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SYMPOSIUM: BIOLOGICS AND TISSUE HEALING IN ORTHOPAEDICS
What Is the Effect of Matrices on Cartilage Repair? A Systematic
Review
James D. Wylie MD, Melissa K. Hartley BA,
Ashley L. Kapron PhD, Stephen K. Aoki MD,
Travis G. Maak MD
ÓThe Association of Bone and Joint Surgeons12015
Abstract
Background Articular cartilage has minimal endogenous
ability to undergo repair. Multiple chondral restoration
strategies have been attempted with varied results.
Questions/purposes The purpose of our review was to
determine: (1) Does articular chondrocyte transplantation
or matrix-assisted articular chondrocyte transplantation
provide better patient-reported outcomes scores, MRI
morphologic measurements, or histologic quality of repair
tissue compared with microfracture in prospective com-
parative studies of articular cartilage repair; and (2) which
available matrices for matrix-assisted articular chondrocyte
transplantation show the best patient-reported outcomes
scores, MRI morphologic measurements, or histologic
quality of repair tissue?
Methods We conducted a systematic review of PubMed,
CINAHL, and MEDLINE from March 2004 to February
2014 using keywords determined to be important for
articular cartilage repair, including ‘‘cartilage’’, ‘‘chon-
dral’’, ‘‘cell source’’, ‘‘chondrocyte’’, ‘‘matrix’’,
‘‘augment’’, ‘‘articular’’, ‘‘joint’’, ‘‘repair’’, ‘‘treatment’’,
‘‘regeneration’’, and ‘‘restoration’’ to find articles related to
cell-based articular cartilage repair of the knee. The articles
were reviewed by two authors (JDW, MKH), our study
exclusion criteria were applied, and articles were deter-
mined to be relevant (or not) to the research questions. The
Methodological Index for Nonrandomized Studies (MIN-
ORS) scale was used to judge the quality of
nonrandomized manuscripts used in this review and the
Jadad score was used to judge the quality of randomized
trials. Seventeen articles were reviewed for the first
research question and 83 articles were reviewed in the
second research question from 301 articles identified in the
original systematic search. The average MINORS score
was 9.9 (62%) for noncomparative studies and 16.1 (67%)
for comparative studies. The average Jadad score was 2.3
for the randomized studies.
Results Articular chondrocyte transplantation shows bet-
ter patient-reported outcomes at 5 years in patients without
chronic symptoms preoperatively compared with micro-
fracture (p =0.026). Matrix-assisted articular chondrocyte
transplantation consistently showed improved patient-
reported functional outcomes compared with microfracture
(p values ranging from \0.001 to 0.029). Hyalograft C
1
(Anika Therapeutics Inc, Bedford, MA, USA) and Chon-
dro-gide
1
(Genzyme Biosurgery, Kastrup, Denmark) are
Each author certifies that he or she, or a member of his or her
immediate family, has no funding or commercial associations (eg,
consultancies, stock ownership, equity interest, patent/licensing
arrangements, etc) that might pose a conflict of interest in connection
with the submitted article.
All ICMJE Conflict of Interest Forms for authors and Clinical
Orthopaedics and Related Research
1
editors and board members are
on file with the publication and can be viewed on request.
Clinical Orthopaedics and Related Research
1
neither advocates nor
endorses the use of any treatment, drug, or device. Readers are
encouraged to always seek additional information, including FDA-
approval status, of any drug or device prior to clinical use.
Each author certifies that all investigations were conducted in
conformity with ethical principles of research.
Electronic supplementary material The online version of this
article (doi:10.1007/s11999-015-4141-0) contains supplementary
material, which is available to authorized users.
J. D. Wylie, A. L. Kapron, S. K. Aoki, T. G. Maak (&)
Department of Orthopaedic Surgery, University of Utah,
590 Wakara Way, Salt Lake City, UT 84108, USA
e-mail: Travis.Maak@hsc.utah.edu; travis.maak@gmail.com
M. K. Hartley
School of Medicine, University of Utah, Salt Lake City, UT,
USA
123
Clin Orthop Relat Res
DOI 10.1007/s11999-015-4141-0
Clinical Orthopaedic
s
and Related Research
®
A Publication of
The Association of Bone and Joint Surgeons®
the matrices with the most published evidence in the lit-
erature, but no studies comparing different matrices met
our inclusion criteria, because the literature consists only of
uncontrolled case series.
Conclusions Matrix-assisted articular chondrocyte trans-
plantation leads to better patient-reported outcomes in
cartilage repair compared with microfracture; however,
future prospective research is needed comparing different
matrices to determine which products optimize cartilage
repair.
Level of Evidence Level IV, therapeutic study.
