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Medicine
The American Journal of Sports
http://ajs.sagepub.com/content/41/5/1090
The online version of this article can be found at:
DOI: 10.1177/0363546513479018
2013 41: 1090 originally published online March 4, 2013Am J Sports Med
Yong Sang Kim, Eui Hyun Park, Yong Chan Kim and Yong Gon Koh
With Osteochondral Lesions of the Talus
Clinical Outcomes of Mesenchymal Stem Cell Injection With Arthroscopic Treatment in Older Patients
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Clinical Outcomes of Mesenchymal
Stem Cell Injection With Arthroscopic
Treatment in Older Patients With
Osteochondral Lesions of the Talus
Yong Sang Kim,
*
MD, Eui Hyun Park,
*
MD,
Yong Chan Kim,
*
MD, and Yong Gon Koh,
*
y
MD
Investigation performed at Yonsei Sarang Hospital, Seoul, Korea
Background: The ideal treatment for osteochondral lesions of the talus (OLTs) is still controversial, especially in older patients.
Recently, mesenchymal stem cells (MSCs) have been suggested for use in the cell-based treatment of cartilage lesions.
Purpose: To compare the clinical outcomes of MSC injection and arthroscopic marrow stimulation treatment with those of arthro-
scopic marrow stimulation treatment alone for the treatment of OLTs in older patients.
Study Design: Cohort study; Level of evidence, 3.
Methods: Among 107 patients with OLTs treated arthroscopically, only the patients older than 50 years (65 patients) were
included in this study. Patients were divided into 2 groups: 35 patients (37 ankles) treated with arthroscopic marrow stimulation
treatment alone (group A) and 30 patients (31 ankles) who underwent MSC injection along with arthroscopic marrow stimulation
treatment (group B). Clinical outcomes were evaluated according to the visual analog scale (VAS) for pain, the American Ortho-
paedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale, and the Roles and Maudsley score. The Tegner activity scale was
used to determine outcomes in activity levels.
Results: The mean VAS score in each group was significantly improved (P \ .05) from 7.2 6 1.1 to 4.0 6 0.7 in group A and from
7.1 6 1.0 to 3.2 6 0.9 in group B. The mean AOFAS score in each group was also significantly improved (P \ .05) from 68.0 6 5.5
to 77.2 6 4.8 in group A and from 68.1 6 5.6 to 82.6 6 6.4 in group B. There were significant differences in mean VAS and AOFAS
scores between the groups at final follow-up (mean, 21.8 months; range, 12-44 months) (P \ .001). The Roles and Maudsley
score showed significantly greater improvement in group B than in group A after surgery (P = .040). The Tegner activity scale
score was significantly improved in group B (from 3.5 6 0.7 to 3.8 6 0.7; P = .041) but not in group A (from 3.5 6 0.8 to 3.6
6 0.6; P = .645). Large lesion size (109 mm
2
) and the existence of subchondral cysts were significant predictors of unsatisfac-
tory clinical outcomes in group A (P = .04 and .03, respectively). These correlations were not observed in group B.
Conclusion: Injection of MSCs with marrow stimulation treatment was encouraging in patients older than 50 years compared with
patients treated with marrow stimulation treatment alone, especially when the lesion size was larger than 109 mm
2
or a subchon-
dral cyst existed. Although still in the early stages of application, MSCs may have great potential in the treatment of OLTs in pa-
tients older than 50 years, and more evaluations of its effect should be performed.
Keywords: mesenchymal stem cell; arthroscopic marrow stimulation treatment; osteochondral lesion of the talus
Osteochondral lesion of the talus (OLT) is a broad term
used to describe an injury or abnormality of the talar artic-
ular cartilage and adjacent bone. The various methods of
surgical treatment for OLTs have been introduced from
marrow stimulation techniques such as subchondral dril-
ling, curettage, microabrasion, and microfracture, to
restorative techniques such as osteochondral autograft
transfer, mosaicplasty, and frozen osteochondral allo-
grafts, which were developed to transfer articular hyaline
cartilage to replace the injured area.
z
Articular hyaline
cartilage is avascular and has poor regenerative capabil-
ities, and injuries that do not penetrate the subchondral
plate have no stimulus for an inflammatory reaction and
healing.
23,40
The principal aim of the marrow stimulation
treatments is the recruitment of pluripotent mesenchymal
y
Address correspondence to Yong Gon Koh, MD, Department of
Orthopedic Surgery, Yonsei Sarang Hospital, 478-3, Bangbae-dong,
Seocho-gu, Seoul, Korea (e-mail: ygkokr@naver.com).
*
Center for Stem Cell and Arthritis Research, Department of Orthope-
dic Surgery, Yonsei Sarang Hospital, Seoul, Korea.
The authors declared that they have no conflicts of interest in the
authorship and publication of this contribution.
The American Journal of Sports Medicine, Vol. 41, No. 5
DOI: 10.1177/0363546513479018
Ó 2013 The Author(s)
z
References 5, 6, 20, 28, 31, 43, 44, 50.
1090
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cells from the bone marrow that leads to fibrous tissue cov-
ering the lesion.
