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Autologous Chondrocyte Implantation

(ACI) for Knee Cartilage Defects
A Review of Indications, Technique, and Outcomes

Michael Krill, MD Abstract

» Autologous chondrocyte implantation (ACI) was first developed in
Nicholas Early, MD
Joshua S. Everhart, MD, MPH
David C. Flanigan, MD
Investigation performed at Ohio State
University Wexner Medical Center,
Columbus, Ohio
the late 1980s for the treatment of articular cartilage defects in the
knee. The first generation of ACI utilized a periosteal patch to contain
the cultured chondrocyte solution within the defect. Because of
issues with periosteal graft hypertrophy, ACI with use of a collagen
membrane patch (second-generation ACI) was developed. Finally,
the application of chondrocytes within a matrix (third-generation
ACI) was created to improve cell delivery, to allow for minimally
invasive implantation, to better replicate normal cartilage architec-
ture, and to accelerate patient rehabilitation. As of December 2016,
only 1 third-generation ACI product (matrix-induced autologous
chondrocyte implantation, or MACI) has been cleared for marketing
by the U.S. Food and Drug Administration (FDA) and is available in
the United States.

» ACI (regardless of generation) is effective for the treatment of high-

grade tibiofemoral cartilage defects. However, issues with coronal
alignment, ligament laxity/instability, and meniscal deficiency must
be addressed or the outcomes following ACI will be poor.

» Because of the extended time that is required for graft maturation,

special consideration must be given to return-to-play protocols as
athletes can regain strength and neuromuscular coordination well
before the graft has sufficiently matured.

T
he complex structure of ar-
ticular cartilage allows for
nearly frictionless gliding and
effective shock-absorption in
joints throughout the body, but it has limited
regenerative potential when injured1,2. The
most common locations for chondral lesions
in the knee in athletes are the patellofemoral
joint (37%, including the trochlea [24%] and
patella [13%]), followed by the femoral
condyle (25%) and the tibial plateau (25%)3.
Patients with symptomatic defects often will
present with long-standing activity-related
knee pain and swelling4.
Operative intervention for cartilage de-
fects is reserved for symptomatic lesions that
fail to respond to conservative treatment5-8,
and multiple procedures for addressing high-
grade cartilage defects in young active patients
have been described (Table I)5,6,9-12. Among
the treatments with published long-term
outcomes data and commercial availability in
the United States, microfracture and osteo-
chondral autograft transfer (OAT) or
mosaicplasty are effective, inexpensive op-
tions for defects measuring ,2 cm in
diameter2,10,13. Osteochondral allografts
(OCA) are another important treatment

Disclosure: No external funds were received in support of this study. On the Disclosure of Potential
COPYRIGHT © 2018 BY THE JOURNAL Conflicts of Interest forms, which are provided with the online version of the article, one or more of the
OF BONE AND JOINT SURGERY, authors checked “yes” to indicate that the author had a relevant financial relationship in the
INCORPORATED biomedical arena outside the submitted work (http://links.lww.com/JBJSREV/A293).

JBJS REVIEWS 2018;6(2):e5 · http://dx.doi.org/10.2106/JBJS.RVW.17.00078 1

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TABLE I Surgical Treatment Options for High-Grade Cartilage Defects in Young Active Patients*

Treatment Advantages Disadvantages

Microfracture Inexpensive; works well on Symptom relief tends to decline over

small defects ,2 cm2 time; worse results seen when used
on larger defects
Osteochondral autograft transfer Inexpensive; excellent Cannot be used on larger defects;
(OAT)/mosaicplasty treatment option for defects potential for donor-site morbidity
,2 cm2 in athletes
Osteochondral allograft (OCA) Fast rehabilitation protocol; Expensive; availability of allograft
can be used on defects of dictates surgery scheduling; limited
varying size and subchondral options for revision if graft fails
bone involvement; ideal for
athletes with large defects
who cannot commit to a long
recovery
Autologous chondrocyte Durable symptom relief; Expensive; requires a 2-stage
implantation (ACI)† superior clinical operation; historically long
improvement versus rehabilitation protocol for first and
microfracture; can treat large second-generation ACI; however,
defects recent trials have demonstrated
safety of accelerated return to sports
(9 months) with MACI