Introduction
Articular cartilage is aneural and avascular and nourished
only by synovial fluid. As a result of its lack of blood
supply, it has minimal endogenous ability to repair artic-
ular surface defects [28]. Focal articular cartilage defects
are common at the time of arthroscopy with 19% of ar-
throscopies having focal chondral or osteochondral defects
[15]. Injured articular cartilage can lead to early joint
degeneration if symptomatic and left untreated [31]; thus,
multiple treatment strategies have been proposed for
articular cartilage repair [30].
The most often used treatment in the United States is
palliative chondroplasty followed by marrow stimulation
techniques such as microfracture with restorative tech-
niques, including autologous chondrocyte transplantation
with osteochondral transfer being much less common [26].
Microfracture relies on perforation of the subchondral bone
of the articular cartilage defect, leading to the egress of
marrow components, including stem cells and growth fac-
tors to stimulate repair [12,39]. Alternatively, either
autogenous or allogeneic articular chondrocytes can be
implanted into the defect in either a one-stage or a two-stage
procedure. The implant procedure is referred to as autolo-
gous chondrocyte transplantation and, in the setting of
juvenile allogeneic cartilage, is referred to as particulated
juvenile articular cartilage. The currently available partic-
ulated juvenile articular cartilage in the United States is
DeNovo-Natural Tissue (Zimmer, Warsaw, IN, USA) [9].
Implant procedures can also be supplemented with
biologic matrices to stimulate cartilage matrix organization
and synthesis. In the setting of microfracture, this is
referred to as autologous matrix- (or collagen-)induced
chondrogenesis [11,37] and, in the setting of chondrocyte
implantation, is known as matrix-assisted chondrocyte
transplantation or second-/third-generation autologous
chondrocyte transplantation, which is not currently avail-
able in the United States [20]. These biologic matrices are
composed of cartilage extracellular matrix molecules or
biopolymers that function as a scaffold for marrow
components or transplanted chondrocytes to form more
hyaline-like repair tissue in articular cartilage defects [35].
The matrices trap the repair cells in the chondral defect and
provide cell-matrix interactions that are designed to stim-
ulate differentiation into articular chondrocytes and
production of hyaline-like extracellular matrix [35].
Controversies abound regarding the optimal cell-based
chondral repair technique, because there are many emerg-
ing techniques, and there will be many choices for surgeons
and patients to make. Currently, there are no approved
matrix-based techniques in the United States, but outcomes
have been reported elsewhere. Clear superiority has not
been established of one technique over any other, and
published studies have varied in terms of their quality and
in terms of which techniques have been compared with one
another; most reports remain uncontrolled case series or
comparisons to microfracture. It seems to us that the main
goals of treatment might be evaluated in light of clinical
(pain- and function-related), radiographic (MRI morpho-
logic evaluation), and histologic (cartilage healing and
regeneration) endpoints, but studies have varied widely in
terms of how these important endpoints have been
assessed.
Given the controversies, we conducted a systematic
review designed to address two fundamental questions: (1)
Does articular chondrocyte transplantation or matrix-
assisted articular chondrocyte transplantation provide bet-
ter patient-reported outcomes scores, MRI morphologic
measurements, or histologic quality of repair tissue com-
pared with microfracture in prospective comparative
studies of articular cartilage repair; and (2) which available
matrices for matrix-assisted articular chondrocyte trans-
plantation show the best patient-reported outcomes scores,
MRI morphologic measurements, or histologic quality of
repair tissue?
Search Strategy and Criteria
Two authors (JDW, MKH) independently conducted a
comprehensive review of citation databases PubMed, CI-
NAHL, and MEDLINE to confirm that each search was
comprehensive and reproducible. Search terms included:
‘‘cartilage’’, ‘‘chondral’’, ‘‘cell source’’, ‘‘chondrocyte’’,
‘‘matrix’’, ‘‘augment’’, ‘‘articular’’, ‘‘joint’’, ‘‘repair’’,
‘‘treatment’’, ‘‘regeneration’’, and ‘‘restoration’’. All
searches were performed with the last letter replaced by an
asterisk to capture further articles. The final search term
entered in the search fields included a combination of two
searches: (1) ‘‘articular’’ OR ‘‘joint’’ AND ‘‘repair’’ OR
‘‘treatment’’ OR ‘‘regeneration’’ OR ‘‘restoration’’; and (2)
‘‘cartilage’’ OR ‘‘chondral’’ AND ‘‘cell source’’ OR
‘‘chondrocyte’’ OR ‘‘matrix’’ OR ‘‘augment’’. The search
Wylie et al. Clinical Orthopaedics and Related Research
1
123
date range was March 1, 2004, to February 28, 2014. For
all three search engines, filters for English language and
human subjects were applied. PubMed and MEDLINE
searches included an additional filter of clinical trials,
which was not available in CINAHL.
