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Morphological Assessment of MACI Grafts in Patients with Revision Surgery and Total Joint Arthroplasty

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Objective To compare the histological and immunohistochemical characteristics of matrix-assisted chondrocyte implantation (MACI) grafts between patients with revision surgery and patients with total joint arthroplasty. Methods Biopsies of MACI grafts from patients with revision and total joint arthroplasty. The graft tissue characteristics and subchondral bone were examined by qualitative histology, ICRS (International Cartilage Repair Society) II scoring and semiquantitative immunohistochemistry using antibodies specific to type I and type II collagen. Results A total of 31 biopsies were available, 10 undergoing total knee arthroplasty (TKA) and 21 patients undergoing revision surgery. Patients in the clinically failed group were significantly older (46.3 years) than patients in the revision group (36.6 years) ( P = 0.007). Histologically, the predominant tissue in both groups was of fibrocartilaginous nature, although a higher percentage of specimens in the revision group contained a hyaline-like repair tissue. The percentages of type I collagen (52.9% and 61.0%) and type II collagen (66.3% and 42.2%) were not significantly different between clinically failed and revised MACI, respectively. The talar dome contained the best and patella the worst repair tissue. Subchondral bone pathology was present in all clinically failed patients and consisted of bone marrow lesions, including edema, necrosis and fibrosis, intralesional osteophyte formation, subchondral bone plate elevation, intralesional osteophyte formation, subchondral bone cyst formation, or combinations thereof. Conclusions MACI grafts in patients with revision and total joint arthroplasty were predominantly fibrocartilage in repair type, did not differ in composition and were histologically dissimilar to healthy cartilage. Clinically failed cases showed evidence of osteochondral unit failure, rather than merely cartilage repair tissue failure. The role of the subchondral bone in relation to pain and failure and the pathogenesis warrants further investigation.
(A) Clinically failed matrix-assisted chondrocyte implantation (MaCi) graft of the medial femoral condyle (hematoxylin and eosin [H&e] stain; scale bar = 4 mm). arrows indicate the margins of the MaCi graft. asterisk indicates the original cement line and calcified cartilage layer with the area of subchondral bone plate elevation above this line, including grafted and nongrafted area. trabecular bone sclerosis and subchondral bone cyst formation are present. Inset 1: Cells within the deeper layers of the MaCi graft were generally rounder, representing a more chondrocyte phenotype. Inset 2: Cells within the superficial layers of the MaCi graft were generally more elongated, representing a more fibroblast phenotype. Inset 3: incomplete lateral integration between the graft and the remaining cartilage. Inset 4: incomplete integration of the graft with the underlying subchondral bone plate with fibrous tissue within the separation (arrowheads). Inset 5: Marked bone remodeling and osteoclast-mediated (arrows) subchondral bone cyst formation. Inset 6: edge of the subchondral bone plate elevation characterized by multiple small blood vessels extending into the calcified and noncalcified cartilage. Insets 7 and 8: More extensive subchondral bone plate fibrillation and thickening within the grafted area (Inset 7) compared with the nongrafted and nonelevated area (Inset 8). all insets: scale bar = 200 μm. (B) Collagen type ii immunohistochemistry (scale bar = 4 mm). Collagen type ii is distributed throughout the basal layers of the graft, except for the surface. (C) Collagen type i immunohistochemistry (scale bar = 4 mm). Collagen type i is present throughout most part of the graft, but less toward the base of the graft.
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Article
Introduction
Articular cartilage of diarthrodial joints is supported by the
subchondral bone. Between the hyaline articular cartilage
and the subchondral bone, are several structures connecting
these two different tissues to form a tight functional associa-
tion. Together these structures have been commonly referred
to as the osteochondral unit.1 Isolated articular cartilage
defects without subchondral bone changes are common2,3
and their lack of intrinsic healing warrants treatment when
functionally symptomatic. Isolated cartilage defects not only
cause morbidity comparable to advanced osteoarthritis4
but can also initiate secondary osteoarthritic changes.5,6
Moreover, cartilage defects have a propensity to progress
when clinical osteoarthritis has been established.7
The contribution of the subchondral bone in the develop-
ment and progression of osteoarthritis has long been recog-
nized,1,8-10 but its role in cartilage repair techniques has only
recently received more attention.11,12
Autologous chondrocyte implantation (ACI) was first
reported in 1994,13 with the initial technique consisting of a
chondrocyte suspension injected under a periosteal flap
890754CARXXX10.1177/1947603519890754CARTILAGEBeck et al.
research-article2019
1Centre for Orthopaedic Research, Faculty of Health and Medical
Sciences, The University of Western Australia, Nedlands, Western
Australia, Australia
2Knee Research Australia, Benowa, Queensland, Australia
3School of Human Sciences, Faculty of Science, The University of
Western Australia, Nedlands, Western Australia, Australia
4Perth Orthopaedic and Sports Medicine Research Institute, West Perth,
Western Australia, Australia
5Foot & Ankle Department, St. Vincent’s Clinic, Sydney, New South
Wales, Australia
Corresponding Author:
Ming-Hao Zheng, Centre for Orthopaedic Research, Faculty of Health
and Medical Sciences, The University of Western Australia, 2nd Floor
M-Block QEII Medical Centre, Nedlands, Western Australia 6009,
Australia.
Email: minghao.zheng@uwa.edu.au
Morphological Assessment of MACI
Grafts in Patients with Revision
Surgery and Total Joint Arthroplasty
Aswin Beck1, David Wood1, Christopher J. Vertullo2,
Jay Ebert3, Greg Janes4, Martin Sullivan5, and Ming-Hao Zheng1
Abstract
Objective. To compare the histological and immunohistochemical characteristics of matrix-assisted chondrocyte implantation
(MACI) grafts between patients with revision surgery and patients with total joint arthroplasty. Methods. Biopsies of
MACI grafts from patients with revision and total joint arthroplasty. The graft tissue characteristics and subchondral
bone were examined by qualitative histology, ICRS (International Cartilage Repair Society) II scoring and semiquantitative
immunohistochemistry using antibodies specific to type I and type II collagen. Results. A total of 31 biopsies were available,
10 undergoing total knee arthroplasty (TKA) and 21 patients undergoing revision surgery. Patients in the clinically failed
group were significantly older (46.3 years) than patients in the revision group (36.6 years) (P = 0.007). Histologically, the
predominant tissue in both groups was of fibrocartilaginous nature, although a higher percentage of specimens in the
revision group contained a hyaline-like repair tissue. The percentages of type I collagen (52.9% and 61.0%) and type II
collagen (66.3% and 42.2%) were not significantly different between clinically failed and revised MACI, respectively. The
talar dome contained the best and patella the worst repair tissue. Subchondral bone pathology was present in all clinically
failed patients and consisted of bone marrow lesions, including edema, necrosis and fibrosis, intralesional osteophyte
formation, subchondral bone plate elevation, intralesional osteophyte formation, subchondral bone cyst formation, or
combinations thereof. Conclusions. MACI grafts in patients with revision and total joint arthroplasty were predominantly
fibrocartilage in repair type, did not differ in composition and were histologically dissimilar to healthy cartilage. Clinically
failed cases showed evidence of osteochondral unit failure, rather than merely cartilage repair tissue failure. The role of the
subchondral bone in relation to pain and failure and the pathogenesis warrants further investigation.
Keywords
MACI, osteochondral unit, revision surgery, subchondral bone, total knee arthroplasty
2 CARTILAGE 00(0)
sutured to the surrounding healthy cartilage, known as peri-
osteum-covered ACI (PACI).13 Subsequent advancements
in biomaterials allowed the replacement of the periosteum
with fibrin glue–stabilized collagen and hyaluronan-based
scaffolds, known as matrix-assisted chondrocyte implanta-
tion (MACI) technique.14
While the scientific literature increasingly supports the clin-
ical outcomes and usage of PACI and MACI techniques,15-19
far less attention has been paid to the failures of this tech-
nique. A recent systematic review reported an overall fail-
ure rate of 14.9% in 4294 patients undergoing ACI, most
commonly within the first 5 years following implantation.20
LaPrade et al.21 illustrated that failed ACI is predominantly
composed of fibrous tissue and fibrocartilage with variable
positivity for both type I and type II collagen. This study
evaluated osteochondritis dissecans lesions repaired with
PACI, not MACI. Histological differences in repair tissue
could be expected between these 2 techniques, as the for-
mer utilizes a cell solution covered with living tissue (peri-
osteum) to initiate repair, whereas the latter initiates repair
with a cell-scaffold construct adhered to the subchondral
bone.13,22
Subchondral bone alterations following ACI techniques
have been observed,11,12,23-26 although their clinical signifi-
cance remain subject of debate. Recognizing articular carti-
lage and the subchondral bone as one functional unit, we
investigated the histological aspects of the subchondral
bone.
