State of the Art
Rotator cuff pathology: state of the art
1
Department of Orthopaedic
Surgery and Traumatology,
Shoulder, Elbow and
Orthopaedic Sports Medicine,
Inselspital, Bern University
Hospital, University of Bern,
Bern, Switzerland
2
Leni & Peter May Department
of Orthopedics, Icahn School of
Medicine at Mount Sinai, Mount
Sinai Health System, New York
City, New York, USA
3
Department of Orthopaedic
Surgery, Tohoku University
School of Medicine, Sendai,
Japan
Correspondence to
Dr Eiji Itoi, Department of
Orthopaedic Surgery, Tohoku
University School of Medicine,
1-1 Seiryo-machi, Aoba-ku,
Sendai 980-8574, Japan; ​
itoi-​eiji@​med.​tohoku.​ac.​jp
Received 12 December 2016
Revised 31 May 2017
Accepted 1 June 2017
Published Online First
4 July 2017
To cite: Zumstein MA,
Künzler M, Hatta T, et al.
JISAKOS 2017;2:213–221.
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074. Copyright © 2017 ISAKOS
Matthias A Zumstein,1 Mike Künzler,1 Taku Hatta,2 Leesa M Galatz,3 Eiji Itoi2
Abstract
The rotator cuff tendon undergoes degeneration and tear
quite commonly in the elderly population and was rarely
observed in patients under 50 years of age. In addition to
ageing, smoking, diabetes mellitus and other comorbidities
are known to be the risk factors of tendon tear. Bony
anatomy of the acromion relative to the glenoid plays a
role on the onset of degenerative cuff tears. The biological
responses of chronic tendinopathy, degenerative tear and
the following muscle atrophy and fatty infiltration are
regulated by macrophages. Age, tear size and chronicity
have direct influence on healing after rotator cuff repair.
Systematic reviews have shown that there is better healing
in larger tears with a double row repair compared with a
single row repair, but no differences in clinical outcome.
The tendon healing is characterised by a fibrovascular scar
response rather than by regenerating normal tendon tissue.
As a result, the material and structural properties are much
weaker than the normal tendon-to-bone interface. With this
knowledge, better repair techniques and repair methods
are expected to be developed for better healing of the
tendon.
Introduction
The shoulder joint is the one with the greatest
range of motion in our body. As a result, the rotator
cuff muscles and tendons, the mover and stabiliser
of the shoulder joint, are often times involved in
various pathological conditions, such as rotator
cuff tear, calcified tendinitis, frozen shoulder, labral
tear, bicipital tendinitis and so on. In this article,
we focus on the rotator cuff tear, the most common
pathology of the shoulder joint. We would like to
introduce how common this pathology is observed
as well as risk factors related to rotator cuff tears
in the first chapter of epidemiology. In the second
chapter, we are discussing the pathology of rotator
cuff tendons and muscles, especially contemplating
the biological responses to tendinopathy and
tendon degeneration as a potential result of skeletal
morphological changes. In the last chapter, we high-
light the healing process of tendon-to-bone junction
after the tendon repair, which is far different from
the normal structure of tendon-to-bone junction.
Epidemiology of rotator cuff tear
Prevalence of rotator cuff tear
Rotator cuff tear is one of the most common causes
of shoulder pain and disability of shoulder function.
Regarding the prevalence, classical studies using
cadaveric specimens have reported it to range from
3% to 39% for full-thickness rotator cuff tear.1–6
Since advanced radiological techniques enable to
assess the condition of rotator cuff tendons non-in-
vasively in live subjects, there have been several
studies that demonstrate the epidemiology of the
rotator cuff tear and its age-related, degenera-
tive characteristics. Sher et al7 investigated MRI
obtained from 96 asymptomatic shoulders and
demonstrated that a rotator cuff tear was present in
33 shoulders (34%); among these, 14 shoulders had
the full-thickness rotator cuff tear and 19 shoulders
had the partial tear. In addition, they showed the
prevalence of full-thickness and partial-thickness
tears increased significantly with subject’s age
(p<0.001 and 0.05, respectively).
For larger scale analysis to reveal the preva-
lence of full-thickness rotator cuff tears, several
studies applied sonographic examination to detect
the rotator cuff tears in asymptomatic shoul-
ders. Tempelhof et al8 assessed 411 asymptomatic
shoulders using ultrasound. They found 23% of
the patients who had a rotator cuff tear and an
age-dependent increase of the prevalence; 13% in
50–59 years, 20% in 60–69 years, 31% in 70–79
years and 51% in >80 years. Moosmayer et al9
also reported sonographic observation in 420
asymptomatic volunteers. They found overall 32
subjects (7.6%) with full-thickness rotator cuff tear.
The prevalence was reported to 2.1% for 50–59
years, 5.7% for 60–69 years and 15% for 70–79
years. Additional two sonographic studies also
showed the prevalence of full-thickness rotator
cuff tears in both symptomatic and asymptomatic
subjects.10 Minagawa et al10 reported 22.1% (147
out of 664 subjects) in one village had full-thickness
rotator cuff tear. They found that the prevalence of
the tear was 0% in those under 50 years, 11% in the
50–59 years, 15% in the 60–69 years, 27% in the
70–79 years and 37% in the 80–87 years. They also
demonstrated that symptomatic tears accounted for
35% of all tears and asymptomatic tears for 65%.
The prevalence of tear was significantly greater
in male subjects than in female subjects for 50s
(p<0.001) and 60s (p=0.01), but not for over 70
years. Yamamoto et al11 reported the rotator cuff
tear were present in 20.7% (283 out of 1366 shoul-
ders) of residents of a mountain village. In addition,
they investigated the risk factors for the occurrence
of rotator cuff tear using multivariable analysis and
demonstrated a history of trauma (OR 2.46, 95%
CI 1.33 to 4.53), dominant arm (OR 1.66, 95% CI
1.25 to 2.22), in addition to increased age (OR 1.08
(95% CI 1.07 to 1.10) as risk factors. Most reports
agree in the point that degenerative rotator cuff
tears are only observed above the age of 50 years.
Incidence of rotator cuff tear
Yamamoto et al12 observed the residents in a village
for an average of 3.5 years. There were 464 resi-
dents without a full-thickness rotator cuff tear at
initial examination by ultrasonography. In 3.5 years,
30 of them developed a new full-thickness tear. The
incidence of rotator cuff tear is calculated to be
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30/464/3.5 × 1000=18/1000 person-years. To our knowledge,
this is the only study that has shown an incidence of rotator cuff
tear in a general population.
Risk factors of rotator cuff tear
Daily smoking habit
Although the aetiology of rotator cuff disease is multifactorial,
the daily consumption of favourite items as a cause of rotator
cuff tear has been investigated. Among these, smoking tobacco
has been focused to cause and/or develop the rotator cuff tear.
Itoi et al13 first reported a positive correlation between the size
of rotator cuff tears and the smoking index of the patients.
They indicated larger size of the tear in association with greater
smoking index. Kane et al14 investigated 72 cadaveric shoulders
with focus of a history of smoking. They found macroscopic
rotator cuff tears and microscopic rotator cuff degeneration
were more frequently seen in shoulders with smoking history
than in those without any smoking history. Baumgarten et al15
also reported that smoking increased the incidence of rotator
cuff tears in a dose-dependent and time-dependent manner
from a cohort study. Carbone et al16 analysed the correlation
between smoking habit and size of rotator cuff tear in patients
who underwent arthroscopic rotator cuff repair. They concluded
that the total number of cigarettes smoked in life had a posi-
tive relationship with the size of rotator cuff tear. More recently,
Jeong et al17 investigated 486 asymptomatic subjects using ultra-
sonography. They revealed smoking history significantly affected
the prevalence of the full-thickness rotator cuff tear; 9.4% of
smokers had a rotator cuff tear, whereas 3.7% of non-smokers
had a tear (p=0.002).