31,40
These treatments provide acceptable
clinical results over midterm follow-up periods but often
fail in the long term because of biomechanical insufficiency
of the regenerative fibrocartilage and scar tissue that
results from these methods.
5,33
Subsequently, OLTs may
not respond to these marrow stimulation treatments, and
the articular surface may continue to deteriorate and lead
to degenerative arthritis of the ankle joint, especially in
older patients.
12,53,61
Several recent studies have reported
less favorable outcomes of arthroscopic marrow stimulation
treatment for OLTs in older patients.
17,26,42
Therefore, the
initial treatment of OLTs in older patients is very important
to halt the progression to degenerative arthritis.
Recently, mesenchymal stem cells (MSCs) were proposed
as a new option for the treatment of articular cartilage
defects because of their ability to differentiate into various
lineages, including osteoblasts and chondrocytes.
10,21,55
In
the literature, only a few studies have reported on the appli-
cation of MSCs for the treatment of OLTs.
22,25
The goals of this study were (1) to investigate the clini-
cal outcomes and postoperative activity levels of patients
older than 50 years treated with injection of MSCs along
with arthroscopic marrow stimulation for OLTs, (2) to com-
pare the outcomes thereof with those of arthroscopic mar-
row stimulation treatment alone, and (3) to identify the
prognostic factors associated with poor outcomes for OLTs.
MATERIALS AND METHODS
We retrospectively reviewed 107 consecutive patients (112
ankles) with a diagnosis of OLTs who were treated with
arthroscopic marrow stimulation from May 2008 to December
2011. All patients had localized OLTs with symptoms of ankle
joint pain or functional limitations despite a minimum of 3
months’ nonoperative management. Nonoperative treatment
options included ankle bracing, physical therapy, and nonste-
roidal anti-inflammatory drugs. If the patients had chronic
lateral ankle instability, ankle bracing and taping were rec-
ommended to decrease the occurrence of ankle sprains, and
a structured physical therapy program focused on peroneus
streng thenin g exercise and proprioceptive-based rehabilita-
tion of the ankle was also performed.
Patients with previous surgical treatments and patients
with arthritic changes of their ankle joint or deformity of
the axis of the ankle on plain radiographs were excluded.
Of a total of 112 ankles, the first 77 ankles (May 2008 to
September 2010) were treated with arthroscopic marrow
stimulation alone, and the next 35 ankles (October 2010
to December 2011) were treated with MSC injection along
with arthroscopic marrow stimulation. To investigate the
effect of age on the outcome of patients after arthroscopic
marrow stimulation treatment with or without the injec-
tion of MSCs, we used an age limit (50 years) as a cutoff
to define ‘‘older’’ patients.
This study was approved by the institutional review
board of our hospital. Among the 107 patients, 65 patients
older than 50 years (68 ankles) were included; there were
33 men and 32 women. The average age was 56.8 years
(range, 51-73 years), the average preoperative body mass
index (BMI) was 26.9 (range, 20.8-33.4), and the average
duration of symptoms was 22.1 weeks (range, 16-34
weeks). We divided these 65 patients into 2 groups: 35
patients (37 ankles) who were treated with arthroscopic
marrow stimulation alone (group A) and 30 patients (31
ankles) who underwent arthroscopic marrow stimulation
treatment along with MSC injection (group B). The mean
follow-up period was 21.8 months (range, 12-44 months):
23.9 months (range, 18-44 months) in group A and 19.7
months (range, 12-26 months) in group B (P = .078). There
were no significant differences in basic characteristics
between the groups regarding patient sex, BMI, duration
of symptoms before surgery, or follow-up period (Table 1).
Clinical and Radiological Analysis
For clinical evaluation, the visual analog scale (VAS) for
pain and the American Orthopaedic Foot and Ankle Soci-
ety (AOFAS) Ankle-Hindfoot Scale were utilized. The Roles
and Maudsley score was used to evaluate patient satisfac-
tion with clinical results. The Tegner activity scale
65
was
used to determine sporting and activity levels. Although
the Tegner activity scale was originally intended for the
knee, it also facilitates outcomes research in sports medi-
cine. The period required to return to sports activity after
surgery was also investigated.
At preoperative and final follow-up examinations, we
obtained anteroposterior and lateral weightbearing radio-
graphs to assess the ankle joint for degenerative arthritis.
We performed magnetic resonance imaging (MRI) to mea-
sure the size and location of lesions and to evaluate any
associated lesions (eg, subchondral cyst) before surgery.
To avoid potential bias, an independent observer who
TABLE 1
Demographic Data
a
Group A Group B Total P
Ankles/patients, n 37/35 31/30 68/65
Sex, male/female, n 16/19 17/13 33/32 .23
Body mass index 27.2 6 4.2 26.6 6 3.8 26.9 6 4.0 .58
Follow-up period, mo 23.5 6 4.4 20.1 6 4.7 21.8 6 4.3 .12
Duration of symptoms, wk 21.9 6 6.9 22.3 6 6.1 22.1 6 6.4 .76
a
Values are expressed as mean 6 standard deviation unless otherwise indicated.
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was a musculoskeletal trained radiologist, not involved in
the care of the patients and blinded to the intention of
this study, evaluated the MRI scans. The width and length
of the OLTs were measured with coronal, sagittal, and
axial MRI scans, and the largest dimension was selected.