*All listed therapies have at least 5-year outcomes data and are commercially available in the United States. Multiple additional
treatment options have been reported but either lack long-term outcomes data or are not commercially available in the U.S.
†The advantages and disadvantages of ACI are discussed in greater detail throughout this review.

option as they can be used for defects of
various sizes and those with subchondral
bone involvement and have been shown to
allow for fast rehabilitation and return to
sports10,14. Finally, autologous chondro-
cyte implantation (ACI) is a cell-based
cartilage-restoration therapy that has been
the topic of substantial research over the
last several decades. Recently, third-
generation ACI, known as matrix-induced
autologous chondrocyte implantation
(MACI), has been cleared for
marketing by the U.S. Food and Drug
Administration (FDA). The purpose of
the present article is to review the current
literature regarding use of ACI for the
treatment of articular cartilage defects of
the knee. In this review, we will outline
the basic science, currently accepted
indications and contraindications,
surgical techniques, outcomes, and limi-
tations of ACI.
Basic Science
Articular cartilage has unique charac-
teristics resulting from the complex re-
lationship of chondrocytes and an
extracellular matrix composed of colla-
gen fibers and proteoglycans1. The
proteoglycans provide elasticity,
whereas the cross-linked collagen fibers
provide stiffness and shear strength1.
The cellular portion represents only 1%
to 3% of the total tissue mass1. The

TABLE II Stages of ACI Graft Maturation

Stage Time Frame Graft Characteristics

Implantation 0 to 6 wk Chondrocytes in solution, extracellular

matrix has not yet formed
Transition/proliferation stage .6 to 12 wk Soft, primitive repair tissue
Early maturation stage .12 to 26 wk Repair begins to solidify; matrix consists
mainly of type-II collagen, aggrecan, and
other matrix proteins; defect is not
completely filled
Late maturation stage .26 wk to 3 yr Defect filling completes; chondrocytes and
matrix have reached full maturity;
integration between repair tissue graft,
native cartilage, and underlying
subchondral bone is complete

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extracellular matrix is composed high rate of type-II collagen expression Indications

of specific glycosaminoglycans,
including chondroitin sulfate and
keratan sulfate as well as hyaluronan15.
Glycosaminoglycans are located
around the chondrocytes and link the
chondrocytes together along with
other components of the extracellular
matrix.
The goal of cartilage-restoration
procedures is to reconstitute the native
articular surface with mature and orga-
nized hyaline or hyaline-like
cartilage1,5,6,11,16,17. DiBartola et al.
showed that a higher proportion of hy-
aline cartilage in repair tissue correlated
with better clinical outcomes6. Some
third-generation ACI scaffolds have
been designed to assist in the preserva-
tion of the chondrogenic phenotype of
the implanted chondrocytes18. A recent
study analyzed the gene expression of the
cultured chondrocytes that were
implanted during 30 third-generation
ACI procedures and demonstrated a
highly chondrogenic phenotype and a
without dedifferentiation19.
Four clear stages of tissue matu-
ration following ACI have been iden-
tified (Table II)15. The first stage (0 to
6 weeks after implantation) is the
implantation stage15. During the
transition and proliferation stage (.6
to 12 weeks), the cultured chondro-
cytes begin to fill the chondral defect
with repair tissue that is soft and
primitive15. During the early matura-
tion stage (.12 to 26 weeks), the
chondrocytes begin to produce a ma-
trix of mainly type-II collagen, aggre-
can, and other matrix proteins and the
soft repair graft begins to solidify15.
During the late maturation stage (.26
weeks to 3 years), new tissue com-
pletely fills the lesion and chondro-
cytes and matrix reach full maturity
and expression of hyaline/hyaline-like
cartilage15. Integration between the
repair-tissue graft, native cartilage, and
underlying subchondral bone is
complete15.
Several general indications for ACI are
widely accepted in the literature (Table
III). The patient must be willing to
commit to the extended recovery process
required for ACI. The ACI procedure
historically has been employed follow-
ing the failure of a prior cartilage pro-
cedure such as chondroplasty or
marrow-stimulating procedures; such
prior procedures often have been
selected because of lower cost or a shorter
recovery process5. Ruta et al. reported
that ACI is the most frequently utilized
operative technique after an initial failed
surgical intervention5. However, it
should be noted that failure rates for ACI
as a revision procedure are higher than
for ACI as an initial procedure20, and
most insurance companies cover use of
MACI for isolated symptomatic lesions
involving $2 cm2 of the femoral con-
dyle or patella.
The standard ACI procedure can
be applied to high-grade lesions without
subchondral bone involvement.