Diabetes mellitus
Regarding the comorbidity that might affect the development
of the rotator cuff tear, Jeong et al17 reported the prevalence
of full-thickness rotator cuff tear significantly increases with
the presence of diabetes mellitus. Among 486 asymptomatic
subjects, full-thickness rotator cuff tear was present in 7.7% of
those with diabetes mellitus in contrast to 4.5% of those without
the history (p=0.0418).
Other factors
Moreover, several factors have been reported to be potentially
associated with the occurrence of rotator cuff tears. A system-
atic review18 demonstrated that individuals with an adverse lipid
profile might have an increased risk to cause tendon patholo-
gies including rotator cuff tear. The meta-analysis revealed
higher serum levels of total cholesterol (TC), low-density lipo-
protein cholesterol and triglycerides as well as lower levels of
high-density lipoprotein cholesterol in those with the Achilles
tendinopathy or rotator cuff tears.18 In addition, chronic alcohol
consumption has also shown to be associated with the preva-
lence of rotator cuff tears. Passaretti et al19 reported excessive
alcohol consumption as a risk factor of rotator cuff tears in
both male with OR 3.0 (95% CI 1.5 to 6.0) and female with
OR 3.6 (95% CI 1.7 to 7.8). There is a report showing a negative
effect of non-steroidal anti-inflammatory drugs (NSAIDs) on
tendon healing.20 However, totally opposite data have also been
reported.21 They investigated the effect of licofelone, an inhib-
itor of 5-lipoxygenase and cyclooxygenase (COX)-1 and COX-2
enzymes on the tendon–bone healing process in rat rotator cuff
repair models and revealed increased fibrocartilage formation
at the enthesis with biomechanical improvement. The effect of
NSAIDs on rotator cuff tear is yet to be determined (table 1).
214
Table 1  Risk factors of rotator cuff tear
Factors OR (95% CI) References
Increased age 1.08 (1.07 to 1.10) 11
History of trauma 2.46 (1.33 to 4.53) 11
Dominant arm 1.66 (1.25 to 2.22) 11
Smoking
Diabetes mellitus
Hyperlipidaemia
Alcohol 3.0 (1.5 to 6.0) for male 19
3.6 (1.7 to 7.8) for female
Pathology of rotator cuff tendons and muscles
Anatomical variances predisposing to rotator cuff tear
With the large humeral head sitting on the small glenoid, the
shoulder joint has a unique anatomy requiring dynamic stabilisation
of the glenohumeral joint. This dynamic stabilisation depends on a
distinct interplay of the rotator cuff muscles.22 When the anatomy
of the joint varies from the ‘ideal’ anatomical shape, the well-orches-
trated interplay between the muscles is disturbed causing an imbal-
ance of the forces. This imbalance sets the muscles and tendon of
the rotator cuff prone to degenerate through repetitive trauma and
thereby leading to degenerative rotator cuff tear. Anatomical vari-
ances associated with rotator cuff tear were found in the acromial
arch as well as in the vertical glenoid orientation. Nevertheless, it is
important to note that these variances are mostly seen in patients
with degenerative rotator cuff tear and not in traumatic rotator
cuff tears.23 Ever since the first description of the impingement
syndrome by Charles Neer24 and the classification of the acromial
morphology by Bigliani et al,25 numerous measurements for the
acromial shape have been described and found to be associated with
rotator cuff tear.26 27 The classification of the acromial morphology
and the measurements that determine its relation to the scapular
anatomy (ie, acromial slope and acromial angle) focus on the shape
of the acromion and thus neglect the dimensions of the acromion
and its relation to the glenoid and humeral head.
The influence of bony anatomy
The lateral extent of the acromion, the so-called acromion index
(AI),28 measures the distance from the glenoid cavity to the tip
of the acromion relative to the distance from the glenoid cavity
to the most lateral part of the humeral head. The AI and thereby
the lateral extension of the acromion is increased in patients
with rotator cuff tear and also with rotator cuff retears.29 It
is hypothesised that the increase of lateral extension causes a
higher upward pulling force of the deltoid muscle during active
abduction of the arm and thereby pressing the humeral head into
the acromial arch causing the supraspinatus muscle to impinge.28
Most of the subsequent studies investigating AI with rotator cuff
tear support the association between a high AI and the occurrence
of full thickness rotator cuff tear;23 30 31 however, some studies
could not reproduce the findings.32 33 These controversial results
indicate that the shape of the acromion has an influence on the
genesis of rotator cuff tear and the orientation of the glenoid.
Compared with healthy controls, patients with rotator cuff tear
have an increased inclination of the glenoid fossa. In addition,
glenoid anteversion was associated with tears of the posterior
muscles and retroversion with tears of anterior muscles.34
The critical shoulder angle (CSA)
To combine the lateral extension of the acromion with glenoid
inclination, Moor et al35 developed the concept of the CSA.
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074

Figure 1  Measurement of the critical shoulder angle (CSA) in the antero-
posterior radiography of the shoulder. The CSA is the angle between the
line connecting the superior glenoid rim with the inferior glenoid rim and
the line connecting the inferior glenoid rim with the most lateral acromion
edge.
The CSA measures the angle between a line connecting the supe-
rior and inferior glenoid margins and a line connecting the infe-
rior margin with the most lateral border of the acromion on true
anteposterior radiographs of the shoulder (figure 1). Deviations
from A CSA >35° (grade 3) indicates an increased inclination
and/or lateral extension of the acromion that is associated with
the occurrence of rotator cuff tears. Normal shoulders have a
CSA that lies between 30° and 35° (grade 2) and a CSA <30°
(grade 1) is associated with a higher rate of osteoarthritis.35
The CSA measurement strongly correlates with the AI measure-
ment27 and was shown to have a higher sensitivity and specificity
than other measurements of acromion morphology to detect
rotator cuff tear.36 37 Recent studies confirmed the significantly
higher CSA in patients with rotator cuff tear (RCT), although
they questioned the classification of CSA in RCT to be >35°.38 39
Biomechanics of the critical shoulder angle
A possible biomechanical explanation why patients with a high
CSA are more likely to have rotator cuff tear and patients with
a low CSA osteoarthritis goes back on the concept of glenohu-
meral joint compressing and shearing forces.28 In a biomechanical
computer model, the increase of CSA had a positive correlation
with upward translation of the humeral head.40 This correlation
was true for both factors, glenoid inclination as well as lateral
extension of the acromion.41 A CSA >35° destabilises the gleno-
humeral joint and increases the superior shear forces from deltoid
activity during the glenohumeral motion to 80° abduction to in
a biomechanical model.42 The increase in superior shear forces
occurs in higher CSA values due to increase of both lateral
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074
State of the Art
extension of the acromion42 as well as glenoid inclination.41
This increase in superior shear forces require up to 44% higher
supraspinatus muscle activity to compensate and maintain the
­glenohumeral joint alignment. This causes chronic overload to
the supraspinatus muscle with a peak of the superior shear forces
between 40° and 90° thoracohumeral abduction.42 43 This inter-
esting yet surprising finding indicates that not overhead motions
increase stress to the rotator cuff tendon but daily activities where
the arm does not exceed 90° abduction.
