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2010;92:2604-2613. doi:10.2106/JBJS.I.01744 J Bone Joint Surg Am.
Nicola Maffulli, Umile Giuseppe Longo and Vincenzo Denaro
Novel Approaches for the Management of Tendinopathy
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The Journal of Bone and Joint Surgery
Current Concepts Review
Novel Approaches for the Management
of Tendinopathy
By Nicola Maffulli, MD, MS, PhD, FRCS(Orth), Umile Giuseppe Longo, MD, and Vincenzo Denaro, MD
Investigation performed at the Centre for Sports and Exercise Medicine, Queen Mary University of London, London,
England; and Campus Biomedico University, Rome, Italy
äTendinopathy is a failed healing response of the tendon.
äDespite an abundance of therapeutic options, very few randomized prospective, placebo-controlled trials have
been carried out to assist physicians in choosing the best evidence-based management.
äEccentric exercises have been proposed to promote collagen fiber cross-link formation within the tendon, thereby
facilitating tendon remodeling. Overall results suggest a trend for a positive effect of eccentric exercises, with no
reported adverse effects. Combining eccentric training and shock wave therapy produces higher success rates
compared with eccentric loading alone or shock wave therapy alone.
äThe use of injectable substances such as platelet-rich plasma, autologous blood, polidocanol, corticosteroids,
and aprotinin in and around tendons is popular, but there is minimal clinical evidence to support their use.
äThe aim of operative treatment is to excise fibrotic adhesions, remove areas of failed healing, and make multiple
longitudinal incisions in the tendon to detect intratendinous lesions and to restore vascularity and possibly
stimulate the remaining viable cells to initiate cell matrix response and healing.
äNew operative procedures include endoscopy, electrocoagulation, and minimally invasive stripping. The aim of
these techniques is to disrupt the abnormal neoinnervation to interfere with the pain sensation caused by ten-
dinopathy.
äRandomized controlled trials are necessary to better clarify the best therapeutic options for the management of
tendinopathy.
Evolving Concepts in Tendinopathy: New Theories
Tendinopathies account for a substantial proportion of overuse
injuries associated with sports
1
and are a common cause of
disability
2,3
. Most major tendons, such as the Achilles, patellar,
rotator cuff, and forearm extensor tendons (among others), are
vulnerable to overuse, which induces pathological changes in
the tendon
4
.
The term ‘‘tendinopathy’’ is a generic descriptor of the
clinical conditions (both pain and pathological characteristics)
associated with overuse in and around tendons
5
. The histo-
logical descriptive terms ‘‘tendinosis’’ (a degenerative patho-
logical condition with a lack of inflammatory change) and
‘‘tendonitis’’ or ‘‘tendinitis’’ (implying an inflammatory pro-
cess) should be used only after histopathological confirmation
5
.
However, it should be kept in mind that, despite the use of the
term ‘‘tendinosis,’’ at histopathological examination the essence
of a tendinopathic lesion is a failed healing response, with
haphazard proliferation of tenocytes, intracellular abnormali-
ties in tenocytes, disruption of collagen fibers, and a subsequent
increase in noncollagenous matrix
6,7
. Tendinopathic tendons
Disclosure: The authors did not receive any outside funding or grants in support of thei r research for or preparation of this work. Neither they nor a member
of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.
2604
COPYRIGHT Ó2010 BY THE JOURNAL OF BONE AND JOINT SURGERY,INCORPORATED
J Bone Joint Surg Am. 2010;92:2604-13 ddoi:10.2106/JBJS.I.01744
have an increased rate of matrix remodeling, leading to a me-
chanically less stable tendon that is probably more susceptible
to damage
8
. Histological studies of surgical specimens from
patients with established tendinopathy consistently show either
absent or minimal inflammation
9-11
. They generally also show
hypercellularity, a loss of the tightly bundled collagen fiber
appearance, an increase in proteoglycan content, and com-
monly neovascularization
12,13
. Inflammation seems to play a
role only in the initiation, but not in the propagation and
progression, of the disease process
14
. Competing theories have
been proposed to explain the pathogenesis of tendinopathy at
specific stages and presentations of the condition
15-18
. A con-
tinuum of tendon pathology from asymptomatic tendons to
tendon tears has been proposed
19,20
.
