Development of a Mouse Model of Supraspinatus Tendon Insertion

Site Healing
Rebecca Bell,1 Peter Taub,2 Paul Cagle,1 Evan L. Flatow,1 Nelly Andarawis-Puri1
1
Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York 10029, New York, 2Division of
Plastic and Reconstructive Surgery at Mount Sinai, New York, New York
Received 7 April 2014; accepted 8 August 2014
Published online 18 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jor.22727

ABSTRACT: Supraspinatus (SS) tendon tears are common musculoskeletal injuries whose surgical repair exhibits the highest incidence
of re-tear of any tendon. Development of therapeutics for improving SS tendon healing is impaired by the lack of a model that allows
biological perturbations to identify mechanisms that underlie ineffective healing. The objective of this study was to develop a mouse
model of supraspinatus insertion site healing by creating a reproducible SS tendon detachment and surgical repair which can be
applied to a wide array of inbred mouse strains and genetic mutants. Anatomical and structural analyses confirmed that the rotator
cuff of the mouse is similar to that of human, including the presence of a coracoacromial (CA) arch and an insertion site that exhibits a
fibrocartilagenous transition zone. The surgical repair was successfully conducted on seven strains of mice that are commonly used in
Orthopaedic Research suggesting that the procedure can be applied to most inbred strains and genetic mutants. The quality of the
repair was confirmed with histology through 14 days after surgery in two mouse strains that represent the variation in mouse strains
evaluated. The developed mouse model will allow us to investigate mechanisms involved in insertion site healing. ß 2014 Orthopaedic
Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:25–32, 2015.

Keywords: supraspinatus healing; tendon repair; murine; rotator cuff

Rotator cuff function and stability is achieved through
the cooperative role of several musculotendinous com-
ponents which regularly subject the supraspinatus
(SS) tendon to high and complex loads. Consequently,
tendon tears affect over 20% of the general population
and up to 55% of the population over the age of 60.1–5
It is likely that the complex loading environment of
the rotator cuff that led to development of the SS
tendon tear also impedes healing and is responsible
for its highest re-tear rate of any repaired tendon with
an incidence of 20–90%.6,7 Both intrinsic factors, such
as aging and hypovascularity, and extrinsic factors,
such as repetitive impingement by the coracoacromial
(CA) arch have been implicated as contributors to the
development of the degenerative environment and the
high incidence of SS tendon re-tear.
Development of rotator cuff surgical repair models
in sheep, canine, and rat have provided insight into
the role of complex loading in the shoulder on degener-
ation and healing. Large animals, such as sheep and
canine, have been used to evaluate surgical techniques
as their size allows for use of similar approaches and
techniques as those used in humans.8–10 Despite its
small size, the similar anatomy between the rat and
the human, including the presence of a CA arch that
encloses the SS tendon, has made this model particu-
larly conducive for investigation of the role of extrinsic
factors in healing.11,12 In addition, using the rat model
has provided valuable data regarding correlations
between biomechanical changes and injury or altered
loading.13,14 While insightful, development of effective
therapeutics for improving SS tendon healing is
impaired by the lack of a model that allows genetic
Correspondence to: Nelly Andarawis-Puri (T: 212-241-1625; F:
212-876-3168; E-mail: nelly.andarawis-puri@mountsinai.org)
# 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
manipulations to identify biological mechanisms that
underlie the ineffective SS tendon insertion site healing.
While mouse models have been used to examine
degeneration associated with 2–3 rotator cuff tendon
tears without repair15 and defect fill-in of larger or more
readily accessible tendons such as the Achilles, flexor
digitorum longus (FDL) and patellar tendons,16,17 there
are no mouse models that exist to investigate insertion
site healing in the context of the complex rotator cuff
loading environment. Therefore, the objective of this
study is to develop a mouse model of supraspinatus
insertion site healing by utilizing microsurgical methods
to create a reproducible supraspinatus detachment and
surgical repair which can be ultimately applied to a
wide array of inbred mouse strains and genetic
mutants. In addition, as the mouse possesses a CA
arch, the surgical repair model can be coupled with
downhill treadmill running to investigate mechanisms
of supraspinatus insertion healing in the clinically
relevant chronically degenerated environment.
METHODS
To determine the potential scope of applicability of the
surgical methods in all mice, the techniques were evaluated
on a representative set of mouse strains that are commonly
used in orthopaedics. More specifically, the techniques were
evaluated on “wild types” (C57Bl6 and C3H), strains used to
investigate arthritis (Balb/c18–20 and DBA1/J21), strains that
exhibit increased joint laxity (A/J22), and strains used to
investigate healing (MRL/MpJ23 and NOD/ShiLtJ24).
Anatomical Measurements
The purpose of these measurements was twofold. First, we
wanted to confirm that the mouse and human exhibited an
anatomically similar rotator cuff, a structurally similar SS
tendon insertion, and a similar anatomical relationship
between the CA arch and SS tendon during daily motion.
For this analysis, the fibrocartilage region was assessed in
toluidine blue stained sections (n ¼ 6 C57Bl6), and the