TABLE III Indications and Contraindications for ACI*

Indication Contraindication

Failed microfracture surgery or other
cartilage procedure
Willingness to undergo a long rehabilitation
process; faster RTS protocols (9 months)
after MACI than after first or second-
generation ACI (10 to 18 months)
Desire to return to sports or high-impact
activities
High-grade femoral condylar cartilage
lesions with or without shallow subchondral
bone involvement
Lesion size $2 cm2
Younger age, particularly ,25 years;
however, ACI results less affected by
increased patient age than microfracture9
Continued symptoms after an adequate trial
of nonoperative treatment (physical therapy
and activity modification)
More aggressive initial treatment can be
considered for young athletes presenting
with large lesions
Deep (.8 mm) subchondral bone involvement
Patient unable or unwilling to comply with long
rehabilitation process/activity restrictions during
recovery
.50% joint-space narrowing on weight-bearing
radiographs22
Obesity (defined as BMI .35 kg/m2)29
Tobacco use30
Inflammatory arthropathy22
Unaddressed causes of increased loading (knee coronal
alignment, meniscal deficiency, ligamentous laxity,
patellar maltracking)22
ACI for use on patellar lesions is an off-label indication
for first and second-generation ACI but is covered by
most insurers for MACI; good outcomes have been
reported when patellar maltracking addressed33,34

*RTS 5 return to sports, and BMI 5 body mass index.

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Additionally, lesions with shallow sub-
chondral bone involvement can be
addressed with ACI and simultaneous
bone-grafting via the so-called sandwich
technique21. ACI is an accepted first-
line treatment option for large femoral
condylar defects in active patients22.
Although the definition of large varies, a
widely accepted value is $2.0 cm2. ACI
also should be considered to be a reliable
option for patients seeking to return to
physical activity or competitive and
professional athletics involving high-
impact joint forces as it offers superior
results in comparison with allograft
transfer and microfracture surgery23.
The best results have been reported for
patients under 25 years of age24, al-
though patients 25 to 40 years old25 and
selected patients above 40 years old also
can have good results26-28. Results are
improved if the cartilage lesions are
treated early, within 12 to 18 months
after the initial onset of symptoms10.
Contraindications
Several general contraindications have
been proposed for ACI (Table III). Pa-
tients demonstrating concurrent
degenerative disease, particularly .50%
joint-space narrowing on weight-
bearing radiographs, are not ideal can-
didates22. Inflammatory arthritis is also a
proposed relative contraindication, al-
though this proposal is based on expert
opinion as we are not aware of any
studies that have evaluated the outcomes
of ACI in this setting22. Patients with a
body mass index (BMI) of .35 kg/m2
have worse outcomes after cartilage-
repair therapies29. Tobacco use also has
been associated with worse outcomes
after ACI30. Any potential cause of ex-
cessive loading of the graft site (meniscal
deficiency, coronal malalignment, pa-
tellar maltracking, or ligamentous laxity)
must be addressed before or during the
ACI procedure22. Full recovery follow-
ing ACI historically has been extensive
and can take as long as 18 months10,
although accelerated rehabilitation pro-
tocols following MACI have been able to
return patients to activities within 9
months31,32. Regardless, patients who
cannot participate in the necessary re-
habilitation or comply with postopera-
tive restrictions may not be optimal
candidates for ACI. Finally, the use of
older (first and second-generation) ACI
for the treatment of the patella is an off-
label indication in the United States.
Although good results have been repor-
ted following the use of ACI for such
lesions, the results perhaps are not as
good as those following the use of ACI
for isolated trochlear lesions33,34. The
use of MACI for the treatment of pa-
tellar lesions is covered by most insur-
ance companies in the U.S.
Techniques
A major difference between ACI and
other cartilage-restoration procedures is
that ACI requires 2 stages (Table IV).
The first stage is an autologous chon-
drocyte harvesting procedure. The
chondrocytes are typically harvested
arthroscopically from lesser weight-
bearing areas, most commonly on the
distal femoral notch. The goal is to har-
vest 200 to 300 mg of cartilage, which
then undergoes in vitro culture expan-
sion. The in vitro culture expansion
utilizes industrial techniques that
maintain the chondrocyte’s basic phe-
notype but increase the total number of
chondrocytes. Individual protocols vary