Failed healing and tendinopathic features have been as-
sociated with chronic overload, but the same histopathological
characteristics also have been described when a tendon is un-
loaded: stress shielding seems to exert a deleterious effect
9
.
Unloading a tendon induces cell and matrix changes similar to
those seen in an overloaded state and decreases the mechanical
integrity of the tendon
19,20
.
Despite an abundance of therapeutic options, very few
randomized prospective, placebo-controlled trials have been
conducted to assist physicians in choosing the best evidence-
based management
21,22
. Treatments that have been investigated
with use of a randomized controlled trial design include
nonsteroidal anti-inflammatory medications
23-25
, eccentric ex-
ercise
26-30
, glyceryl trinitrate patches
31-33
, sclerosing injections
34
,
aprotinin injections
35-37
,ultrasound
38
, and shock wave treat-
ment
39-50
. What may appear clinically as an acute tendinopathy
is actually a well-advanced failure of a chronic healing response
in which there is neither histological nor biochemical evidence
of inflammation
23
. The available literature suggests that, in the
absence of an overt inflammatory process, there is no rational
basis for the use of nonsteroidal anti-inflammatory drugs in
chronic tendinopathy
51
.
In this Current Concepts Review, we report the best
available evidence for the management of tendinopathy and
provide a comprehensive and up-to-date review of the devel-
opment of future modalities for treatment.
Nonoperative Management Options
Eccentric Exercises
Eccentric exercises have been proposed to promote collagen
fiber cross-link formation within the tendon, thereby facili-
tating tendon remodeling (see Appendix)
52
. Evidence of his-
tological changes following a program of eccentric exercise is
lacking, and the mechanisms by which eccentric exercises may
help to relieve the pain of tendinopathy remain unclear.
Eccentric exercises have been proposed to counteract the
failed healing response that underlies tendinopathy by pro-
moting collagen fiber cross-linkage within the tendon, thereby
facilitating tendon remodeling
50
. The concept of eccentric ex-
ercises is based on the structural adaptation of the musculo-
tendinous units to protect them from increased stresses and
thus prevent reinjury.
The basic principles in an eccentric loading regimen are
unknown, although it has been speculated that forces generated
during eccentric loading are of a greater magnitude than those
in concentric exercises
53
. It is possible that eccentric exercises
do not just exert a beneficial mechanical effect, but also act
on pain mediators, decreasing their presence in tendinopathic
tendons. Although microdialysis has shown raised intra-
tendinous glutamate levels
54
and substance P and neurokinin-1
receptor
55
to be significantly higher in Achilles tendons with
painful tendinopathy than in normal, pain-free tendons, and
treatment with eccentric training has shown good clinical re-
sults with diminished tendon pain during activity, in vivo
results have shown that successful treatment with eccentric
training is not associated with lowered intratendinous gluta-
mate levels
54
. Also, as the exercise regimen is supposed to
produce pain and if the patient does not experience pain load is
added to produce pain during the exercise, it is possible that
progressive habituation to painful stimuli occurs
52,56-58
. Color
Doppler sonography demonstrated decreased neovasculariza-
tion following eccentric training intervention
59
.
Excellent clinical results have been reported both in
athletic and sedentary patients
26,60
, although these results were
not reproduced by other study groups
26,61
. In general, the
overall trend suggests a positive effect of eccentric exercises,
with no reported adverse effects
52
. In one study, the combina-
tion of eccentric training and shock wave therapy produced
success rates that were higher than those with eccentric loading
alone or shock wave therapy alone
30
.