The aim of our study was therefore to examine the histo-
logical and immunohistological features of MACI grafts in
patients with revision and total joint arthroplasty and to
investigate the subchondral bone status in patients with
total joint arthroplasty.
Material and Methods
Patients
Between 2000 and 2006, our institution served as the
Australian national reference center for examination of
biopsy tissues obtained from MACI grafts. Included biop-
sies were obtained either from (1) MACI grafts requiring
revision arthroscopy due to graft failure or another reason
requiring arthroscopy or from (2) knees that had further
degenerated and had progressed toward total knee arthro-
plasty (TKA). The decision as to whether the graft had clin-
ically failed and/or revision arthroscopy was indicated, or
whether joint arthroplasty was indeed now the best surgical
option for the patient, was undertaken by the treating
surgeons.
The tissues obtained from patients undergoing repeat
arthroscopy were either cartilage repair tissue biopsies or
osteochondral biopsies (3 mm diameter) taken as part of a
chondroplasty of symptomatic hypertrophic tissue at the
graft site of patients with the primary complaint of “pain,
clicking, and catching” of the graft. For clinically failed
patients, osteochondral slabs including the graft area were
collected as part of a TKA procedure. Patients undergoing
TKA presented with recurring and worsening pain follow-
ing MACI, which failed to respond to conservative treat-
ment, with evidence of degenerative joint disease (and
progression thereof) such that TKA was considered the
most appropriate treatment. Patient consent for treatment
and use of the biopsy for research purposes was obtained
and ethical approval was given by the Human Research
Ethics Committee of our institution.
Histology
Routine histology was performed to evaluate and character-
ize the repair tissue. Samples were placed in 4% paraformal-
dehyde for 48 hours prior to processing. Samples containing
mineralized tissue were decalcified in 10% EDTA (ethylene-
diaminetetraacetic acid), pH 7. For osteochondral slabs from
arthroplasty patients, multiple sections 3 mm apart through
the entire graft were performed prior to paraffin embedding.
Samples were sectioned to 4-µm-thick slices and routinely
stained with hematoxylin and eosin, toluidine blue/fast
green, and safranin O/fast green stain.
All stained samples were evaluated by bright-field
microscopy to characterize tissue as hyaline-like, fibrocarti-
lage, or fibrous tissue based on cellularity (density, shape,
and presence of lacunae) and matrix appearance as previ-
ously reported by Zheng et al.22 For osteochondral samples,
qualitative analysis of the subchondral bone was performed
as described by Zanetti et al.27 Bone marrow edema was
defined as presence of swollen fat cells surrounded by
eosinophilic staining, marrow fibrosis as replacement of fat
cells by fibrous tissue, and marrow necrosis as formation of
foam cells and presence of swollen fat cells with loss of
nuclei. Trabecular bone structure was evaluated for pathol-
ogy, consisting of necrosis (characterized as loss of nuclei),
sclerosis, and repeated remodeling (characterized by bone
formation with reversal lines and bone resorption with
increased osteoclastic activity). Alterations of the subchon-
dral bone, recognized as clinical conditions by Orth et al.,28
were reported accordingly. The grading system as described
by Aho et al.29 was applied on the subchondral bone below
and distant to the repair tissue in normal tissue as control. In
brief, grade 0 is characterized by a thin subchondral bone
plate (SBP) with direct connections between the bone mar-
row and the articular cartilage via open fenestrae, grade 1
by some subchondral bone sclerosis with remaining open
fenestrae, grade 2 by a distinct increase in SBP thickness,
absence of fenestrae, and presence of SBP fibrillation and
grade 3 by severe sclerosis and flattening of the SBP.
Additionally, ICRS (International Cartilage Repair Society)
II scoring was performed as previously described.30 As
Beck et al. 3
blinding was impossible due to obvious differences in the
nature of the sample, they were analyzed twice by the same
investigator, 6 months apart. The average score was taken if
the difference between the 2 time points was less than 10
units. If the difference between the 2 scores was greater
than 10 units, the sample was evaluated by a board-certified
pathologist and consensus between the 2 evaluators was
reached.
Immunohistochemistry
Sections deparaffinized in xylene, rehydrated with decreas-
ing ethanol solutions, and rinsed in distilled water.
Enzymatic antigen retrieval (Pepsin, Abcam ab128991) was
performed at 37°C for 15 minutes and endogenous peroxi-
dase activity was blocked using 3% H2O2 in 96% ethanol
for 10 minutes at room temperature. Nonspecific binding
sites were blocked with 10% fetal bovine serum (FBS) in
0.1% Triton X100 in TBS (Tris-buffered saline) for 1 hour
at room temperature. Samples were then incubated at 4°C
overnight with primary antibodies against rabbit anti-human
collagen type I (Abcam, ab34710, dilution 1:500) and
mouse anti-chicken collagen type II (Developmental
Studies Hybridoma Bank, Iowa, strain II-II6B3, dilution to
2 µg/ml). Antibody was detected using anti-rabbit (Sigma
A0545) and anti-mouse antibodies (Sigma A9917) diluted
at 1:1000 for Col I and II, respectively. Peroxidase staining
was done following the instructions of the manufacturer
(Liquid DAB+ substrate chromogen system, DAKO).
Sections were counterstained using Gill’s hematoxylin and
saturated in lithium carbonate until they turned blue, dehy-
drated in ethanol, cleared in xylene, and mounted. Negative
control samples were incubated in 5% FBS instead of the
primary antibodies. Positive control samples consisted of
an osteochondral section from a nonarthritic joint.
For evaluation of the immunostained sections, the total
area of cartilage was measured using Bioquant Osteo soft-
ware (v13.2.6, Bioquant, Nashville, TN). Areas of positive
staining were measured using semiautomatic thresholding
and the percentage of positively stained tissue, regardless of
the staining intensity, was calculated.
Micro-Computed Tomography
If performed, osteochondral blocks underwent micro-com-
puted tomography (micro-CT) scanning prior to decalcifi-
cation. Samples were scanned in 70% ethanol in a micro-CT
scanner (SkyScan 1176; Bruker-microCT, Kontich, Belgium)
at 50 kV, 500 µA, 240 ms exposure time, rotation step of
0.3, 360° degree of rotation, and an isotropic resolution of
17.78 μm, using a 0.5 mm-thick Al filter.
Images of each specimen were reconstructed using the
manufacturer’s software (NRecon v 1.7.1.0; Bruker-microCT,
Kontich, Belgium). For evaluation of the trabecular bone
microarchitecture, cylinder-shaped volumes of interest (VOI)
with a diameter of 7 mm were selected semiautomatically to
mimic core-extraction samples in the grafted area and in an
area distant to the graft, excluding cysts manually, if pres-
ent. The height of the cylinders did not exceed 4 mm. Bone
morphometric parameters (bone volume fraction [BV/
TV], BS/BV, trabecular thickness, and trabecular separa-
tion) were calculated using CTAnalyzer software (Bruker-
microCT, Kontich, Belgium).
Statistics
Results are expressed as mean ± SD. Data were not nor-
mally distributed, and therefore nonparametric analysis was
performed (Kruskal Wallis and Mann-Whitney U test). The
Fisher exact test was used to investigate relations between
demographic data. Differences were considered significant
at P 0.05. All calculations were performed with SPSS
(version 22.0; IBM Corp.). Post hoc power analysis was
performed using the G*Power computer program.31
Results
Demographics
Biopsies were available from 31 patients, including 10
undergoing total knee arthroplasty (TKA) and 21 patients
undergoing revision surgery. Seventeen of the revision sur-
geries were performed on knee joints and 4 on ankle joints.
Demographic characteristics are described in Table 1.
