Hyaline cartilage forms the articular surface of the
femoral condyle. Studies have shown that implantation of autologous
chondrocytes into the articular defect can result in the development of
hyaline-like cartilage [see Clinical Studies].1,2,3,4,5 Normal
hyaline cartilage consists of chondrocytes ( ≤ 5% total volume) and
extracellular matrix (≥ 95% total volume). The matrix contains a variety
of macromolecules, including type II collagen and proteoglycan. The structure
of the matrix allows the hyaline cartilage to absorb shock and withstand
shearing and compression forces. Normal hyaline cartilage also has an extremely
low coefficient of friction at the articular surface. Damage to articular
cartilage from acute or repetitive trauma often results in pain and disability.
However, because hyaline cartilage is avascular, spontaneous healing of large
defects is not believed to occur in humans.
A variety of surgical procedures have been used in
attempts to promote repair of articular cartilage, and a few studies have
evaluated the histology resulting from these interventions. Generally,
procedures such as marrow stimulation techniques (MST) have been shown to
produce fibrocartilage or hybrid mixtures of fibrocartilage and hyaline
cartilage. Published data show that autologous chondrocyte implantation (ACI)
is more likely than MST to result in hyaline-like cartilage at the repair site.1,2,4,5
However, because of differences in study design, lesion size and concomitant
patient conditions, these data are not sufficient to draw conclusions
concerning the long-term correlation of histology and clinical outcomes.
Animal Pharmacology And/Or Toxicology
Bioactivity of autologous chondrocytes implanted under a
periosteal patch was reported in the BLA for three rabbit studies6,7,8
of up to 52 weeks duration post-implant and one dog study9 of up to
18 months duration post-implant.
Histologic evaluations were performed at 8, 12 and 52 weeks.
Improved healing of experimental defects implanted with autologous chondrocytes
was observed compared to periosteal flap alone at 8, 12 and 52 weeks.
Histologic evaluations were performed at 6 and 12 weeks
and 12 and 18 months. Autologous chondrocytes showed improved healing compared
to both empty defects and to defects covered with periosteum alone at 6 and 12
weeks. However, by the 12 and 18 month evaluations, the repair tissue had
deteriorated so that no advantage of ACI over periosteum alone controls was
Beyond histologic variability of the defect site, no
adverse tissue reaction was identified in any animals in these studies.
Five additional large animal, post-approval studies were
Three of four goat studies were 16 weeks in duration. In
the fourth study, the goats were sacrificed immediately after periosteal
membrane placement. Despite difficulty in post-operative management of goats
and resulting subchondral plate collapse in some animals in the 16-week
studies, results from all four studies suggested that chondrocytes may
contribute to histological repair of focal cartilage lesions. In the only
bilateral joint study, serious subchondral collapse and uniformly poor repair resulted
in inconclusive data. No safety issues were identified in any of these studies.
The 8-week study included two experimental arms in order
to model repair of cartilage lesions with or without subchondral penetration.
Both models exhibited destruction/dislodgement of the periosteal flap; however,
results suggested that chondrocytes may contribute to histologic repair in
cartilage defects with subchondral penetration.
While the defects in all animal models exhibited highly
variable repair tissue quality (resulting in only moderate histologic scores)
the best repairs with implanted chondrocytes produced hyaline-like cartilage
characterized by matrix predominating in type II collagen and saffranin-O or
toluidine blue staining proteoglycan. Chondrocyte labeling in one of the rabbit
studies8 and in an independent study in goats by Dell'Accio et al10
demonstrated that the hyaline-like matrix in these defects was the product of
the implanted autologous chondrocytes.
Clinical information regarding the use of autologous
cultured chondrocytes was obtained from 2 open-label, observational studies
consisting of a series of patients treated in Sweden and the Cartilage Repair
Registry. Patients in the Swedish series received an autologous cultured
chondrocyte product similar to Carticel®.
The series consists of 153 patients who received
autologous chondrocyte implantation for various defects of the knee. Patients
presented with cartilage defects of the femoral condyle, patella, tibia, a
combination of these, or osteochondritis dissecans, with or without comorbidity
such as anterior cruciate ligament insufficiency requiring reconstruction.