JOURNAL OF ORTHOPAEDIC RESEARCH JANUARY 2015 25

26 BELL ET AL.

Figure 1. Human (A) supraspinatus insertion27 site showing the transition from tendon (T) to fibrocartilage (FC) to mineralized
fibrocartilage with the tidemark (TM). Similar structure is observed through the transition from tendon to bone in the mouse (B).

structure was compared to human sections from the litera-
ture (Fig. 1).25–28 In addition, the relationship between the
SS tendon and the CA arch at different arm positions was
determined in a cadaver mouse by placing a radiopaque wire
into the insertion site of the supraspinatus perpendicular to
the tendon. Radiographs were captured at full flexion
(Fig. 2A), at neutral position (Fig. 2B), and at extension
(Fig. 2C). At full flexion, the insertion site (red arrow) is
more medial than the arch (yellow arrow) and moves
laterally as the arm is extended, as occurs through the
transition from full abduction to neutral position in humans.
As the arm travels to extension, the insertion site moves
under the arch to a more lateral position. Overhead motion
in humans, as in overhead reaching and swimming can lead
to impingement of the SS tendon by the CA arch. Similarly,
the mouse is required to use full flexion daily with SS tendon
impingement likely occurring by the CA arch while reaching
for food and while in full flexion during downhill motion.
Second, we wanted to determine the range in anatomical
measurements among the mouse strains for which our
techniques are expected to be effective. For this analysis, a
total of three 11–16 week-old male mice per strain (C57Bl6,
MRL/MpJ, DBA1/J, C3H, NOD, A/J, Balb/c, The Jackson
Laboratory, Bar Harbor, ME) were sacrificed, and the
construct consisting of the humerus, scapula, and the four
attached rotator cuff musculotendinous units (Fig. 3A) was
isolated. The bony anatomy and the CA arch were visually
confirmed to be similar to human in all strains (Fig. 3B).
For comparisons across mouse strains, ImageJ was used
on high resolution images to measure and average the width
of the SS tendon at three locations starting immediately
medial to the humeral head and continuing every 0.5 mm
along the length with the portion located under the arch as
the last measurement. As the ability of the humeral head to
accommodate a bone tunnel is essential to success of the SS
tendon repair, the bone density was measured for each of the

Figure 2. Radiographs (A–C) and corresponding images of mouse walking (D–F) at full flexion (A, D), neutral (B, E) and extension
(C, F). Yellow arrow indicates CA arch and red arrow indicates radiopaque marker of the insertion site of the supraspinatus tendon.

