 15g Vitamin-C enriched gelatin ingestion on markers of collagen synthesis [65]. Subjects who consumed gelatin 1 hour before exercise showed double the amount of type I collagen precursor in their blood versus controls indicating increased collagen synthesis. To date, no clinical trial has examined whether this kind of supplementation can be beneficial clinically in the treatment or prevention of tendinopathy.

 

8.3 Non-Steroidal Anti-Inflammatory Drugs

 

NSAID usage in common in sport [66] with self-medicating being legal in most countries. Sportspersons use NSAIDs for their analgesic and anti-inflammatory effects. Particular attention therefore needs to be paid to the potential beneficial or deleterious effects of this class of pharmacological agents.

 

NSAIDs principal mechanism of action is to block the cyclooxygenase (COX) enzyme of the Arachidonic Acid-Prostaglandin pathway. These prostaglandins play a role in activation of mesenchymal stems cells [67-68] and therefore the potential for NSAIDs to disrupt this process is clear. For example treating myoblasts with a COX-2 inhibitor blocks stretch-induced proliferation [69].

 

In tendons mechanical stretch of stretch-dependent calcium channels leads to the influx of Ca2+ which will activate phospholipase-A2 [68]. This enzyme catalyses the conversion of phospholipids into arachidonic acid in the tenocyte cytoplasm. Downstream release of prostaglandin-E2 [70], via the COX-1 and COX-2 dependent pathway is an important mediator of the proliferation of tendon stem cells [71]. Specifically, Ibuprofen has also been shown to inhibit tendon cell proliferation in a dose-dependent manner [72].

NSAIDs also disrupt the balance of expression of matrix metalloproteinases and TIMP’s (Tissue-inhibitors of MMP’s) [73-74] with the potential to impair collagen formation. MMP inhibition is also a property of the antimicrobial agent Doxycycline [6]. Both Ibuprofen and Doxycycline have been advocated as potential therapeutic agents for tendons [14] though current research would suggest they may be harmful to tendon structure.

 

Christensen et al examined the effects of running as a stimulus to tendon collagen synthesis [75]. Subjects were exposed to a 36km running stimulus and NH2-terminal propeptide of Type I (PINP) collagen, and PGE2 concentrations were measured in the patella tendon by microdialysis. Measurements were taken before and 72 hours after the run. Peritendinous concentrations of PINP increased significantly in the control group, but subjects treated with Indomethacin, an NSAID, had a completely abolished response. No post-exercise rise in PINP was observed in the Indomethacin treated runners. The NSAID treated group also showed no rise in PGE2 production post-exercise.

 

8.4 Corticosteroids

 

With renewed interest in the role of inflammation in tendinopathy, Corticosteroids may gain new relevance in tendinopathy management. Corticosteroids (CTS) are potent anti-inflammatory agents, and peri-tendinous injections are commonly used to treat presumed tendon inflammation (tendinitis). The inflammation suppressing activity of CTS is well known, however CTS may also have a direct analgesic action on nociceptive C-fibres.

 

Dexamethasone has been shown to have direct effects on glucocorticoid receptors [76] and inhibitory potassium channels [77]. CTS have been shown to raise the threshold required to produce an action potential in injured nerves, leading to a reduction in neuropathic pain [78]. Oral CTS may also have centrally acting effects on pain perception. Bogdanov et al administered hydrocortisone to rats and subjected them to a painful stimulus. The rats demonstrated increasing pain sensitivity thresholds in a dose-dependent manner to CTS [79].

 

Corticosteroids are effective in producing pain relief when injected into peritendinous tissue [56], however the effects tends to wane over a period of 12 weeks. Furthermore, judicious use of CTS injections is recommended given the association with spontaneous tendon rupture [80]. Although the strength of this correlation is unknown, systematic reviews [35] have demonstrated evidence of reduced tenocyte viability, reduced collagen synthesis and mechanical weakening of steroid exposed tendons. Spang et al demonstrated that tenocytes exposed to dexamethasone displayed reduced Scleraxis gene expression (a transcription factor essential for tendon development), as well as reduced mRNA levels of Col1 and Col3, though were unable to verify if the Dexamethasone concentrations used in vitro were comparable to clinical doses [81]. Muto et al confirmed a reduction in maximal load at failure in triamcinolone treated rat achilles tendons, however the deleterious effect was almost completely mitigated by co-administrated with PRP [82].