Extracorporeal Shock Wave Therapy
Extracorporeal shock wave therapy to address the failed healing
response of a tendon is becoming more widely used among the
medical community (see Appendix)
50
. Typical characteristics
are high peak-pressure amplitudes (500 bar) with rise times of
<10 ns, a short life cycle (10 ms), and a frequency spectrum (16
to 20 MHz) ranging from the audible to the far ultrasonic
level
62
. This rapid rise is followed by periods of pressure dis-
sipation and negative pressure before a gradual return to the
ambient pressure. The shock wave entering the tissue may be
reflected or dissipated, depending on the properties of the
tissue. The energy of the shock wave may act through me-
chanical forces generated directly or indirectly via cavitation
63
.
The rationale for the clinical use of extracorporeal shock wave
therapy is stimulation of soft-tissue healing and inhibition of
pain receptors.
There is no consensus on the use of repetitive low-energy
extracorporeal shock wave therapy, which does not require
local anesthesia, versus the use of high-energy extracorporeal
shock wave therapy, which requires local or regional anesthe-
sia
63
. In several well-conducted randomized controlled trials,
low-energy extracorporeal shock wave therapy was adminis-
tered once a week for three or four consecutive weeks, with
final assessment undertaken twelve weeks after the last shock
wave therapy session
30,50
. At the time of a four-month follow-
up, eccentric loading and low-energy shock wave therapy
showed comparable results
62
, whereas eccentric loading alone
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was less effective than the combination of eccentric loading and
repetitive low-energy shock wave treatment
30
.
When used, high-energy extracorporeal shock wave
therapy is administered only one time.
Low-energy shock wave therapy has been proposed for
tendinopathy to stimulate soft-tissue healing and inhibit pain
receptors
30,63-65
. Low-energy shock wave therapy or eccentric
training for the management of Achilles tendinopathy pro-
duced comparable results in a randomized controlled trial
50
,
and both management modalities showed outcomes superior
to those of no intervention
50
. However, the results of low-energy
shock wave therapy were disappointing in another study
66
.
Use of Injectable Substances
A wide variety of substances have been injected and are rou-
tinely injected in and around tendons.
High-Volume Injections: Normal Saline Solution, Corticosteroids,
and Anesthetics
Neovascularization is a characteristic feature of Achilles and
patellar tendinopathy; it is generally accompanied by nerve
ingrowth and normally is not present in patients without ten-
don pathology
67,68
. The ingrowth of new blood vessels and as-
sociated nerves from the peritendinous tissues may be a source
of pain
69
. Histopathological studies showed immunoreactions
for neurokinin-1 receptor and alpha-1-adrenoreceptor in bi-
opsy specimens from the ventral area of tendinopathic Achil-
les
70
and patellar
71
tendons as well as elevated levels of the
neurotransmitter glutamate and the presence of its receptor,
N-methyl-d-aspartate receptor type 1
71-73
.
The hypothesized rationale behind this management mo-
dality was that high-volume injections of normal saline solution,
corticosteroids, or anesthetics would produce local mechanical
effects causing new blood vessels to stretch, break, or occlude.
Occluding and possibly breaking these vessels would lead to the
accompanying nerve supply also being damaged by either trauma
or ischemia, therefore decreasing the pain in patients with resis-
tant Achilles tendinopathy.
Preliminary studies showed that high-volume injectio n of
normal saline solution, corticosteroids, or anesthetics reduces
pain and improves short and long-term function in patients
with Achilles
74
or patellar
75
tendinopathy, regardless of their
symptoms (see Appendix). High-volume injection is safe and
relatively inexpensive, with the potential to offer an alternative
to operative treatment, resulting in a quicker return to sports
76
.
Hydrocortisone acetate is used in the high-volume in-
jections, primarily to prevent an acute mechanical inflamma-
tory reaction produced by the large amount of fluid injected in
the proximity of the tendon. The injection is performed under
ultrasound guidance, so that corticosteroids have no direct
action on the tendon itself. The role of corticosteroids in the
management of tendinopathy is still debated. Meta-analysis of
the effects of corticosteroids has shown that published data are
insufficient to determine the risk of rupture following cortico-
steroid injections
77
, and we do not advocate their intraten-
dinous injection
76
.