The PubMed search yielded 137 articles; the CINAHL
search yielded 190 articles; and the MEDLINE search
yielded 48 articles. The searches were then combined into
one database to remove duplicate papers and we were left
with 301 articles to consider. Abstracts were then reviewed
for relevance to the proposed research questions. Only
articles relating to cell-based articular cartilage repair of
the knee were considered. Articles pertaining to osteo-
chondral autograft or allograft transplantation were
excluded. In addition, all unpublished studies, proceedings/
abstracts, and non-English language studies were excluded
from our analysis. The reference lists of selected articles
were then searched to identify relevant articles that may
have been missed by the initial search process. Available
matrices for matrix-assisted chondrocyte transplantation
identified in our systematic search were then searched by
name in PubMed to ensure a comprehensive inclusion of
available articles for each product.
All Levels of Evidence (I–IV) were considered. Case
series and retrospective studies (Levels of Evidence III and
IV) were excluded for the comparison of microfracture,
autologous chondrocyte transplantation, and matrix-assis-
ted chondrocyte transplantation as a result of the
availability of more rigorous randomized controlled trials
and prospective comparative studies (Level of Evidence I
or II). Alternatively, because of limited availability of
prospective comparative studies designed to evaluate dif-
ferent matrices for matrix-assisted chondrocyte
transplantation, all Levels of Evidence (I–IV) were con-
sidered (Fig. 1). As a result of our decision to include
retrospective reports, we could not pool data or formally
analyze publication bias or heterogeneity.
Seventeen studies were identified that were relevant to
our first research question and met the inclusion and
exclusion criteria. These studies are described individually
in Appendices 1 and 2 (Supplemental materials are avail-
able with the online version of CORR
1
). Eleven different
matrix-based techniques were identified in our search
(Table 1). Hyalograft
1
C (Anika Therapeutics Inc, Bed-
ford, MA, USA) and matrix-assisted chondrocyte
implantation (MACI
1
Chondro-gide
1
membrane [Gen-
zyme Biosurgery, Kastrup, Denmark]) are the most
commonly reported procedures with MACI
1
having been
completed in 6000 patients worldwide [5]. The search
identified 83 articles on 11 matrices: MACI
1
/Chondro-
gide
1
, 27 articles; Hyalograft
1
C, 21 articles; Bioseed
1
C
(BioTissues Technology, Freiburg, Germany), six articles;
Cartilage Regeneration System (CaReS
1
) (Arthro Kinetics
Biotechnology, Krems/Danube, Austria) and atelocollagen
(RMS Innovations UK, Hertfordshire, UK), five articles
each; Novocart
1
3D (Aesculap Implant Systems LLC,
Center Valley, PA, USA), five articles; osteochondral
biomimetic scaffold, three articles; NeoCart
TM
(Histogen-
ics, Waltham, MA, USA), Chondron
TM
(Sewon
Cellontech, Seoul, Korea), and DeNovo-NT, two articles
each; and Cartipatch
1
(Tissue Bank of France, Lyon,
France), and Condrograft
1
(BR Medical, Monterrey,
Mexico), one article each. Of note, Hyalograft
1
C has been
recently removed from the European market by the Euro-
pean Medical Association as a result of concerns with
manufacturing processes and the design of clinical studies
that were submitted for preliminary approval prompting the
company to remove their application for approval.
Quality of the literature was quantified by the Method-
ological Index for Nonrandomized Studies (MINORS)
scale for nonrandomized studies and the Jadad scale for
randomized studies. The average Jadad score for the 12
randomized studies was 2.3 out of 5. The average MINORS
score for comparative studies was 16.1 out of 24 (67.3%)
Fig. 1 Flow diagram shows systematic search for study articles.
Matrices in Cartilage Repair
123
and the average score for non-comparative studies was 9.9
out of 16 (61.6%).
A systematic review of the selected articles was per-
formed to extract: number of patients, Level of Evidence,
length of followup, size of defect treated, matrix used (if
applicable), patient-reported outcomes measured, MRI
morphologic evaluation scale used, histologic grading scale
measured, and other pertinent findings reported.
Results
Studies Comparing Microfracture, Chondrocyte
Transplantation, and Matrix-assisted Chondrocyte
Transplantation
Randomized and comparative studies of patient-reported
outcomes measures, radiologic evaluation, and histologic
evaluation of autologous chondrocyte transplantation
compared with microfracture showed varying results with
matrix-assisted collagen transplantation techniques dem-
onstrating better patient-reported outcomes than autologous
chondrocyte transplantation when compared with micro-
fracture (Appendix 1).
