Snchez-Ibez, et al.

, Rheumatology (Sunnyvale)

Rheumatology: Current Research 2015, 5:4

http://dx.doi.org/10.4172/2161-1149.1000173

Review Article Open Access

New Treatments for Degenerative Tendinopathy, focused on the Region-Specific

of the Tendon
Jose Manuel Snchez-Ibez1,2*, Maria Elisa Fernndez1, Joan Carles Monllau3,4, ngel Alonso-Dez2, Jess Snchez-Garca2 and Jose Luis Snchez-
Snchez5
1Department of Sports Rehabilitation, CEREDE Sports Medicine and Rehabilitation Clinic, Barcelona, Spain
2Department of Medicine, Surgery and Anatomy, University of Len, Len, Spain
3Department of Orthopaedic Surgery and Traumatology, Parc de Salut Mar, Universitat Autnoma de Barcelona, Barcelona, Spain
4Catalan Institute of Traumatology and Sports Medicine (ICATME), Hospital Universitari Dexeus, Universitat Autnoma de Barcelona, Barcelona, Spain
5Department of Physical Therapy, University of Salamanca, Salamanca, Spain
*Corresponding author: Jose Manuel Snchez-Ibez, CEREDE Sports Medicine and Rehabilitation Clinic, C/ Doctor Roux n 8-10 bajos, Barcelona 08017, Spain, Tel:
+34934523510; E-mail: [email protected]
Received date: September 09, 2015; Accepted date: October 20, 2015; Published date: October 26, 2015
Copyright: 2015 Snchez-Ibez JM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Tendinopathy is a common, painful, overuse disorder associated with a failure of the tendon repair process and
has a low potential for healing with the usual techniques. Although many different treatment methods have been
described, there is no consensus regarding the optimal treatment for this condition.

Therefore, new treatments for tendinopathies drawn from the existing literature as well as from their own
experience dealing with this condition to deal with this delicate pathology have been developed over last few
decades. Although some treatments like eccentric training, the EPI technique, extra-corporeal shock wave therapy
(ESWT), hyaluronic acid (HA), platelet-rich plasma (PRP) are being established as the main therapeutic models,
there are still questions to be answered as well as the need for a clear treatment protocol to be established.

This brief review aims to update recent information on the treatment approaches of tendinopathy focused on the
specific area of the tendon.

Keywords: Tendinopathy; EPI technique; Treatment approaches players [13] and also represents two thirds of all pathologies of the
knee between these two sports [10].
Introduction The traditional model of "tendonitis" as an inflammatory process is
The tendons play an essential role in the musculoskeletal system by now obsolete since the appearance of several publications, which have
transferring the tensile loads from muscle to bone so as to enable joint described the pathological process of the tendon as mainly
motion and stabilization [1]. Tendons have the ability to adapt to load degenerative (tendinosis) [14,15]. This is justified due to the absence of
changes, increasing collagen synthesis as a result of acute and inflammatory cells, the presence of areas of collagen degeneration,
prolonged physical exercise training [2,3]. Despite this ability to adapt myxoid degeneration and an increase in fundamental substance and is
physiological loads, tendinopathies represent a clinical problem which associated with a failure of the tendon repair process [14,15].
affects both professional and recreational athletes as well as people Tendinopathy is a clinical diagnosis and typically is based on
involved in repetitive work [4,5]. Tendinopathies overuse represents medical history and clinical findings. Imaging techniques: such as
30% to 50% of all sports injuries and result in a significant amount of color doppler sonography (CDS) and magnetic resonance imaging
morbidity and spending health cost [6]. More than 28 million patients (MRI) are valuable tools to confirm the diagnosis and provide
in the United States have tendon damage annually [7]; it is estimated guidance for treatment [16].
that they could cost the United States health system some $30 billion
per annum [8]. The tendon injury can occur in the tenotendinous region, as in the
Achilles tendon. However, most of the tendon pathology and pain is
The etiology includes lifestyle, loading pattern, biological variables located in the osteotendinous, such as elbow lateral patellar tendon
(genetics, age, sex) as well as different pharmacological agents [9]. and the medial epicondyle tendons and tendons in the groin [17].
The Achilles tendon and patellar tendon are most affected, in both While osteotendinous and tenotendinous and are morphologically
elite and recreational athletes, in sports that heavily load the lower different region in normal state, the occurrence of extracellular matrix
extremities [10]. Achilles tendinopathy is more prevalent in the lower pathology induced cellular changes are indistinguishable [18].
extremity, with a frequency of 5.9% in sedentary and about 50% for Tendinopathies are in the main accompanied by an excessive
endurance athletes [10,11]. Patellar tendinopathy is most common nociceptive signalling from the tendon, causing pain and restricted
involvement in the knee and its prevalence has been reported to be mobility [19]. Mechanisms driving these structural and neurological
44.6% in elite volleyball players [12] and 31.9% in elite basketball changes are not fully understood. A more recent theory ascribes part of