Platelet-Rich Plasma
Platelet-rich plasma is a bioactive component of whole blood,
which is now being widely tested in different fields of medicine
for its possibilities in aiding the regeneration of tissue with poor
healing potential
78-82
.
The use of platelet-rich plasma to help wound-healing
has been proposed since the early 1980s
83
. Its use in orthopaedic
surgery, especially for augmentation of bone-grafting, began
during the present decade, although to date there is no defin-
itive evidence that it improves bone healing
84
. The use of
platelet-rich plasma to improve tendon healing has been ad-
vocated only recently
85-87
. In general, the concentration of
platelets in platelet-rich plasma is higher than that in blood
88,89
.
Dense granules may play a role in tissue modulation and
regeneration by releasing their content of adenosine, serotonin,
histamine, and calcium. The alpha granules release transforming
growth factor-b, platelet-derived growth factor, and vascular
endothelial growth factor, with concentrations increasing line-
arly with increasing platelet concentration. The released cyto-
kines bind to transmembrane receptors on the surface of local
or circulating cells and induce intracellular signaling. This may
result in the production of proteins responsible for cellular che-
motaxis, matrix synthesis, and proliferation
86
.
Tendon healing occurs through three overlapping phases
(inflammation, proliferation, and remodeling), which are
controlled by a variety of growth factors
86,90-92
. The rationale for
the use of platelet-rich plasma to promote tendon healing is the
high content of these cytokines and cells in hyperphysiologic
doses of platelet-rich plasma. Several studies on the application
of platelet-rich plasma to promote tendon healing are ongoing
worldwide, although the exact mechanisms by which platelet-
rich plasma promotes tendon healing are still not clear (see
Appendix). One of the main advantages is that platelet-rich
plasma is autologous and is prepared at the time of treatment
(point of care) and therefore has an excellent safety profile. De
Vos e t a l.
93
performed a stratified, block-randomized, double-
blind, placebo-controlled trial of fifty-four patients with Achilles
tendinopathy treated, at a single center, with exercises (usual
care) as well as injection of either platelet-rich plasma or saline
solution (the placebo group). The authors concluded that,
compared with the saline-solution injection, the platelet-rich-
plasma injection did not result in greater pain relief or im-
provement in activity.
Autologous Blood Injection
An injection of autologous blood for the management of ten-
dinopathy has been reported
94
. The aim of this treatment is to
provide cellular and humoral mediators to induce healing in
areas where the healing response has failed (see Appendix). The
use of autologous blood injection is thought to lead to tendon
healing through collagen regeneration and the stimulation of a
well-ordered angiogenic response
89
. It has been hypothesized
that transforming growth factor-band basic fibroblast growth
factor carried in the blood will act as humoral mediators to
induce the healing cascade
95,96
. Although the results of labora-
tory studies are encouraging, such studies have always involved
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healthy tendons or surgically induced lesions, given the lack of
a good experimental model for tendinopathy. At present, it is
unclear whether these results can be extrapolated to tendino-
pathic tendons
89
. So-called needling of the tendon has been
described in conjunction with the use of autologous blood.
However, it could be difficult to distinguish between the effect
of needling and the effect of autologous blood injection
96
.
Polidocanol
In patients with chronic painful Achilles tendinopathy, there is
neovascularization outside and inside the ventral part of the
tendinopathic area
97,98
. Local anesthetic injected in the area of
neovascularization outside the tendon may result in a pain-free
tendon, indicating that this area is involved in pain generation.
These are the bases for the injection of the sclerosing substance
polidocanol (Aetoxisclerol; Kreussler Pharma, Wiesbaden,
Germany) under ultrasonography and color Doppler guidance
in the area with neovessels outside the tendon
99-104
.
Injections with polidocanol in a randomized controlled
trial showed the potential to reduce tendon pain during activity
in patients with chronic painful midportion Achilles tendino-
pathy (see Appendix)
102
.