Micro-CT was performed on 2 clinically failed patients who
underwent TKA.
The average age at MACI implantation was older in the
clinically failed group who underwent subsequent TKA
(46.3 years) than the group who underwent revision (36.6
years, P = 0.007).
The mean graft survival time was 26.8 months for those
who underwent knee replacement, which was not signifi-
cantly longer (P = 0.94) than survival time for the revision
patients (17.8 months). Defect sizes were on average 4.3
and 4.8 cm2 for TKA and revision patients, respectively, and
were not significantly different (P = 0.68). There was no
significant association between gender and classification
group (P = 0.697) and lesion location and classification
group (P = 0.464).
Histological and Histopathological Observations
Representative histological features of the TKA patients are
illustrated in Figure 1. The predominant cartilage type in
TKA was fibrocartilage (70%), only 10% had a predomi-
nantly hyaline-like cartilage and 20% had a predominantly
fibrous nature. The repair tissue morphology often con-
sisted of a mixture of areas with randomly organized fibers
4 CARTILAGE 00(0)
and areas with less birefringence. Increased birefringence
coincided with more elongated cell types, and thus more
fibrous nature of the tissue, although vascularization was
only occasionally seen.
The tissue surface often showed several degrees of fibril-
lation (Fig. 1), cleft formation, poor organization of colla-
gen fibers, and elongated cells (Fig. 1). Deeper layers
similarly showed poor organization, but cells were often
rounder (Fig. 1) and tidemark formation was rarely
observed. Integration of the repair tissue with the subchon-
dral bone was highly variable and often a thin layer of
fibrous tissue could be observed if integration was incom-
plete (Fig. 1), separating the repair tissue from the subchon-
dral bone. Abnormal mineralization within the basal layers
of the defect was frequently observed and could more spe-
cifically be described as intralesional osteophyte formation
(30%) and elevation of the subchondral bone plate (40%)
(Fig. 1) according to Orth et al.28 Subchondral bone cyst
formation was observed in 2 patients (20%) (Fig. 1). Using
the grading system recently developed by Aho et al.,29 the
subchondral bone plate below the graft was grade 2 or 3 in
all specimens and was always higher than the grade of the
perigraft area (grade 0 or 1 in all cases).
In comparison with TKA patients, the different cartilage
types in revision patients were more evenly distributed with
hyaline-like cartilage counting for 28.5%, fibrocartilage
43%, and fibrous tissue 28.5%. Tissue characteristics were
similar to TKA patients, although generally the tissue sur-
face, basal integration of the tissue scored better and less
vascularization and abnormal mineralization was seen (rep-
resentative image in Fig. 2). From the observed differ-
ences, ICRS II scores for abnormal calcification within the
cartilage defect area and vascularization were significantly
different between the 2 groups (Table 2), thus indicating
more abnormal mineralization within the basal layers of
the repair tissue in TKA patients. Excluding ankle cases
retained the same significant differences, but additionally
showed a significantly better basal integration in knee revi-
sion surgery compared with TKA (P = 0.014).
Interestingly, the average percentage of collagen type 2
was higher in the TKR group (61.0%) compared with the
revision group (44.2%), although the difference was not
significant (Table 2). The reverse was similarly true for col-
lagen type I. For TKA patients, 70% had a ratio Col II %/
Col I % higher >1, compared with 38% in revision patients.
Using the qualitative evaluation criteria of the subchon-
dral bone as outlined by Zanetti et al.,27 all TKA patients
had various extents of subchondral bone marrow edema,
necrosis, and fibrosis, albeit minimal to mild in most cases.
Trabecular abnormalities were also frequently present with
predominantly trabecular necrosis, increased bone remodel-
ing as evidenced by new bone formation, reversal lines, and
osteoclastic activity. All revision surgery patients had bone
marrow fibrosis, which varied from minimal to marked and
only a small number had some bone marrow edema and
necrosis. Trabecular bone changes consisted primarily of
trabecular necrosis, and there was only minimal bone
remodeling in a few patients.
Comparison of MACI Histology between
Anatomical Sites
The prevalence of graft tissue type, regardless of undergo-
ing arthroplasty or revision surgery, in the different ana-
tomic locations is illustrated in Figure 3 and the ICRS II
tissue morphology and overall scores, and percentage col-
lagen types I and II in Figure 4.
Knee Joints. Within the knee joints, patients with lesions on
the patella scored significantly worse than patients with
lesions in the medial femoral condyle (MFC) for tissue mor-
phology, fill type, deep zone and overall assessment. Fibrous
tissue was present in all patients (5/5) undergoing MACI
treatment for patella lesions (Figs. 3-5), but only 2 out of 5
patients underwent joint replacement surgery. Collagen type
I accounted for more than 95% of the repair tissue in all
patella samples and less than 5% was collagen type II. Sub-
chondral bone pathology was rarely present (Fig. 5).
Ankle Joints. Ankle revisions contained overall better quality
of tissue with none of the 4 patients receiving MACI treat-
ment developing fibrous repair tissue. Ankle revisions
scored significantly better in cartilage parameters (tissue
morphology, P = 0.018; deep zone assessment, P = 0.047;
and overall assessment, P = 0.018) compared with knee
revision surgeries, but worse in basal integration (P = 0.005)
(Fig. 6) and subchondral bone health (P = 0.039) (Fig. 6).
Table 1. Patient Demographics for Patients Undergoing Total
Knee Arthroplasty (TKA) and Revision Surgery.
Characteristic TKA (n = 10) Revision (n = 21)
Age, years, mean (SD) 46.3 (5.00) 36.6 (9.43)
Graft survival time,
months, mean (SD)
26.8 (25.54) 17.8 (10.3)
Sex, n (%)
Male 3 (30) 9 (43)
Female 7 (70) 12 (57)
Defect size, cm2,
mean (SD)
4.3 (2.00) 4.8 (4.00)
Lesion location, n (%)
Knee 10 (100) 17 (81)
Medial femoral
condyle
7 (70) 10 (59)
Patella 2 (20) 3 (17)
Trochlea 1 (10) 2 (12)
Unknown 2 (12)
Ankle 4 (19)
Beck et al. 5
Figure 1. (A) Clinically failed matrix-assisted chondrocyte implantation (MACI) graft of the medial femoral condyle (hematoxylin
and eosin [H&E] stain; scale bar = 4 mm). Arrows indicate the margins of the MACI graft. Asterisk indicates the original cement
line and calcified cartilage layer with the area of subchondral bone plate elevation above this line, including grafted and nongrafted
area. Trabecular bone sclerosis and subchondral bone cyst formation are present. Inset 1: Cells within the deeper layers of the
MACI graft were generally rounder, representing a more chondrocyte phenotype. Inset 2: Cells within the superficial layers of
the MACI graft were generally more elongated, representing a more fibroblast phenotype. Inset 3: Incomplete lateral integration
between the graft and the remaining cartilage. Inset 4: Incomplete integration of the graft with the underlying subchondral bone
plate with fibrous tissue within the separation (arrowheads). Inset 5: Marked bone remodeling and osteoclast-mediated (arrows)
subchondral bone cyst formation. Inset 6: Edge of the subchondral bone plate elevation characterized by multiple small blood
vessels extending into the calcified and noncalcified cartilage. Insets 7 and 8: More extensive subchondral bone plate fibrillation
and thickening within the grafted area (Inset 7) compared with the nongrafted and nonelevated area (Inset 8). All insets: scale
bar = 200 μm.
(B) Collagen type II immunohistochemistry (scale bar = 4 mm). Collagen type II is distributed throughout the basal layers of the graft, except for the
surface. (C) Collagen type I immunohistochemistry (scale bar = 4 mm). Collagen type I is present throughout most part of the graft, but less toward
the base of the graft.
6 CARTILAGE 00(0)
The subchondral bone pathology in ankle patients was charac-
terized primarily by marked bone marrow fibrosis (Fig. 6).
Age at implantation was negatively associated with the
score for chondrocyte clustering (ρ = −0.622, P = 0.001)
and abnormal calcification (ρ = −0.511, P = 0.03) when all
samples were included. A negative association between age
at implantation and chondrocyte clustering (ρ = −0.577,
P = 0.010) persisted when TKA patients were excluded.