We reconfirmed the lesion size through an arthroscopic
examination, and the defect size was calculated by the
ellipse formula (Figure 1B). We compared the size meas-
urements (width, length, and size) based on MRI with
those determined by arthroscopic examination, and
a good correlation was found by linear regression analysis
(r = 0.76; P \ .001).
Surgical Technique
The arthroscopic marrow stimulation procedure was per-
formed in a standardized manner in every case. After accu-
rate debridement of all unstable and damaged cartilage in
the lesion, a microfracture was performed, 3 to 4 mm apart
in areas where the subchondral bone was intact (Figure 1A).
Multiple perforations perpendicular to the joint surface
were made by a 2.5-mm, 90° microfracture awl (Linvatec,
Largo, Florida), as described by Steadman et al.
62
For areas
with losses of subchondral bone, abrasion arthroplasty was
performed by removing loose chondral or osteochondral
fragments with a ring-shaped or curved curette and by trim-
ming damaged cartilage with a power shaver until a stable,
smooth articular surface was created. When there were sub-
chondral cysts, the cysts were decompressed by removal of
cystic materials. The tourniquet was released after this pro-
cedure, and adequate bone bleeding at microfracture holes
was confirmed (Figure 2C). For group B, the injection of
MSCs isolated at 1 day before arthroscopic surgery was per-
formed after the arthroscopic procedure.
After surgery, a short leg splint was applied for 2 weeks,
and after sutures were removed, we recommended
Figure 1. (A) The arthroscopic view showing the process of making the hole in the subchondral bone with a microfracture awl
after the debridement of all unstable and damaged cartilage in the lesion. (B) The size of the osteochondral lesion was calculated
by the ellipse formula.
Figure 2. (A) Preoperative anteroposterior radiograph of the left ankle. The radiolucent lesion was observed in the medial talar
dome. (B) Magnetic resonance imaging scan. T2-weighted coronal image showing the osteochondral lesion, subchondral cyst,
and subchondral bone edema in the medial talar dome. (C) The arthroscopic views showing the process of making the hole in
the subchondral bone with a microfracture awl after the debridement of all unstable and damaged cartilage in the lesion. The
cyst was decompressed by removal of cystic materials (arrow), and adequate bone bleeding at microfracture holes was con-
firmed after the tourniquet was released. (D) Anteroposterior radiograph of the left ankle at 24 months after surgery. Degenerative
arthritic change was observed in the medial aspect of the ankle joint.
1092 Kim et al The American Journal of Sports Medicine
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tolerable weightbearing activities for patients without
associated lesions. There were 37 patients (20 patients in
group A and 17 patients in group B) who received a lateral
ligament reconstruction along with the arthroscopic treat-
ment. In patients who had a history of recurrent sprains or
chronic ankle instability, ankle bracing and taping were
recommended to decrease the occurrence of ankle sprains,
and a structured physical therapy program focused on per-
oneus strengthening exercise and proprioceptive-based
rehabilitation of the ankle was also performed. If the insta-
bility was not improved after these treatments and the
ruptured anterior talofibular ligament or calcaneofibular
ligament was identified on MRI, lateral ligament recon-
struction was performed, as described by Kim et al.
38
For
those patients, we recommended postoperative short leg
walking cast immobilization with partial weightbearing
for 4 weeks. Patients began both active and passive range
of motion exercises to the ankle joint at 4 weeks after sur-
gery. Sports or high-impact activities were limited for at
least 3 months.
Sample Collection and MSC Isolation
The MSCs were derived from the fat pad harvested from the
buttock of the patients. One week before the buttock fat pad
harvesting procedure, patients were restricted from con-
suming corticosteroids or nonsteroidal anti-inflammatory
drugs. One day before arthroscopic surgery, we harvested
the fat pad tissue through tumescent liposuction. The
patient was placed in the prone position under intravenous
anesthesia. After surgical preparation, a hollow blunt-
tipped cannula was introduced into the subcutaneous space
through a small incision, and the subcutaneous adipose tis-
sue was infiltrated with a mixture solution to minimize
blood loss and tissue contamination by peripheral blood cells
before aspiration. The mixture solution was made of 500 mL
of 0.9% saline solution supplemented with 10 mL of 2%
lidocaine (400 mg/20 mL), 4 mL of 8.4% sodium hydrogen
carbonate (20 mL), and 0.7 mL of 0.1% epinephrine
(1 mg/mL). The liposuction material was aspirated by gentle
suction, and the buttock fat pad was collected (see Appendix
Figure S1, available in the online version of this article at
http://ajsm.sagepub.com/supplemental).
The MSCs derived from the buttock fat pad were isolated
as described previously.
19,67
Briefly, the pad was minced
and washed extensively with phosphate-buffered saline
and an equal volume of 0.1% collagenase type 1 (Worthing-
ton Biochemical Corp, Lakewood, New Jersey). The tissue
was placed in a rotary incubator at 37°C, with continuous
agitation for 3 hours. After digestion, the lipoaspirates
were centrifuged at 1200g for 10 minutes to separate the
lipoaspirate and the collagenase. The lipoaspirates were
then washed 3 times to remove any remaining collagenase.