TABLE IV Technique Considerations

Stage 1: chondrocyte harvest Native cartilage (200 to 300 mg) harvested from low-
contact area of intercondylar notch or trochlea;
chondrocytes proliferated in vitro
Stage 2: graft implantation and periosteal Graft implantation can occur as early as 5 to 9 weeks
patch harvest (first-generation ACI only) after initial cartilage harvest. Periosteum is harvested
from the anteromedial aspect of proximal part of tibia, 3
to 5 cm below pes anserinus insertion
Approach Mini-arthrotomy necessary for first and second-
generation ACI; mini-arthrotomy or arthroscopic
implantation for third-generation ACI
Defect preparation Unstable cartilage must be removed until there is a
stable rim with vertical shoulders; calcified cartilage
layer removed with a ring curet; subchondral bone cysts
addressed with bone-grafting (sandwich technique); if
subchondral bone is sclerotic (often the case with prior
failed microfracture or chronic lesions), burr until a thin
rim remains
Graft seal For first and second-generation defects, seal must be
watertight to prevent leakage; periosteal/collagen
patch circumferentially sutured in place and sealed with
fibrin glue
Graft handling Minimize manipulation of chondrocytes; excessive
manipulation can increase cell death

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by vendor, but most utilize an initial
collagenase digestion to free chondro-
cytes from minced cartilage, followed by
culture within liquid media35.
The second stage of the ACI pro-
cedure is chondrocyte reimplantation
into the defect, typically 5 to 9 weeks
after the initial procedure36. Proper
preparation of the chondral defect is
imperative at the time of reimplanta-
tion15. The walls of the defect are
debrided to stable, healthy cartilage15.
The lesion is debrided down to the
subchondral bone and calcified cartilage
is removed, with particular care being
taken not to penetrate the subchondral
bone if possible15. The sandwich tech-
nique involving ACI and concomitant
bone-grafting can be utilized to address
lesions with shallow subchondral bone
involvement21. The second stage of the
contemporary third-generation ACI
procedure (MACI) is most commonly
performed through a mini-arthrotomy.
Performing the second stage of MACI
procedures utilizing an all-arthroscopic
technique also has been shown to have
successful clinical results32,36.
The first-generation ACI proce-
dure involves the use of a periosteal
patch that is harvested from the subject
and sutured over the defect5. The cul-
tured cells are then injected under the
periosteal patch into the defect5. A
common complication associated with
the first-generation procedure is perios-
teal patch hypertrophy in the years fol-
lowing the procedure, necessitating
additional procedures to debride the
periosteal patch overgrowth5.
The second-generation ACI pro-
cedure was developed to address the
complications associated with the initial
technique and to improve the ease of the
procedure. The chondrocyte culture
suspension is covered with a bio-
absorbable type I and III porcine colla-
gen membrane instead of a periosteal
patch5. Suturing of the patch to articular
cartilage is still necessary, and thus cell
leakage and chondrocyte distribution
can still be an issue.
The third-generation ACI proce-
dure, sometimes also referred to as
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MACI, was developed to decrease
complications associated with suturing a
defect cover over the repair4, to allow the
procedure to be performed minimally
invasively, and to accelerate rehabilita-
tion of the patient. This technique in-
volves the implantation of a
chondrocyte-seeded biocompatible
scaffold in the articular defect5. The
implant is fixed in place with fibrin glue
and no membrane cover. Third-
generation ACI can be performed as an
all-arthroscopic procedure for reim-
plantation or with use of a mini-
arthrotomy, although a recent cadaveric
study demonstrated decreased cell via-
bility in association with the use of an all-
arthroscopic technique32,36.
Cell Viability for Implantation
Mechanical manipulation of chondro-
cytes can cause cell death, and the extent
of cell death is proportional to the
amount of cell handling36. Chondro-
cytes for first and second-generation
ACI implantation are delivered from the
laboratory in a suspension. Chondro-
cytes for the third-generation procedure
are preloaded onto a membrane scaffold
at the laboratory and are delivered ready
for implantation36. The amount of
handling and manipulation of the im-
plant to prepare it for an arthroscopic
procedure may lead to additional chon-
drocyte cell death36. A small cadaveric
study by Biant et al. demonstrated that
16 times more viable cells remain on the
membrane scaffold after implantation
when the procedure is performed via a
mini-arthrotomy as compared with
arthroscopically36.
Outcomes
The ACI technique has now been in use
for .20 years, and outcomes have been
reported with regard to defect size, age,
return to sports, use in revision surgery,
failure rates, functional outcomes,
imaging and histological outcomes, and
cost efficacy (Table V). It should be
noted that most long-term ACI out-
come studies have evaluated the results
of early-generation ACI techniques; it is
possible that newer-generation
|
techniques may afford improved long-
term outcomes, although this has yet to
be definitively proven.
Defect Size
Currently, ACI is not often utilized for
small chondral lesions (,2 cm2)23,37, al-
though lesions measuring $2 cm2 have
been well studied. Bentley et al.38, in a
randomized controlled trial involving
100 patients who were followed for a
minimum of 10 years, compared the re-
sults of ACI and OAT for the treatment of
lesions measuring .4 cm2. The ACI
group experienced better functional out-
come scores and lower failure rates (17%
compared with 55%)38. ACI has dem-
onstrated superior outcomes compared
with microfracture for the treatment of
large lesions23. Although ACI is currently
recommended for larger defects, studies
have demonstrated declining outcomes as
defect size increases24. In a case series of
45 elite soccer players treated with ACI,
those who reported excellent or good
outcomes had smaller defect sizes com-
pared with those who reported fair or
poor results (5.0 6 0.5 compared with
8.5 6 1.9 cm2, p , 0.05)23. The players
who reported excellent or good results
also had a greater likelihood of returning
to sport, indicating that improved results
are associated with smaller “large” defects.
Treatment After Initial Failure
ACI historically has been used in the
revision setting after a failed previous
cartilage procedure, most commonly
microfracture or chondroplasty5. The
failure rates of ACI in the revision
setting are higher than those in the
primary setting; Minas et al. reported
that the failure rate was substantially
higher following ACI performed
after a failed microfracture (26%) than
it was following ACI performed as a
primary procedure (8%)20.The
failure rate for ACI as a revision pro-
cedure as reported by Minas et al.20
(26% after a minimum of 2 years of
follow-up) is similar to
that reported by Zaslav et al.39 in a
noncomparative study (24% after 4
years of follow-up).
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TABLE V Outcomes of ACI*