MACI survival time was positively associated with the
formation of a tidemark (ρ = 0.542, P = 0.037) when all
samples were included. For revision patients subchondral
bone health was positively associated with chondrocyte
clustering (ρ = 0.790, P = 0.020) and basal integration
(ρ = 0.713, P = 0.031).
Subchondral Bone Structure of MACI with TKA
Patients who underwent TKA had specimens of subchon-
dral bone tissue, which enabled the assessment of the sub-
chondral bone structure. One specimen was characterized
Figure 2. Matrix-assisted chondrocyte implantation (MACI) knee revision surgery specimen (left to right: hematoxylin and eosin
[H&E] stain, toluidine blue–safranin O stain, and Col type II stain, scale bar = 4 mm). The original calcified cartilage is clearly visible on
the toluidine blue stain (asterisk) with newly formed bone above. The repair tissue contains collagen type II throughout. Insets 1 and
2: Cells are primarily round-shaped in different layers of the graft, but the matrix is poorly organized. Inset 3: the subchondral bone
marrow shows bone marrow edema and mild fibrosis. All insets: scale bar = 200 μm.
Table 2. ICRS II Scores and Percentage Col Type II and Col Type I for TKA and Revision Surgery.
TKA (n = 10), Mean (± SD) Revision Surgery (n = 21), Mean (± SD) P
Tissue morphology 48.3 (± 24.2) 48.8 (± 25.6) 0.69
Matrix staining 50.0 (± 27.8) 46.5 (± 31.7) 0.82
Cell morphology 49.0 (± 28.1) 43.2 (± 31.3) 0.62
Chondrocyte clustering 60.3 (± 31.2) 73.3 (± 28.5) 0.28
Surface architecture 30.3 (± 37.4) 58.6 (± 37.6) 0.14
Basal integration 70.9 (± 32.0) 90.0 (± 21.2) 0.09
Formation tidemark 24.7 (± 27.5) 16.9 (± 24.8) 0.32
Subchondral bone abnormalities 49.7 (± 35.8) 65.3 (± 30.7) 0.37
Abnormal calcification/ossification 35.3 (± 44.5) 91.5 (± 22.3) <0.01*
Vascularization 56.8 (± 37.3) 81.3 (± 33.4) 0.04*
Surface/superficial assessment 30.0 (± 30.5) 53.9 (± 34.5) 0.12
Mid/deep zone assessment 53.3 (± 27.2) 63.8 (± 23.9) 0.31
Overall assessment 47.0 (± 25.4) 55.8 (± 24.5) 0.35
Col type II 61.0 (± 33.4) 44.2 (± 37.9) 0.37
Col type I 52.8 (± 37.5) 60.238 (± 35.6) 0.69
ICRS II = International Cartilage Repair Society II; TKA = total knee arthroplasty.
*Significant differences.
Beck et al. 7
by marked subchondral bone plate elevation and subchon-
dral bone cyst formation in the grafted area (Fig. 7) and the
other one by subchondral bone plate erosion (Fig. 7).
Bone morphometric parameters showed a 2.2-fold increase
in bone volume percentage in the grafted area, characterized
by increased trabecular thickness and decreased trabecular
Figure 3. Repair tissue type distribution within different anatomical locations (MFC = medial femoral condyle). All patellar grafts
consisted of primarily fibrous tissue whereas none of the ankles contained fibrous tissue. The majority of MFC specimens consisted of
fibrocartilaginous tissue.
Figure 4. Average (±SD) ICRS II scores for tissue morphology and overall assessment and percentage collagen type II and collagen
type I in 4 different anatomic locations (MFC = medial femoral condyle). Tissue morphology and overall assessment scores were
highest for ankle grafts and lowest for patellar grafts and were significantly different from each other. There was significantly more
collagen type II in MFC graft tissue compared to patellar graft tissue.
8 CARTILAGE 00(0)
separation (Table 3). The Structure Model Index was closer
to 0 in the grafted area indicative of trabeculae to be more
plate-like than rod-like (Table 3).
Power Calculation
A 1-sided post hoc power analysis using the G*Power com-
puter program31 indicated that a total of 102 specimens
would be needed to detect medium effects (d = 0.51) with
80% power using a Mann-Whitney U test with α at 0.05.
Discussion
The data of the present study show that there was no signifi-
cant difference in histological features of MACI grafts
between patients with revised surgery and arthroplasty. The
majority of cases in both groups contained fibrocartilagi-
nous repair tissue, although hyaline-like tissue was more
frequently observed in the revision group. Clinically failed
TKA patients were significantly older, had more abnormal
calcification and vascularization within the graft tissue
compared with patients undergoing revision surgery. The
observed subchondral bone pathology of differing degrees
was present in all TKA patients, and hence we propose that
the mechanism of failure is of the entire osteochondral unit
and joint, rather than just failure of the cartilage repair tis-
sue. The MACI grafting procedure succeeded in generating
and maintaining repair tissue within symptomatic cartilage
defects as evidenced by histology but failed to preserve
joint function in patients therefore proceeding to TKA.
Other studies have observed similar graft tissue to this
study following failed cartilage restoration procedures. For
ACI procedures, LaPrade et al. evaluated repair tissue of 6
periosteal-ACI failures for the treatment of osteochondral
dissecans.21 All specimens were characterized as primarily
fibrocartilaginous tissue with variable amounts of type II
and type I collagen. The failure mode however differed,
with patients experiencing pain following dislodged or par-
tially dislodged graft tissue.
In contrast to our study, LaPrade et al.21 reported a ratio
of Coll II %/Col I % of <1 in all ACI patients, whereas we
found this ratio <1 in only 30% of the cases. A minimal
degree of graft integration with the subchondral bone may
be needed to form or maintain type II collagen as nondis-
lodged tissue in the microfracture-treated specimens in the
study by LaPrade et al.21 formed more collagen type II com-
pared with collagen type I. This is further supported by find-
ings of Nehrer et al.32 who similarly demonstrated fibrous
tissue in detached repair tissue compared to more hyaline-
like tissue where the PACI graft had bonded with the sub-
chondral bone. Nehrer et al.32 reported fibrous tissue as the
most common type in PACI, accounting for 60% of the
cross-sectional area.32 None of the patients in our study were
evaluated because of graft detachment, a failure mechanism
Figure 5. Clinically failed patella matrix-assisted chondrocyte implantation (MACI). (A) Hematoxylin and eosin (H&E) stain,
overview (scale bar = 4 mm). Arrows indicate the margins of the MACI graft. Marked surface fibrillation and clefting and poor
lateral integration of the graft with the surrounding cartilage are present. Besides a small subchondral bone plate erosion (asterisk)
and intralesional osteophyte (arrow head) at the junction of the graft tissue with the surrounding cartilage tissue, there are minimal
changes within the trabecular bone. Inset 1 (scale bar = 200 μm): Graft tissue consisted primarily of high-cellular fibrous tissue with
an abundance of blood vessels throughout. (B) Scale bar = 4 mm. Collagen type II immunohistochemistry. Minimal collagen type II is
present and is primarily localized within the base of the repair tissue. (C) Scale bar = 4 mm. Collagen type I is present within all layers
of the graft tissue.
Beck et al. 9
now largely avoided by improved fixation technique with
fibrin glue and collagen matrix. Differences in ACI tech-
nique (MACI vs. PACI) may account for different failure
mechanisms, but tissue characteristics do not seem to differ.
Tissue characteristics in “failed cases” may also not depend
on treatment method as Kaul et al. similarly found fibrocar-
tilaginous tissue following bone marrow stimulation proce-
dures in patients with early osteoarthritis.33
We found fibrous tissue in all patients undergoing MACI
treatment for patella lesions and although considered infe-
rior quality tissue, it was interesting to note that only 2 out
of 5 patients underwent joint replacement surgery. While a
certain degree of poorly regenerated tissue thus seems to be
acceptable in the patellofemoral joint, it is also probable
that surgeons are less likely to offer TKA for patellofemoral
lesions, a selection bias evident in this study.