After the last round of centrifugation, cells in the aspirates
were counted using a hemocytometer. After the stem cells
were isolated, a mean of 3.9 3 10
6
(range, 1.8 to 9.3 3
10
6
) stem cells was prepared (see Appendix Figure S2, avail-
able online). Before injection, bacteriological tests were per-
formed on the samples (to ensure the absence of
contamination), and the viability of the cells was assessed
usingthemethylenebluedyeexclusiontest.
Statistical Analysis
The principal dependent variables of clinical outcomes
were the VAS, AOFAS scale, and Tegner activity scale at
the final follow-up. Paired t tests were conducted for the
evaluation of changes in preoperative and final follow-up
values, and 1-way analysis of variance (ANOVA) was per-
formed for the comparison of results between the groups.
Either the x
2
test or Fisher exact test was used to compare
categorical data. Multivariate logistic regression analyses
were used to assess the various factors (such as sex,
BMI, duration of symptoms, size and location of OLT, exis-
tence of subchondral cyst, and additional surgery) indepen-
dently associated with satisfaction with clinical results for
each group. The median values are used as standard val-
ues for dividing the groups. We defined satisfactory clinical
results as a VAS score of less than 4 points, an AOFAS
score of more than 80, and a good or excellent Roles and
Maudsley score at the final follow-up. For the logistic
regression models, we reported odds ratios and 95%
TABLE 2
Clinical and Functional Results
a
Group A Group B
Preoperatively Final Follow-up Preoperatively Final Follow-up
VAS
b
7.2 6 1.1 4.0 6 0.7 7.1 6 1.0 3.2 6 0.9
AOFAS Ankle-Hindfoot Scale
b
68.0 6 5.5 77.2 6 4.8 68.1 6 5.6 82.6 6 6.4
Roles and Maudsley score,
b
n (%)
Excellent 0 (0) 5 (14) 0 (0) 10 (33)
Good 0 (0) 14 (38) 1 (3) 14 (45)
Fair 14 (38) 12 (32) 11 (36) 6 (19)
Poor 23 (62) 6 (16) 19 (61) 1 (3)
Tegner scale
b
3.5 6 0.8 3.6 6 0.6 3.5 6 0.7 3.8 6 0.7
a
Values are expressed as mean 6 standard deviation unless otherwise indicated. AOFAS, American Orthopaedic Foot and Ankle Society;
VAS, visual analog scale.
b
Statistically significant differences observed between the groups (P \ .05).
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confidence intervals (CIs) relative to a chosen reference
group. Statistical analysis was performed using SPSS soft-
ware version 12.0.1 (SPSS Inc, Chicago, Illinois), with sig-
nificance defined as P \ .05.
RESULTS
Clinical Outcomes and Sports Activities at Follow-up
Clinical outcomes and activity levels from preoperative to
final follow-up in each group are summarized in Table 2.
The mean VAS score in each group was significantly
improved (P \ .05) from 7.2 6 1.1 to 4.0 6 0.7 in group
A and from 7.1 6 1.0 to 3.2 6 0.9 in group B, and there
was a significant difference in the mean VAS score
between the groups at final follow-up (P \ .001). The
mean AOFAS score in each group was also significantly
improved (P \ .05) from 68.0 6 5.5 to 77.2 6 4.8 in group
A and from 68.1 6 5.6 to 82.6 6 6.4 in group B, with a sig-
nificant difference in the mean AOFAS score between the
groups at final follow-up (P \ .001). According to the Roles
and Maudsley score, 19 of 37 (52%) patients in group A and
24 of 31 (78%) patients in group B showed good to excellent
results. The Roles and Maudsley score showed significantly
greater improvement in group B than in group A after sur-
gery (P = .040). Patients returned to sports activities on
average at 17.3 6 2.1 weeks in group A and at 15.4 6 1.9
weeks in group B after surgery (P =.666).Activitylevels
according to the Tegner activity scale were significantly
improved in group B (from 3.5 6 0.7 to 3.8 6 0.7;
P = .041) but not in group A (from 3.5 6 0.8 to 3.6 6 0.6;
P = .645). There was a significant difference in Tegner
activity scale scores between the groups at final follow-up
(P = .004).
Association Between Variables of OLT
and Clinical Outcome
The mean size of OLTs was 108.7 6 34.6 mm
2
.Foreach
group, the mean lesion size was 102.7 6 31.4 mm
2
in group
A and 118.9 6 47.9 mm
2
in group B (P =.126).Toanalyze
the association of the size of OLTs with clinical results, we
divided the patients according to lesion size into large lesion
size (109 mm
2
) and small lesion size (\109 mm
2
)groups.