When thoracohumeral abduction exceeds 90°, a higher CSA
leads to inferior translation of the humeral head in normal shoul-
ders as shown in an in-vivo model.44 This counterintuitive effect
may be explained by a downward directed lever arm through
the surrounding soft tissue that is pressed into the acromial arch
during deltoid activity in abduction above 90°. With the increase
in lateral extension of the acromion, the deltoid moment arm is
higher producing a larger downward directed force and causing
the evasive movement of the humerus in the inferior direc-
tion.43 In patients with rotator cuff tear, no such correlation was
observed indicating that the joint is destabilised with the loss of
supraspinatus muscle function.44
For clinical routine use, it is important that the radiographs are
accurately taken, because if the viewing angle on the radiographs
differs from the true anteroposterior direction, CSA measurement
may not be accurate.45 If no radiograph of sufficient quality is avail-
able, the CSA can be measured in CT scans instead46 and in MRI
scans with less accuracy.47 Together with age and trauma, the CSA
accurately predicts rotator cuff tears. The risk to develop a rotator
cuff tear can be calculated with the input of the three variables in
the rotator cuff tear score formula. A score >10 predicts postero-
superior rotator cuff tear with a sensitivity 84% and specificity of
81%.36 Other studies confirmed the CSA as a predictor for rotator
cuff tear27 and associated higher CSA values with massive rotator
cuff with tear of more than one muscle.48 Furthermore, a CSA
measurement >38° was associated with a 15 times higher risk of
retear after rotator cuff repair.49 With the CSA, a reliable measure-
ment for anatomical variety that may lead to rotator cuff tear was
found, and it also explains why rotator cuff tear and osteoarthritis
are usually mutually exclusive.
Biological changes in rotator cuff tear
The previously discussed anatomical varieties in the glenohu-
meral joint cause repetitive trauma to the rotator cuff muscles
through subacromial impingement.38 Together with chronic
overuse, this may lead to degeneration of the musculotendinous
unit. Due to its insertion on the superior part of the humeral
head, the supraspinatus muscle is more exposed to the previ-
ously described superiorly directed shearing forces than the other
rotator cuff muscles and therefore the most commonly injured.
Generally, degenerative changes in the musculotendinous unit
are induced by a combination of external and internal triggers
that lead to chronic tendinopathy. The complex interplay of
these factors was reviewed in extend by Seitz et al.50 Chronic
tendinopathy is the inflammatory response of the hypocellular
tendon tissue with infiltration of inflammatory cells that induce
the degradation of the extracellular matrix (ECM) and drive the
resident tenocytes to undergo apoptosis.51 52 Once the tendon
is completely torn, subsequent degenerative processes in the
muscle are initiated. Inflammatory cells infiltrate into the muscle
and initiate the degradation of muscle fibres.53 54 This results in
atrophy of the muscle with loss of sarcomeres in series and leads
to both decrease of muscle fibre cross section and muscle fibre
length. The loss of muscle volume is associated with an increase
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in pennation angle that causes an enlargement of the intermy-
ofibrillar and intramyofibrillar spaces. The free space is then
filled with connective tissue and the degenerated muscle fibres
are replaced by fat cells. An advanced fatty infiltration marks the
irreversible end point of the degeneration of the musculotendi-
nous unit.55 The cellular and molecular processes in tendon and
muscle degeneration share some common mechanisms, which
are indeed to date only partially understood.
Inflammation is the first response to injury
Recent research has revealed the important role of inflamma-
tory processes during tendinopathy and muscle degeneration.56
Commonly, this response is divided into three stages: mechan-
ical stress induces the inflammatory response, which increases
the permeability of the tissue’s vasculature. Immediately neutro-
phils invade into the site of injury. These cells are the first-line
response and stimulate M1 macrophages that enter the site
of injury to remove cell debris and to regulate the subsequent
proliferative phase. During the proliferative phase, a temporary
scar tissue that is rich in unstructured collagen type III is formed
by invading fibroblasts. This temporary scar acts as a scaffold for
the formation of highly structured type I collagen tendon tissue
during the following remodelling phase.57
Macrophages regulate the degeneration
M1 macrophages are proinflammatory and release inflammatory
cytokines (interleukin1-ß (IL1-ß) and tumour necrosis factor α
(TNFα)) that sustain inflammatory processes. The cytokines
activate specific intracellular cascades in tendon and muscle
cells and attract fibroblasts that produce a disorganised collagen
scaffold. Subsequently, M1 macrophages switch their pheno-
type and become alternatively activated M2 macrophages.58 M2
macrophages have a wide spectrum of functions and so far it
remains controversial if the different subsets are only function-
ally different or distinct subpopulations.53 They have anti-in-
flammatory properties and are thought to regulate the tissue’s
regeneration and remodelling of the scar tissue. During early
remodelling, regulatory M2 macrophages (Mreg) promote
reorganisation of the disorganised collagen scaffold. They are
usually beneficial in re-establishing tissue integrity and promote
homeostasis.59 In a chronic inflammatory state, remodelling is
redirected by a different subtype of M2 macrophages (M2a)
that promote excessive remodelling.59 M2a macrophages release
excessive amounts of growth factors (ie, transforming growth
factor beta 1 (TGFß1)) that lead to specific reactions in the
tendon and muscle cells discussed later. Generally, these cyto-
kines cause the fibroblasts to excessively deposit ECM compo-
nents and thus cause fibrosis.59 On the intracellular level, the
inflammatory cytokines mobilise intracellular protein cascades
that have common pathways but differ in their end product
depending on the tissue type. M1 macrophages release IL1-ß and
TNFα and their binding upregulates the expression of nuclear
factor kappa B (NF-κB). NF-κB expression is modulated by poly
[adenosine diphosphate ribose] polymerase 1 (PARP-1), which in
turn has distinct influences on other degenerative cascades in the
tendon and muscle after injury. The disturbance of this interac-
tion by deletion or downregulation of PARP-1 leads to a lower
inflammatory reaction, which protects muscle from damage
secondary to unloading in a mouse model of RCT.60
Mechanisms of tendon degeneration
The upregulation of NF-κB is a crucial step but potentially detri-
mental in the response of tenocytes to proinflammatory cytokines
216
(IL1-ß and TNFα). NF-κB upregulation leads to apoptosis of
tenocytes and the upregulation of metalloproteinases that degrade
the ECM and downregulates the collagen producing proteins.61
During the proliferative phase, the anti-inflammatory M2reg
macrophages increase scar tissue formation rather than promote
the regeneration of normal tendon tissue. They attract fibroblasts
from the epitenon/peritenon to infiltrate into the tendon, which
have increased transcription of genes encoding for collagen and
thereby form a scar tissue that mainly consist of the collagen type
III, which is mechanically unstable. M2reg macrophages resolve
inflammation and promote subsequent tissue regeneration.62 63
During the following remodelling phase, the ECM is reorganised
by replacing the mechanically inferior collagen type III matrix
by a mechanically stronger collagen type I matrix. This process
requires the tendon to be mechanically loaded. The mechanism
how mechanical forces are transduced into biomechanical signals
are not fully understood, but integrins—transmembrane proteins
linking the ECM with the cytoskeleton—play an important role