In six studies comparing autologous chondrocyte trans-
plantation with microfracture that described three distinct
groups of patients, early studies showed no difference in
patient-reported outcome measures between the two
methods [17,18,42]; however, two studies at 3 and 5 years
postoperatively in the same study group found improved
patient-reported outcomes with autologous chondrocyte
transplantation compared with microfracture when con-
trolling for patient duration of symptoms before surgery.
Patients with less than 3 years of symptoms before
undergoing autologous chondrocyte transplantation had 10-
point higher overall Knee Injury and Osteoarthritis Out-
come Scores (KOOS) compared with microfracture at 5
years postoperatively (p =0.026 for overall KOOS) [33,
43]. However, patients who had lesions with chronicity of
symptoms greater than 3 years had poorer outcomes with
autologous chondrocyte transplantation [43]. Microfracture
outcomes worsened with larger lesions, whereas autolo-
gous chondrocyte transplantation outcomes did not [18]. At
1 year postoperatively, autologous chondrocyte transplan-
tation showed better histomorphometry (p =0.003) and
overall histologic evaluation (p =0.012) scores on biopsy
specimens compared with microfracture [34].
All five comparative studies of matrix-assisted chon-
drocyte transplantation and microfracture showed
significant improvements at 2- to 7.5-year followup in
International Knee Documentation Committee (IKDC)
scores: 12-point increase at 5 years (p \0.001) [21] and 17-
point increase at mean 7.5 years (p =0.005) [19]; Lysholm
scores: 26-point increase at 2 years (p =0.005) [4]; and all
KOOS subscores: approximately 10 points higher for all
scales at 2 years (p values ranging from \0.001 to 0.029)
[32]; Appendix 1). Prospective comparative studies between
autologous chondrocytes transplantation and matrix-assis-
ted chondrocyte transplantation showed more hyaline-like
tissue in the matrix-assisted group (p =0.01) [25]
Table 1. Matrix-assisted chondrocyte transplantation implants
Implants Description
Hyalograft C Scaffold composed of Hylaff11, a benzyl esther of hyaluronic acid
CaReS/CaReS-1S 3-D Type I collagen matrix purified from rat-tail collagen; CaReS-1S used in single-stage surgery without
cocultured cells
Chondro-gide/MACI Bilayer membrane made of porcine Type I/III collagen; Chonro-gide used as collagen membrane for traditional
ACI, MACI when cells precultured with membrane
NeoCart Type I collagen scaffold cultured with cells in a bioreactor to create implant
Novocart 3D 3-D Type I collagen scaffold with chondroitin sulfate
Atelocollagen 3% Type I collagen gel covered in either a periosteal, synovial tissue flap or collagen membrane, or mixed with
fibrinogen/thrombin
Cartipatch Vegetal hydrogel composed of agarose and alginate
Bioseed C Scaffold composed of fibrin, polyglycolic/polylactic acid with polydioxanone
Chondron Fibrin gel compound mixed in 1:1 ratio with chondrocyte suspension
Condrograft Tridimensional matrix of semisolid collagen
Osteochondral biomimetic
scaffold
Three-layered biomimetic scaffold with Type I collagen in the cartilage layer, 60% Type I collagen and 40%
hydroxyapatite in the tidemark layer, and mineralized blend of 30% Type I collagen and 70% hydroxyapatite in
the subchondral bone layer
DeNovo–NT Particulated juvenile allograft articular cartilage placed into the defect with fibrin glue
3-D =three-dimensional; CaReS =Cartilage Regeneration System, CaReS-1S Cartilage Regeneration Systems One Step’ MACI =matrix-
assisted chondrocyte implantation; ACI =autologous chondrocyte implantation; NT =natural tissue.