Of interest, despite the fact that more revision patients
contained hyaline like repair tissue, 62% of revision patients
had a Col I%/Col II % >1 compared with 30% of TKA
patients. In many instances, specimens from revision
patients consisted of biopsies from the surface of the repair
site. It is unclear whether this hypertrophic surface repre-
sents a tissue composition indicative of the repair as a
whole, or only the upper portion of the repair. We frequently
observed increased levels of type 1 collagen toward the sur-
face of the repair tissue. In our study, patients undergoing
TKA were significantly older than patients undergoing revi-
sion surgery. The question whether age is a limiting factor
for MACI remains controversial. Some studies have found
a negative association of age with outcome,34,35 while others
have found no such association.36-38 Recent guidelines
advise on careful selection above the age of 50 years.39 Our
Figure 6. Revision ankle matrix-assisted chondrocyte implantation (MACI) graft. Hematoxylin and eosin (H&E) stain, scale bar
= 3 mm. The graft surface is smooth and cells are primarily round shaped throughout the entire graft (Insets 1 and 2). Cell
clustering is present at the surface. Inset 3 (toluidine blue–fast green staining) Clefting at the base of graft tissue (asterisk) near
the tidemark. The subchondral bone plate shows marked proliferative islands within the calcified cartilage layer (arrows). Scale bar
insets = 200 μm.
10 CARTILAGE 00(0)
study included 5 patients 50 years (3 TKA patients 51, 51,
and 52 years and 2 revision patients 50 and 50 years).
The effect of preexisting osteoarthritis on MACI treat-
ment could not be examined in our study due to its design;
however, ACI in the presence of osteoarthritis is controver-
sial in the literature.
Minas et al.40 reported an overall failure rate of 12 out of
155 knees in 153 patients (8%) with early osteoarthritic
changes undergoing ACI, selected with the specific aim of
delaying arthroplasty surgery. Arthroplasty in failed cases
was performed at an average of 38 months after ACI, which
was longer compared with our study. Interestingly, almost
half of the patients receiving ACI in the authors’ series
included patients with early osteoarthritic changes (153 out
of 328 patients with follow-up over 2 years) indicating a
greater tendency to perform ACI in early arthritic knees than
in other series. Morphological and qualitative information
on the graft tissue was not given. Moreover, Hollander
et al.41 did not find a negative effect of osteoarthritis on graft
repair, but on the contrary osteoarthritis was shown to
enhance tissue regeneration. Despite these interesting obser-
vations, Filardo et al.42 observed a failure rate of 27.5% in
Figure 7. Micro-computed tomography (micro-CT) images (scale bar = 4 mm). (A) Marked subchondral bone overgrowth and 3
subchondral bone cysts are present. (B) The grafted area contains subchondral bone plate erosion with a steep sharp osseous rim
(osteophyte) protruding toward the cartilage.
Table 3. Bone Morphometric Parameters for the Trabecular Bone in the Graft and Perigraft Area.
Specimen BV/TV (%) BS/BV (1/mm) Tb.Th (mm) Tb.Sp (mm) Tb.N (1/mm) SMI
MFC, 55 year old female, 72
months post-MACI graft area
34.4 15.7 0.22 0.44 1.60 0.6
MFC, 55 year old female, 72
months post-MACI peri-graft area
15.5 25.0 0.14 0.65 1.11 1.2
MFC, 46 year old male, 43 months
post-MACI peri-graft area
22.3 20.9 0.17 0.50 1.30 1.2
BV/TV = percentage bone volume; BS/BV = bone surface/bone volume ratio; Tb.Th = trabecular thickness; Tb.Sp = trabecular separation;
Tb.N = trabecular number; SMI = Structure Model Index.
Beck et al. 11
44 patients with osteoarthritis (Kellgren grade 2 and 3)
treated with ACI and suggested that once the osteoarthritic
process had started, the potential of ACI is compromised
regardless of the severity of the joint condition.
The observation of different degrees of subchondral
bone pathology in all clinically failed TKA patients, signifi-
cantly worse abnormal calcification and vascularization in
TKA patients are interesting and could suggest subchondral
bone and endochondral ossification may play a pivotal role
in clinically failed patients.
In recent years, the importance of the subchondral bone
in cartilage repair strategies has gained interest.11,12,24,43
Despite the frequent observation of subchondral bone alter-
ations and pathology,24 its clinical significance and correla-
tion with pain remain controversial, while in osteoarthritis
the subchondral bone is a well-recognized source of pain.1,8-10
We observed subchondral bone changes in all patients that
underwent TKA due to clinical failure. The changes were
often localized and more extensive below the graft tissue,
although subchondral bone plate elevation also extended
beyond the grafted area. Vasiliadis et al.24 reported intrale-
sional osteophyte formation in 64% of patients and sub-
chondral bone cyst formation in 39% of patients, 9 to 18
years following ACI treatment, but failed to find signifi-
cant correlation between clinical outcome and subchondral
bone abnormalities. However, they considered its occur-
rence a negative prognostic factor.24 Impaired bone and
cartilage regeneration processes, altered biomechanical
loading, disturbed mechanisms of cartilage–subchondral
bone crosstalk, and pathological vascularization or angio-
genesis have been proposed as potential causes.28 Although
it has been proposed that overgrowth of the subchondral
bone leads to narrowing of the repair tissue,28 this was not
our observation, as the repair tissue was always at least as
thick as the nongrafted cartilage, but repair tissue protruded
above the normal position of the cartilage surface. More
research needs to be undertaken to investigate the patho-
physiology and clinical significance of the subchondral
bone pathology.
Patella repair tissue had the worst tissue composition. In
the original report of the MACI technique, Brittberg et al.13
similarly reported significantly worse clinical and morpho-
logical outcomes for patients with patella lesions. Adressing
patella malalignment has led to improved outcomes, similar
to other anatomic locations.44 A certain degree of patella
malalignment could not be ruled out in our cohorts.
Ankle MACI grafts in our study performed overall better
and none of the specimens had fibrous repair tissue. Other
studies have similarly reported good to excellent outcomes
and a negative association with age >40 years.45,46 Three
out of 4 patients in our study were younger than 40 years.
Interestingly, Dixon et al.45 observed a high proportion of
patients with magnetic resonance imaging evidence of
complete defect filling, complete integration of borders, an
intact graft surface and homogeneous signal within the graft
in patients with persistent pain, implying that failure to
relieve pain may not necessarily indicate technical failure
of the procedure.
Our data suggest that repair tissues in revised MACI
repair and clinically failed MACI are similar. However, this
study has several limitations and conclusions need to be
approached with caution.
Because of the retrospective nature of the study, the
number of specimens in each group could not be controlled
for and limited statistical power because of small sample
size may have contributed to limiting the significance of
some of the statistical comparisons. Specimens from revised
MACI grafts contained several biopsies from the surface of
the graft site. This tissue may not represent the composition
within the entire graft. Similarly, 3-mm diameter osteo-
chondral samples from the center of the defect may also not
represent the entire graft. Indeed, similar to Laprade et al.,21
we found large variation in tissue composition throughout
the entire sample in the knee arthroplasty slabs.
Patients classified as clinical failures may be completely
or partially a consequence of other pathologic changes
within the joint and thus sources of pain not directly related
to the MACI treatment. In other words, clinically failed
cases may contain biologically and functionally adequate
repair tissue, but the repair tissue failed to prevent degen-
eration of the entire joint. After all, cartilage does not con-
tain nerve endings and pain can persist despite excellent
cartilage defect infill.45,47
Although the histological and immunohistological eval-
uation of biopsies yield important data regarding the qual-
ity of repair tissue, their correlation with clinical symptoms
and function remains unclear. Intuitively, tissue with char-
acteristics closer to native hyaline articular should be
superior in function and more durable, but frequently
fibrocartilaginous repair tissue seems sufficient. Hollander
et al.,41 for example, collected 2mm diameter biopsies of
23 patients undergoing follow-up arthroscopy for nonclini-
cal reasons following ACI procedures and found that 43%
of patients had fibrocartilaginous tissue 6 to 25 months
after the ACI procedure. Peterson et al.48 found primarily
fibrous tissue in biopsy samples of 4 out of 12 patients with
good to excellent clinical grading at a mean follow-up of
54.3 months.