Outcomes by defect size • Limited data for small defects (,2 cm2)
• Best outcomes demonstrated for defects measuring $2 cm2
• Very large defects (mean, 8.5 cm2) have worse outcomes than smaller
“large” defects (4 to 8 cm2)23
Return to sports • Higher RTS rates with ACI than microfracture10
• Average time to RTS for first and second-generation ACI is 10 to 18
months10
• Safety of accelerated RTS protocols demonstrated for MACI31,32
• RTS outcomes best in high-level athletes with short duration of symptoms24
Outcomes by age • Best results for patients ,25 years of age24, good results for patients 25 to
40 years of age25
• Some decline in results with age, but ACI performs better than
microfracture for patients .40 years of age26-28
Clinical failure rates • Overall 10-year failure rates reported to range from 17% to 26%38
• Failure rates higher after revision of primary cartilage surgery (24% to
26%) than after primary treatment (8%)20,39
• Failure rates higher for large, chronic (median, 3 years) lesions (42.5%)50
Imaging-based outcomes • MRI findings often do not match clinical improvement5
• Subchondral edema, cysts, or intralesional osteophytes often present
even with high patient-reported knee function23
Histological outcomes • Hyaline-like tissue produced in most cases5
• Hyaline content appears to increase with time6, matches hyaline content
of age-matched cadaveric tissue by 20 months postop52.
Cost efficacy • ACI is cost-effective over time
• Up-front costs are high, and almost all additional costs occur early as a
result of early failure or reoperation
• Cost-efficacy estimates for cost per QALY over 10 years have ranged from
$6,791 to $9,46612,55

*RTS 5 return to sports.