Rheumatology (Sunnyvale) Volume 5 Issue 4 1000173

ISSN:2161-1149 RCR, an open access journal
Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 2 of 12

the tendinosis changes to an increased production of biochemical tendinopathy but fail to modify the histological structure of the tendon
agents, such as substance P (SP) [20] and NMDAR1 glutamate receptor [26,27].
[20-22].
The aim of non-steroidal anti-inflammatory drugs (NSAIDs) is to
Overall tendinopathies are characterized by prolonged, localized reduce inflammation by inhibiting the synthesis of inflammatory
pain, associated with physical activity requiring cyclic mechanical factors (inflammatory cells, prostaglandins, interleukins, etc.) and their
stimuli. Patients respond poorly to most conservative treatments, use has been popular in the management of tendinopathy for years
however, a broad spectrum of disorders of the tendon within the [28]. NSAIDs affect the activity of tenocytes and glycosaminoglycan
concept of tendinopathy that share some common characteristics synthesis [29,30]. While their use can be justified on a reactive
(paratendinitis, tendinitis, tendon overuse injuries, spontaneous tendinopathy, the tendon's response upon loading can be affected by a
tendon rupture, calcifying tendinitis) or gaps, often converge in the potential inhibition of collagen synthesis [31] as well as have a
same tendon (Figure 1). In this sense, there is no single etiology and detrimental effect on muscle adaptation [32].
pathogenesis that can explain all these processes [17].
Possible mechanisms of action of corticosteroid injection include a
reduction in extrinsic or intrinsic inflammation, reduction in the
proliferation of tenocytes, anti-angiogenic activity, and the inhibition
of scar formation, some anti-nociceptive action or a combination of
these mechanisms [33].
The literature suggests that the majority of patients may experience
a short-term improvement in terms of pain and/or function but in
exchange for a high risk of relapse in the medium term and with side
effects that may even lead to a rupture of the tendon [34]. Two recent
systematic reviews showed worse results from the use of
glucocorticoids in comparison to other treatments and the placebo
group in the medium and long-term [35,36].
Konsgaard et al. [37] reported that heavy slow resistance training
also resulted in significant improvement compared with corticosteroid
injections.

Eccentric exercises
Eccentric exercise has shown to cause an upregulation of insulin-
Figure 1: Transverse ultrasound of patellar tendinopathy with area like growth factor (IGF-I). This upregulation of IGF-I is associated
of fibrillar rupture (hypoechogenic foci surrounded by connective with cellular proliferation and matrix remodelling within the tendon
reinforcement). Tendon degeneration in its most proximal and deep [38].
portion (critical area to receive higher tensile strength during tissue
stress). Programs of eccentric exercise have been proposed as a key element
in strength training in rehabilitation because they can supposedly
counteract the response of defective healing that apparently underlies
Treatment options have changed over the last decade in parallel to tendinopathy by promoting the creation of collagen fibers within the
the pathophysiological and histopathological findings in tendon [39,40]. The literature places increasing emphasis on the
tendinopathies. Since the underlying pathology of chronic importance of a proper choice of the load used [41].
tendinopathy can be defined as a "defective healing response,
The continuum model in tendinopathy (reactive tendinopathy,
treatment should aim to encourage regeneration of the tendon, pain
tendon dysrepair and degenerative tendinopathy) provides a reasoned
modulation and the restoration of the biomechanical properties
basis for believing that the protocol to be performed depends on the
[23,24].
current clinical presentation [17]. The protocol proposed by Alfredson
In this paper the authors will update the knowledge about et al. is generally used [39]. It consists of three sets of 15 repetitions,
tendinopathy and current treatments focused on the region-specific of performed twice a day, seven days a week for 12 weeks.
the tendon drawn from the existing literature as well as from their own
Ohberg et al. [42] examined tendon structure by grey-scale
experience dealing with this condition. Some of these treatments are
ultrasound in 26 tendons with Achilles tendinosis, which had been
eccentric training, the EPI technique, extra-corporeal shock wave
treated with eccentric exercise. Remarkably, after a mean follow up of
therapy (ESWT), hyaluronic acid (HA), platelet-rich plasma (PRP) are
3.8 years, 19 of 26 tendons had a more normalised structure, as gauged
other treatment options [25].
by their thickness and by the reduction of hypoechoic areas.

Anti-inflammatory therapy Visnes et al. [43] suggested that eccentric training had a positive
effect on patellar tendinopathy and recommended that athletes
Conventional conservative treatments have generally been used suspend sports activity during rehabilitation.
empirically to reduce pain and inflammation. These treatments include
relative repose or activity modification, cold, stretching, orthopedic The gradual progression from eccentric-concentric to eccentric
supports, physiotherapy and biomechanical correction. They are followed by a faster loading can benefit patients with Achilles
usually employed initially in acute and the more hyperalgesic phase of tendinopathy cannot start with a program proposed by eccentric

Rheumatology (Sunnyvale) Volume 5 Issue 4 1000173

ISSN:2161-1149 RCR, an open access journal
Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 3 of 12

Alfredson et al. [39] due to pain or weakness of the sural triceps muscle
[44].
Isoinertial eccentric training (YoYoTechnology AB, Stockholm,
Sweden) resulted in an improvement of muscle function and reduced
pain in patients with patellar tendinopathy [45]. The combination of
EPI technique and isoinertial eccentric exercise offers good results in
the treatment patellar tendinopathy [46].