Similarly, Saris et al.17 evaluated 116 biopsies in a pro-
spective randomized trial comparing MACI with microfrac-
ture. Two years following treatment both treatments showed
very good structural repair and similar mean ICRS II over-
all assessment scores (±63.8). Despite similar histological
appearance, MACI-treated patients performed clinically
significantly better than microfracture-treated patients.17
The mean overall assessment scores in revised MACI in our
study (55.8) was lower, although similar to MACI treated
patients in the study by Saris et al.17 It is clear that, besides
12 CARTILAGE 00(0)
cartilage repair tissue composition, other factors must con-
tribute to clinical success or failure.
As a noninvasive technique and with the ability to follow
patients over time, magnetic resonance imaging has pro-
vided valuable information in regards to cartilage repair and
avoids some of the limitations of biopsies, but studies have
similarly shown a poor correlation between repair tissue
structural parameters and clinical outcome.24,49,50
Another limitation of the current study is the inability to
blind the investigators to the groups, an inherent limitation
of the sampling method. Additionally, the different sizes in
specimens (blocks for TKA vs. cylinders for clinically
intact grafts) and the nature of tissue (osteochondral and
cartilage shavings for clinically intact grafts) leads to a
comparison of heterogeneous sample groups. Similarly,
pathology of the subchondral bone was heterogeneous and
certain aspects such as the position of the subchondral bone
plate in the osteochondral biopsy samples relative to the
surrounding subchondral bone could not be determined.
The decision to offer TKA or revision arthroscopy was
undertaken by the treating surgeons. Although specific
clinical scores and/or patient-reported outcome measures
(PROMs) collected at the time of revision surgery would
have been useful for the analysis and interpretation of our
data, this information is not routinely collected from
patients in a clinical setting and is rarely used as part of the
decision-making process for arthroplasty surgery. There
are no agreed criteria for patients to have a knee replace-
ment and the decision to proceed with TKA is typically a
patient’s preference-based decision.51
We used immunohistochemistry to measure the per-
centage of type I and II collagen within the repair tissue by
measuring the total area of positive immunostaining,
regardless of staining intensity, within the total grafted
area. Although immunohistochemistry provides informa-
tion about the distribution of the collagen subtypes and an
indication of the amount of positively stained tissue, it can
be argued that this is not a true quantitative method,52 as
results may be affected by potential inconsistencies in
methodology (such as thickness of tissue in sections and
antigen retrieval protocols).53 Additionally, the limited asso-
ciation between antigen presence and staining intensity
above and below a certain threshold of bound antibody
combined with the subjectivity in assessment, make stain-
ing intensity an unreliable method.53
Micro-CT imaging of clinically failed specimens was
performed in only 2 out of 10 cases and illustrations may
therefore not be representative of all clinically failed MACI
grafts. The low number of available micro-CT data was due
to delayed recognition of the subchondral bone involved in
the pathology and therefore only the most recent samples
underwent micro-CT scanning.
In summary, the most prevalent tissue in revised and
clinically failed MACI biopsies was of fibrocartilaginous
nature and there was no significant difference in composi-
tion between the 2 groups. Subchondral bone pathology of
differing degrees was present in all clinically failed MACI
biopsies and failure of the osteochondral unit, rather than
the graft repair tissue is probably more appropriate termi-
nology. Further investigation into the cause of joint pain
and tighter definition of failure are needed.
Acknowledgments and Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Ethical Approval
Ethical approval was given by the Human Research Ethics
Committee of our institution (approval number: 2003-31).
Informed Consent
Patient consent for treatment and use of the biopsy for research
purposes was obtained.
Trial Registration
Not applicable.
ORCID iD
Aswin Beck https://orcid.org/0000-0002-0095-6454
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... dral bone changes in the context of cartilage repair exposed variable patterns, including the formation of subchondral bone cysts (Figure 1), intralesional osteophytes, generalized upward migration of the subchondral bone plate, and the presence of residual marrow stimulation hole(s), together with peri-hole or generalized bone resorption (Table 1). 51,52 With a view of systematically exploring each of these morphologic changes in both preclinical 46,47,[53][54][55][56][57] and clinical 25,[58][59][60][61][62][63][64][65][66] settings, an adjustable algorithm has been recently proposed to radiographically analyze them ( Figure 2). 52 In this algorithm, the projected tidemark and cement line serve as topographical landmarks. ...
... McCarthy et al. found subchondral bone cysts under the lesion area in 14.7% patients treated with either first-or second-generation ACI at 1 year postoperatively, 25 considerably lower than the data from previous cohorts treated with microfracture (38.5% at 1 year postoperatively) from Cole et al. 58 Correspondingly, a recent clinical investigation from biopsies of patients undergoing total knee arthroplasty as a salvage procedure for failed second-generation ACI with an average graft survival period of 26.8 months identified subchondral bone cyst formation within 20% of patients. 61 In a 9-18 years follow-up study, subchondral cysts were reported in 38.8% knee defects treated with firstgeneration ACI. 59 Merkeley et al. identified the presence of severe BME (grade IV) as a predictive factor for graft failure (n = 8) among patients (n = 38) receiving a salvage second-generation knee ACI for failed prior marrow stimulation. ...
... However, such a relationship may not be directly inferred to the different settings of the repair of focal cartilage defects in the knee. Currently available crosssectional 25,59,61,66 or cohort 58,65 studies do not allow identifying a causal relationship between the occurrence of subchondral bone cysts and clinical or radiographic outcomes of articular cartilage repair. For instance, ACI graft failure has been associated with BME, as the rate in patients with severe BME (83.7%) was significantly higher than in patients without severe BME (6.5%) at 60 months postoperatively. ...
Article
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Subchondral bone cysts represent an early postoperative sign associated with many articular cartilage repair procedures. They may be defined as an abnormal cavity within the subchondral bone in close proximity of a treated cartilage defect with a possible communication to the joint cavity in the absence of osteoarthritis. Two synergistic mechanisms of subchondral cyst formation, the theory of internal upregulation of local proinflammatory factors, and the external hydraulic theory, are proposed to explain their occurrence. This review describes subchondral bone cysts in the context of articular cartilage repair to improve investigations of these pathological changes. It summarizes their epidemiology in both preclinical and clinical settings with a focus on individual cartilage repair procedures, examines an algorithm for subchondral bone analysis, elaborates on the underlying mechanism of subchondral cyst formation, and condenses the clinical implications and perspectives on subchondral bone cyst formation in cartilage repair.
... Despite all the attempts to refine the treatment of cartilage lesions in osteoarthritis with MSC injections, effective regeneration of cartilage could not be demonstrated, which led to the next generation of surgical techniques to place the cells in a scaffold in a prepared subchondral bed of cartilage defect as in autologous chondrocyte implantation and matrix-assisted chondrocyte implantation techniques [58][59][60]. With a limited potential for cartilage to heal, engineered chondrogenesis plays a major role in regenerating a cartilaginous tissue. ...
Article
Study DesignMeta-analysis.Objectives Our objective is to review the randomized controlled trials (RCTs) that have been conducted previously on the topic of osteoarthritis of the knee to assess and compare the efficacy and safety of autologous and allogeneic sources of mesenchymal stromal cells (MSCs) in the treatment of osteoarthritis.Materials and methodsWe searched the electronic databases PubMed, Embase, Web of Science, and the Cochrane Library until August 2021 for randomised controlled trials (RCTs) analysing the efficacy and safety of autologous and allogeneic sources of MSCs in the management of knee osteoarthritis. These searches were conducted independently and in duplicate. The outcomes that were taken into consideration for analysis were the visual analogue score (VAS) for pain, the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), the Lysholm score, and adverse events. The OpenMeta [Analyst] software was utilised to carry out the analysis in the R platform.ResultsIn total, 21 studies with a total of 936 patients were considered for this analysis. Because none of the studies made a direct comparison of the autologous and allogeneic sources of MSCs, we pooled the results of all of the included studies of both sources and made a comparative analysis of how the two types of MSCs fared in their respective applications. Although both allogeneic and autologous sources of MSCs demonstrated significantly better VAS improvement after 6 months (p = 0.006, p = 0.001), this trend was not maintained after 1 year for the allogeneic source (p = 0.171, p = 0.027). When compared to their respective controls based on WOMAC scores after 1 year, autologous sources (p = 0.016) of MSCs performed better than allogeneic sources (p = 0.186).A similar response was noted between the sources at 2 years in their Lysholm scores (p = 0.682, p = 0.017), respectively. Moreover, allogeneic sources (p = 0.039) of MSCs produced significant adverse events than autologous sources (p = 0.556) compared to their controls.Conclusion Our analysis of literature showed that autologous sources of MSCs stand superior to allogeneic sources of MSC with regard to their consistent efficacy for pain, functional outcomes, and safety. However, we strongly recommend that further studies be conducted that are of a high enough quality to validate our findings and reach a consensus on the best source of MSCs for use in cellular therapy treatments for knee osteoarthritis.