JOURNAL OF ORTHOPAEDIC RESEARCH JANUARY 2015

 DEVELOPMENT SUPRASPINATUS TENDON MOUSE MODEL
Figure 3. Anatomy of Mouse Rotator Cuff showing (A) humerus with four attached RC musculotendinous units and (B) needle passed
through CA arch.
strains using ImageJ on X-ray images acquired at 50 kVp for
1.5 min. An aluminum step wedge was used to quantify the
gray values for each humeral head and the bone density was
reported in millimeter of aluminum equivalent.29 Using the
aluminum wedge, the sensitivity of the measurement was
0.05 mm.
Surgical Procedure
Mice were positioned in a right lateral decubitus position.
The incision was made starting just above the elbow of the
forepaw and directed posterior and inferior to the ear.
Subcutaneous flaps were mobilized with blunt dissection
until deltoid was identified with the overlying vasculature
identifying the borders of the muscle (Fig. 4A). The deltoid
was released with sharp dissecting scissors, first along the
posterior border and then just distal to the vessel (Fig. 4B).
The humerus was then grasped for stability just distal to the
head. It was adducted and externally rotated to visualize
the CA arch. Blunt dissection between the humeral head and
the CA arch was used to visualize the rotator cuff (Fig. 4D).
A 7-0 PDS suture with BV-1 needle was placed in a figure-of-
eight fashion through the SS tendon (Fig. 4E and F), and the
tendon was sharply released with a micro-scalpel (Fig. 4G).
Full mobility of the tendon was confirmed and debridement
of the insertion site performed. With the humerus stabilized,
the BV-1 needle of a 7-0 PDS suture was used to create a
tunnel within the bone of the humeral head transversely
from posterior to anterior (Fig. 4H). The entrance of the bone
tunnel was done at the insertion site of the supraspinatus
avoiding the infraspinatus (IS) tendon and the exit avoided
the subscapularis (Fig. 4I). The suture was ligated, bringing
the tendon back down to its original insertion site (Fig. 4J,
K, and L). The deltoid was reflected back over the humerus
and the skin incision closed with running 6–0 prolene
sutures. Buprenex was administered post-surgery and every
12 h for the next 48 h.
Surgical Evaluation
Metrics of surgical success were defined to assess success at
the time of surgery as well as at 14 days postoperatively. At
the time of surgery, the procedure was deemed successful if
the tendon was properly returned to its insertion site with no
major complication (i.e., bone breaking, tendon tearing). To
27
assess the reliability and reproducibility of the surgical
techniques, in addition to the 40 mice that were specifically
dedicated for this study, an additional 94 mice that were
allotted for other studies, were included for assessment of
the initial success of the surgery (Table 1). At 14 days after
surgery, the surgery was deemed successful if the tendon
remained securely attached to the humeral head with
histological confirmation that tension was maintained with
no gapping between the tendon and the bone. Accordingly,
with IACUC approval, survival surgeries were conducted for
evaluation at 14 days in C57Bl6 (n ¼ 10) and MRL/MpJ
(n ¼ 6) mice. Additional C57Bl6 (n ¼ 3) mice were also
analyzed 7 days after surgery.
Tolerance to Surgical Procedures
To assess the ability of the mice to tolerate the surgery, the
mice were monitored daily by evaluating their grooming as
well as their use of the injured arm. Animal weights were
measured weekly to confirm that the animals did not suffer
from a loss of appetite (weight loss) or diminished activity
(weight gain). As weakness and pain is expected to be
manifested in gait changes, a subset (n ¼ 8 C57Bl6) of mice
were further analyzed by assessing their gait prior to surgery
and 4, 7, 10, and 14 days post-surgery. For gait assessment,
mice walked at 10 cm/s for 5 s on a DigiGait system (Mouse
Specifics Inc., Quincy, MA). Paw area (cm2), shared stance
(%), stride length (cm), and stance width (cm) were measured
(Fig. 5). Paw area, the area recorded at peak stance, has
been shown to be reduced with chronic pain.29 Shared stance,
the percent of stance that the hind paws contact the belt at
the same time, is indicative of weakness.30 Stance width, the
width between the centroid of each front paw, is indicative of
the ability of the animal to load the limb.
Biomechanics
A total of six C57Bl6 mice were sacrificed 14 days post-
surgery with the humerus and SS tendon construct dissected
out of the injured limb as well as the contralateral limb. The
humerus was potted in PMMA and the supraspinatus was
gripped with custom grips at gauge length of 3 mm. The
humerus was held at a 30˚ angle with the supraspinatus
being parallel to the actuator. A preload of 0.05 N was held
for a minute prior to the ramp to failure at 1%/s (0.03 mm/s).
JOURNAL OF ORTHOPAEDIC RESEARCH JANUARY 2015
28 BELL ET AL.