Wylie et al. Clinical Orthopaedics and Related Research
1
123
Table 2. Functional outcomes of different matrix-assisted chondrocyte transplantation implants
Implants Followup
(years)
Number of studies
(Level of Evidence)
(number of patients)
Mean lesion
size (cm
2
)
Patient-reported pain and function scores
Hyalograft C 2, 3, 5, 6, and 7;
some patients,
up to 10
19 (1-I, 3-II, 15-IV)–908 2.1–4.5 30- to 40-point increase in IKDC scores; 25- to 35-point
increases in Lysholm scores; 3- to 4-point increase in the
Tegner activity scale; outcomes improved for up to 2
years, then stable through midterm; less improvement in
patients with underlying osteoarthritis, patellar lesions,
and lower preoperative scores; improved outcomes in
younger patients with single defects; underlying
osteoarthritis led to decreased scores from 2 years to
midterm
CaReS/CaReS-1S 2 and 4 2 (2-IV)–131 0.8–5.4 25- to 30-point increase in IKDC scores; decrease in VAS
pain score by 2 to 3.5 points; improvement in SF-36 PCS
by 8 points; similar scores at 2 and 4 years
Chondro-gide/MACI 2 and 5 22 (4-I, 1-II, 17-IV)–799 2.7–8.3 25- to 40-point increases in IKDC scores; 25- to 30-point
increases in KOOS subscales; improvement in quality of
life and sports subscales from 2 to 5 years; otherwise
stable scores from 2 to 5 years; 25- to 40-point increases
in Lysholm scores; 3- to 4-point decreases in VAS pain
scores; outcomes improved at 2 years with accelerated
rehabilitation protocols; generally worse outcomes with
multiple lesions, longer symptoms, and isolated patella
lesions
NeoCart 2 2 (2-IV)–38 2.2–2.6 25- to 35-point increases in IKDC scores; 2-point
improvement in VAS pain scores; 15-point improvement
in KOOS pain score
Novocart 3D 2 4 (4-IV)–127 4.1–12.1 20- to 35-point increases in IKDC scores; less improvement
in series with larger lesions; decreases in VAS pain by 2
to 3 points; increase in Tegner activity scores by 2
points; improvement in KOOS subscores by 20 to 30
points with normal scores in pain/ADL; lower scores in
sports and quality of life; better scores at 2 years in
patient who returned to sports at [12 months
postoperatively
Atelocollagen 2 and 5/6 3 (3-IV)–114 3.6–3.75 30-point increases in Lysholm score and original knee
score; Lysholm scores in 90s at midterm followup;
improvement to 2 years, then stable at midterm
Cartipatch 2 1 (1-IV)–17 3.0 40-point improvement in IKDC scores
Bioseed C 2 and 4 5 (1-III, 4-IV)–162 3.5–4.8 30- to 35-point improvement in Lysholm scores; 20- to 25-
point improvement in IKDC scores; similar
improvements at 2 and 4 years
Chondron 2 2 (2-IV)–128 5.2–5.8 Approximately 40-point improvement in Lysholm score,
Knee Society scores (A and B), and Cincinnati knee
score; 5-point improvement in Tegner activity score;
improvement in KOOS subscores by 10 to 30 points with
greatest improvement in sports scale, but lowest overall
scores in sports and quality of life
Condrograft 1 1 (1-IV)–15 No mean
reported;
range
1.5–8.0
KOOS scores of 84 at 1-year follow-up; WOMAC
improved from 56 to 17 (no published 2-year followup)
Osteochondral
biomimetic scaffold
2 and 5 3 (3-IV)–84 2.9–3.5 35- to 40-point improvements in IKDC scores; 2- to 2.5-
point improvement in Tegner; improvement up to 2
years, then stable at 5 years
DeNovo-NT 2 2 (2-IV)–43 2.7 and 2.4 25-point improvements in IKDC; 3-point decrease in VAS
pain; 20-point increases in all KOOS subscales, with
lower overall scores in sports and quality of life; similar
final followup scores between condyle and patella lesions
CaReS =Cartilage Regeneration System, CaReS-1S Cartilage Regeneration Systems One Step; IKDC =International Knee Documentation
Committee; VAS =visual analog scale; PCS =Physical Component Summary; KOOS =Knee Injury and Osteoarthritis Outcomes Score;
ADL =activities of daily living; NT =natural tissue.
Matrices in Cartilage Repair
123
(Appendix 2). However, findings from the studies also
showed no difference in patient-reported outcome scores
between matrix-assisted chondrocyte transplantation and
autologous chondrocytes transplantation [3,10,14,23,44].
Studies on Matrices for Matrix-assisted Cartilage
Repair
Overall, each product has similar improvements in patient-
reported outcome scores as a result of surgery in the lit-
erature. These have been aggregated from Level I to Level
IV studies (Table 2). However, given the predominance of
case series data and paucity of reports directly comparing
two techniques, we could not control for defect size or
other confounding variables. For example, some matrices
were mostly used in patients with relatively smaller defects
(Hyalograft
1
C, NeoCart
TM
), whereas others were mostly
used in patients with large defects (MACI
1
, Novocart
3D
1
, Chondron
TM
). Nonetheless, most matrices had sim-
ilar MR observation of cartilage repair tissue (MOCART)
scores and defect fill at 1- or 2-year followup, signifying a
similar tissue healing response (Table 3). There was a
scarcity of histologic data, but most outcomes showed a
majority of hyaline-like and mixed hyaline/fibrocartilage
repair tissue with 50% of cases that used this measure
reported as hyaline-like (Table 4). Direct comparison of
the data was again difficult because the studies included
patients who had biopsies at different time points after
surgery. The tissue appeared to mature for at least 18
months after surgery with more hyaline-like tissue from
biopsies the further out from surgery [24].