in a process termed mechanosensing. With chronical overload or
unloading, the processes are redirected into chronic tendinopathy
and the macrophages switch into the profibrotic M2a subtype
and overexpress growth factors that promote neovascularisation
(vascular endothelial growth factor (VEGF)) and fibrosis (TGF-ß)
in the attempt to promote healing.59 TGF-ß expression is highly
variable during the regenerative process depending on the injury
mechanism, and its role during degenerative and regenerative
processes is not entirely understood.64 TGF-ß is activated during
regeneration after tendon injury and is an important mediator
during normal tendon development and homeostasis. However,
overexpression of TGF-ß induces fibrosis and tenocyte apop-
tosis.65 In this way, it can have beneficial and maleficent effects on
the tendon tissue.66
Muscle degeneration
Regeneration and degeneration are in balance during normal muscle
homeostasis due to mutual interactions between atrophy and regen-
eration. Overloading of the muscle leads hypertrophy of the muscle
fibres and conversely unloading of the muscle disturbs the balance
and induces pathways that ultimately lead to the degradation of
the fibres.67 Similarly to the reaction in tendons, inflammatory cells
enter the muscle during the initial inflammatory phase. With the
release of IL-1ß and TNFα, they trigger the intracellular activa-
tion of NFκB (figure 2). In muscle fibres, NF-κB has an important
influence on the degeneration after muscle injury. It regulates the
expression of inflammatory cytokines that lead to rapid apop-
tosis or necrosis of muscle fibres. The cell debris of these fibres
are phagocytised by macrophages. Not all muscle fibres undergo
immediate destruction by apoptosis or necrosis. Most of the fibres
degenerate through a process that allows controlled degradation
of the muscle fibres by the ubiquitin-proteasome system. NF-κB
promotes muscular atrophy and fibre degradation directly by acti-
vating the effectors of the ubiquitin-proteasome system. For this
process, activation of intermediary cytokines is not necessary. The
polyubiquinated fibre components are then degraded through
proteolysis by the proteasome. This degenerative process removes
excessive muscle fibres, and sustained activation of NF-κB inhibits
the onset of regenerative processes by downregulating the expres-
sion of the myogenic regulatory factors (MRFs). This inhibition of
myogenic differentiation and regeneration is the third major effect
of NF-κB in muscle degeneration. Although inhibited by NF-κB,
the muscle retains its remarkable ability to regenerate. Soon after
injury, the M1 macrophages switch to M2reg macrophages that
secrete anti-inflammatory IL-10 and promote myogenesis. During
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074
 State of the Art
M2a macrophages. These cells trigger the secretion of TGF-ß and
myostatin from the fibroblasts in the ECM.64 Myostatin belongs to
the TGF-ß superfamily and is a potent inhibitor of muscle hyper-
trophy and thus muscle regeneration. The inhibition of regenerative
pathways directs the postinjury reaction to atrophy and fibrosis.69
With this induction of degenerative pathways, M2a macrophages
influence the balance of muscular homeostasis towards degener-
ation. This overpowers the regenerative pathways and leads to
the progression of atrophy, retraction and fibrosis. Ultimately, the
muscle fibres degenerate, and the free space is filled with fat vacu-
oles. Additionally, adipocytes infiltrate from the vasculature into
the free intermyofibrillar and intramyofibrillar space. The regula-
tion of this fatty infiltration is not entirely understood, but mutual
interaction of proadipogenic pathways and regenerative MRFs
Figure 2  Schematic drawing of the extracellular and intracellular were described.70 This interaction is influenced by PARP-1 and its
processes involved in the degeneration of muscle cells. As shown, NF-kB absence directs the balance towards regeneration.71 In addition,
plays a central role in the inflammatory processes and is activated by myostatin and TGF-ß inhibit proadipogenic pathways and thereby
extracellular inflammatory cytokines. Transcriptional activation of NF-kB is delay the onset of fatty infiltration during the presence of M2a
promoted by the poly-(ADP-ribose) polymerase 1 (PARP-1), which plays macrophages.
thereby a crucial role in NF-kB regulated processes. IL-1ß, Interleukin 1 Taken together, the regulation of muscle homeostasis and reac-
beta; MyoD, myogenenic factor 3; NF-kB, nuclear factor kappa B; TGF-ß, tion to injury is a complex interplay between degenerative and
tumour growth factor ß; TNF-α, tumour necrosis factor alpha. regenerative processes. Muscles exhibit a remarkable ability to
regenerate injured muscle fibres to remain its structural integrity
the proliferative phase, satellite cells and mesenchymal stem cells after injury under normal circumstances with continued loading
(MSCs) are activated and undergo proliferation and differentiation. of the tendon. However, with sustained unloading, the degener-
This process is orchestrated by the MRFs which, in cooperation ative processes overpower regeneration and ultimately lead to
with other endocrine growth factors, instigate the development fatty infiltration. A pathological such as a rotator cuff tear marks
mature myocytes from precursor cells.68 a potential for the irreversible end-point of the muscle’s degen-
In chronic rotator cuff tear, the unloading of the muscle erative processes72 (table 2).
persists,55 and M2reg macrophages switch to become profibrotic
Tendon Healing
Rotator cuff tendon healing has received increased attention over
Table 2  Characteristics of important pathological changes in tendon the past several years. While rotator cuff repair enjoys a histor-
and muscle ical record of good results, studies that examine the antatomic
Common pathological changes integrity of the tendon after repair reveal a much higher rate
 Inflammatory NF-kB activation of retear than expected.73 Several factors are associated with
cytokines Infiltration of macrophages/neutrophils failure of tendon healing including, age, medical comorbidities,
 M1 macrophages Proinflammatory tear size, presence of degenerative changes in the tendon and
Remove cell debris muscle (chronicity) and environmental factors. To add to the
Promote disorganised collagen scaffold complexity, whether this is actual retear or failure of healing, is
 M2reg macrophages Resolve inflammation debatable. Clinical studies document this healing phenomenon
Reorganise preliminary collagen scaffold and a body of basic science research has evaluated this process
Tendon tissue regeneration
on a more in-depth level.
Muscle proliferation and regeneration
 M2a macrophages Induction of myostatin/TGF-ß
Neovascularisation (VEGF) Clinical healing
Fibrosis/scar tissue formation Failure of healing has been documented for over two decades.
Inhibition of muscle regeneration
One of the original manuscripts to include this information by
Delay of fatty infiltration
Harryman et al,74 evaluated the anatomic integrity of rotator
Tendon
cuff tears with ultrasound. After open rotator cuff repair, they
 NFkB upregulation Tenocyte apoptosis
Upregulation of metalloproteinases
found higher rates of recurrent tears in larger tears. They
reported better outcomes in patients with intact cuffs. With
 Metalloproteinases ECM/collagen matrix degradation
data extrapolation, age seems a significant factor. A few years
 TGF-ß Highly variable mediator of regeneration and
degeneration
later, Liu and Baker75 reported 70% of repairs had defects with
a higher incidence in larger tears. They did not find differences
Muscle
in outcome.
 NF-kB upregulation Muscle cell apoptosis
Muscle fibre degradation
As arthroscopic repairs became the standard of care, Galatz
Inhibition of regenerative processes et al73 76 found that 17 of 18 repairs of massive rotator cuff
 Myostatin/TGF-ß Fibrosis and degeneration tears had retears after single row repair. Importantly, these were
Inhibition of hypertrophy and regeneration massive tears and all but one patient were over 60 years of age.