 

High-volume image guided injections of saline and small doses of hydrocortisone have been used to treat painful tendons. Chan et al described the technique in both Achilles [83] and Patella tendons [84]. It is proposed that the pain of tendinopathy is related to neo-vascularisation [85] and neo-innervation [86]. After anaesthetising with 10mls of 0.5% bupivacaine, a pressurised volume of saline (40mls) is introduced between the anterior aspect of the Achilles tendon and Kager’s fat pad. The injectate is presumed to mechanically traumatise or occlude the neovessels, leading to ischaemia and necrosis of the nerve supply. Pain relief following the procedure is immediate and sustained for up to 6 months follow-up.

 

The weakness of the above studies was the lack of a control group, however the work has been followed up recently by Boesen et al [87]. This 3-armed study compared HVIGI versus PRP versus Placebo. All treatment groups also followed a 12-week eccentric loading programme. The placebo consisted of an injection of only a few drops of saline. All 3 groups improved, however, both HVIGI and PRP outperformed placebo in this study. Pain relief and improvement in VISA-A were approximately double in the HVIGI group compared to PRP at 6 weeks and 12 weeks, and comparable at 24 weeks. In terms of VAS, HVIGI and PRP performed more comparably. It was noted that patient satisfaction was very high in the HVIGI in the short term (6 weeks) but began to wane at 24 weeks, whereas it was sustained in the PRP group. From a radiological perspective, tendon thickness was reduced in both the HVIGI and PRP groups at all time points. The same research group followed-up this study [88] utilising HVIGI with and without the steroid content. Both groups improved with superior outcomes present when CTS was included in the preparation.

 

8.5 Platelet-rich plasma (PRP)

 

Research findings into the efficacy of PRP have been hindered to some degree by the lack of standardisation of PRP contents. The main variables in PRP content relate to the degree of platelet concentration [89-90] white cell content [91], exercise and activation of the injectate with calcium [92].

 

NSAIDs may also have a deleterious role in the efficacy of platelet-rich plasma. Schippinger et al prepared PRP in subjects exposed to various NSAIDs prior to orthopaedic surgery [93]. Whilst platelet numbers were unaffected, platelet function (aggregation) was significantly impaired in the NSAID treated patients versus control subjects.

 

There is certainly evidence of effect of PRP on tenocyte activity [89] and evidence of accelerated healing from a histological and radiological perspective [48]. The clinical efficacy of PRP in tendinopathy has been challenged by some Level 1 trial results [94] however recent systematic reviews and metanalyses tend to favour the superiority of PRP over Placebo [95-96].

 

Recently Abate et al combined PRP and HVIGI to assess potential synergy of the techniques [97]. HVIGI are known to have powerful immediate and short-term effects which are not expected to sustain beyond 6 months, whereas PRP takes longer to produce symptom improvement but the effects are expected to be sustained. In this study patients treated with both PRP and HVIGI had improved outcomes compared to those treated with only one of the treatments.

 

8.6 Hyaluronic Acid

 

Recent research indicates that Hyaluronic Acid (HA) mediates its anti-inflammatory effects via binding to the CD44-antigen present on many inflammatory cells [98-99]. HA binding to CD44 inhibits expression of pro-inflammatory Interleukin-1b in particular [99] leading to a decline in production of several MMP isoforms. Wu et al demonstrated High Molecular Weight HA-treated tenocytes expressed significantly lower levels of MMP-1 and MMP-3 [98]. In a linked clinical trial, ten human patients with long head of biceps (LHB) tendinopathy were treated with 3 weekly injections of HMW-HA, with a significant fall in VAS at one month. This clinical study had no control group for comparison. Similar results were not obtained for low molecular weight HA.

 

High-molecular weight HA (HMW-HA) also mediates analgesic effects at stretch-activated ion channels, decreasing mechanosensitivity and blocking the pain response [99].

HA may also have effects on other aspects of tenocyte physiology. Tenocyte activity falls in response to detraining. Salamanna et al demonstrated that peri-tendinous HA injections maintained the viability of tenocytes compared to saline treated controls, as well as maintaining Type I collagen production and suppressing Il-1b and MMP expression [100]. In a separate study looking at human rotator cuff tendon derived cells, HA was again shown to maintain cell viability and proliferation [101].