Figure 4. Vascular landmarks (A) to identify the lateral proximal deltoid to guide deltoid detachment (B and C). Exposure of the
supraspinatus (SS) tendon (seen between the scissor blades) (D). Passage of a suture through the distal SS tendon (E and F), without
damaging the subscapularis tendon (Sub). Reattachment of the SS tendon to the humerus (J, K, and L).

The maximum force, displacement at maximum force, stiff-
ness, and failure location were recorded for both injured and
contralateral limbs.
Histology
C57Bl6 mice were sacrificed either at day 0, 7 days or
14 days (n ¼ 3/timepoint) post-surgery. After sacrifice, the
construct consisting of the humerus, scapula, the four
attached rotator cuff musculotendinous units, and CA arch
was dissected, embedded in plastic, and then sectioned at
200 mm. The sections were then polished down to 100 mm and
stained using Toluidine Blue to observe the morphology of
the tissue at the different timepoints. Killian et al.31 previ-
ously determined the gap size to correlate with the strength
of the repair. The gap size has been previously measured
during gross dissection by measuring the distance from the
tendon to the humeral head during tissue harvest. Due to
the small size of the mouse, gross gaps were not visibly
obvious at the time of dissection, motivating measurement of
the gap from the location of the surgical holes seen in the

JOURNAL OF ORTHOPAEDIC RESEARCH JANUARY 2015

 DEVELOPMENT SUPRASPINATUS TENDON MOUSE MODEL 29

Table 1. Surgical Repair Was Deemed Successful at Day 0 if the Tendon Was Properly Returned to its Insertion Site
With No Major Complication

Feasibility of
Anatomical Surgical Procedures Across Success of Surgical Success of
Assessment Representative Strains (Day 0) Reattachment (Day 0) Survival Surgeries
N¼ 3/strain ¼ 21# 3/strain ¼ 21# (19&, 21#, 94 ) ¼ 134 19&
Outcome NA 20/21 130/134 19/19
Surgical repair was deemed successful in survival surgeries if the tendon remained securely attached to the humeral head with
histological confirmation of no gapping between the tendon and the bone. “ ” denotes that 94 of those mice were used for other studies.
A shared common symbol (“#”, “&”) indicates that the same animals were used.

histological sections. The suture hole was identified in each Measurements of millimeter aluminum equivalents
of the surgical repair specimens. The distance between the (mmAl) values showed that MRL/MpJ humeral head
suture hole and humeral head was recorded. We considered was denser than that of A/J (significant) and NOD/
the distance at day 0 to represent a successful repair and ShiLtJ (trend) (Fig. 6).
compared the values from 7 days and 14 days to day 0 to
assess any gapping of the repair site. Tolerance to Surgical Procedures
At time of surgery, 130 of 134 (97%) supraspinatus
Statistical Analysis
surgical repairs were deemed successful with the four
For anatomical measurements, a Kruskal–Wallis test was
used with a Dunn’s post-test to determine differences
between the strains of mice evaluated. A repeated-measures
ANOVA with Bonferroni’s post-test comparing each time Table 2. Animal Weights and Tendon Widths for the
point to baseline was used for gait analysis to determine Seven Mouse Strains Evaluated
when the animals return to baseline indicating normal gait.
A paired t-test was used to compare the biomechanical Strain Weight (g) Tendon Width (mm)
parameters for the injured tendons. Significance, denoted by
“ ” was set at p < 0.05, and a trend, denoted by “#”, was set C57Bl6 29.1  0.4 1.02  0.11
at p < 0.10. C3H 30.2  2.4 1.07  0.18
Balb/c 28.2  1.2 0.96  0.11
RESULTS DBA1/J 24.9  1.3 1.13  0.06
Anatomical Measurements A/J 26.3  2.4# 1.00  0.14
Comparisons between the seven mouse strains that MRL/MpJ 45.4  3.9 ,# 0.93  0.08
were evaluated confirmed that all possessed the same NOD/ShiLtJ 27.9  0.8 1.06  0.34
vascular landmarks allowing the surgical methods A shared “ ” or “#” indicates a significant difference or trend
developed to be directly applicable to all the strains between the two groups respectively.
evaluated. Further dissection confirmed that all the
mouse strains evaluated possessed a CA arch that
passes over the supraspinatus insertion site when the
humerus is in full flexion as occurs in humans during
overhead activities.11 There was significant difference
(p ¼ 0.016) in weights between mouse strains with the
MRL/MpJ strain being significantly higher than the
DBA1/J strain (Table 2). No significant difference was
found in the tendon width between the seven strains
(p ¼ 0.618).