... Recently, Beck et al., with the histological evaluation on MACI implants, observed that all failed implants were characterized by fibrous involution independently from patients' clinical conditions [28]. Those results may explain the poor correlation we observed between clinical and radiological scores at long-term FU. ...
Article
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Objective To evaluate the long-term evolution of matrix-induced autologous chondrocyte implantation (MACI) with magnetic resonance (MR) arthrography and verify the correlation between radiological and clinical findings. Materials and methods Twenty-six patients (20 m/6f) were diagnosed with knee chondral injuries and treated with MACI implantation. Each patient received MR arthrography and clinical examination at mid-term (range 22–36 months) and long term (range 96–194 months) after surgery. MR arthrography was performed with dedicated coil and a 1.5-Tesla MR unit. The modified MOCART scale was used to evaluate the status of chondral implants. Implant coating, integration to the border zone, and the surface and structure of the repaired tissue were evaluated. Presence of bone marrow oedema was evaluated. The Cincinnati Knee Rating System (CKRS) was used for clinical assessment. Results At long term, 4/26 patients had complete alignment; 5/26 had a complete integration of the margins; in 4/26 cases, the implant surface was undamaged; in 14/26 cases, the reparative tissue was homogeneous. In 9/26 cases, the implant showed isointense signal compared to articular cartilage, while the presence of subchondral bone oedema was documented in 19/26 cases. The average radiological score decreased from 59.2 (mid-term) to 38.6 (long term). The average clinical score decreased from 8.9 to 8.3. Conclusions Decrease in clinical results was not significant (0.6 points p = .06), but mMOCART scores decreased significantly ( p = .00003). Although imaging studies showed deterioration of the grafts, the patients did not have significant clinical deterioration (231/250).
... Limited subchondral cyst formation was observed in some participants in zones beneath the area of chondral regeneration or at the interface of regenerative and native cartilage. These cysts were stable between 12 and 36+ months and have been observed in other cartilage graft techniques including Matrix-induced Autologous Chondrocyte Implantation and microfracture [67]. ...
Article
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Aim: To evaluate the safety and efficacy of adipose-derived mesenchymal stem cell (ADMSC) therapy in combination with arthroscopic abrasion arthroplasty (AAA) in advanced knee osteoarthritis (OA). Materials & methods: 27 patients with Grade IV OA of the knee underwent AAA and ADMSC therapy (50 × 10 ⁶ ADMSCs at baseline and 6 months). Clinical outcome was assessed over 36 months. Structural change was determined using MRI. Results: Treatment was well tolerated with no serious adverse events. Clinically significant improvements in pain and function were observed. Reproducible hyaline-like cartilage regeneration was seen in all participants. Conclusion: ADMSC therapy combined with AAA in Grade IV OA results in reproducible pain, functional and structural improvements. This represents a joint preservation technique for patients with advanced OA of the knee. Trial registration number: ACTRN12617000638336
Article
Background The contribution of the subchondral bone in the development and progression of osteoarthritis (OA) has long been recognized, but its role in cartilage repair procedures has only recently attracted more attention. Purpose To explore the correlation between the cartilage repair tissue (RT) and the subchondral bone marrow lesions (BMLs) after matrix-associated autologous chondrocyte implantation (MACI) in the knee joint. Material and Methods A total of 30 patients who underwent MACI in the knee from January 2015 to June 2018 and follow-up magnetic resonance imaging (MRI) scan were recruited in this study. The MRI results of cartilage RT were evaluated using T2* relaxation time. Subchondral BMLs were also qualitatively evaluated by use of the two-dimensional proton density-weighted fat-suppressed (2D-PD-FS) and three-dimensional dual-echo steady-state (3D-DESS) sequences. Results The univariate analysis displayed a significant negative correlation between subchondral BMLs and cartilage RT ( P < 0.01). In the minimally adjusted model (only age, sex, and body mass index [BMI] adjusted), the results did not show obvious changes (β = –6.54, 95% confidence interval [CI] = –10.99 to –2.09; P = 0.008). After adjustment for the full models (age, sex, BMI, defect size, combined injury, and preoperative duration of symptoms adjusted), the connection was also detected (β = –6.66, 95% CI –11.82 to –1.50; P = 0.019). Conclusion After MACI, the subchondral BMLs are significantly correlated with cartilage RT-T 2 * relaxation time. The role of subchondral bone in cartilage repair procedures should not be underestimated.
Article
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Objective Osteoarthritis (OA) has often regarded as a disease of articular cartilage only. New evidence has shifted the paradigm towards a system biology approach, where also the surrounding tissue, especially bone is studied more vigorously. However, the histological features of subchondral bone are only poorly characterized in current histological grading scales of OA. The aim of this study is to specifically characterize histological changes occurring in subchondral bone at different stages of OA and propose a simple grading system for them. Design 20 patients undergoing total knee replacement surgery were randomly selected for the study and series of osteochondral samples were harvested from the tibial plateaus for histological analysis. Cartilage degeneration was assessed using the standardized OARSI grading system, while a novel four-stage grading system was developed to illustrate the changes in subchondral bone. Subchondral bone histology was further quantitatively analyzed by measuring the thickness of uncalcified and calcified cartilage as well as subchondral bone plate. Furthermore, internal structure of calcified cartilage-bone interface was characterized utilizing local binary patterns (LBP) based method. Results The histological appearance of subchondral bone changed drastically in correlation with the OARSI grading of cartilage degeneration. As the cartilage layer thickness decreases the subchondral plate thickness and disorientation, as measured with LBP, increases. Calcified cartilage thickness was highest in samples with moderate OA. Conclusion The proposed grading system for subchondral bone has significant relationship with the corresponding OARSI grading for cartilage. Our results suggest that subchondral bone remodeling is a fundamental factor already in early stages of cartilage degeneration.
Article
Objective: Cartilage injuries are one of the most frequent causes of knee pain. Other causes such as meniscus tears, synovial plica, synovitis, partial and total ligament ruptures are rather easy to identify by standard diagnostic methods and diagnostic arthroscopy. In this study we are describing two other clinical states, which could be the cause of the knee pain and should be addressed before a decision for operative treatment of cartilage injury has been made by a surgeon. Materials and Methods: Two patients with isolated focal defects due to previous trauma to the knee were diagnosed both using magnetic resonance imaging preoperatively and intraoperatively during arthroscopy. These were operated arthroscopically with standard procedure for microfracture. Both patients had treatment failure without a sign of significant improvement after six and twelve months. Results: Second look arthroscopy was performed in both cases due to the treatment failure and close to normal cartilage was found in the patella in first case and both in trochlea and medial femoral condyle in other case. No other cause of pain could be identified both with second look arthroscopy and magnetic resonance imaging done 6-12 months postoperatively. The patients were diagnosed with neuralgic pain in one case, and nociceptive pain in other case. Conclusion: These states are rare, but have to be addressed by the surgeon before making the decision about the operative treatment. By doing so, one could avoid eventual treatment failure and exposition of the patient to an unnecessary risk of complications during the surgery.
Chapter
Autologous chondrocyte implantation (ACI) was one of the first tissue engineering products, utilizing autologous chondrocytes grown in culture and reimplanted in a second-stage procedure to repair large chondral defects. Originally developed with the use of a periosteal flap, the current generation ACI procedure is performed with chondrocytes adherent to a collagen membrane (MACI).