EPI technique
In recent years, the intratissue percutaneous electrolysis (EPI)
technique has become more relevant in the scientific literature [46-48]
given the good results yielded in the treatment of patellar degenerative
tendinopathy in comparison to other previous conservative treatments.
This technique, created by Snchez-Ibez [49,50] and who have
over 15 years experience in its use, uses a flow of cathodic current
directed exclusively to the area of degenerated tendon through an Figure 2: A) Treatment of patellar tendinopathy with ultrasound-
ultrasound-guided needle that brings about an organic reaction that guided EPI- MTR device (EPI Advanced Medicine, Barcelona,
leads to rapid regeneration of the degenerated tendon. Spain). B) Ultrasound longitudinal view of patellar tendinopathy
The application of ultrasound-guided EPI technique produces a with area of fibrillar rupture. C) Treatment is directed exclusively to
non-thermal electrochemical reaction centered on degenerated tissue the area of tendon injury. Note the electrochemical reaction (white
(tendinosis). This leads to a controlled local inflammatory reaction that area) produced on the tip of the needle, just in the area of damaged
leads to the regeneration of damaged tissue [48,51]. tissue. D) Longitudinal ultrasound view of patellar tendinopathy,
three weeks post-treatment with EPI technique. Note that the area
In experimental studies with human tendon injury, there has been a of fibrillary rupture has been replaced by new connective tissue.
disproportionate expression of certain cytokines and matrix
metalloproteinase (MMPs), prostaglandin E2 (PGE2), interleukin-6
(IL-6 ) and interleukin-1b (IL-1b ) [52,53]. IL-1b in turn increases the
production of matrix metalloproteinase-1 (MMP-1), matrix Extra-corporeal shock wave therapy (ESWT)
metalloproteinase-3 (MMP-3) and prostaglandin E2 (PGE-2) [53].
Several clinical trials have evaluated the use of extra-corporeal
A recent experimental study [48] showed that with the use of EPI shock waves therapy (ESWT) for the treatment of patients with
technique in patellar tendinopathy increase of anti-inflammatory chronic tendinopathy with divergent results [28,54,55]. Multiple
proteins, like peroxisome proliferator-activated receptor gamma variables are associated with this therapy, the type of shock wave
(PPAR-). These proteins play a key role in the inhibition of expression generator (electrohydraulic, electromagnetic or piezoelectric), the wave
of proinflammatory molecules secreted by macrophages, such as tumor type (radial or focal), the intensity (total energy per shock waves/
necrosis factor alpha (TNF-), IL-6 and IL-1, thus producing in the session), the frequency and the protocol of application and repetitions
treated tissue a highly beneficial molecular response during [56].
degenerative tendinopathy. This, in turn, results in an increase of the
Some of the effects of ESWT on tendinopathies like the inhibition of
expression of vascular endothelial growth factor (VEGF) and vascular
nociception with the release of substances which inhibit pain
endothelial growth factor receptor 2 (VEGFR-2), mediators
(endorphins), the increase in the permeability of cell membranes of
responsible for angiogenesis anti-inflammatory response. The EPI
neurons and cellular damage that could create immediate analgesia
technique makes for the activation of molecular and cellular
have been described [25].
mechanisms of the tendon responsible for phagocytosis and the
regeneration of degenerated tissue. Other biological effects of ESWT described, are the induction of
specific growth factors (TGF-1 and IGF-1) which play an important
In recent research to evaluate the therapeutic effects EPI technique
anabolic and mitogen role, increased blood flow, mediators of the
on the patellar tendinopathy [46]. The results documented were good
inflammatory process, and increased release of hydroxyproline
and stable with the Victorian Institute of Sport Assessment-Patella
tenocytes of proliferation and collagen synthesis [57].
(VISA-P) score, Tegner scores and Roles and Maudsley score, and
terms of clinical and functional improvement in patellar tendinopathy However, evidence of the effectiveness of ESWT in the treatment of
and providing a follow-up of 10 year. tendinopathy is inconsistent, still so, it is widely used in sports
medicine and physiotherapy [58]. It appears that the combination of
The EPI technique (Figure 2) achieves a much localized organic
treatments may have a synergistic effect and lead to better results. In
reaction in the clinical focus by using a specially designed device for
this sense, a study showed better results by combining the ESWT and
this purpose (EPI Advanced Medicine, Barcelona, Spain. EPI
eccentric exercises than by performing eccentric exercises alone [59,
technique videos online: www.epiadvanced.com), which leads to the
60].
rapid regeneration of degenerated tissue. This leads to the production
of new immature collagen fibers that become mature by means of
eccentric stimulus [47], thereby obtaining good results in the short and
long-term in terms of pain and function.

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Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 4 of 12

