Ongoing studies of cell-based therapies for articular cartilage defects in Japan
Orthopedic Research and Reviews
Ongoing studies of cell-based therapies for articular cartilage defects in Japan
Takahiro Ogura 1
Akihiro Tsuchiya 0
Shuichi Mizuno 1
0 Funabashi Orthopaedic Hospital Sports Medicine Center , Funabashi, Chiba , Japan
1 Department of Orthopedic Surgery, Brigham and w omen's Hospital and Harvard Medical School , Boston, MA , USA
Recently, cell-based therapies have generated great interest in the repair of articular cartilage defects and degeneration. Surgical treatments for these indications have multiple options, including marrow stimulation, osteochondral autograft transplant, and autologous chondrocyte implantation. The autologous chondrocyte implantation technique has been improved using a cell scaffold and other devices. Meanwhile, advanced cell-based therapies, including cultured stem cell treatment, have been studied in clinical trials. Most studies have been designed and authorized by institutional review boards and/or the regulatory agencies of the investigators' countries. For cellular products in regenerative medicine, regulations of many countries are amenable to expedited approval. This paper aims to provide an update on ongoing and prospective cell-based therapies, focusing on articular cartilage injury at designated institutions authorized by the Japanese Pharmaceutical and Medical Device Agency.
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Small defects (<2–4 cm2)
MF
<2.5 cm2
Arthroscopic procedure
Only routine instrument needed
OAT
1–4 cm2
Miniarthrotomy
Filled with own hyaline cartilage
Suitable for osteochondral defects
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microfracture.9 The indication for this treatment is generally
a lesion area of less than 2.5 cm2. As this technique can be
conducted minimally invasively and with routine surgical
.vdow l.yno instruments, it is widely used for cartilage defects. This
/ww sue technique involves penetration into the subchondral bone
:/tsp lan to release bone marrow elements, including stem cells and
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faollcolowt-uapndstustdimiesuloaftemcicarrotiflraagceture indicated that cartilage defects were filled with fibrous
tissue between 1 and 2 years post surgery.11,12 Moreover,
the regenerated tissue was biomechanically suboptimal and
eventually failed.13 In randomized studies of microfracture,
the early revision rate was 2.5% before 2 years, 23% at year 2,
and 31% thereafter by year 5.14
Another intervention is OAT, or so-called “mosaicplasty”.
The indication for this treatment is generally a lesion area
within approximately 2–4 cm2. This technique involves
harvesting autologous osteochondral plugs from the
femoral condyle and/or trochlea and transplanting them into the
cartilage defect. Ultimately, the defect is filled with pieces of
harvested hyaline cartilage and the underlying subchondral
bone.15 However, OAT has concerns regarding donor tissue
morbidity, unmatched shape of the host and donor
cartilage surfaces, and a limitation of defect size. Randomized
studies for the same indication regarding the superiority of
OAT compared with microfracture have been somewhat
controversial. Patients treated with OAT had significantly
better clinical outcomes according to the International Cartilage
Repair Society (ICRS) score 10 years postoperatively than
microfracture (P,0.001).16 In addition, OAT maintained a
significantly higher activity level according to Marx Activity
Rating Scale scores than microfracture by 5 years (P=0.02).17
On the other hand, a follow-up study with a median of
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9.8 years indicated no significant difference between OAT
and microfracture based on Lysholm scores, Knee Injury and
Osteoarthritis Outcome Score (KOOS), muscle strength, and
radiographic outcome.18 Therefore, microfracture and OAT
still require more information for appropriate indications
and outcomes.
ACI
ACI was developed in the early 1990s to treat focal defects
in the knee joint.19 Since then, over 15,000 ACI procedures
have been performed in the USA, and over 20,000 had been
performed in Europe by 2010.20 Briefly, ACI requires two
surgeries. First, cartilage fragments are harvested from the
nonweight-bearing site in the patellofemoral condyle. The
fragments are enzymatically digested for isolation of
chondrocytes followed by cell number expansion in monolayer
culture. At the second surgery several weeks after cartilage
harvest, a suspension of the chondrocytes is injected into the
defect, and covered with the harvested periosteum flap from
the tibia of the same leg.
Proof of concept of ACI was demonstrated using a rabbit
model prior to clinical study.21 In this animal model, synovitis
and osteophyte formation are markedly decreased in the joint
treated with ACI compared to the nontreated joint. In
addition, the articular cartilage surface was smooth and glistening
white, similar to normal hyaline cartilage. Histologically, the (...truncated)