For locating the osteochondral lesion, we divided the talar
dome into 2 parts sagittally and demarcated medial and lat-
eral lesions. There were 25 medial and 12 lateral lesions in
group A and 22 medial and 9 lateral lesions in group B (P =
.781). We also investigated the existence of subchondral
cysts in each group. The subchondral cysts existed in 16
patients from group A and 12 patients from group B (P =
.523). When considering a VAS score of less than 4 points,
an AOFAS score more than 80, and a good or excellent Roles
and Maudsley score at the final follow-up as a satisfactory
clinical outcome, large lesion size (109 mm
2
) and the exis-
tence of subchondral cysts were significant predictors of
unsatisfactory clinical outcomes, with an odds ratio of 4.43
(95% CI, 0.86-22.77) and 7.62 (95% CI, 1.24-46.73), respec-
tively, compared with small lesion size (\109 mm
2
)and
the nonexistence of subchondral cysts in group A (P =.04
and P = .03, respectively). These correlations were not
observed in group B. No association was found between
the location of OLTs and clinical outcomes in both groups
(see Appendix Table S1, available online).
Associations Between Variables of OLT
and Arthritic Change of the Ankle Joint
Degenerative arthritis of the ankle joint was assessed
according to anteroposterior and lateral weightbearing
radiographs at the final follow-up. If there were bony spurs
around the ankle joint, joint space narrowing compared
with the opposite ankle, or joint margin sclerosis on plain
radiographs, we defined them as degenerative arthritis.
Degenerative arthritis of the ankle joint was observed in
4 cases in group A and 1 case in group B at the final
follow-up (Figure 2). Large lesion size (109 mm
2
) and
the existence of subchondral cysts were significantly asso-
ciated with the development of degenerative arthritis of
the ankle joint in group A (P = .014 and P = .021, respec-
tively), but these associations were not found in group B
(P = .214 and P = .182, respectively). No associations
TABLE 3
Patient Characteristics for Groups by Defect Size and Subchondral Cyst
a
Defect Size, n (%) Subchondral Cyst, n (%)
Factor \109 mm
2
109 mm
2
RR P Absent Present RR P
Sex 0.601 .056 0.710 .243
Male 17 (48.6) 16 (53.3) 21 (52.5) 12 (48)
Female 18 (51.4) 14 (46.7) 19 (47.5) 13 (52)
BMI
b
0.838 .487 0.745 .506
\26.9 20 (40) 15 (55.6) 22 (55) 13 (46.4)
26.9 15 (60) 18 (44.4) 18 (45) 15 (53.6)
Duration of symptoms,
b
wk 0.820 .436 0.439 .544
\22.1 18 (51.4) 12 (36.4) 20 (50) 10 (35.7)
22.1 17 (48.6) 21 (63.6) 20 (50) 18 (64.3)
a
BMI, body mass index; RR, relative risk according to Cox proportional hazards regression analysis.
b
Medial values were used as standard values for dividing the groups.
1094 Kim et al The American Journal of Sports Medicine
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were found between the location of OLTs and the develop-
ment of degenerative arthritis of the ankle joint in both
groups (P = .734 and P = .329, respectively).
Other Prognostic Factors
We used logistic regression models to assess the indepen-
dent effects of patients’ sex, BMI, duration of symptoms,
and additional surgery of lateral ligament reconstruction
on clinical outcomes in each group (see Appendix Table
S1). Median values were used as a standard for dividing
the groups according to patients’ BMI (\26.9 or 26.9)
and duration of symptoms (\22.1 or 21.1 weeks). The lat-
eral ligament reconstructions were performed along with
the arthroscopic treatment in 13 cases of group A and 9
cases of group B (P = .645). All prognostic factors, including
the patient’s sex, BMI, duration of symptoms, and addi-
tional surgery of lateral ligament reconstruction did not
show a significant influence on clinical outcomes (P .
.05). According to Cox regression analysis, there were no
significant correlations between prognostic factors includ-
ing the patient’s sex, BMI, and duration of symptoms,
and defect size or the existence of a subchondral cyst
(P . .05) (Table 3).
Follow-up MRI Assessment and
Second-Look Arthroscopic Surgery
There were 6 patients in group A and 1 patient in group B
who showed clinical failure (poor according to the Roles and
Maudsley score). Among 6 patients of group A, 4 patients
received an osteochondral transplantation after confirming
the failure of microfracture through the follow-up MRI (Fig-
ure 3 C). Second-look art hroscopic surgery wa s performed
before the osteochondral transplantation and revealed that
the cartilage regeneration was poor and unstable fibrotic tis-
sue was covered in the lesion (Figure 3D). Two patients in
group A and 1 patient in group B who showed clinical failure
but refused to receive more evaluation and aggressive surgery
were managed with nonoperative measures, including rest,
immobilization, anti-inflammatory medication, and physical
therapy. Follow-up MRI and second-look arthroscopic surgery
were performed in 1 patient of group B at 8 months after the
initial surgery. We explained the purpose of the follow-up
Figure 3. (A) Preoperative magnetic resonance imaging (MRI) scan of the left ankle in a 51-year-old female patient. T2-weighted
coronal image showing the osteochondral lesion, subchondral cyst, and subchondral bone edema in the medial talar dome.