Article
Background: Matrix-based cell therapy improves surgical handling, increases patient comfort, and allows for expanded indications with better reliability within the knee joint. Five-year efficacy and safety of autologous cultured chondrocytes on porcine collagen membrane (MACI) versus microfracture for treating cartilage defects have not yet been reported from any randomized controlled clinical trial. Purpose: To examine the clinical efficacy and safety results at 5 years after treatment with MACI and compare these with the efficacy and safety of microfracture treatment for symptomatic cartilage defects of the knee. Study design: Randomized controlled trial; Level of evidence, 1. Methods: This article describes the 5-year follow-up of the SUMMIT (Superiority of MACI Implant Versus Microfracture Treatment) clinical trial conducted at 14 study sites in Europe. All 144 patients who participated in SUMMIT were eligible to enroll; analyses of the 5-year data were performed with data from patients who signed informed consent and continued in the Extension study. Results: Of the 144 patients randomized in the SUMMIT trial, 128 signed informed consent and continued observation in the Extension study: 65 MACI (90.3%) and 63 microfracture (87.5%). The improvements in Knee injury and Osteoarthritis Outcome Score (KOOS) Pain and Function domains previously described were maintained over the 5-year follow-up. Five years after treatment, the improvement in MACI over microfracture in the co-primary endpoint of KOOS pain and function was maintained and was clinically and statistically significant ( P = .022). Improvements in activities of daily living remained statistically significantly better ( P = .007) in MACI patients, with quality of life and other symptoms remaining numerically higher in MACI patients but losing statistical significance relative to the results of the SUMMIT 2-year analysis. Magnetic resonance imaging (MRI) evaluation of structural repair was performed in 120 patients at year 5. As in the 2-year SUMMIT (MACI00206) results, the MRI evaluation showed improvement in defect filling for both treatments; however, no statistically significant differences were noted between treatment groups. Conclusion: Symptomatic cartilage knee defects 3 cm2or larger treated with MACI were clinically and statistically significantly improved at 5 years compared with microfracture treatment. No remarkable adverse events or safety issues were noted in this heterogeneous patient population.
Article
Background: Matrix-induced autologous chondrocyte implantation (MACI) has demonstrated encouraging clinical results in the treatment of knee chondral defects. However, earlier studies suggested that chondrocyte implantation in the patellofemoral (PF) joint was less effective than in the tibiofemoral (TF) joint. Purpose: To compare the radiological and clinical outcomes of those undergoing MACI to either the femoral condyles or PF joint. Study design: Cohort study; Level of evidence, 3. Methods: A total of 194 patients were included in this analysis, including 127 undergoing MACI to the medial (n = 94) and lateral (n = 33) femoral condyle, as well as 67 to the patella (n = 35) or trochlea (n = 32). All patients were evaluated clinically (Knee injury and Osteoarthritis Outcome Score [KOOS], visual analog scale, Short Form-36) before surgery and at 3, 12, and 24 months after surgery, while magnetic resonance imaging (MRI) was undertaken at 3, 12, and 24 months, with the MOCART (magnetic resonance observation of cartilage repair tissue) scoring system employed to evaluate the quality and quantity of repair tissue, as well as an MRI composite score. Patient satisfaction was evaluated. Results: No significant group differences ( P > .05) were seen in demographics, defect size, prior injury, or surgical history, while the majority of clinical scores were similar preoperatively. All clinical scores significantly improved over time ( P < .05), with a significant group effect observed for KOOS activities of daily living ( P = .008), quality of life ( P = .008), and sport ( P = .017), reflecting better postoperative scores in the TF group. While the PF group had significantly lower values at baseline for the KOOS activities of daily living and quality of life subscales, it actually displayed a similar net improvement over time compared with the TF group. At 24 months, 93.7% (n = 119) and 91.0% (n = 61) of patients were satisfied with the ability of MACI to relieve their knee pain, 74.0% (n = 94) and 65.7% (n = 44) with their ability to participate in sport, and 90.5% (n = 115) and 83.6% (n = 56) satisfied overall, in the TF and PF groups, respectively. MRI evaluation via the MOCART score revealed a significant time effect ( P < .05) for the MRI composite score and graft infill over the 24-month period. While subchondral lamina scored significantly better ( P = .002) in the TF group, subchondral bone scored significantly worse ( P < .001). At 24 months, the overall MRI composite score was classified as good/excellent in 98 TF patients (77%) and 54 PF patients (81%). Conclusion: MACI in the PF joint with concurrent correction of PF maltracking if required leads to similar clinical and radiological outcomes compared with MACI on the femoral condyles.
Article
Background: Osteoarthritis is a significant cause of burden to the ageing population and knee replacement is a common operation for treatment of end-stage disease. We aimed to explore these factors to help understand patients' decision-making, which is critical in informing patient-centred care. These can be used to enhance decision-making and dialogue between clinicians and patients, allowing a more informed choice. Methods: The study consisted of two focus groups, in a patient cohort after total knee replacement followed by more in-depth interviews to further test and explore themes from the focus groups, in patients in either the deliberation stage or the decision-making stage. Results: Using qualitative research methods (iterative thematic analysis) reviewing decision-making and deliberation phases of making informed choices we found nine key themes that emerged from the study groups. Conclusions: An awareness of the deliberation phase, the factors that influence it, the stress associated with it, preferred models of care, and the influence of the decision-making threshold will aid useful communication between doctors and patients.
Article
Long-term results of autologous chondrocyte implantation and matrix-assisted autologous chondrocyte transplantation in the knee are satisfying, but not enough attention has been paid to the evaluation of failures. Thus, a systematic review of the literature was performed, underlining a failure rate in the 58 included articles of 14.9% among 4294 patients, most of them occurring in the first 5 years after surgery, and with no difference between autologous chondrocyte implantation and matrix-assisted autologous chondrocyte transplantation. Failures are very heterogenously defined in the current literature. A widely accepted definition is needed, and a comprehensive definition taking into consideration the patient's perception of the outcome, not just the surgeon's or researcher's point of view, would be advisable. Finally, there is no agreement on the most appropriate treatment of failures, and further studies are needed to give better indications to properly manage patients failed after cartilage procedures. Level of evidence: Level IV.
Article
In diarthrodial joints, the articular cartilage, calcified cartilage, and subchondral cortical and trabecular bone form a biocomposite - referred to as the osteochondral unit - that is uniquely adapted to the transfer of load. During the evolution of the osteoarthritic process the compositions, functional properties, and structures of these tissues undergo marked alterations. Although pathological processes might selectively target a single joint tissue, ultimately all of the components of the osteochondral unit will be affected because of their intimate association, and thus the biological and physical crosstalk among them is of great importance. The development of targeted therapies against the osteoarthritic processes in cartilage or bone will, therefore, require an understanding of the state of these joint tissues at the time of the intervention. Importantly, these interventions will not be successful unless they are applied at the early stages of disease before considerable structural and functional alterations occur in the osteochondral unit. This Review describes the changes that occur in bone and cartilage during the osteoarthritic process, and highlights strategies for how this knowledge could be applied to develop new therapeutic interventions for osteoarthritis.
Article
Objective Bone marrow stimulation surgeries are frequent in the treatment of cartilage lesions. Autologous chondrocyte implantation (ACI) may be performed after failed microfracture surgery. Alterations to subchondral bone as intralesional osteophytes are commonly seen after previous microfracture and removed during ACI. There have been no reports on potential recurrence. Our purpose was to evaluate the incidence of intralesional osteophyte development in 2 cohorts: existing intralesional osteophytes and without intralesional osteophytes at the time of ACI. Study Design We identified 87 patients (157 lesions) with intralesional osteophytes among a cohort of 497 ACI patients. Osteophyte regrowth was analyzed on magnetic resonance imaging and categorized as small or large (less or more than 50% of the cartilage thickness). Twenty patients (24 defects) without intralesional osteophytes at the time of ACI acted as control. Results Osteophyte regrowth was observed in 39.5% of lesions (34.4% of small osteophytes and 5.1% of large osteophytes). In subgroup analyses, regrowth was observed in 45.8% of periosteal-covered defects and in 18.9% of collagen membrane–covered defects. Large osteophyte regrowth occurred in less than 5% in either group. Periosteal defects showed a significantly higher incidence for regrowth of small osteophytes. In the control group, intralesional osteophytes developed in 16.7% of the lesions. Conclusions Even though intralesional osteophytes may regrow after removal during ACI, most of them are small. Small osteophyte regrowth occurs almost twice in periosteum-covered ACI. Large osteophytes occur only in 5% of patients. Intralesional osteophyte formation is not significantly different in preexisting intralesional osteophytes and control groups.