In Achilles and patellar tendinopathy, there is evidence of
neural ingrowth in conjunction with neovascularization. In-
jections of polidocanol close to the tendon seem to be re-
markably safe.
Of 150 patients in whom Achilles tendinopathy had been
managed with polidocanol, two experienced a complication
105
.
One patient who had insertional Achilles tendinopathy sus-
tained a total rupture in the proximal part of the tendon at the
end of an 800-m running race, and the other patient sustained
a partial rupture in the midportion of the tendon, where he
previously had received four intratendinous corticosteroid
injections.
Intratendinous Injections of Corticosteroids
The use of corticosteroid injections ishighly controversial
14,106-110
.
There is a lack of good-quality research data to support the
widespread use of these drugs. There are numerous case reports
of tendon rupture after corticosteroid injections in patients
111,112
.
Animal studies have suggested that local corticosteroid injections
may lead to a reduction in tendon strength
113
, but this finding is
not universal
114
.
At present, there is insufficient evidence from which to
draw firm conclusions on the utility of local corticosteroid
treatments for Achilles tendinopathy (see Appendix). Three
randomized controlled trials
115-117
showed different results in
terms of the effects of local corticosteroids on healing, with two
studies demonstrating some benefit
115,116
and the other showing
none
117
. A meta-analysis of the effects of corticosteroid injections
showed little benefit
77
. The safety of corticosteroid injections can
be enhanced with the use of ultrasound imaging needle guid-
ance. With the high-volume-injection technique, the needle is
kept extratendinous and outside the peritendinous space
118
,so
that the fluid is injected only in the Kager triangle (for the
Achilles tendon) or in the Hoffa body (for the patellar tendon).
Operative Treatment
The objectives of operative treatment are to excise fibrotic ad-
hesions, remove or debride areas of failed healing, restore vas-
cularity, and possibly stimulate viable cells to initiate protein
synthesis and to promote healing
13,119
. Recent studies have shown
that multiple longitudinal tenotomies trigger neoangiogenesis in
the Achilles tendon, with increased blood flow
120
. This would
result in improved nutrition and a more favorable environment
for healing.
Multiple percutaneous longitudinal tenotomies can be
performed when conservative management has failed in patients
who have isolated tendinopathy with no involvement of the
paratenon and a well-defined nodular lesion <2.5 cm long
121
.
This procedure may be ultrasound guided to confirm the precise
location of the area of tendinopathy
121-123
. It is a simple procedure
and can be performed in an ambulatory setting with the use of
local anesthesia and without a tourniquet.
Percutaneous longitudinal ultrasound-guided internal
tenotomy of the Achilles tendon can be also performed on an
outpatient basis. However, it requires the use of high-resolution
ultrasound to properly locate the tendinopathic area and to
place the initial stab incision
121-123
. Complications (with wound-
healing) are minimal and lead to no long-term morbidity. The
technique is not as effective in patients with pantendinopathy.
Radiofrequency Microtenotomy
Radiofrequency microtenotomy is a safe and effective proce-
dure for managing patients with chronic tendinopathy (see
Appendix). It is a technically simple procedure to perform and
has been proposed to produce a rapid and uncomplicated re-
covery
124-127
. It is hypothesized that the mechanism of action
may be to induce acute degeneration and/or ablation of sensory
nerve fibers. Early degeneration followed by later regeneration
of nerve fibers after bipolar radiofrequency treatment may
explain long-term postoperative pain relief
124-127
.
Neovessel Destruction
Pathological nerve ingrowth accompanies pathological neo-
vascularization in the tendinopathic tendon, and it has been
considered as a possible cause of the pain. Some authors have
attempted to disrupt the abnormal neoinnervation to interfere
with the pain sensation caused by tendinopathy. Endoscopy
128-133
,
electrocoagulation
134
, and minimally invasive stripping
135-138
have
been proposed to achieve this aim. Endoscopy allows direct
visualization of the area of tendinopathy and allows use of a
motorized shaver or diathermy to destroy neovessels.