Autologous matrix- (or collagen-) induced chondrogen-
esis have shown good short-term (2-year) clinical outcomes.
Autologous matrix-induced chondrogenesis, with the use of
Chondro-gide
1
, demonstrated a 4-point decrease in visual
analog scale (VAS) pain scores and a 35-point improvement
in Lysholm scores at 2 years [11]. Autologous collagen-
induced chondrogenesis, with the use of atelocollagen,
demonstrated a 30-point increase in Lysholm scores at 2
years [37]. Additionally, MRI followup data demonstrated
reparative tissue with similar T2 characteristics to hyaline
cartilage at 1-year followup after autologous collagen-
induced chondrogenesis [40]. However, the only
Table 3. MRI outcomes of different matrix-assisted chondrocyte transplantation implants
Implants Followup
(years)
Number of studies
(Level of Evidence)
(number of patients)
MRI evaluation
Hyalograft C 2–7 8 (3-II, 5-IV)–241 MOCART scores in the low 70s, dGEMRIC values approximately 80% of normal
hyaline cartilage; most studies subjective description of MRI findings without
quantification; majority of patients with good to complete filling of defect
CaReS/CaReS-1S 2 and 4 2 (1-II, 1-IV)–25 MOCART scores in the high 70s, improving to the 80s at 4 years in small patient
population with small defects (80s in defects \1cm
2
)
Chondro-gide/
MACI
2 and 5 14 (1-II, 13-IV)–534 MOCART scores in the high 60s to 70s; T2 scores similar to control hyaline
cartilage; majority had good-to-complete defect filling
NeoCart 2 1 (1-IV)–8 Majority had good-to-complete defect fill but repair areas had continued
prolongation at 2 years, indicating repair tissue structurally different from control
cartilage
Novocart 3D 2 43(3-IV)–83 MOCART scores high 60s to mid-70s at 2-year followup; improvement from 1- to
2-year followup
Atelocollagen 2 and [5 2 (2-IV)–84 MOCART scores in the low 70s at 2 years and greater than at 5-year followup;
improvement between 1- and 2-year followup, without significant improvement
after 2 years
Cartipatch 2 1 (1-IV)–15 Majority with defect fill and ‘‘signal similar to surrounding cartilage’’
Bioseed C 2 3 (1-II, 2-IV)–70 Majority had good-to-complete defect filling with normal to hyperintense signal
intensity
Chondron 2 1 (1-IV)–30 Mean Henderson MRI scores improved from 14.4 to 7.0 at 2-year followup
Condrograft NA NA No reported MRI studies
Osteochondral
biomimetic
scaffold
2 and 5 3 (3-IV)–68 MOCART scores improved from high 60s to 70s at 1 and 2 years to mid-70s at 5-
year followup; showing improved integration into subchondral bone over time
Denovo-NT 2 2 (2-IV)–43 Majority had complete defect filling; T2 signal similar to control cartilage
CaReS =Cartilage Regeneration System, CaReS-1S Cartilage Regeneration Systems One Step; MOCART =MR observation of cartilage
repair tissue; dGEMRIC =delayed gadolinium-enhanced MRI of cartilage; MACI =matrix-assisted chondrocyte implantation; NA =not
applicable; NT =natural tissue.
Wylie et al. Clinical Orthopaedics and Related Research
1
123
comparative study between autologous matrix-induced
chondrogenesis and microfracture was hampered by the
inability to recruit enough patients into the trial; as such,
meaningful comparisons could not be made [2]. Cartilage
Regeneration System–One Step (Arthro-Kinetics Biotech-
nology, Krems/Danube, Austria) is a similar single-step cell-
free procedure for treating smaller defects that uses the same
membrane as Cartilage Regeneration System and its use has
shown a 30-point increase in patient IKDC scores and a 2.5-
point decrease in VAS pain scores at 4-year followup [36].
Discussion
Articular cartilage defects are common in patients under-
going arthroscopy [15]; however, the most frequently used
US treatments are designed to address symptoms without
restoring hyaline cartilage [26]. Cartilage restoration
techniques have evolved in the last 20 years, from micro-
fracture to autologous chondrocyte transplantation, and
matrix-assisted chondrocyte transplantation is available
outside the United States. Given the rapid expansion in
treatment options, we sought to provide an evidence-based
answer to two fundamental comparative questions in car-
tilage restoration: (1) Does articular chondrocyte
transplantation or matrix-assisted articular chondrocyte
transplantation provide better patient-reported outcomes
scores, MRI morphologic measurements, or histologic
quality of repair tissue compared with microfracture in
prospective comparative studies of articular cartilage
repair; and (2) which available matrices for matrix-assisted
articular chondrocyte transplantation show the best patient-
reported outcomes scores, MRI morphologic measure-
ments, or histologic quality of repair tissue ?