Platelet-rich plasma (PRP) of those who were injected, compared with those of whom received
injections of local anesthetics only, supported the superiority of the
Platelets are nonnucleated cytoplasmic bodies derived from tested treatment, with significant differences in the values recorded
megakaryocyte precursors. They play a pivotal role in hemostasis and (p<0.005) [71].
wound healing via the formation of fibrin clots. Therefore, increasing
platelet concentration in injured tissue and may result in an The use of polidocanol (a vascular sclerosing agent) has been put
exponential release of diverse bioactive factors and, subsequently, forth for the treatment of the same [72]. Polidocanol is used to sclerose
enhance the healing process [61]. areas of high intratendinous blood flow, which is sometimes called
"neovascularization", visible histopathologically [73] and in vivo by
Injections with platelet rich plasma (PRP) has been used for the means of high-resolution ultrasound with color doppler.
treatment of tendinopathy with the aim of providing cellular and
humoral mediators to induce healing in areas of degeneration. Despite Some studies have reported effects using polidocanol for patellar
the long road ahead toward establishing an agreed protocol on the use tendinopathy, tennis elbow or Achilles tendinopathy [72,74,75].
of PRP [62,63], it is a widespread treatment option for the treatment of Studies that associate sclerosing injections and eccentric training
chronic tendon injuries and its beneficial effects have been have shown a decrease in pain during eccentric training, resulting in
demonstrated in several studies [70]. complete resolution of pain in the short term Achilles tendinopathy
A recent experimental study showed that with the use of PRP in [26].
patellar tendinopathy, there was an increase in fibroblasts and bone Zeisig et al. [76] they reported that maintained sclerosis
marrow stem cells inside of and around the injury. Cell proliferation neovascularization in lateral elbow epicondylitis was a good predictor
was twice as high and the PRP-treated group also showed a significant of positive clinical effect at 2 years follow-up.
increase in type I and III collagen when compared to the control group
[64]. Another in vitro study in humans showed that following the
application of PRP, there was increased cellular proliferation, collagen
High-volume image guided injection (HVIGI)
production in tenocytes, an overexpression of the receptor of vascular Different methodologies have been described when applying
endothelial growth factor-A (VEGF-A) and an increase in the HVIGI. In one study in athletes with achilles tendinopathy, patients
concentration of transforming growth factor beta (TGF-B), indicating were treated with 10 ml of 0.5% bupivacaine hydrochloride injection
an increase in the production of type I and III collagen [65]. Despite plus 40 ml saline solution and 25 mg of aprotinin. The HVIGI with
everything described, it should be noted that there are different aprotinin showed a significant improvement in pain and function in
techniques for the preparation of PRP, thus obtaining different both the short and long term follow up of 12 months [77].
volumes and concentrations of platelets [66,67].
Study groups like those of Chan et al. [78] reported good results
Filardo et al. [68] evaluate the therapeutic effects of multiple PRP with the use of high volume image-guided injections (HVIGI) in the
injections on the healing of chronic refractory patellar tendinopathy. treatment of tendinopathy mainly of the Achilles and patellar tendon,
The results documented were good and stable with the VISA-P score. claiming that they significantly reduce pain and improve function.
The ultrasound measurements showed that tendon thickness and
neovascularization level gradually decrease over time, despite an initial This intervention uses large volume injections of saline solution,
increase after the injection cycle. corticosteroids or an anesthetic that make the neovessels stretch, break
or occlude. Occlusion or interruption of neovessels supposedly also
Dallaudire et al. [69] also aimed to assess the efficacy and tolerance affects the innervation that it accompanies [79].
of intratendinous injection of PRP to treat tendinopathy. This study
included 41 patients had patellar tendinopathy. The average WOMAC Hyaluronic acid (HA)
scores of 41 patients with patellar tendinopathy improved from 38 to
16 at the 6-week follow-up and more improved (6 scores) at 32-month Possible biological effects of hyaluronic acid (HA) in tendinopathies
follow-up. No clinical complication was reported during follow-up. be related with an anti-inflammatory activity, enhanced cell
This study demonstrates that the ultrasound-guided injection of PRP proliferation, and collagen deposition, besides the lubricating action
allows rapid healing of tendon with good tolerance. on the sliding surface of the tendon.
Another study of randomised control trials (RCT) by Dragoo et al. Study groups like those of Petrella et al. [80] determined the efficacy
[70] compared a regimen of eccentric exercises combined with either of periarticular HA injections in patients with chronic lateral
ultrasound-guided PRP injection or ultrasound-guided dry needling epicondylosis. Pain, both at rest and after grip testing, was significantly
alone in the treatment of patellar tendinopathy. The PRP group showed reduced in the study group compared to controls.
significantly better improvement than the dry needling group in VISA- Muneta et al. [81] reported good results with the use of HA in the
P score at 12 weeks. However, at 26-week follow-up, the difference treatment of patellar tendinopathy. After treatment, 94% of patients
between the PRP and dry needling groups dissipated in all assessed were rated in excellent in good conditions complained of some degree
scores, such as VISA-P, Tegner, VAS, and short form-12 (SF-12) scores. of limitation.

Sclerosant injections (polidocanol) Injections of the MMP-inhibitor (Aprotinin)

Based on the theory that neovascularization are associated with an Tendinopathies, are characterized by changes in expression and
underlying mechanism due to overuse in tendinopathies. The activity of various metalloproteinase enzymes that degrade the matrix
randomized, double-blind trial by Alfredson and hberg focused on which are consistent with increased proteolytic activity in the
the potential benefit of the sclerosing substance polidocanol on chronic degenerate tendons [25].
tendinopathies. The VAS pain and the patients satisfaction at 3 months

Rheumatology (Sunnyvale) Volume 5 Issue 4 1000173

ISSN:2161-1149 RCR, an open access journal
Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 5 of 12