(B) The arthroscopic views after microfracture and decompression of the subchondral cyst without mesenchymal stem cell
(MSC) injection. (C) Follow-up T2-weighted coronal image at 12 months after surgery. Cartilage defect, subchondral cyst, and
subchondral bone edema were still observed in the medial talar dome. (D) Second-look arthroscopic surgery revealed that the
cartilage regeneration was poor and unstable fibrotic tissue was covered in the lesion. (E) Preoperative MRI scan of the left ankle
in a 54-year-old female patient. Osteochondral lesion with separation of the subchondral plate and subchondral bone edema in
the medial talar dome was observed. (F) Arthroscopic views after microfracture and MSC injection were performed. (G) Follow-up
T2-weighted coronal image at 8 months after surgery. Although MRI revealed subchondral irregularities within the repaired area,
the previous cartilage defect was entirely filled up. (H) Second-look arthroscopic surgery revealed that the cartilage defect was
completely covered with smooth tissue, considered to be the cartilage.
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MRI and second-look arthroscopic surgery to this patient and
receivedwrittenconsent.Inthispatient,follow-upMRIand
second-look arthroscopic surgery revealed that the cartilage
defect was completely covered with smooth tissues, consid-
ered to be the cartilage (Figure 3, G and H).
DISCUSSION
A number of retrospective studies have assessed the
results of marrow stimulation treatment in OLTs.
§
In
these studies, various factors involved with marrow stimu-
lation treatment, including the age of the patients, the size
and location of OLTs, and the existence of subchondral
cysts, were reported.
15,16,20,30,59,60
We retrospectively
reviewed 65 consecutive patients (68 ankles) who had
a diagnosis of OLT and were treated with arthroscopic
marrow stimulation treatment along with or without
MSC injection and investigated the clinical outcomes and
prognostic factors associated with this treatment. To our
knowledge, this is the first in vivo study presenting a clin-
ical report of MSC injection along with arthroscopic mar-
row stimulation treatment for OLTs.
Several recent studies have indicated that older
patients seem to do well with arthroscopic treatment
for OLTs,
16,20,32
while several authors have reported
less favorable outcomes of marrow stimulation procedures
for the treatment of OLTs in older patients.
17,26,42
Chuckpaiwong et al
17
retrospectively evaluated a total of
105 patients with OLTs who underwent arthroscopic
microfracture and reported significant improvements in
the outcome of surgical treatment in younger patients
(mean, 38.6 6 10.6 years) compared with older patients
(mean, 44.1 6 9.7 years) (P = .029). Ferkel et al
20
retrospec-
tively evaluated a total of 64 patients. Twenty-seven
patients were 32 years of age or younger, and 23 were older
than 32 years. The older age group had an AOFAS score of
80, while the younger group had a score of 88. Giannini
and Vannini
26
reported that marrow stimulation treat-
ment should be used in patients younger than 50 years
for better results. Age-dependent results after microfrac-
ture of chondral lesions in the knee have already been
described in previous studies. In a case series of 72 patients
treated arthroscopically with microfracture for full-thick-
ness chondral defects, Steadman et al
62
found that patients
younger than 35 years improved more than did those
between 35 and 45 years of age. In our study, we chose
to investigate the effect of MSCs on the outcomes of
patients older than 50 years. Although the overall clinical
outcomes, including VAS and AOFAS scores, were signifi-
cantly improved in both the patients undergoing arthro-
scopic marrow stimulation treatment alone (group A) and
those with arthroscopic marrow stimulation and MSC
injection (group B) (P \ .05 for each), there were signifi-
cant differences in mean VAS and AOFAS scores between
the groups at final follow-up (P \ .001) (Table 2). Also, the
Roles and Maudsley score showed significantly greater
postoperative improvement in patients in group B
compared with those in group A (P = .040). Activity levels
according to the Tegner activity scale were significantly
improved only in group B (P = .041) (Table 2). Therefore,
we discerned that the injection of MSCs along with arthro-
scopic microfracture would potentially be useful for better
clinical results in patients older than 50 years.
The principal aim of the marrow stimulation treatments
in OLTs is revascularization of the bony defect.
23,27,40,59
Articular hyaline cartilage is avascular and has poor
regenerative capabilities; therefore, injuries that do not
penetrate the subchondral plate have no stimulus for an
inflammatory reaction and healing. Through marrow stim-
ulation treatments, when the depth of the OLT extends to
the subchondral bone, marrow cells are stimulated to pro-
duce new tissue in an attempt to fill the defect.
1,53
How-
ever, in previous in vitro studies, several authors
reported an age-related decline in the number of MSCs
in the bone marrow.
9,18,46,52
Therefore, marrow stimula-
tion treatment alone without additional MSC injection
for OLTs has less favorable outcomes in older
patients.
17,26,42
From this point of view, we hypothesized
that the injection of MSCs along with arthroscopic micro-
fracture may be helpful for the treatment of OLTs in older
patients. These results were in accordance with our
hypothesis, as previously mentioned: the clinical outcomes
of injection of MSCs along with marrow stimulation treat-
ment in older patients (group B) showed significantly
greater improvement than those who received marrow
stimulation treatment alone (group A).