Return to Sports
Given the high incidence of cartilage in-
juries in athletes, return to sports is often
one of the major treatment goals.
Campbell et al., in a recent systematic re-
view, found increased rates of return to
sports after OAT or ACI as compared
with microfracture surgery but found no
significant differences between OAT and
ACI or between first and second-
generation ACI10. Krych et al., in a recent
meta-analysis of 46 studies with a mean
duration of follow-up of 47 months,
reported that the rate of return to some
level of sports activity (not necessarily the
pre-injury level) was more frequent after
treatment with OAT (93%), OCA
(88%), and ACI (82%) than after micro-
fracture (58%)13. In the meta-analysis,
OAT provided the fastest return to sports
(5.2 6 1.8 months) compared with
microfracture, OCA, and ACI13. Most
providers do not clear athletes to return to
sports until 10 to 18 months following
first or second-generation ACI, although
earlier clearance may be indicated for
low-impact activities10. However, accel-
erated rehabilitation protocols have been
shown to safely return patients to activities
within 9 months after MACI31,32.
Kon et al., in a study of professional
and semiprofessional soccer players
returning to sports after either micro-
fracture or second-generation ACI
surgery, found similar International Knee
Documentation Committee (IKDC)
scores at 2 years of follow-up; however,
both IKDC scores and the level of sports
activity decreased steadily from 2 years to
the latest follow-up (mean, 7.4 years) in
the microfracture group, whereas out-
comes were stable in the ACI group40.
Mithöfer et al. also analyzed professional
and recreational soccer players (n 5 45)
who underwent ACI24. In that study,
33% of the players returned to soccer,
including 83% of competitive-level
players and 16% of recreational players.
Of the returning players, 80% returned to
the same competitive level and 87%
maintained their level of performance.
They noted that return to sports was most
successful for young (,25 years), high-
level athletes with a shorter duration of
preoperative symptoms24. In another
study evaluating return to high-impact
sports, a higher competitive level and an
age of ,40 years were found to be positive
predictors of return to sports25. Mithöfer
et al. suggested that the longer duration of