Aprotinin is a broad spectrum inhibitor of matrix metalloproteinase lower of re-injury rate compared with the re-injury rate obtained with
(MMPs) [82]. It is suggested that by inhibiting the enzymes that break the conventional non cellular based management [98,99].
down or degrade tendons, the healing response may be promoted.
An experimental study conducted by Lacitignola et al. [100] showed
In a study by Orchard et al. [83] with 430 patients suffering from in an in vivo collagenase-induced superficial digital flexor
patellar and Achilles tendinopathy treated with local injections of tendinopathy study of horses, that when injected with autologous
aprotinin, the results showed that, at a minimum follow-up of 3 BMSCs intratendinous it produced a regeneration effect on the tendon.
months (range 3-54 months), 76% of patients improved clinically and
Also adipose derived stem cells were showed to be effective in the
functionally.
treatment of equine tendinopathies leading to normal horse activity
Brown et al. [84] conducted a randomized control trial study (RCT) recovery [101].
the use of aprotinin in the treatment of Achilles tendinopathy, 26
Obaid et al. [102] perform a RCT study of 40 human patients
patients divided into 2 groups, one group with aprotinin injection and
diagnosed with Achilles tendinosis, a group that was treated with
another group with saline (placebo). There were no significant
autologous stem cells derived from skin and other serum group saline
difference scores in VISA-A (p=0.946) at 52 weeks of follow-up.
(placebo). Clinical outcomes were assessed with VAS and VISA-A
questionnaire at 3 and 6 months follow-up. Significant improvements
Stem cells in the experimental group compared to the placebo group in VISA-A
In the last few decades, several emerging strategies including with (p=0.02) and VAS (p<0.001) scores were found.
mesenchymal stem cells (MSC) have been proposed to enhance tendon In theory, pluripotent stem cells can be isolated and then be
healing. Stem cells are undifferentiated cells with ability of self- integrated into an area of need of the tendon. Once stem cells are at the
renewing and differentiating in progenitor or precursor cells. The latter desired location, either by local signaling or by the addition of
are committed cells for a specific cell lineage, but are not able to self- exogenous factors, they can lead pluripotent cells to differentiating into
renew [85]. the desired cell line [25].
Human MSCs have been isolated from adipose tissue, umbilical
cord, placenta, peripheral blood, connective tissues of the dermis and Surgery
skeletal muscle [86-91].
Historically, surgery has been proposed as a salvage technique if
A stem cell population has been recently identified in human other treatments fail [103,104], showing similar functional results
tendons, residing in a unique tendon extracellular matrix (ECM) niche using an open or arthroscopic technique [105], and the latter with less
[92]. comorbidity. With surgery, the removal of the degenerated tissue or
calcifications in order to promote the tissue response is generally
Tendon stem cells (TSCs) have been described in 2007 by Bi et al.
sought.
[92]. These stem cells present in mature tendon have multi-
differentiation and self-renewal potential [92]. They can differentiate Lorbach et al. [106] performed a prospective study to evaluate the
into other cell types, like muscle or fat cells. These cells have been clinical results of arthroscopic resection of the lower patellar pole in
implicated as possible cause of chronic tendinopathy because of the patients with patellar tendinopathy. The main conclusion was that
erroneous differentiation into abnormal matrix components causing arthroscopic resection of the lower patellar pole as a minimal invasive
fatty degeneration and calcification. These cells are still in the method to treat patellar tendinopathy provides satisfactory clinical
preclinical experimentation stage but have great potential for tendon results in knee function and pain reduction with fast recovery and
therapy in the future [93]. return to sport activities.
TCSs could be involved in tendon homeostasis, remodelling, and Kelly examined the results of arthroscopic tendon debridement with
repair, by ensuring replacement of mature cells lost, or in the excision of the distal pole of the patella for refractory patellar
pathogenesis of tendinopathy, as this tendon disorder is associated tendinopathy [107]. He concluded that arthroscopic excision of the
with chondroid and fatty degeneration, and ossification [94]. distal patellar pole with tendon debridement holds promise for the
treatment of refractory patellar tendinopathy.
Since the tendon cell rate is low like its biological turnover, it has
recently been proposed that adult stem cells would be good candidates Shelbourne et al. [108] reported that surgical removal of necrotic
for the regeneration of the tendon [95]. However, the exact role in the tissue, surgical stimulation of remaining tendon, and aggressive
healing process of stem cells implanted into the tendon remains rehabilitation after patellar tendonectomy could allow athletes to
uncertain. One possibility is that they differentiate into tenocytes and return to sports. Overall, tendonectomy, surgical tendon stimulation,
are involved in healing by producing collagen and remodeling. It has and aggressive post-operative rehabilitation were found to be a safe,
also been suggested that the mononuclear bone marrow stem cells effective way to return high-level athletes to their sports.
(BM-MNC) can aid in healing by acting as "growth factor pumps"
Analysis of the surgical treatments is complicated given the
rather than through terminal differentiation [96].
differences between both techniques, as well as the heterogeneity of the
In vitro research has shown encouraging results with the use of stem samples and the different protocols used postoperatively [105].
cells for the treatment of degenerative diseases, like tendinopathy, of
the musculoskeletal system [97]. Discussion
Bone marrow mesenchymal cells (BMSCs) have been shown Treatment of tendon injuries is a subject of frequent debate in sports
effective in the management of superficial digital flexor tendon injuries medicine and physiotherapy. Multiple techniques have been described
in horses; BMSCs were inoculated in the injured tendons leading to for their treatment and although some of them [46,56,71,106,107].

Rheumatology (Sunnyvale) Volume 5 Issue 4 1000173

ISSN:2161-1149 RCR, an open access journal
Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 6 of 12