Endoscopy-Assisted Treatment
Tendoscopy may allow endoscopic access to several tendons,
including the posterior tibial tendon
129
, the peroneal ten-
dons
128,139
and the Achilles tendon
131,132,140,141
(see Appendix).
This operative technique provides access to the posterior aspect
of the ankle and subtalar joints. Also, extra-articular structures
of the hindfoot such as the os trigonum, the flexor hallucis
longus, and the deep portion of the deltoid ligament can be
accessed
130
.
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Thermann et al.
132
described a different technique of
endoscopic debridement of the ventral neovascularized area,
the peritenon, and the Achilles tendon and reported good
short-term clinical results in eight patients.
Best Modalities for Management of Tendinopathy
In general, it would be reasonable to treat a patient with ten-
dinopathy with physical therapy involving a program of eccen-
tric exercises, to be performed for twelve weeks. If the condition
does not respond to this intervention, shock wave therapy or a
nitric oxide patch might be considered, although data on their
efficacy are limited. If the condition does not respond to those
interventions, injections could be considered. The use of oper-
ative treatment should be discussed with the patient after at least
three to six months of nonoperative management. Moreover,
patients should understand that symptoms may recur with ei-
ther conservative or operative approaches.
The Future and Conclusions
In the last few decades, biomaterials have become critical
components in the development of effective new medical
therapies for wound care
142,143
. Many new tissue-engineered
materials have been introduced, including artificial polymers,
biodegradable films, and biomaterials derived from animal or
human tissues
143,144
.
Biological scaffolds are protein-based extracellular matri-
ces, usually derived from human or animal connective tissues
145
.
Advantages of biological scaffolds include a well-defined three-
dimensional microstructure (allowing host cell integration) and
natural porosity (which provides a much larger space for host
cell attachment, proliferation, and migration and assists gas and
metabolite diffusion). These proprieties allow biological scaf-
folds to quickly interact with host tissue and induce new tissue
formation faster than synthetic scaffolds. Limitations of bio-
logical scaffolds are their poor mechanical properties, undefined
rate of degradation, variation in biocompatibility, propensity to
induce an inflammatory response, and potential for implant
rejection
145
.
On the other hand, synthetic scaffolds are manufactured
from chemical compounds
145
, which permit better control of
the chemical and physical properties, leading to stronger me-
chanical strength and consistency in quality. However, the
biocompatibility of synthetic scaffolds is very poor, as they can
never be absorbed or integrated into host tissue. High inci-
dences of postoperative infection, and chronic immune re-
sponses, have been reported with the use of such materials
145
.
A genetic component has been implicated in tendino-
pathies, but investigations into the genetic factors involved in
their etiology are still in their infancy
146-148
. An enhanced un-
derstanding of these factors holds the promise of new ap-
proaches to the prevention and management of these common
conditions. Additional randomized controlled trials are nec-
essary to better clarify the best therapeutic options for the
management of tendinopathy.
Appendix
Tables summarizing the studies on the various treatments
of tendinopathy are available with the electronic version
of this article on our web site at jbjs.org (go to the article
citation and click on ‘‘Supporting Data’’). n
Nicola Maffulli, MD, MS, PhD, FRCS(Orth)
Centre for Sports and Exercise Medicine,
Queen Mary University of London,
Barts and The London School of Medicine and Dentistry,
Mile End Hospital,
275 Bancroft Road,
London E1 4DG,
England.
E-mail address: n.maffulli@qmul.ac.uk
Umile Giuseppe Longo, MD
Vincenzo Denaro, MD
Department of Orthopaedic and Trauma Surgery,
Campus Biomedico University,
Via Alvaro del Portillo,
200, 00128 Rome, Italy.
E-mail address for U.G. Longo: g.longo@unicampus.it.
E-mail address for V. Denaro: denaro@unicampus.it
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