 

Level 1 trials of HA in tendinopathy are lacking. Fogli et al presented a cohort of 71 tendons (Lateral elbow, Achilles, Patella) treated with 3 weekly peritendinous HA injections with significant reduction in VAS at days 7, 14 and 56 [102]. Lynen et al compared HA against shockwave therapy in Achilles tendinopathy with superior VAS scores for HA at 1, 3 and 6 months [103]. Finally Flores et al utilised a protocol of physiotherapy versus physiotherapy plus HA injection in Supraspinatus tendinopathy [104]. VAS scores did not differ significantly, however treated patients required less rehabilitation and returned to previous activities sooner.

 

8.7 Prolotherapy

 

Prolotherapy, or proliferative therapy aims to provoke inflammation and scar tissue formation, leading to contraction and stiffening of injured tendons and ligaments. In a case series of 43 Achilles intra-tendinous tears, 70% responded to single injection of ~1ml of a 25% dextrose/0.25% bupivacaine preparation followed by 4-6 weeks in a walking boot [105]. In a meta-analysis of 6 studies Morath et al found clear evidence in favour of prolotherapy for painful tendinopathy [106].

 

8.8 Autologous Tenocyte implantation

 

The use of autologous tenocytes to facilitate healing brings tendinopathy management into the era of regenerative medicine. To date only a few reports have been published utilising such techniques.

 

Although not technically tenocytes, skin-derived fibroblasts have been used to treat recalcitrant Achilles tendinopathy [107]. Obaid et al conducted a randomised and double-blinded study on 40 Achilles tendons. Fibroblasts were suspended in autologous plasma and injected directly under ultrasound guidance into areas of tendinopathy. Control tendons were injected with saline. At six month follow-up the fibroblast treated group had significantly superior VISA and VAS scores compared to controls. Ultrasound evaluation demonstrated improved appearances, in particular reduction in hypoechoic areas of tendon.

 

Wang et al used actual tenocytes biopsied from patella tendon to treat common extensor origin tendinopathy (Tennis elbow) [108]. 20 patients reported improvements in VAS from 5.94 at initial assessment to 0.76 at 12-months. MRI follow-up demonstrated significant improvement in MRI T2 high signal.

 

Schwab et al used palmaris longus derived tenocytes to treat a subscapularis intrasubstance tear in an elite swimmer who had failed to improve despite various conservative treatment strategies [109]. The athlete was able to return to training seven weeks post-procedure, pain free and an MRI conducted seven months post-injection revealed near complete healing of the tear.

 

Finally Bucher et al used patella tendon derived tenocytes to treat refractory gluteal tendinopathy [110]. Twelve female patients had previously undergone a mean of 3.2 corticosteroid injections to the area. At 12-month evaluation patients had improvements in Oxford Hip Score, VAS and SF-36 which was sustained at 2 years. In most patients MRI appearances did not improve, despite improvement in symptoms.

 

Autologous tenocyte implantation promises to become an option in the management of refractory tendinopathy, together with accelerated healing of partial and complete tendon ruptures. The technique is laborious and expensive, since biopsied cells must be cultured in vitro before infiltration into pathological tendons. Further trials must compare the efficacy of tenocytes against standard therapy and placebo.

 

8.9 Extracorporeal shockwave therapy (ESWT)

 

The mechanism of action of ESWT in tendons remains unknown. Mechanical vibration of the cytoskeletal structure may induce a degree of mechanotransduction, neovascularisation or growth factor release. Two main subtypes of ESWT – focused and radial are used in clinical practice with variables levels of evidence for each.

 

A health technology assessment commissioned by Washington State Healthcare authority reviewed 59 trials of sufficient quality for analysis. It concluded that there was mostly moderate to low quality evidence of efficacy for ESWT in tendinopathies and fasciopathy [111]. Mani-Babu et al examined 20 studies concluding ESWT is an effective therapy in gluteal tendinopathy, patella tendinopathy and achilles tendinopathy, however combining ESWT with eccentric loading yields only a further 1.5cm improvement in VAS and 14 points in VISA-A indicating the treatment cannot lead to clinically significant improvements in symptoms when used in isolation [112]. Liao et al examined 29 trials of ESWT in lower limb tendinopathy concluding both radial and focused ESWT demonstrated efficacy at immediate follow-up, 3, 6 and > 12 months [113].

 

9. Summary

 

There is a growing body of evidence that early tendinopathy has an inflammatory aetiology, and is more than a simple condition of damage and inadequate repair. Future therapies may include novel anti-inflammatory agents. Modern imaging techniques are increasingly able to track tendon healing and further refine loading regimes. Evidence is growing for modern biological techniques, in particular Platelet-Rich plasma and Autologous Tenocyte Implantation which may encourage tendon regeneration.

 

 

 

 

 

 

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