To date, there is no consensus on the optimal treatment of It is considered that hypoxia could be responsible for
tendinopathies. It has been suggested that the incomplete neovascularization in tendinopathies, capillary flow and post-capillary
understanding of the underlying mechanisms (etiology of the pressure decreased following 12 weeks of eccentric loading [120].
condition), limits the ability to develop effective treatment strategies
In the treatment of tendinopathy, there is conflicting evidence that
[108]. Are emerging as the most accepted treatment option, more
eccentric exercises are superior to other load programs [119]. Eccentric
RCT's are still needed to clearly establish what the therapeutic protocol
work on an inclined plane did not improve functional outcomes when
therapeutic to follow should be.
it was done during a competitive season in volleyball [121]. In another
Doubts have mainly centered on the fact that there are few study, continuous sporting activity did not compromise clinical
controlled prospective studies that analyze all aspects of tendinosis, outcomes at 12 months, as long as the sport was introduced
and few studies that investigate the early stages of these processes and incrementally ensuring minimal pain during and after loading [122].
their healing mechanisms. The exact mechanism by which Eccentric decline squat training and heavy slow resistance training
tendinopathy develops in humans remains the target of numerous showed good long-term clinical results, and heavy slow resistance
investigations. A variety of degenerative characteristics associated training also resulted in advantages in pathological improvement and
tendinopathies, including accumulation glycosaminoglycan (GAG), increased collagen turnover [37].
calcification and lipid accumulation nerve damage and
Some authors have demonstrated better results with eccentric
hyperinnervation, is one of the theories whose publications are scarce,
exercise on corporeal tendinopathies in comparison with
despite its special interest in explaining the possible pathophysiological
enthesopathies [35].
mechanisms of pain in tendinopathy [109].
Further studies are needed to assess the unique effects of an
In several studies it has been shown that there is a correlation
eccentric strengthening program. Eccentric loading should be
between tendinopathy and hyperinnervation, citing that the
considered in conjunction with the concentric rather than just
production of nerve growth factor (NGF) and the corresponding
eccentric loading in Achilles and patellar tendinopathy. Patients with
hyperinnervation could be induced by repetitive ischemic crisis in
marked muscle weakness may benefit from a program of progressive
osteotendinous union [110,111]. This growth of nerve fibers, which
eccentric-concentric loading [122]. On the other hand, maximal
causes chronic pain, could be part of a process of abnormal tissue
eccentric loading may be best for some groups of patients and permit
repair, preceded by repetitive micro trauma [112].
adaptive changes in the tendon [45].
Despite its prevalence, the precise pathogenic mechanisms of
Despite the fact that the eccentric muscle workout has become the
tendinopathy are not clear and, as a result, current treatments of
dominant conservative strategy in treating Achilles and patellar
tendinopathies are largely empirical and not always efficient [17,113].
tendinopathy, up to 45% of patients do not respond to this treatment
The continuum model of tendon pathology was proposed to provide a
[123].
model for the staging of tendon pathology and to assist clinicians in
managing this often complex condition. The model presents clinical, A recent study suggests that sedentary subjects with Achilles
histological and imaging evidence for the progression of tendon tendinopathy may show less promising results with eccentric exercise
pathology as a three-stage continuum: reactive tendinopathy, tendon therapy compared to athletic subjects [124].
disrepair and degenerative tendinopathy [17].
In the treatment of chronic lateral epicondylalgia where they were
The use corticosteroids are by far the most utilized treatment in all randomly assigned to three groups, one assigned to a stretching
painful tendinopathy. Da Cruz et al. [114] investigated the role of program, another to eccentric strengthening and the last to eccentric
corticosteroid injections in Achilles tendinopathy, at final follow-up strengthening with stretching, no significant difference was observed
(12 weeks), they were not able to find a significant higher improvement either in the evaluation of strength or the visual analog pain scale
within the intervention group in any of the primary outcomes [125].
measured.
Despite some good results reported with eccentric programmes
Others authors [115] consider that in the absence of an [123,126], it is still unclear as to the more effective exercise protocol, its
inflammatory process, there is no rational basis for the use of NSAIDs frequency, load and dosage.
in chronic tendinopathy.
Despite over 15 years of experience in the use of the EPI technique
Chen et al. [116] believe that local infiltration of corticosteroids is and its widespread deployment in sporting clubs around the world, this
associated with an increased risk of spontaneous tendon rupture. technique has grown in relative to scientific dissemination in recent
years [46].
A review study conducted by Dean et al. [117] reported that the
effects of corticosteroid injection, reduce cell viability, cell proliferation An experimental study showed that after application of the
is reduced, degrades collagen, produces higher tendon necrosis, degenerated tendon EPI technique, an increase in anti-inflammatory
decreases the mechanical properties of the tendon, and it produces proteins, like PPAR- has been observed after treatment with the EPI
significant long-term tissue damage and tendon cells. technique. These proteins play a key role in the inhibition of expression
of proinflammatory molecules secreted by macrophages, such as TNF-
One of the clinical effects that eccentric exercises might have in
, IL-6 and IL-1 [127] thus producing in the treated tissue a highly
tendinopathy is in pain modulation due to changes in glutamate
beneficial molecular response during tendinopathy. This, in turn,
content or in the central nervous system with increased activation of
results in an increase of the expression of VEGF and VEGFR-2,
inhibitory neurons and cortical reorganization [71,118]. There is little
mediators responsible for angiogenesis anti-inflammatory response
evidence that isolated eccentric exercise reduces pain in tendinopathy
[128,129].
compared with concentric exercise [119].

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ISSN:2161-1149 RCR, an open access journal
Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 7 of 12