Delay of fatty infiltration In spite of this anatomic result, the average American Shoulder
 Proadipogenic factors Fatty infiltration and Elbow Surgeons score improved from 44 to 88. Bishop,
ECM, extracellular matrix; NF-κB, nuclear factor kappa B; TGF-ß, tumour necrosis et al evaluated the early results after arthroscopic and open
factor ß; VEGF, vascular endothelial growth factor. repair.77 Their healing rates were similar after both techniques;
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074 217
 State of the Art
Figure 3  A rat supraspinatus tendon stained for collagen type I. (A) The uninjured tendon has tightly organised construct with a clear four-zone insertion
site. (B) The injured and repaired specimen show a disorganised, hypercellular tendon without a definitive four-zone insertion site 8 weeks from the time of
surgery.
however, in larger tears over 3 cm, there were more defects in
the arthroscopic group (open 62% vs 24% arthroscopic intact).
Boileau et al78 evaluated results after arthroscopic repair. Seven-
ty-one per cent of patients had healed repairs, but age was a
significant factor in healing. In fact, if patients were over age
65, there was only a 43% chance of healing a single tendon tear.
This is one of the first manuscripts to evaluate age as an indepen-
dent variable. Lichtenberg et al79 found similar results, and age
was a significant prognostic factor in healing as older patients
had lower healing rates.
Not all studies agree however. Oh et al80 analysed 177
rotator cuff repairs. With multivariate analysis, age was not an
independent factor, but rather fatty degeneration and retrac-
tion were strongly associated with failure of healing. Impor-
tantly, age, retear and degenerative changes in the muscle are
colinear variables, so large, well-powered studies are neces-
sary to investigate this. Other studies show very high rates of
healing. Keener et al found an over 90% healing rate after
arthroscopic repair.81 This study was designed to compare
rehabilitation protocols and included younger patients with
smaller tears. Similarly, Lafosse et al82 found a high healing rate
after arthroscopic repair, and these repairs were in younger,
healthy patients. Clearly, there are trends that coincide with
epidemiology of rotator cuff tears, and most agree that age,
tear size and chronicity have direct influence on healing after
rotator cuff repair.
Iannotti et al evaluated the timing of failure of cuff healing
after rotator cuff repair.83 In this multicentre study of 113
patients with rotator cuff repairs of 1–4 cm in size, 17% had
recurrent defects seen on serial MRIs. The majority of the
tears occurred 12–26 weeks after arthroscopic cuff repair.
There was a linear increase in retears over this time period.
A retrospective, cohort study of 1600 patients showed a 13%
retear rate. Although similar improvements were seen in range
of motion and pain levels with overhead activity, supraspinatus
and external rotation power were greater in the shoulders with
intact repairs.84 Factors associated with retear were tears size and
patient age.85 A study by Tham et al showed an increase in vascu-
larity and bursal thickness after repair, and the tendon thickness
remained constant and similar to the opposite side in shoulders
evaluated by ultrasound after repair.86
Tear construct
Aprelava87 introduced the idea of restoring the footprint of the
rotator cuff. The anatomy of the cuff insertion is such that the
enthesis is several millimetres to a centimetre in width. Following
218
that, new repair techniques focused on restoring the footprint.
Cadaveric studies88 89 documented increased pull out strength
with the new double row repairs in terms of pull out strength,
maintenance of integrity with cyclic loading and contact pres-
sure. While this is the case in cadaveric studies, the clinical
results are more mixed.
Sugaya et al90 compared single versus double row repair
in 80 shoulders with postoperative MRIs. Twenty-two out of
39 repairs had defects after single row repairs. Eleven out of
41 repairs had defects after double row repair. This was one
of the first studies to demonstrate improvement in structural
outcome with double row repair. Franceschi et al91 showed
better healing with fewer defects after double row repair;
however, the mechanical advantage did not translate to a
better clinical result as there were no differences in functional
outcomes between the groups. Charousset et al92 found similar
results. Healing was better with double row, but there were
no differences in constant score. Two systematic reviews93 94
evaluated single versus double row repair. Overall, there was
better healing in larger tears with a double row repair, but no
differences in clinical outcome.
Another study evaluating single row repairs prospectively
found 90% of the repairs intact for single tendon tears and
83% intact in two tendon tears. Outcome results were good.
These findings suggest that patient biology may have the
greatest impact on healing potential. While the reasons are not
definitively elucidated, differences in patients’ age, activity,
pain thresholds and expectations may cloud the findings. Indi-
cations for double row may ultimately vary according to these
certain variables.
Basic science of tendon healing
Tendon healing occurs by the formation of hypervascular
poorly organised ECM that slowly remodels with time to a
construct that can bear load. Animal studies have shown that
healing response is characterised by a fibrovascular scar
response rather than by regenerating normal tendon tissue
(figure 3).95–99 Structural properties represent the strength (ie,
pull out strength) of the tissue and achieve approximately ½
those of normal tissue. The material properties represent the
tissue quality or the viscoelastic properties of the repair. Mate-
rial properties achieve only about 1/5 to 1/10 of normal tissue.
Thus, in animal studies, the repaired insertion sites accrue
strength by laying down a larger volume of tissue with inferior
viscoelastic properties relative to normal tissue.95 The tissue is
more vascular and less organised. The tendon often heals in
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074

Table 3  Histologic characteristics of Normal and healing tendon
tissue
Normal tissue Healing tissue
Highly aligned collagen fibres Poorly aligned collagen fibres
Little vascularity More vascularised
Hypocellular Increased cellularity
Organised four-zone insertion site Poor formation of fibrocartilage and
mineralised fibrocartilage at insertion site
No inflammation Inflammatory cells at early time points
Mainly type I collagen Higher type III collagen content
a more elongated or stretched out condition, due to altered
viscoelastic properties (table 3).
Future perspectives
Both skeletal morphological changes as well as biological
changes may influence the development of chronic rotator
cuff tears. By knowing the mechanisms of tendon and muscle
Box 1 List of 10 key articles 
1. Sher JS, Uribe JW, Posada A, et al. Abnormal findings on
magnetic resonance images of asymptomatic shoulders.
J Bone Joint Surg Am 1995;77:10–5.
2. Minagawa H, Yamamoto N, Abe H, et al. Prevalence of
symptomatic and asymptomatic rotator cuff tears in the
general population: from mass-screening in one village.
Journal of Orthopaedics 2013;10:8–12.
3. Yamamoto A, Takagishi K, Kobayashi T, et al. Factors involved
in the presence of symptoms associated with rotator cuff
tears: a comparison of asymptomatic and symptomatic
rotator cuff tears in the general population. J Shoulder
Elbow Surg 2011;20:1133–7.
4. Moor BK, Wieser K, Slankamenac K, et al. Relationship of
individual scapular anatomy and degenerative rotator cuff
tears. Journal of shoulder and elbow surgery / American
Shoulder and Elbow Surgeons  (et al.) 2014;23:536–41.
5. Millar NL, Hueber AJ, Reilly JH, et al. Inflammation is present
in early human tendinopathy. The American Journal of Sports
Medicine 2010;38:2085–91.
6. Lichtnekert J, Kawakami T, Parks WC, et al. Changes in
macrophage phenotype as the immune response evolves.
Current Opinion in Pharmacology 2013;13:555–64.