Figure 6. Relative bone density measurements deduced from

Figure 5. Gait Analysis. Square indicates paw area (cm2). gray values of the humeral head for each strain of mouse. The
Dashed line indicates stride length (cm) and solid line indicates region enclosed by the yellow circle indicates the location of the
stance width (cm). gray value measurements.

JOURNAL OF ORTHOPAEDIC RESEARCH JANUARY 2015

30 BELL ET AL.
Figure 7. Gait Analysis. The surgery had no effect on (A) stance width of the front paws, (B) shared stance of the hind paws, and (D)
paw area of the injured front paw. (C) Stride length of the injured front paw was reduced but modulated to pre-injury levels by
14 days.
failures that occurred being attributable to broken
humeral heads (Table 1).
Gross observations of mice undergoing the survival
surgeries confirmed that the surgery was well tolerat-
ed and that the mice resumed normal behavior within
12 h after the surgery. There were no significant
weight changes with all mice maintaining weights
that were within 10% of the pre-surgery weight. The
mice appeared well-groomed and continued normal
cage activity throughout the study.
Gait analysis mostly confirmed the gross analysis.
No significant changes in paw area, stance width, and
shared stance were found between pre-surgical mea-
sure and at any time point evaluated post-surgery.
Stride length was significantly reduced at 4 and
7 days post-surgery but was modulated towards pre-
surgical levels by 10 days with no measurable differ-
ences by 14 days (Fig. 7C).
Biomechanical Assessment
At the time of dissections, the tendon was visibly
attached to the bone with suture with no signs of
gapping in all samples. There were significant
decreases in maximum load and stiffness and an
increase (trend) in displacement at maximum load
(Table 3) for the injured samples compared to the
contralaterals. The failure location for all of the
contralateral tendons occurred in the midsubstance,
whereas the injured tendons all failed at the repair
site.
JOURNAL OF ORTHOPAEDIC RESEARCH JANUARY 2015
Histological Assessment
At 14 days post-surgery, histological assessment con-
firmed that the surgeries on all 10 C57Bl6 and 6 MRL/
MpJ, the SS tendon remained attached at the inser-
tion site with no gapping (Fig. 8), as well as the 3
C57Bl6 at 7 days. The no gapping was confirmed by
the distance from the suture hole to the humeral head.
The day 0 distance 262.7  20.7 mm, 7 days distance of
297.8  33.3 mm and the 14 days distance of 242.3 
19.3 mm.
DISCUSSION
We have developed a mouse model of SS tendon
insertion healing through surgical detachment and
reattachment in the context of the complex rotator cuff
loading environment. Despite anatomical similarities
between the mouse and human, the small size of the
mouse has previously been an obstacle to investigating
supraspinatus insertion healing, although studies that
investigate degeneration associated with unrepaired
detachment of two or three rotator cuff tendons have
Table 3. Biomechanical Evaluation of Injured Tendon
14 Days Post Surgrey Compared to its Contralateral
Max. Stiffness Disp. at Max.
Load (N) (N/mm) Load (mm)
Injured 0.45  0.14 0.39  0.09 2.15  0.99
Contralateral 1.22  0.52 2.37  1.6 0.95  0.59
 DEVELOPMENT SUPRASPINATUS TENDON MOUSE MODEL
Figure 8. Histological assessment of the repaired supraspina-
tus tendon. The naı̈ve structure in (A). The tendon was returned
back to the insertion site at (B) day 0. The tendon remained
attached with no gapping at (C) 7 days and (D) 14 days post-
surgery.
been successfully conducted.15 The present study
focused on feasibility of a novel technique that may be
used for a wide array of mice. The potential applica-
tions of this model with any of the widely available
mouse strains and genetic mutants may be used to
investigate the countless biological mechanisms that
underlie supraspinatus insertion healing. They will
also be integral to development of effective therapeu-
tics to reduce the particularly high rate of injury and
re-tear of SS tendons. We have shown that the
procedure is reproducible and have confirmed histolog-
ically the reattachment of the tendon at its proper
insertion site. We have also shown the feasibility of
biomechanical assessment of the SS tendon at 14 days
post-surgery when the healing tissue is weak and
disorganized presenting a challenge to isolation and
gripping for mechanical testing.