In another recent study by Snchez-Ibez and co-workers [46] it PRP injections should be avoided in patients suffering from
has been illustrated that when treatment with the US-guided EPI infection, tumoral disease, coagulation disorders and changes in the
technique and eccentric exercises in patellar tendinopathy it resulted in number of platelets [135].
extensive improvement in the knee function and a rapid return to the
The use of polidocanol injection is based on the belief that
previous level of activity after few sessions. The limitation of this study
neovascularizations are associated with the mechanism underlying
is the absence of a control group of subjects.
tendinopathy due to overuse. Although it is unclear whether this is a
References to the use of the EPI technique in combination with causal agent in the pathophysiology of tendinopathy [140]. In fact,
eccentric exercise can be found in the literature. In those cases the EPI these "neovessels" may be associated with the ingrowth of nerves in the
technique focuses on biological tissue recovery, leaving the functional areas of pathological tendons [141] and it is possible that nerve fibers
recovery of tissue biomechanics to eccentric exercise. are the pain generators in chronic tendinopathy [142]. A priori,
polidocanol injections may not only sclerose the veins, but may also
The EPI technique is mainly contraindicated in patients with
eliminate the pain nerve fibers [25]. Although polidocanol injections
tumors, articular or systemic infection and bleeding disorders [49].
appear to provide pain relief, it is unclear what role they can play in
Regarding the effectiveness of extra-corporeal shock waves therapy tendon healing in tendinopathy.
(ESWT) for tendinopathy, according to published studies, conclusive
Hoksrud et al. [74] reported reduced pain after ultrasound-guided
results cannot be drawn because the clinical effects are unclear
sclerosing in patients with patellar tendinopathy, contradictory results
[130,131]. The effectiveness of ESWT may depend on the stage of
were recently presented in a retrospective study [143] in which
tendinopathy, it seems more appropriate in degenerative tendinopathy
sclerosing injections in 48 patients with chronic Achilles tendinopathy
and where conservative treatment has little or no effect [17].
revealed less promising results than expected [143]. Even though
The mechanisms of the therapeutic effect of ESWT in tendinopathy capilliary blood flow may decrease by around 25% [144] some authors
with calcification are also uncertain. It has been proposed that the say that there is no relationship between changes shown in ultrasound
increased pressure within the therapeutic focus produces a and tendon function after sclerosing treatment.
fragmentation and cavitation effect within calcifications and leads to
Willberg et al. [145] compared the clinical effects in patellar
the disruption and disintegration of calcium deposit [132].
tendinopathy after treatment with sclerosing polidocanol injections
Some studies have shown that ESWT is as effective as surgery, but and arthroscopic shaving. After treatment, the patients treated with
cheaper, and this treatment seems to be a supplement for the treatment arthroscopic shaving had a significantly lower visual analogue score
of those tendinopathies who are refractory to conventional therapies (VAS) score at rest and during activity, and were significantly more
[133]. In this sense, studies using high-energy ESWT do better in the satisfied compared with the patients in the sclerosing injection group.
tendinopathies than those using low-energy ESWT [54]. This is
Prospective comparative studies involved small numbers of patients:
consistent with a recent study that showed ESWT had no effect in
polidocanol injections were superior to lidocaine injections [75], and
athletes with patellar tendinopathy who actively compete [130].
similar results were found when compared with patients undergoing
Currently, there is a controversy relative to the utilization of ESWT in
mini-open surgery [146].
the treatment of patellar tendinopathy [134] as well as in Achilles
tendinopathy [54]. Although some studies that associate sclerosing injections with
eccentric training have shown a decrease in pain [26], further studies
With the use of the platelet-rich plasma (PRP), the intention is to
to evaluate its safety (possible nerve damage) and effectiveness, to
enhance the natural healing process at the site of injury through the
determine the injection protocol (volume/concentration) and its
action of growth factors (PDGF, IGF-1, VEGF, bFGF, TGF-1, EGF,
combination with other therapies are needed [141].
etc.) to promote matrix synthesis and the healing of injured tissue
[135]. It should be noted that the delicate balance between these Avoid injection of polidocanol in patients who previously had an
growth factors may have important implications in the control of allergic reaction to polidocanol or diagnosed with a blood clotting
angiogenesis and fibrosis [135]. disorder. Nor it is recommended in pregnant or latency [141].
Although many studies have been reported positive results using While some authors advocate the use of high-volume image guided
PRP [136,137], others have shown the same effect in comparison with injection (HVIGI) in treating refractory tendinopathy [77,147]. Pre-
a placebo [138,139]. De Vos et al. [139] found no significant differences liminary studies have shown that a HVIGI with normal saline, local
between the group of patients with Achilles tendinopathy treated with anaesthetic and corticosteroid can significantly reduce pain and
PRP and the group treated with saline (placebo) to kept under review improve short- and long-term function in patients with Achilles
24 weeks; these results agree with de Jonge et al. [138]. tendinopathy [77,78,147] reported results are not conclusive nor
homogeneous enough to establish a protocol for use.
At the same time, many questions are raised about what the optimal
concentration of platelets should be, in which phase of the injury is it HVIGI adverse effects are similar to those of other injection
better to do infiltration or how it should be prepared [66]. Caution is techniques. Caution must be exercised with the administration of the
warranted when comparing different PRP studies, different types of diluted corticosteroid, for possible risk of tendon rupture and should
PRP or PRP-derived products have been used, with a variety of platelet not be injected into the ducts inside and outside the tendon [77].
concentrations, inclusion of leucocytes, the use of anticoagulant and
Hyaluronic acid (HA) is actively secreted by the tendon sheath it is
the use of activating agents.
an important component of the synovial fluid, which allows a smooth
Through the present research, it is hard to draw a clear conclusion tendon gliding, and provides nutrition to tendon itself [148].
for the effectiveness of PRP treatment on tendinopathy. Moreover, it is an important component of tendon structure, being
largely present in extracellular space.