7. Killian ML, Lim CT, Thomopoulos S, et al. The effect of
unloading on gene expression of healthy and injured rotator
cuffs. Journal of Orthopaedic Research : Official Publication
of the Orthopaedic Research Society 2013;31:1240–8.
8. Schmutz S, Fuchs T, Regenfelder F, et al. Expression of
atrophy mRNA relates to tendon tear size in supraspinatus
muscle. Clinical Orthopaedics and Related Research
2009;467:457–64.
9. Galatz LM, Sandell LJ, Rothermich SY, et al. Characteristics
of the rat supraspinatus tendon during tendon-to-bone
healing after acute injury. Journal of Orthopaedic Research:
Official Publication of the Orthopaedic Research Society
2006;24:541–50.
10. Thomopoulos S, Hattersley G, Mertens L RM, et al. The
localised expression of extracellular matrix components in
healing tendon insertion sites: an in situ hybridization study.
Journal of Orthopaedic Research 2002;20:454–63.
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074
State of the Art
degeneration, we might be able to develop various means
to slow down this degenerative process for the purpose of
prevention and treatment of degenerative rotator cuff tears.
Although the most commonly performed surgery, rotator cuff
repair achieves fibrovascular scar formation at the tendon–
bone junction rather than the regeneration of normal tendon–
bone junction. Hopefully, we will be able to find a method to
regenerate the normal tendon-to-bone junction in the future
(box 1).
Contributors  MAZ: author of the tendon pathology section. MK: author of the
tendon pathology section. TH: author of the epidemiology section. LMG: author
of the tendon healing section. EI: author of the epidemiology section, entire
management and planning.
Competing interests  None declared.
Provenance and peer review  Commissioned; externally peer reviewed.
© International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports
Medicine (unless otherwise stated in the text of the article) 2017. All rights reserved.
No commercial use is permitted unless otherwise expressly granted.
References
1 Codman EA, Akerson IB. The pathology associated with rupture of the supraspinatus
tendon. Ann Surg 1931;93:348–59.
2 Fukuda H, Mikasa M, Ogawa K. et al. The partial thickness tear of the rotator cuff.
Orthop Trans 1983;11:237–8.
3 Ozaki J, Fujimoto S, Nakagawa Y, et al. Tears of the rotator cuff of the shoulder
associated with pathological changes in the acromion. A study in cadavera. J Bone
Joint Surg Am 1988;70:1224–30.
4 Grant JCB, Smith CG. Age incidence of rupture of the supraspinatus tendon. Anat Rec
1948;100:666.
5 Petersson CJ, Gentz CF. Ruptures of the supraspinatus tendon. the significance
of distally pointing acromioclavicular osteophytes. Clin Orthop Relat Res
1983;174:143–8.
6 Wilson CL, Duff G. Pathologic study of degeneration and rupture of the supraspinatus
tendon. Arch Surg 1943;47:121–35.
7 Sher JS, Uribe JW, Posada A, et al. Abnormal findings on magnetic resonance images
of asymptomatic shoulders. J Bone Joint Surg Am 1995;77:10–15.
8 Tempelhof S, Rupp S, Seil R. Age-related prevalence of rotator cuff tears in
asymptomatic shoulders. J Shoulder Elbow Surg 1999;8:296–9.
9 Moosmayer S, Smith HJ, Tariq R, et al. Prevalence and characteristics of asymptomatic
tears of the rotator cuff: an ultrasonographic and clinical study. J Bone Joint Surg Br
2009;91:196–200.
10 Minagawa H, Yamamoto N, Abe H, et al. Prevalence of symptomatic and
asymptomatic rotator cuff tears in the general population: from mass-screening in one
village. J Orthop 2013;10:8–12.
11 Yamamoto A, Takagishi K, Kobayashi T, et al. Factors involved in the presence of
symptoms associated with rotator cuff tears: a comparison of asymptomatic and
symptomatic rotator cuff tears in the general population. J Shoulder Elbow Surg
2011;20:1133–7.
12 Yamamoto A, Takagishi K, Shitara H, et al. Longitudinal study for rotator cuff tears in
the general population (abstract). J Shoulder and Elbow Surgery 2015;24:e347.
13 Itoi E, Minagawa H, Konno N, et al. Smoking habits in patients with rotator cuff tears.
Katakansetsu 1996;20:209–11.
14 Kane SM, Dave A, Haque A, et al. The incidence of rotator cuff disease in smoking and
non-smoking patients: a cadaveric study. Orthopedics 2006;29:363–6.
15 Baumgarten KM, Gerlach D, Galatz LM, et al. Cigarette smoking increases the risk for
rotator cuff tears. Clin Orthop Relat Res 2010;468:1534–41.
16 Carbone S, Gumina S, Arceri V, et al. The impact of preoperative smoking habit on
rotator cuff tear: cigarette smoking influences rotator cuff tear sizes. J Shoulder Elbow
Surg 2012;21:56–60.
17 Jeong J, Shin DC, Kim TH, et al. Prevalence of asymptomatic rotator cuff tear and their
related factors in the korean population. J Shoulder Elbow Surg. In Press. 2017;26.
18 Tilley BJ, Cook JL, Docking SI, et al. Is higher serum cholesterol associated with
altered tendon structure or tendon pain? A systematic review. Br J Sports Med
2015;49:1504–9.
19 Passaretti D, Candela V, Venditto T, et al. Association between alcohol consumption
and rotator cuff tear. Acta Orthop 2016;87:165–8.
20 Cohen DB, Kawamura S, Ehteshami JR, et al. Indomethacin and celecoxib impair
rotator cuff tendon-to-bone healing. Am J Sports Med 2006;34:362–9.
21 Oak NR, Gumucio JP, Flood MD, et al. Inhibition of 5-LOX, COX-1, and COX-2
increases tendon healing and reduces muscle fibrosis and lipid accumulation after
rotator cuff repair. Am J Sports Med 2014;42:2860–8.
22 Day A, Taylor NF, Green RA. The stabilizing role of the rotator cuff at the shoulder--
responses to external perturbations. Clin Biomech 2012;27:551–6.
219
 State of the Art
23 Balke M, Liem D, Greshake O, et al. Differences in acromial morphology of shoulders
in patients with degenerative and traumatic supraspinatus tendon tears. Knee Surg
Sports Traumatol Arthrosc 2016;24:2200–5.
24 Neer CS. Anterior acromioplasty for the chronic impingement syndrome in the
shoulder: a preliminary report. J Bone Joint Surg Am 1972;54:41–50.
25 Bigliani LU, Morrison DS, April EW. The morphology of the acromion and its
relationship to rotator cuff tears. Orthop Trans 1986;10:228.
26 Kitay GS, Iannotti JP, Williams GR, et al. Roentgenographic assessment of acromial
morphologic condition in rotator cuff impingement syndrome. J Shoulder Elbow Surg
1995;4:441–8.
27 Pandey V, Vijayan D, Tapashetti S, et al. Does scapular morphology affect the integrity
of the rotator cuff? J Shoulder Elbow Surg 2016;25:413–21.
28 Nyffeler RW, Werner CM, Sukthankar A, et al. Association of a large lateral extension
of the acromion with rotator cuff tears. J Bone Joint Surg Am 2006;88:1889–90.
29 Zumstein MA, Jost B, Hempel J, et al. The clinical and structural long-term
results of open repair of massive tears of the rotator cuff. J Bone Joint Surg Am
2008;90:2423–31.