Following autologous chondrocyte implantation, patients
were followed for various durations. Clinical followup ranged from 1 week to 94
months; 86 patients had at least 18 months of follow-up. Most patients had arthroscopic
evaluation; a subset had biopsy and histological evaluations. All patients were
retrospectively classified as having one of three clinical outcomes: resumed
all activities, some improvement, or no improvement. Clinical outcomes were
also reported for patient subgroups including: 1) 40 patients with femoral
condyle lesions, 2) 12 patients with osteochondritis dissecans lesions and 3)
22 patients who failed a prior debridement.
Clinical Outcome - Patients With Femoral Condyle Lesions
A total of 78 of 153 patients had femoral condyle lesions
with or without co-morbidity. Patients had one or more defects ranging in size
from < 1-20 cm². Of the patients with femoral condyle lesions, 40 were
evaluable after at least 18 months (median = 25; range = 18 to 94 months).
Clinical outcomes for the 40 patients are summarized in Table 5.
Table 5: Patient Response to Treatment
||Resumed All Activities
|Femoral Condyle plus other Non-Cartilage Repair
Clinical Outcome - Patients With Osteochondritis
Of the 12 patients who received autologous cultured
chondrocytes for treatment of an osteochondritis lesion, 6 of the 12 had “resumed
all activities”, 4 had “some improvement” and 2 had “no improvement” after the
18-month (median = 25; range = 18-94 months) follow-up period.
Clinical Outcome - Failed Earlier Procedures
Debridement of the cartilage defect is often performed
along with administration of autologous cultured chondrocytes. To help
differentiate the effects of the autologous cultured chondrocyte implantation
procedure from those of debridement alone, an analysis was performed on 22
patients who had failed prior debridement and had a follow-up period after
autologous cultured chondrocyte implantation which was at least as long as the time
period to failure of their initial debridement. At the end of follow-up, 5 of
the 22 patients had a functional outcome rating of “resumed all activities”, 8
of the 22 patients had a rating of “some improvement” and 9 of the 22 patients
had a rating of “no improvement”. Thus, 13 of the 22 patients (59%) who had
failed an earlier debridement had outcomes that were more favorable and durable
following autologous cultured chondrocyte implantation than their previous
debridement without cells.
Twenty-two (22) patients in the Swedish series had
histological evaluation of biopsies from the implant site one or more years
after their autologous chondrocyte implantation. Fifteen (15) of those patients
had defects of the femoral condyle and 7 had defects of the patella. Six (6) of
the 15 femoral condyle biopsies showed hyaline-like cartilage, 5 had a mixture
of hyaline and fibrocartilage, and 4 had only fibrocartilage. Of the 6 biopsies
with hyaline-like cartilage, 2 had minimal to no surface irregularities and 4
had some surface irregularities (e.g., fissures, fibrillations, etc.).
As an objective outcome evaluation, 86 of the 153
patients had a follow-up arthroscopy for investigational purposes at 18 months
or more post-implantation. In some cases, the quality of repair observed at
arthroscopy was considered to be supportive of the clinical or functional
outcomes. A substantial number of patients were noted at arthroscopy to have
tissue hypertrophy [see ADVERSE REACTIONS].
Cartilage Repair Registry
The Cartilage Repair Registry (CRR) was established upon
the introduction of Carticel® into orthopedic practice in March of 1995. The
CRR was designed to prospectively collect the clinical outcomes of Carticel and
other cartilage repair treatments for chondral lesions in the knee. Clinical
data were collected at baseline arthroscopy, implantation, intervals of 6 and
12 months, and annually thereafter; adverse reaction data were collected on an ongoing
basis through CRR adverse reaction collection and spontaneous reporting.
Inclusion in the CRR was based on a qualifying event that was defined as a knee
arthroscopy in which a chondral lesion was identified and a cartilage biopsy
was harvested. Participation in the CRR was voluntary, and not all patients
biopsied or implanted were included. As of November 21, 1997, 891 patients had
been implanted worldwide, and 644 of these patients were included in the CRR.
Functional outcomes were based on responses to a modified version of the
Cincinnati Knee Rating System.
Data from a subset of 191 US patients in the CRR as of
December 31, 1996 who had undergone repair of lesions on the femoral condyle
(medial, lateral or trochlea) were assessed to support licensure. Patients were
between the ages of 15-57, 66% (126/191) were male, and 34% (64/191) were
female and one patient's gender was not reported. Of these 191 patients, 38 had
at least 12 months of follow-up. At study baseline, these 38 patients' mean
rating of overall condition was 3.2, which is defined as fair to poor:
limitations that affect activities of daily living-no sports possible. At 12
month follow-up, these patients reported an overall condition score of 6.4
defined as good: some limitation with sports but can participate if patient
compensates. Although these patients were rated according to outcome
measurements different from those used in the Swedish series, the results were consistent
with the Swedish experience.