A review of the literature revealed significant correla-
tions between defect size and clinical outcomes of arthro-
scopic treatment of OLTs. Giannini and Vannini
26
reported that arthroscopic treatment seems to be the treat-
ment of choice for lesions smaller than 150 mm
2
and that it
may also be attempted in lesions from 150 to 200 mm
2
.Choi
et al
16
retrospectively evaluated a total of 120 ankles with
OLTs that underwent arthroscopic microfracture and
reported that the patients with osteochondral lesions
smaller than 150 mm
2
had better results than did those
with larger lesions. Gobbi et al,
27
using the Pearson correla-
tion analysis, showed an inverse relationship between
defect size and outcome (microfracture: r = –0.92; osteochon-
dral transplantation: r = –0.89). Chuckpaiwong et al
17
reported a strong correlation between lesion size and suc-
cessful outcome. They found excellent results in patients
with osteochondral lesions smaller than 15 mm, regardless
of location.
17
These results are consistent with the outcomes
of our study, which found significant correlations between
defect size and clinical outcomes. In our study, the mean
size of OLTs was 108.7 6 34.6 mm
2
, and to analyze the asso-
ciation of the size of OLTs with clinical results, we divided
the patients according to lesion size into large lesion size
(109 mm
2
) and small lesion size (\109 mm
2
) groups, and
patients with OLTs larger than 109 mm
2
had worse results
than those with smaller lesions in group A (P = .04). How-
ever, this correlation was not observed in group B (P =
.23) (see Appendix Table S1). Accordingly, we discerned
that the injection of MSCs had an influence on the better
outcomes of treatment in patients older than 50 years and
with OLTs larger than 109 mm
2
.
§
References 8, 15, 17, 20, 30, 59, 60, 64.
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at YONSEI UNIV LIBRARY on May 7, 2013ajs.sagepub.comDownloaded from
Osteochondral lesions of the talus associated with
subchondral cysts have been treated with a variety of
procedures. Two studies have reported good to excellent
results in 74% to 80% of patients treated for small
(\50 mm
2
) cystic lesions with marrow stimulation
alone.
30,45
Authors of other studies have recommended
against the use of marrow stimulation alone in the treat-
ment of cystic lesions based on the results of their stud-
ies.
20,59,60
Kumai et al
43
recommended osteochondral
autografts/allografts or autologous chondrocyte implanta-
tion as the initial treatment in patients with associated
subchondral cysts larger than 6 mm in depth, as these
patients did not do well with routine marrow stimulation
treatments. It has been postulated that synovial cysts
can be caused by synovial fluid intrusion through a defect
in the articular cartilage.
41
Second-look arthroscopic sur-
gery after talar osteochondral drilling has also shown
irregular chondral surfaces.
24,36
In our study, the subchon-
dral cysts existed in 16 cases of group A and 12 cases of
group B (P = .523). In addition, the clinical outcome was
significantly worse in patients with subchondral cysts
than those without subchondral cysts in group A (P =
.03). However, this correlation was not observed in group
B(P = .35) (Appendix Table S1). Although we cannot pro-
vide a definitive explanation for the exact effect of MSCs
on the subchondral cyst, we consider the possibility that
injecting MSCs influenced the better outcomes of treat-
ment in patients older than 50 years and with subchondral
cysts. More evaluations are required to investigate the
mechanism of MSCs in the healing process of OLTs.
Biomechanical studies of human ankle articular cartilage
have led some authors to conclude that cartilage lesions such
as OLTs may be related to the disparity of the mechanical
properties in the different regions of the ankle.
4
The softest
tissue of the talar dome appears to be on the posteromedial
talar dome.
4
Additionally, stiffer articular cartilage is found
on the tibial side when compared with the talar side, which
may account for the low frequency of tibial OLTs.
4
We
attempted to correlate our results with regard to location
on the talus, but no association was found between the loca-
tion of OLTs and clinical outcomes in both groups (Appendix
Table S1). Several authors have reported no difference in
outcome based on the location of an OLT.
20,54,60
The development of late osteoarthritis in patients with
OLTs treated with surgical intervention remains contro-
versial.
7,11,47,66
Angermann and Jensen
2
reported the
development of degenerative changes in 6% to 17% of the
overall patient population. Canale and Belding
13
reported
degenerative changes in more than 50% of their patients.
In contrast, other authors described late osteoarthritis as
an uncommon complication of OLTs.
7,47,66
Ferkel et al
20
reported that their long-term outcomes deteriorated with
time in 35% of 50 cases. Although the exact reason for
arthritic change is unknown, pre-existent degenerative
changes and the lack of durability of fibrocartilage may
have contributed to the deterioration of results.
20
In our
study, degenerative arthritic changes of the ankle joint
were observed in 4 cases (11%) in group A and 1 case (3%)
in group B at the final follow-up (Figure 2). We found that
large lesion size (109 mm
2
) and the existence of
subchondral cysts were significantly associated with the
development of degenerative arthritis of the ankle joint in
group A (P =.014andP = .021, respectively), but these asso-
ciations were not found in group B (P =.214andP =.182,
respectively). Therefore, we considered that the injection
of MSCs influenced the development of arthritic changes.
However, the follow-up period of our study was relatively
short (mean, 21.8 months), and these results may change
over a longer follow-up period, as the durability of the
regenerated fibrous cartilage after marrow stimulation
treatment is known to deteriorate as time passes.
20,44
Therefore, long-term evaluations are required to investigate
the association between the effect of MSCs and the develop-
ment of degenerative arthritis of the ankle joint.