30 Miyazaki AN, Itoi E, Sano H, et al. Comparison between the acromion index and
rotator cuff tears in the Brazilian and Japanese populations. J Shoulder Elbow Surg
2011;20:1082–6.
31 Balke M, Schmidt C, Dedy N, et al. Correlation of acromial morphology with
impingement syndrome and rotator cuff tears. Acta Orthop 2013;84:178–83.
32 Ames JB, Horan MP, Van der Meijden OA, et al. Association between acromial index
and outcomes following arthroscopic repair of full-thickness rotator cuff tears. J Bone
Joint Surg Am 2012;94:1862–9.
33 Hamid N, Omid R, Yamaguchi K, et al. Relationship of radiographic acromial
characteristics and rotator cuff disease: a prospective investigation of clinical,
radiographic, and sonographic findings. J Shoulder Elbow Surg 2012;21:1289–98.
34 Tétreault P, Krueger A, Zurakowski D, et al. Glenoid version and rotator cuff tears.
J Orthop Res 2004;22:202–7.
35 Moor BK, Bouaicha S, Rothenfluh DA, et al. Is there an association between the
individual anatomy of the scapula and the development of rotator cuff tears or
osteoarthritis of the glenohumeral joint?: A radiological study of the critical shoulder
angle. Bone Joint J 2013;95-B:935–41.
36 Moor BK, Röthlisberger M, Müller DA, et al. Age, trauma and the critical shoulder
angle accurately predict supraspinatus tendon tears. Orthop Traumatol Surg Res
2014;100:489–94.
37 Moor BK, Wieser K, Slankamenac K, et al. Relationship of individual scapular anatomy
and degenerative rotator cuff tears. J Shoulder Elbow Surg 2014;23:536–41.
38 Li X, Xu W, Hu N, et al. Relationship between acromial morphological variation
and subacromial impingement: a three-dimensional analysis. PLoS One
2017;12:e0176193.
39 Chalmers PN, Salazar D, Steger-May K, et al. Does the critical shoulder Angle Correlate
with Rotator Cuff Tear Progression? Clin Orthop Relat Res 2017;475:1608–17.
40 Engelhardt C, Farron A, Becce F, et al. Effects of glenoid inclination and acromion
index on humeral head translation and glenoid articular cartilage strain. J Shoulder
Elbow Surg 2017;26.
41 Moor BK, Kuster R, Osterhoff G, et al. Inclination-dependent changes of the critical
shoulder angle significantly influence superior glenohumeral joint stability. Clin
Biomech 2016;32:268–73.
42 Gerber C, Snedeker JG, Baumgartner D, et al. Supraspinatus tendon load during
abduction is dependent on the size of the critical shoulder angle: a biomechanical
analysis. J Orthop Res 2014;32:952–7.
43 Viehöfer AF, Gerber C, Favre P, et al. A larger critical shoulder angle requires more
rotator cuff activity to preserve joint stability. J Orthop Res 2016;34:961–8.
44 Peltz CD, Divine G, Drake A, et al. Associations between in-vivo glenohumeral joint
motion and morphology. J Biomech 2015;48:3252–7.
45 Suter T, Gerber Popp A, Zhang Y, et al. The influence of radiographic viewing
perspective and demographics on the critical shoulder angle. J Shoulder Elbow Surg
2015;24:e149–58.
46 Bouaicha S, Ehrmann C, Slankamenac K, et al. Comparison of the critical shoulder
angle in radiographs and computed tomography. Skeletal Radiol 2014;43:1053–6.
47 Spiegl UJ, Horan MP, Smith SW, et al. The critical shoulder angle is associated with
rotator cuff tears and shoulder osteoarthritis and is better assessed with radiographs
over MRI. Knee Surg Sports Traumatol Arthrosc 2016;24:2244–51.
48 Blonna D, Giani A, Bellato E, et al. Predominance of the critical shoulder angle in
the pathogenesis of degenerative diseases of the shoulder. J Shoulder Elbow Surg
2016;25:1328–36.
49 Garcia GH, Liu JN, Degen RM, et al. Higher critical shoulder angle increases the risk of
retear after rotator cuff repair. J Shoulder Elbow Surg 2017;26:241–5.
50 Seitz AL, McClure PW, Finucane S, et al. Mechanisms of rotator cuff tendinopathy:
intrinsic, extrinsic, or both? Clin Biomech (Bristol, Avon). 26. England: 2010 Elsevier
Ltd. 2011;1–12.
51 Benson RT, McDonnell SM, Knowles HJ, et al. Tendinopathy and tears of the
rotator cuff are associated with hypoxia and apoptosis. J Bone Joint Surg Br
2010;92:448–53.
52 Dean BJ, Gettings P, Dakin SG, et al. Are inflammatory cells increased in painful
human tendinopathy? A systematic review. Br J Sports Med 2016;50:216–20.
220
53 Novak ML, Weinheimer-Haus EM, Koh TJ. Macrophage activation and skeletal muscle
healing following traumatic injury. J Pathol 2014;232:344–55.
54 Gumucio JP, Davis ME, Bradley JR, et al. Rotator cuff tear reduces muscle fiber specific
force production and induces macrophage accumulation and autophagy. J Orthop Res
2012;30:1963–70.
55 Meyer DC, Farshad M, Amacker NA, et al. Quantitative analysis of muscle and tendon
retraction in chronic rotator cuff tears. Am J Sports Med 2012;40:606–10.
56 Millar NL, Hueber AJ, Reilly JH, et al. Inflammation is present in early human
tendinopathy. Am J Sports Med 2010;38:2085–91.
57 Angeline ME, Rodeo SA. Biologics in the management of rotator cuff surgery. Clin
Sports Med 2012;31:645–63.
58 Arnold L, Henry A, Poron F, et al. Inflammatory monocytes recruited after skeletal
muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp
Med 2007;204:1057–69.
59 Lichtnekert J, Kawakami T, Parks WC, et al. Changes in macrophage phenotype as the
immune response evolves. Curr Opin Pharmacol 2013;13:555–64.
60 Kuenzler MB, Nuss K, Karol A, et al. Neer award 2016: reduced muscle
degeneration and decreased fatty infiltration after rotator cuff tear in a poly(ADP-
ribose) polymerase 1 (PARP-1) knock-out mouse model. J Shoulder Elbow Surg
2017;26:733–44.
61 Spiesz EM, Thorpe CT, Chaudhry S, et al. Tendon extracellular matrix damage,
degradation and inflammation in response to in vitro overload exercise. J Orthop Res
2015;33:889–97.
62 Schwartz AJ, Sarver DC, Sugg KB, et al. p38 MAPK signaling in postnatal tendon
growth and remodeling. PLoS One 2015;10:e0120044.
63 Sugg KB, Lubardic J, Gumucio JP, et al. Changes in macrophage phenotype and
induction of epithelial-to-mesenchymal transition genes following acute Achilles
tenotomy and repair. J Orthop Res 2014;32:944–51.
64 Killian ML, Lim CT, Thomopoulos S, et al. The effect of unloading on gene expression
of healthy and injured rotator cuffs. J Orthop Res 2013;31:1240–8.
65 Jiang C, Shao L, Wang Q, et al. Repetitive mechanical stretching modulates
transforming growth factor-β induced collagen synthesis and apoptosis in human
patellar tendon fibroblasts. Biochem Cell Biol 2012;90:667–74.
66 Maeda T, Sakabe T, Sunaga A, et al. Conversion of mechanical force into TGF-β-
mediated biochemical signals. Curr Biol 2011;21:933–41.