Two post-approval studies were conducted and completed as
a condition of approval for Carticel®: the Registry Based Study (RBS) and the
Study of the Treatment of Articular Repair (STAR).
Registry-Based Study (RBS)
The RBS was a retrospective analysis of data collected
for a cohort of 97 US patients treated between March of 1995 and March of 1997.
Of the 97 patients enrolled, 95% completed 1-year follow-up, 80% completed
2-year follow-up and 74% completed 3-year follow-up. Of these 97 patients, 44
were part of the subset of 191 US patients in the CRR described above. A
limitation of this study is the lack of a control group. Patients included in this
study had a prior non-Carticel cartilage repair procedure (e.g., debridement or
marrow stimulation procedure) performed at the time of the index arthroscopy,
subsequently failed this procedure and went on to receive Carticel. In the 5
years prior to the index arthroscopy for the study, this patient population had
received prior knee surgeries to include: 47% (46/97) of patients had at least
one debridement/lavage of a cartilage defect, 25% (24/97) of patients had a
bone marrow stimulation procedure, 31% (30/97) had at least one diagnostic
arthroscopy, 30% (29/97) had at least one meniscus repair/meniscectomy and 10%
(10/97) of patients had a ligament repair/reconstruction performed on the
Using a modified Cincinnati Knee Rating System at study
baseline, this patient population had a mean overall condition score of 3.1
defined as fair to poor: limitations that affect activities of daily living-no
sports possible. Patients included were between the ages of 16-56, 69% (67/97)
were male and 31% (30/97) were female. For the type of defect, 62% (60/97) of
the defects were acute while 37% (36/97) were chronic. Of the treated defects, 75%
(73/97) were treated on the medial femoral condyle (MFC), 26% (25/97) on the
lateral femoral condyle (LFC) and 19% (18/97) on the trochlea. Adverse
reactions collected during this study are provided in Adverse Reactions (6).
Study Of The Treatment Of Articular Repair (STAR)
The STAR study was an open-label within patient
comparison of a prior non-Carticel (index) procedure to implantation of
Carticel for articular cartilage defects of the distal femur. All patients had
experienced an inadequate response to a prior non-Carticel surgical treatment,
defined as both: a) patient and surgeon agreement that the patient's
symptoms/function required surgical re-treatment of the defect and b) the
patient's rating of the overall condition of the knee was a score ≤ 5
using the Modified Cincinnati Knee Rating System. In this patient population,
the median time to meet the failure criteria was 3.4 months for the prior
non-Carticel procedure and 90% of patients failed within 10.3 months. Patients
who met these criteria were treated with Carticel and assessed every 6 months
for up to 4 years.
Treatment failure for Carticel was defined as any of the
following: a) the patient underwent surgical retreatment that violated the
subchondral bone or reimplantation with Carticel for the same index defect, b)
complete delamination or removal of the graft, or c) the patient's rating of
the overall condition of the knee using the Modified Cincinnati Knee Rating
System failed to improve from the baseline knee score over 3 consecutive 6-month
A total of 154 patients were treated with Carticel. At
the index surgery required for study entry, patients had one or more of the
following interventions: 120 patients (78%) had debridement, 44 patients (29%)
had microfracture, 18 (12%) had subchondral drilling, 10 (6%) had abrasion
arthroplasty, and 7 (5%) had an osteochondral autograft. The mean lesion size
was 4.6 (Â} 3.2, SD) cm². Fifty patients (32%) had multiple lesions in the
reference knee and 29 patients had Carticel implanted in more than one lesion.
Lesions that were implanted were located on the medial femoral condyle in 109
patients, lateral femoral condyle in 32 patients and trochlea in 46 patients.
