Ongoing studies of cell-based therapies for articular cartilage defects in Japan

Orthopedic Research and Reviews, Dec 2014

Ongoing studies of cell-based therapies for articular cartilage defects in Japan Takahiro Ogura,1 Akihiro Tsuchiya,2 Shuichi Mizuno1 1Department of Orthopedic Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 2Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan Abstract: 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. Keywords: autologous chondrocyte implantation, mesenchymal stem cell, knee joint

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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. - 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 d a o l n w o d s w e i v e R d n a h c r a e s e R c i d e p o h tr O 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 th rso froedm rpeoF rgerpoawirt.h10fHacotwoersv,erw, hhiicstholfoogrimc 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 submit your manuscript | www.dovepress.com Dovepress 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)


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Takahiro Ogura, Akihiro Tsuchiya, Shuichi Mizuno. Ongoing studies of cell-based therapies for articular cartilage defects in Japan, Orthopedic Research and Reviews, 2014, pp. 1-10, DOI: 10.2147/ORR.S74068