67 Schmutz S, Fuchs T, Regenfelder F, et al. Expression of atrophy mRNA relates to
tendon tear size in supraspinatus muscle. Clin Orthop Relat Res 2009;467:457–64.
68 Frey E, Regenfelder F, Sussmann P, et al. Adipogenic and myogenic gene expression in
rotator cuff muscle of the sheep after tendon tear. J Orthop Res 2009;27:504-9.
69 Dong Y, Lakhia R, Thomas SS, et al. Interactions between p-Akt and Smad3 in
injured muscles initiate myogenesis or fibrogenesis. Am J Physiol Endocrinol Metab
2013;305:E367–E375.
70 Hu E, Tontonoz P, Spiegelman BM. Transdifferentiation of myoblasts by the adipogenic
transcription factors PPAR gamma and C/EBP alpha. Proc Natl Acad Sci U S A
1995;92:9856–60.
71 Kuenzler M, Nuss KM, Karol A, et al. ASESNeer Award 2016: reduced muscle
degeneration and decreased fatty infiltration after rotator cuff tear in a PARP-1
knock-out mouse model. In: , (ed). ASES speciality day march 2016; Orlando, FL:
ASES; 2016.
72 Guo W, Flanagan J, Jasuja R, et al. The effects of myostatin on adipogenic
differentiation of human bone marrow-derived mesenchymal stem cells are mediated
through cross-communication between Smad3 and Wnt/beta-catenin signaling
pathways. J Biol Chem 2008;283:9136–45.
73 Galatz LM, Ball CM, Teefey SA, et al. The outcome and repair integrity of completely
arthroscopically repaired large and massive rotator cuff tears. J Bone Joint Surg Am
2004;86-A:219–24.
74 Harryman DT, Mack LA, Wang KY, et al. Repairs of the rotator cuff. Correlation of
functional results with integrity of the cuff. J Bone Joint Surg Am
1991;73:982–9.
75 Liu SH, Baker CL. Arthroscopically assisted rotator cuff repair: correlation of functional
results with integrity of the cuff. Arthroscopy 1994;10:54–60.
76 Paxton ES, Teefey SA, Dahiya N, et al. Clinical and radiographic outcomes of failed
repairs of large or massive rotator cuff tears: minimum ten-year follow-up. J Bone
Joint Surg Am 2013;95:627–32.
77 Bishop J, Klepps S, Lo IK, et al. Cuff integrity after arthroscopic versus open rotator
cuff repair: a prospective study. J Shoulder Elbow Surg 2006;15:290–9.
78 Boileau P, Brassart N, Watkinson DJ, et al. Arthroscopic repair of full-thickness
tears of the supraspinatus: does the tendon really heal? J Bone Joint Surg Am
2005;87:1229–40.
79 Lichtenberg S, Liem D, Magosch P, et al. Influence of tendon healing after arthroscopic
rotator cuff repair on clinical outcome using single-row Mason-Allen suture
technique: a prospective, MRI controlled study. Knee Surg Sports Traumatol Arthrosc
2006;14:1200–6.
80 Oh JH, Kim SH, Kang JY, et al. Effect of age on functional and structural outcome after
rotator cuff repair. Am J Sports Med 2010;38:672–8.
81 Keener JD, Galatz LM, Stobbs-Cucchi G, et al. Rehabilitation following arthroscopic
rotator cuff repair: a prospective randomized trial of immobilization compared with
early motion. J Bone Joint Surg Am 2014;96:11–19.
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074

82 Lafosse L, Brozska R, Toussaint B, et al. The outcome and structural integrity of
arthroscopic rotator cuff repair with use of the double-row suture anchor technique.
J Bone Joint Surg Am 2007;89:1533–41.
83 Iannotti JP, Deutsch A, Green A, et al. Time to failure after rotator cuff repair: a
prospective imaging study. J Bone Joint Surg Am 2013;95:965–71.
84 Robinson HA, Lam PH, Walton JR, et al. The effect of rotator cuff repair on early
overhead shoulder function: a study in 1600 consecutive rotator cuff repairs.
J Shoulder Elbow Surg 2017;26:20–9.
85 Le BT, Wu XL, Lam PH, et al. Factors predicting rotator cuff retears: an analysis of
1000 consecutive rotator cuff repairs. Am J Sports Med 2014;42:1134–42.
86 Tham ER, Briggs L, Murrell GA. Ultrasound changes after rotator cuff repair:
is supraspinatus tendon thickness related to pain? J Shoulder Elbow Surg
2013;22:e8–15.
87 Apreleva M, Ozbaydar M, Fitzgibbons PG, et al. Rotator cuff tears: the effect of
the reconstruction method on three-dimensional repair site area. Arthroscopy
2002;18:519–26.
88 Tuoheti Y, Itoi E, Yamamoto N, et al. Contact area, contact pressure, and pressure
patterns of the tendon-bone interface after rotator cuff repair. Am J Sports Med
2005;33:1869–74.
8 9 Mazzocca AD, Millett PJ, Guanche CA, et al. Arthroscopic single-row
versus double-row suture anchor rotator cuff repair. Am J Sports Med
2005;33:1861–8.
90 Sugaya H, Maeda K, Matsuki K, et al. Functional and structural outcome after
arthroscopic full-thickness rotator cuff repair: single-row versus dual-row fixation.
Arthroscopy 2005;21:1307–16.
Zumstein MA, et al. JISAKOS 2017;2:213–221. doi:10.1136/jisakos-2016-000074
State of the Art
91 Franceschi F, Ruzzini L, Longo UG, et al. Equivalent clinical results of arthroscopic
single-row and double-row suture anchor repair for rotator cuff tears: a randomized
controlled trial. Am J Sports Med 2007;35:1254–60.
92 Charousset C, Grimberg J, Duranthon LD, et al. Can a double-row anchorage
technique improve tendon healing in arthroscopic rotator cuff repair?: a prospective,
nonrandomized, comparative study of double-row and single-row anchorage
techniques with computed tomographic arthrography tendon healing assessment. Am
J Sports Med 2007;35:1247–53.
93 Duquin TR, Buyea C, Bisson LJ. Which method of rotator cuff repair leads to
the highest rate of structural healing? A systematic review. Am J Sports Med
2010;38:835–41.
94 DeHaan AM, Axelrad TW, Kaye E, et al. Does double-row rotator cuff repair improve
functional outcome of patients compared with single-row technique? A systematic
review. Am J Sports Med 2012;40:1176–85.
95 Galatz LM, Sandell LJ, Rothermich SY, et al. Characteristics of the rat supraspinatus
tendon during tendon-to-bone healing after acute injury. J Orthop Res
2006;24:541–50.
96 Galatz LM, Charlton N, Das R, et al. Complete removal of load is detrimental to
rotator cuff healing. J Shoulder Elbow Surg 2009;18:669–75.
97 Thomopoulos S, Hattersley G, Rosen V, et al. The localized expression of extracellular
matrix components in healing tendon insertion sites: an in situ hybridization study.
J Orthop Res 2002;20:454–63.
98 Kovacevic D, Rodeo SA. Biological augmentation of rotator cuff tendon repair. Clin
Orthop Relat Res 2008;466:622–33.
99 Andarawis-Puri N, Flatow EL, Soslowsky LJ. Tendon basic science: development, repair,
regeneration, and healing. J Orthop Res 2015;33:780–4.
221