The literature we reviewed to answer the questions had
several important limitations. There were few high-quality
comparative studies on cartilage repair techniques. This
was illustrated by our evaluation of the studies reviewed in
the Methods section. The studies most often compared
either autologous chondrocyte transplantation or matrix-
assisted chondrocyte transplantation with microfracture,
which is currently considered the gold standard technique
by regulatory agencies. There were fewer well-controlled
studies comparing matrix-assisted chondrocyte transplan-
tation with autologous chondrocyte transplantation. Even
in the setting of well-controlled studies, subanalyses
showed that factors significantly affecting outcomes were
only discovered in posttrial analyses such as the impact of
duration of patient symptoms before treatment. This fact
clouded some of the early studies comparing autologous
Table 4. Histologic analyses of patient samples from different matrix-assisted chondrocyte transplantation implants
Product Number of studies (Level
of Evidence) (number of
patients with biopsy)
Time of biopsy
postoperatively
Histologic findings
Hyaolgraft C 3 (1- II, 2- IV)–34 Mean: 12–15 months 23 with hyaline-like tissue; 6 with mixed hyaline/
fibrocartilage; and 5 with predominantly fibrocartilage
CaReS/CaReS-1S 1 (IV)–1 16 months Predominantly hyaline cartilage at time of revision
meniscectomy (CaReS-1S)
Chondro-gide/MACI 5 (1- I, 4 – IV)–80 Mean: 12–18 months 30 with hyaline-like tissue; 40 with mixed hyaline/
fibrocartilage or fibrocartilage
NeoCart 0 NA NA
Novocart 3D 0 NA NA
Atelocollagen 1 (IV)–40 12 months ICRS visual assessment score II: mean 70; average mixed
hyaline/fibrocartilage
Cartipatch 1 (IV)–13 24 months 8 of 13 patients with predominantly hyaline cartilage; mean
O’Driscoll histology score: 16/21; mean ICRS histology
score: 14/18
Bioseed C 1 (IV)–4 9 to 12 months 3 of 4 patients with predominantly hyaline cartilage; 1 with
mixed hyaline/fibrocartilage
Chondron 0 NA NA
Condrograft 0 NA NA
Osteochondral
biomimetic scaffold
1 (IV)–1 2 years 1 patient with hyaline-like tissue taken at time of hardware
removal
DeNovo-NT 1 (IV)–8 2 years Immunopositivity for Type II collagen higher than type I in 6
of 8 samples; mostly hyaline-like or mixed hyaline/
fibrocartilage
CaReS =Cartilage Regeneration System, CaReS-1S Cartilage Regeneration Systems- One Step; NA =not applicable; ICRS =International
Cartilage Repair Society; NT =natural tissue.
Matrices in Cartilage Repair
123
chondrocyte transplantation with microfracture. Previous
studies may have demonstrated more striking results if
patient duration of symptoms had been required in the
inclusion criteria [33]. Regarding our second question,
there was almost no literature comparing different matri-
ces. This body of literature relies almost completely on
uncontrolled case series or comparative studies of matrix-
assisted chondrocyte transplantation and microfracture or
autologous chondrocyte transplantation. This precluded the
ability to draw strong conclusions in light of confounding
variables such as defect size and alignment of the joint,
variables that we know are critical to the outcome and
survivorship of cartilage repair procedures [13]. Overall,
the heterogeneity of the studies on cell-based cartilage
repair with or without matrix-assisted technologies pre-
cluded us from performing a pooled data analysis to help us
answer our research questions. This leads to difficulty in
making any definitive conclusions based on the data cur-
rently available.
Another important limitation is the publication bias of
studies with positive results. Studies with positive results
are much more likely to be published and to be published in
journals with a higher impact factor [8]. The report of new
technologies and procedures is more likely to be published
if their outcomes are positive, this can be driven by the
company developing the product, the investigators per-
forming the trial as well as journal reviewers and editors
that control whether a study is published. This leads to
likely an overestimation of the treatment effect of new
technologies based on the preliminary studies and belies
the need for well-controlled clinical trials. Despite these
limitations, the current study summarizes the promise of
matrix-assisted chondrocyte transplantation as a potential
improvement in our treatment of focal cartilage defects
while pointing out what is needed to further our under-
standing of this technology.