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symptoms more commonly seen in rec-
reational athletes could result in more
baseline deconditioning at the onset of
ACI rehabilitation24. In addition, Bjordal
et al. reported that high-level athletes may
have greater motivation to return to sports
after knee surgery, whereas recreational
athletes may choose not to return to sports
because of changing social demands and
avoidance of additional injuries41.
Age
Age limits for the use of ACI are not well-
defined. Younger patients (,25 or ,40
years of age, depending on the study) have
demonstrated an increased rate of im-
proved outcomes and operative success
after ACI24,42,43, although good out-
comes have been demonstrated following
ACI in appropriately selected patients
.40 years of age28,44. Cvetanovich et al.,
in a recent study of patients under the age
of 18 years who were followed for a mean
of .4 years, found that first-generation
ACI was effective for the treatment of
symptomatic, large chondral defects in
adolescent patients45. Despite a high early
reoperation rate of 37.8%, all patients in
the study population reported substantial
improvement in comparison with pre-
operative IKDC and Knee injury and
Osteoarthritis Outcome Score (KOOS)
quality-of-life scores. Another recent
study evaluated 40 patients under the age
of 20 years who were managed with third-
generation ACI and were evaluated for
clinical improvement over 3 years4.
Again, all patients experienced improved
clinical findings compared with matched
adult patients at 6, 12, 24, and 36 months.
Complications, Failure Rates, and
Functional Outcomes
The rate of unplanned reoperations after
first-generation ACI has been reported
to be 27%, primarily for the treatment of
issues with periosteal patch hypertro-
phy, compared with a rate of ,10%
after later-generation ACI5,46. Arthro-
fibrosis is the most commonly reported
complication after arthrotomy-based
ACI procedures46. Failures after ACI
typically occur early, with the majority
of failures occurring within 24 months
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after graft implantation46. Other, less
frequent complications have included
graft delamination, cell leakage, and
complications associated with uneven
chondrocyte transplant distribution5.
As the duration of follow-up con-
tinues to increase, the durable im-
provement in symptoms following ACI
distinguishes this procedure as a valuable
treatment option47. Improvement in
quality of life has been reported in short
and intermediate-term outcomes
studies12,48, although athletes with
symptomatic lesions may experience
greater benefit from ACI in comparison
with non-athletes. Della Villa et al.
compared the results of ACI in athletes
(n 5 31) and non-athletes (n 5 34) and
found that the non-athletic group
demonstrated a lower final IKDC score
at 5 years of follow up than the athletic
group (mean IKDC score [and standard
deviation], 75.7 6 22.4 compared with
90.7 6 11.7)42.
Most long-term studies have
demonstrated durable results following
ACI. A recent 10-year follow-up study
of 100 patients who were managed with
either OAT or ACI showed that the ACI
group had a significantly decreased fail-
ure rate compared with the OAT group
at 10 years (17% compared with 55%; p
, 0.001)38. Another 10-year study, in-
volving 104 patients with a mean
chondral defect size of 4.77 cm2 who
were managed with ACI, demonstrated
a 26% rate of graft failure at 5.7 years49.
Patient-reported functional outcome
scores demonstrated a 63% rate of
excellent results and a 25% rate of good
results, and 98% of all subjects reported
at the end of the study that they would
undergo the procedure again49. How-
ever, it should be noted that higher long-
term failure rates have been reported
following the use of ACI for the treat-
ment of large, chronic lesions. Knutsen
et al., in a recent multicenter random-
ized trial involving patients with large
(median size, 4.5 cm2), chronic (median
duration of symptoms, 36 months)
defects, found high 15-year failure rates
following both ACI (42.5%) and
microfracture (32.5%)50.
|
Histological and Magnetic Resonance
Imaging (MRI) Findings
One perceived benefit of ACI over
microfracture is the ability to regenerate a
more hyaline-like cartilage interface in the
joint6,51. One analysis of second-look
biopsies following ACI demonstrated
that the repair tissue covered most of the
defect area and that a majority of samples
had a hyaline-like new layer5. However,
although the goal is to create a repair of
primarily hyaline cartilage, the superficial
layer of the repaired cartilage displayed
some fibrocartilage properties5. In the
systematic review by DiBartola et al.,
30.9% of first-generation ACI repairs
demonstrated 100% hyaline cartilage and
23.5% of the subjects demonstrated ex-
cellent results according to International
Cartilage Repair Society (ICRS) guide-
lines6. In the same review, 38.3% of
second-generation ACI repairs demon-
strated 100% hyaline cartilage but only
21.5% of the subjects had excellent results
according to ICRS guidelines. For third-
generation ACI repairs, 29.8% of the sites
demonstrated 100% hyaline cartilage and
9% of the subjects had excellent results.
The authors also noted an association of
higher hyaline content with greater time
between surgery and biopsy, suggesting
continued graft maturation with time.
Sharma et al. performed an analysis
of the glycosaminoglycan composition
of repair tissue as compared with age-
matched cadaveric articular cartilage52.
Repair tissue appeared to mature over
time in that study. Biopsy at 12 months
following ACI demonstrated 40% less
hyaluronan when the repair tissue was
compared with the matched cadaveric
tissue; however, by 20 months, the ACI
repair tissue had similar amounts of
hyaluronan as the cadaveric specimens.
Histological evaluations of the
repair-site tissue require an additional
procedure, and noninvasive MRI-based
assessments of cartilage repairs have
been developed. Ruta et al., in a 10-year
follow-up study of 71 subjects, reported
decreased imaging scores as measured
with magnetic resonance observation of
cartilage repair tissue (MOCART) when
ACI repair sites were compared with
7
 | Au t o l o g o u s C h o n d r o c y t e Im p l a n t a t i o n ( AC I ) f o r Kn e e C a r t i l a g e D e f e c t s

TABLE VI Limitations of ACI

High early failure/reoperation rate • Early failure/reoperation rates are high

• Late decline in outcomes less common after ACI than
after microfracture6
Survivorship of hyaline-like tissue compared • ACI produces a higher hyaline content than
with native cartilage unknown microfracture, and greater hyaline content is
associated with better clinical outcomes6
• However, survivorship of “hyaline-like” cartilage
versus native cartilage is unknown
Regional availability varies • Variable availability due to differing international
regulatory requirements57
High up-front costs • High up-front cost of cultured chondrocytes as well as
cost due to early failures or reoperations55
Long delay in graft maturation • Requires long rehabilitation and extended activity
restrictions, delaying return to sports up to 18
months10
• This limitation has been addressed, with recent
studies demonstrating safety of accelerated return to
play at 9 months after MACI31,32