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Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 8 of 12

Several studies have been performed to evaluate the efficacy of HA ultrasound results [155]. As demonstrated by these preliminary
on adhesions, gliding resistance, and tendon healing [149-152]. studies, management of tendinopathies with stem cells is promising
even though more clinical studies are needed to validate this treatment
Despite the promising results of HA injections for treating
approach.
tendinopathy in most of the studies the joint space has been injected
and not into the tendon, and it could be that the modification of the Despite the growing interest in this type of therapy and its expected
synovial fluid exerts a positive effect on the tendon [153]. potential, there are still many open questions to answer in order to
implement these techniques in the tendinopathy treatment protocol.
Avoid introduction of HA into the tendon and the peritendinous fat
Further research is required to identify mechanisms involved in
to avoid delete rating effects [81].
tendon regeneration and in survival, proliferation, and differentiation
Aprotinin injections have been shown to provide clinical of stem cells.
improvement in tendinopathies, most successful in patients with
Although the results shown by some authors with the surgical
Achilles tendinopathy or with patellar tendinopathy [55,82]. Also
treatment of tendinopathy [157-159] showed that surgery did not show
better results have been obtained with aprotinin injections with
advantages over eccentric exercise in their RCT. In addition, the low
corticosteroid injections or saline [82].
predictability of the results obtainable through surgery make it such
Moreover, in 7% of cases systemic allergic reactions occurred when that this technique should be put forward only in selected cases and
aprotinin injections were applied at intervals of 2 to 4 weeks, but if after other conservative options fail.
applied every 6 weeks the reactions of systemic allergy was reduced
It is commonly accepted that surgical treatment must be indicated
significantly to 0-9%. Positive IgG antibodies against aprotinin patients
in motivated patients if carefully followed conservative treatment is
most at risk of an anaphylactic reaction during treatment with this;
unsuccessful after 3-6 months [103,104]. The literature, however, does
therefore the authors recommend that if this type of technique is to be
not clarify which surgical technique is more effective.
used the necessary equipment to treat anaphylaxis should be present
[152].
Conclusion
Brown et al. [84] investigated whether aprotinin could achieve
better improvement than the usual rehabilitation protocol adopted to In this report, a brief review of treatment approaches of
treat Achilles tendinopathy in their RCT. They recorded VISA-A tendinopathy was conducted. Tendinopathy is a condition that causes
scores, tenderness, satisfaction and other clinical parameters and significant pain and disability in many patients. Currently, the etiology
demonstrated no significant statistical differences. of tendinopathy is still unclear, it is multifactorial, and influenced by
intrinsic and extrinsic factors. Tendinopathy often becomes chronic
It has been suggested that the efficacy of stem cells is related to its because the exact pathogenesis remains largely unknown. The
state of differentiation, i.e., the greater the state of differentiation the continuum model of tendon pathology was proposed to provide a
more effective will the effect be in the healing of the tissues in which model for the staging of tendon pathology. Physicians and
they are implanted [154]. Keeping this statement in mind, it should be physiotherapist have a variety of therapeutic options available to treat
remembered that the cells that are better able to differentiate have tendinopathies but, in each case, there is a lack of evidence supporting
lower telomere length and therefore a greater degree of aging during their use as the gold standard treatment. Larger randomized controlled
wound healing and therefore may not be able to complete the trials on the various treatment options and even comparative studies
necessary steps in the process of regeneration and produce a useful and between them are needed to determine the treatment of choice (Gold
sufficient cellular matrix [155]. Standard) for tendinopathies.
Another important aspect concerning the use of stem cells is their
viability during the inflammatory phase of the tendon [154]. During Acknowledgement
the inflammatory phase, different types of cytokines, cytotoxic proteins
and inflammatory factors are released by necrotic tissue and We are grateful to Julita Cuquerella and David MacManus for your
inflammatory cells reduce the possibilities of viability of stem cells in help in editing the manuscript.
the host [97,154].
Author Contributions
Stem cells are promising candidate for the management of
tendinopathies and tendon rupture. However, these cell-based Wrote the first draft of the manuscript: JMS, MEF, JCM, AAD, JSG,
strategies have been investigated only in preclinical studies and the role JSS. Contributed to the writing of the manuscript: JMS, MEF, JCM,
of stem cells needs to be confirmed. Tendon stem cells have been AAD, JSG, JSS. Agree with manuscript results and conclusions: JMS,
hypothesized to have a crucial role in the development of calcifying MEF, JCM, AAD, JSG, JSS. Jointly developed the structure and
tendinopathy due to the erroneous differentiation of tendon stem cells arguments for the paper: JMS, MEF, JCM, AAD, JSG, JSS. Made critical
(TSCs) to chondrocytes or osteoblasts. For this reason it was revisions and approved final version: JMS, MEF, JCM, AAD, JSG, JSS.
hypothesized that the re-direction of the differentiation of resident All authors reviewed and approved the final manuscript.
TSCs or supplementation of mesenchymal stem cells (MSCs)
programmed for tenogenic differentiation may be appealing targets for Disclosures and Ethics
the treatment of tendinopathy in the future [156].
The authors declare that one author has the patent for the EPI
The use of stem cells is in the early stage of clinical application in devices and one author is the creator of the EPI technique.
humans. There is only one clinical study performed on human subjects
showing that inoculation of bone marrow mononuclear cells
(BMMNC) in tendinopathy patellar has good mid-term clinically and

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ISSN:2161-1149 RCR, an open access journal
Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

Page 9 of 12

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Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

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Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

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Citation: Snchez-Ibez JM, Fernndez ME, Monllau JC, Alonso-Dez A, Snchez-Garca J, et al. (2015) New Treatments for Degenerative
Tendinopathy, focused on the Region-Specific of the Tendon. Rheumatology (Sunnyvale) 5: 173. doi:10.4172/2161-1149.1000173

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