Adult mouse mutants have been used to investigate
the role of ECM proteins, such as decorin and bigly-
can, to tendon function.33–35 Mouse mutants have also
been used to investigate mechanisms of tendon defect
healing in injury models, such as central third full
length defect,17 midsubstance biopsy punch in patellar
tendons, and FDL transection.16 However, no models
exist that utilize mouse mutants to investigate mecha-
nisms that can be modulated to improve the clinically
relevant healing after repair of supraspinatus inser-
tion. The structural gradient in the tendon insertion
site into the bone is essential to normal function as it
allows for a gradual transition between two tissues
with highly disparate properties. Surgically reattached
tendons do not effectively restore this structural gradi-
ent, predisposing the healing insertion to a high risk
31
of re-tear. Interestingly, SS tendon re-tear rates are
the highest of all tendon repairs, likely reflecting the
particularly complex loading environment that is
specific to the rotator cuff.
Studies in rat SS tendon, utilizing downhill (10˚)
treadmill running (17 m/min for 1 h/day, 5 days/week)
have reported increased cellularity, loss of tenocyte
morphology, decreased material properties, and in-
creased cross sectional area over time.11,12 Interesting-
ly, a similar 6-week uphill running protocol induced
healthy adaptation in the Achilles tendon, likely
because of their different mechanical environments
and the repetitive impingement that is common to the
SS tendon.36 The presence of a CA arch in the mouse
that passes over the supraspinatus insertion site in
full flexion suggests that similar to the rat model, our
developed surgical repair model in the mouse can be
coupled with downhill treadmill running that induces
degeneration, to investigate healing in chronically
degenerated tendons.
There are several limitations associated with this
mouse model of SS tendon surgical repair. We evaluat-
ed our surgical techniques on seven commonly used
mouse strains that we expect to be representative of
the majority of inbred strains and mutants. We chose
to conduct survival surgeries on C57Bl6 and MRL/
MpJ mice because C57Bl6 is one of the most commonly
used “wild type” mice, and MRL/MpJ exhibits starkly
different properties from other commonly used mouse
strains as it is heavier and exhibits higher bone
density. As C57Bl6 and MRL/MpJ mice are expected
to represent the widest range of possible variation
between mouse strains evaluated, we expect that these
findings can be extended to the remaining mouse
strains evaluated. While it is reasonable to expect that
our methods can extend to mouse strains and mutants
beyond the ones evaluated in this study, it is likely
that the incidence of success of our surgical techniques
would diminish in mouse mutants where the bone
density is significantly decreased or the tendon mor-
phology is extremely altered. Similarly, coupling our
surgical methods with downhill treadmill running is
expected to induce degeneration due to CA arch
impingement, as long the morphology of the CA arch
is not altered by the genetic mutation. To overcome an
inherent limitation of simulating the clinically com-
mon chronic environment prior to introducing the
surgical laceration and repair, collagenase injections
may be necessary if downhill treadmill running is
ineffective in inducing degeneration due to an altered
arch. Future studies will combine treadmill running or
collagenase injections prior to supraspinatus lacera-
tion and repair to investigate supraspinatus insertion
healing in a chronically degenerated environment.
We have developed a mouse model of SS tendon
detachment and repair to investigate biomechanical
mechanisms that are responsible for the clinically
observed poor supraspinatus insertion healing. The
potential applications of this model include testing
JOURNAL OF ORTHOPAEDIC RESEARCH JANUARY 2015
32 BELL ET AL.
hypotheses regarding the role of proteolytic enzymes,
growth factors, and structural proteins in supraspina-
tus insertion site regenerative healing through the use
of genetic mouse mutants. The mouse model is partic-
ularly well suited to identify biological targets for
development of therapeutics.
ACKNOWLEDGEMENTS
The authors acknowledge Ashley Acosta, Damien
Laudier, Anaya Philip, and Harmandeep Singh for
their contributions.
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