healthy cartilage5. Despite poor imaging
findings, subjects still reported im-
provement when functional outcomes
scores were compared with preoperative
values. Most of the studies in the review
by Zhang et al. demonstrated that de-
spite attempting to repair the chondral
lesion, bone marrow edema, subchon-
dral cysts, and intralesional osteophytes
were often present23.
Defect Filling
Advanced imaging has changed how to
monitor and evaluate operative success.
Niethammer et al., in a recent review,
evaluated the degree of defect filling
associated with third-generation tech-
niques53. Filling was measured on
T2-weighted MRI scans with use of the
ICRS classification system. The greatest
growth of graft thickness (0.3 mm, rep-
resenting an increase of 10.7%) was
observed between the third and sixth
months after the procedure. At the end
of the 2-year study, the graft had reached
maximum thickness compared with the
initial postoperative evaluation, with a
mean growth of 0.44 mm (representing
an increase of 15.7%). The subjects with
decreased amounts of graft filling over
the course of the study had a decreased
amount of graft growth between the
third and sixth months, the period
during which most subjects demon-
strated the greatest growth. There was a
high rate of incomplete defect filling at 2
years (44 implants; 55.7%). Despite
these rates of incomplete graft filling,
these findings did not correlate with a
difference in clinical outcomes as mea-
sured with the IKDC system and a visual
analog scale for pain (VAS).
Cost Analysis
Currently published cost analyses of ACI
have focused on first or second-generation
procedures12,54,55. Such procedures have
high up-front costs in association with
rehabilitation and early failures or reop-
erations, although the durable efficacy of
successful ACI treatment results in a fa-
vorable cost-efficacy estimate for ACI
when viewed over a longer-term period
(such as 10 years)55. Efficacy is often
reported in quality-adjusted life years
(QALYs). In 1998, Minas reported that
the cost per QALY for ACI was $6,79112.
Lindahl et al.54 considered the potential
reduction of sick leave and health re-
sources utilized over 10 years if patients
were to undergo a cartilage-repair proce-
dure; they found that ACI could save
$88,000 over 10 years for defects mea-
suring $2 cm2. Samuelson and Brown, in
a recent study evaluating the costs asso-
ciated with different generations of ACI,
found that the cost per QALY for first-
generation ACI was $9,466, compared
with $9,24355 for second-generation
ACI, with the difference largely attribut-
able to a higher rate of secondary surgery
for first-generation ACI as a result of
periosteal patch hypertrophy55.
Limitations
ACI has several known limitations (Table
VI). Early reoperations and failures are
not uncommon, although the rates of
both appear to be lower in association
with newer-generation ACI5,46.
Although biopsy specimens following
ACI have a hyaline content that is com-
parable with that following other
cartilage-restoration procedures, most
biopsy specimens are not 100% hyaline
cartilage6,9,51; the long-term survivorship
of mostly hyaline cartilage graft in com-
parison with native cartilage is not known
at this time. A major limitation of ACI is
the length of rehabilitation required to
allow the repair tissue adequate time to
remodel and mature, with some studies
demonstrating a delayed return to sports
of as long as 18 months5,10,13,56, although
recent trials have demonstrated the safety
of accelerated return-to-sport protocols
following MACI31,32. Regulatory re-
quirements for medical products differ by
country and may limit the international

8 FEBRUARY 2018 · VOLUME 6, ISSUE 2 · e5


availability of, and research on, ACI57.
Prolonged procedure approval may delay
appropriate delivery of ACI treatment57.
Other limitations include costs and in-
surance reimbursement, particularly for
off-label indications for first and second-
generation ACI, such as patellar lesions,
which respond differently than trochlear
lesions and often require concomitant
procedures like osteotomies33,34.
Conclusion
ACI is an effective technique for the
treatment of articular cartilage lesions in
appropriately selected patients. Ongoing
research will clarify the effectiveness of
newer-generation techniques. As tech-
niques evolve and longer-term outcomes
become available, indications and long-
term expectations will continue to change.
Michael Krill, MD1,
Nicholas Early, MD2,
Joshua S. Everhart, MD, MPH2,
David C. Flanigan, MD1,2
1The
Ohio State University College of
Medicine, Columbus, Ohio
2Sports
Medicine, Department of Ortho-
paedics, Ohio State University Wexner
Medical Center, Columbus, Ohio
E-mail address for D.C. Flanigan: david.
flanigan@osumc.edu
ORCID iD for D.C. Flanigan: 0000-0001-
8876-7043
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