Cartilage repair is an evolving field. The only conclu-
sion that could be drawn from high-quality studies in the
available literature was that matrix-assisted chondrocyte
transplantation has led to better patient-reported outcomes
than microfracture without definitive clinical evidence to
show better morphologic repair tissue on MRI or histologic
analysis. Unfortunately, the clinical outcomes used in all of
these studies are short-term surrogate markers for the most
important outcome of joint preservation or conversion to
knee arthroplasty. To definitively determine the best tech-
nique for cartilage repair, we will need long-term high-
quality studies that determine which of these techniques
helps patients delay the need for knee arthroplasty. Ideally,
this would come from large randomized controlled studies
of patients with the three techniques discussed. In lieu of
this evidence, large prospectively collected cohorts with
homogenous data collection methods as suggested by the
International Cartilage Repair Society [16,29] could help
give us a more definitive answer to this question. This
would include consistent use of uniform patient-reported
measures of pain and function, MRI morphologic mea-
sures, and histologic analysis methods. In addition, these
cell-based techniques will need to be compared with other
techniques not detailed in this review including osteo-
chondral transplantation to understand the best procedures
for patients. Microfracture is an accepted treatment for
small lesions, but it is not the current treatment of choice
for larger lesions [30]. Unfortunately, larger lesions are of
particular interest for cell-based therapies. Autologous
chondrocyte transplantation and osteochondral transfer are
the treatments most often used for larger defects; therefore,
studies designed to evaluate matrix-assisted chondrocyte
transplantation compared with autologous chondrocyte
transplantation and osteochondral transfer, rather than mi-
crofracture—which has already demonstrated inferiority in
cases of larger defects [30]—should be encouraged.
In regard to which matrices are best to use for matrix-
assisted chondrocyte transplantation, the data are of poorer
quality and even matrices with the most available data are
having trouble gaining regulatory approval. This under-
scores the poor-quality data to support the individual
products currently available. It is encouraging to see ran-
domized controlled trials performed that are starting to give
us answers; for example, the recent randomized controlled
trial of NeoCart
TM
that showed improved pain and function
scores compared with microfracture [6]. The lack of uni-
form outcomes measures also makes it extremely difficult
to compare different products. The lack of high-quality
studies in the field of cartilage repair matrices and the
increased regulations placed on cell-based therapies high-
light the need for large, multicenter, randomized controlled
studies to further substantiate the benefits of different
cartilage repair matrices already demonstrated in small
case series given that the regulatory hurdles placed by the
US Food and Drug Administration (FDA) have hindered
the introduction of matrix-assisted chondrocyte transplan-
tation for cartilage repair [27]. Additionally, the European
Medical Association (EMA) has recently increased regu-
lation of these devices in Europe. Hyalograft
1
C is one of
the most often used and studied matrices for matrix-assis-
ted chondrocyte transplantation, but the EMA removed it
from the European market in early 2013. The EMA
expressed concerns of manufacturing practices and quality
of comparative studies submitted for approval, so the
company withdrew their application for approval based on
the EMA’s preliminary report. However, given the regu-
latory hurdles for matrix-based technologies and the
financial implications of this, the industry has developed
alternatives. The manufacturer of DeNovo-Natural Tissue
combined allograft particulated juvenile cartilage with
Wylie et al. Clinical Orthopaedics and Related Research
1
123
fibrin adhesive to create a product that got regulatory
approval as a minimally processed allograft in the United
States [9,27]. As a cell source, DeNovo-Natural Tissue
offers significant theoretical benefits with increased repli-
cative and matrix synthetic ability compared with adult
chondrocytes [1,22,38]. Similarly, other companies are
producing minimally processed allograft tissue matrices.
The first case series on DeNovo-Natural Tissue recently
was published and shows promising results compared with
other available techniques [9,41]. Time will reveal
whether allograft tissue matrices can fill the need for car-
tilage repair in the United States or whether they will
become substandard treatments that will attain FDA
approval as minimally processed allografts and not inves-
tigational devices, therefore being significantly less
expensive and easier to get to market without the need for
large randomized studies proving efficacy [27].
Future treatments will likely include an optimized combi-
nation of cell sources such as juvenile chondrocytes or the
cadre of stem cell sources currently being investigated in
preclinical studies with matrices interlacing extracellular
matrix molecules and growth factors to support cartilage
regeneration [7]. Until such treatments are available, we need
to further determine the use of available cartilage repair
techniques to pave the way for future innovations. Current
evidence suggests that matrix-assisted chondrocyte trans-
plantation has improved patient-reported outcomes compared
with microfracture. There is no definitive evidence for pref-
erence of one matrix product compared with another given the
lack of comparative studies in the literature. Matrix-assisted
chrondrocyte implantation and Hyalograft
1
C have the most
published studies supporting their use; however, Hyalograft
1
C has recently been removed from the market. Further studies
are needed to confirm the benefits of these products and the
justification of their cost before widespread use. The FDA
approval process may provide an avenue to answer some of
the remaining questions.
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