Recently, MSCs have been suggested for use in the cell-
based treatment of cartilage lesions. Chondrogenesis of
MSCs was first reported by Ashton et al,
3
and a defined
medium for the in vitro chondrogenesis of MSCs was first
described by Johnstone et al,
35
who used micromass culture
with transforming growth factor b and dexamethasone.
Regarding in vitro studies, the transplantation of MSCs
into full-thickness articular cartilage defects has been
attempted under various conditions, and MSCs have been
used with success in hybrid scaffolds to repair osteochondral
defects in animal models.
29,34,39
An animal experiment by
McIlwraith et al
48
investigating MSC use to augment heal-
ing of microfractured chondral defects showed encouraging
results. In their study, they found that arthroscopic and
gross evaluation confirmed a significant increase in repair
tissue firmness and a trend for better overall repair tissue
quality in MSC-treated joints.
48
Immunohistochemical
analysis showed significantly greater levels of aggrecan in
repair tissue treated with MSC injection.
48
Although many studies have been successful, several
questions still persist that limit the clinical application of
these cells for cartilage injury, such as which tissue are
suitable MSCs derived from or what conditions are appro-
priate for cartilage repair. Although still in the early stages
of application, this unique approach may have great poten-
tial in the treatment of human cartilage defects. Although
the clinical outcomes of the injection of MSCs along with
arthroscopic microfracture in OLTs were encouraging in
group B compared with those in group A in our study, we
suggest that basic research and histological evaluations
are required to identify the effect of MSCs in microfrac-
tured chondral defects. However, this study presents, to
the best of our knowledge, the first clinical report of the
injection of MSCs along with arthroscopic marrow stimula-
tion treatment in OLTs.
The source of the MSCs is very important to obtain good
results. The choice of the stem cell source is determined by
the ease of harvesting, population density, and differentia-
tion potential of the cells because their abilities vary among
different tissue sources.
58
Bone marrow–derived stem cells
have been widely studied, and there is a wealth of information
in the literature concerning these cells.
56
However, bone mar-
row harvesting is painful and is associated with donor site
morbidities and risks of wound infection and sepsis.
57
Fur-
thermore, with increasing age, there is a decrease in MSC
numbers, life span, and proliferation and differentiation
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at YONSEI UNIV LIBRARY on May 7, 2013ajs.sagepub.comDownloaded from
potentials.
49,51,63
Therefore, an alternative cell source that is
easy to obtain, has a l ow risk of complications, and has
a high yield of cells with good proliferation and differentiation
potentials that do not decline with age is ideal for enabling
optimal cell-based tissue repair therapies in an aging popula-
tion. In this study, MSCs were derived from the fat pad har-
vested from the buttock of patients. These cells have been
shown to maintain their differentiation potential even in the
later stages of life and may have better chondrogenic potential
than bone marrow–derived MSCs.
58
Moreover, the pain and
morbidity associated with the harvesting of fat pad cells are
considerably less than that associated with bone marrow
cell harvesting.
37
Although the technique of this study was primitive, we
obtained good outcomes in older patients (group B) perhaps
because of the paracrine effects of the injected stem cells. It
is widely known that stem cell therapy has 2 main mecha-
nisms of action. The first is that these cells comprise the
final tissue in human organs. The second mechanism, the
most convincingly proven so far, is the paracrine effects
of the cytokines and growth factors released by the grafted
cells, which favorably influence the microenvironment by
triggering host-associated signaling pathways and lead to
increased angiogenesis, decreased apoptosis, and possibly
induction of endogenous generation.
14
As we mentioned
above, more basic research and histological evaluations
are required to identify the mechanism of action of MSCs
in microfractured chondral defects.
There were 4 patients who showed clinical failure and
received osteochondral transplantation after confirming
the failure of microfracture through follow-up MRI in group
A. However, there were no complications of the injection of
MSCs, including infection, fever, hematoma, tissue hyper-
trophy, adhesion formation, or other major adverse events,
that occurred among the patients. Therefore, we consider
the injection of MSCs to be a safe treatment.
The present study does have some limitations. First, the
number of patients was relatively small, the follow-up
period was short, and data were collected retrospectively.
For more accurate evaluation of the effect of MSCs in
OLTs, a prospective study and a larger series of cases with
a longer follow-up period are required. Second, we used the
VAS, AOFAS scale, and Tegner activity scale to evaluate
the results. Follow-up MRI, second-look arthroscopic sur-
gery, or histological evaluation correlated with clinical out-
comes and power analysis is necessary to identify the effect
of MSCs more precisely. Lastly, the number of MSCs to be
injected to achieve the optimal response is unknown.
In conclusion, this study showed encouraging results for
marrow stimulation treatment with MSC injection com-
pared with marrow stimulation treatment alone for patients
older than 50 years. Furthermore, the injection of MSCs
influenced better outcomes of treatment in patients older
than 50 years when the lesion size was larger than
109 mm
2
or in the presence of a subchondral cyst. We propose
that the injection of MSCs may be helpful in preventing the
development of arthritic changes. Although still in the early
stages of application, MSCs may have great potential in the
treatment of OLTs in patients older than 50 years, and
more evaluations of the effect of MSCs should be performed.
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