Forty patients (26%) had lesions which involved osteochondritis dissecans
Of the 154 patients treated with Carticel, 28 patients
discontinued the study early. The numbers of patients completing the 24 and 48
month follow-up visits are 136 and 115, respectively. The majority of Carticel
patients (N= 117) did not meet failure criteria during the study. By the end of
the study, a total of 37 patients met the treatment failure criteria. Results
for the 40 patients with OCD lesions were comparable to the total study population
as 34 (85%) did not meet the failure criteria for the study and 6 (15%) failed
treatment with Carticel. Table 6 illustrates, during each year of follow-up,
the number of patients who failed Carticel by the surgical criteria along with
the number of patients who failed by the Overall Modified Cincinnati scale
Table 6: Category and Timing of Treatment Failure for
Patients who Met Treatment Failure Criteria (N=37)
|Patients who Failed During the Interval
|Overall Modified Cincinnati Scale criteria
The Overall Modified Cincinnati mean baseline score for
the patient population as a whole was 3.26, poor: significant limitations that
affect activities of daily living, to fair: moderate limitations that affect
activities of daily living, no sports possible. At 48 months, the mean score
was 6.39, good: some limitations with sports but can participate/compensate.
The improvement was statistically significant. Table 7 shows the improvement in
the Overall Modified Cincinnati score over time.
Table 7: Mean Overall Modified Cincinnati Score at
Baseline and Follow-up Visits
|Overall Modified Cincinnati Score1 Mean (SD)
|1Scores are for patients who returned for
follow-up. Patients who failed by score criteria are included and patients who
failed by surgical criteria are excluded from the scores for timepoints after
the failure criteria were met.
In addition to the change over time in activity level as
measured with the Overall Modified Cincinnati Scale, there were similar and
consistent changes in knee symptoms and function as measured with the Knee
Injury and Osteoarthritis Outcome Score (KOOS), a measure of knee-specific
symptoms and function consisting of the following five subscales: pain,
symptoms, sports and recreation, knee-related quality of life, and activities
of daily living. At 12 months post-Carticel® implant, the mean improvement from
baseline for the patient population as a whole in each subscale was as follows:
pain 19 (N = 146), symptoms 15 (N = 147), sports and recreation 17 (N = 129), knee-related
quality of life 18 (N = 147), and activities of daily living 18 (N = 145). At
48 months post-Carticel implant, the mean improvement from baseline was as
follows: pain 24 (N = 100), symptoms 19 (N = 101), sports and recreation 31 (N
= 86), knee-related quality of life 32 (N = 101), and activities of daily
living 23 (N = 99). Adverse reactions collected during this study are provided
in Adverse Reactions.
1. Knutsen G, Engebretsen L, Ludvigsen T, et al. Autologous
chondrocyte implantation compared with microfracture in the knee. J Bone Joint
Surg, 2004; 86A:455-464.
2. Bentley G, Biant LC, Carrington RWJ, et al. A
prospective, randomized comparison of autologous chondrocyte implantation
versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg
3. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of
deep cartilage defects in the knee with autologous chondrocyte transplantation.
N Engl J Med. 1994;331:889-895.
4. Peterson L, Minas T, Brittberg M, et al. Two- to
9-year outcome after autologous chondrocyte transplantation of the knee. Clin
5. Peterson L, Brittberg M, Kiviranta I, et al. Autologous
chondrocyte transplantation. Biomechanics and longterm durability. Am J Sports
6. Peterson L, Menche D, Grande D, et al. Chondrocyte
transplantation-an experimental model in the rabbit. Transactions from the 30th
Annual Orthopedic Research Society, Atlanta, February 7-9, 1984. Palatine, III.:Orthopedic
Research Society, 1984:218. Abstract.
7. Grande DA, Pitman MI, Peterson L, et al. The repair of
experimentally produced defects in rabbit articular cartilage by autologous
chondrocyte transplantation. J Orthop Res. 1989;7(2):208-18.
8. Brittberg M, Nilsson A, Lindahl A, et al. Rabbit
articular cartilage defects treated with autologous cultured chondrocytes. Clin
Orthop Relat Res. 1996 May;(326):270-83.
9. Breinan H, Minas T, Barone L, et al. Histological
evaluation of the course of healing of canine articular cartilage defects
treated with cultured autologous chondrocytes. Tiss Engin 1998; 4(1):101-14.
10. Dell'Accio F, Vanlauwe J, Bellemans, et al. Expanded
phenotypically stable chondrocytes persist in the repair tissue and contribute
to cartilage matrix formation and structural integration in a goat model of
autologous chondrocyte implantation. Journal of Orthopaedic Research 21 2003;