Jae-Deog Jang

A multi-center, randomized, clinical study to compare the effect and safety of autologous cultured osteoblast(Ossron™) injection to treat fractures

BackgroundWe performed a multicenter, open, randomized, clinical study of autologous cultured osteoblast injection for long-bone fracture, to evaluate the fracture healing acceleration effect and the safety of autologous cultured osteoblasts.MethodsSixty-four patients with long-bone fractures were randomly divided into two groups, i.e. those who received autologous cultured osteoblast injection and those who received no treatment. The sum of the difference in the callus formation scores after four and eight weeks, was used as the first efficacy variable.ResultsThe autologous cultured osteoblast injection group showed fracture healing acceleration of statistical significance, and there were no specific patient complications when using this treatment.ConclusionAutologous cultured osteoblast injection should therefore be considered as a successful treatment option for treating long-bone fracture.Trial registrationCurrent Controlled Trials ISRCTN10637905

Potential Application of Temozolomide in Mesenchymal Stem Cell-Based TRAIL Gene Therapy Against Malignant Glioma

Because the tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) selectively kills tumor cells, it is one of the most promising candidates for cancer treatment. TRAIL‐secreting human mesenchymal stem cells (MSC‐TRAIL) provide targeted and prolonged delivery of TRAIL in glioma therapy. However, acquired resistance to TRAIL of glioma cells is a major problem to be overcome. We showed a potential therapy that used MSC‐TRAIL combined with the chemotherapeutic agent temozolomide (TMZ). The antitumor effects of the combination with MSC‐TRAIL and TMZ on human glioma cells were determined by using an in vitro coculture system and an in vivo experimental xenografted mouse model. Intracellular signaling events that are responsible for the TMZ‐mediated sensitization to TRAIL‐induced apoptosis were also evaluated. Treatment of either TRAIL‐sensitive or ‐resistant human glioma cells with TMZ and MSC‐TRAIL resulted in a significant enhancement of apoptosis compared with the administration of each agent alone. We demonstrated that TMZ effectively increased the sensitivity to TRAIL‐induced apoptosis via extracellular signal‐regulated kinase‐mediated upregulation of the death receptor 5 and downregulation of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis protein and cellular FLICE‐inhibitory protein. Subsequently, this combined treatment resulted in a substantial increase in caspase activation. Furthermore, in vivo survival experiments and bioluminescence imaging analyses showed that treatment using MSC‐TRAIL combined with TMZ had greater therapeutic efficacy than did single‐agent treatments. These results suggest that the combination of clinically relevant TMZ and MSC‐TRAIL is a potential therapeutic strategy for improving the treatment of malignant gliomas.

Novel repair technique for articular cartilage defect using a fibrin and hyaluronic acid mixture

We evaluated the cartilage repair potential of a hyaluronic acid and fibrin mixture when transplanted into cartilage defects. Circular, articular, cartilage defects 4-mm in diameter were made in the trochlear region in 21 New Zealand white rabbits divided into three groups. The seven rabbits in the control group underwent microfracture (M group), the seven rabbits in the experimental group underwent microfracture with subsequent injection of hyaluronic acid mixed with fibrin (MH group), and seven rabbits in the other experimental group underwent microfracture followed by injection of bone marrow concentrate and hyaluronic acid mixed with fibrin (MBH group). At week 12 following surgery, the cartilage was observed and histologically compared in the three groups. The surface of the newly generated cartilage was very smooth and even, and we noticed that the entire area was completely regenerated in both experimental groups. The control group showed incomplete and irregular cartilage formation in the defect. In histologic scoring, comparison of the MBH group (M= 2.333) and the M group (M= 9.000) differed significantly (P= 0.046). Therefore, injection of a mixture of bone marrow concentrate, hyaluronic acid and fibrin to treat articular cartilage defects of the knee appears to be an effective method of cartilage regeneration.

Treatment of osteonecrosis of the femoral head using autologous cultured osteoblasts: a case report

IntroductionOsteonecrosis of the femoral head is a progressive disease that leads to femoral head collapse and osteoarthritis. Our goal in treating osteonecrosis is to preserve, not to replace, the femoral head.Case presentationWe present the case of a patient with bilateral osteonecrosis of the femoral head treated with autologous cultured osteoblast injection.ConclusionAlthough our experience is limited to one patient, autologous cultured osteoblast transplantation appears to be effective for treating the osteonecrosis of femoral head.

A subset of paracrine factors as efficient biomarkers for predicting vascular regenerative efficacy of mesenchymal stromal/stem cells

Mesenchymal stromal/stem cells (MSCs) have been developed as a promising source for cell‐based therapies of ischemic disease. However, there are some hurdles in their clinical application such as poor cell engraftment and inconsistent stem cell potency. In this study, we sought to find biomarkers for predicting potency of MSCs for proangiogenic therapy to improve their beneficial effects. Large variations were observed in proangiogenic factor secretion profiles of conditioned media derived from nine different donor‐derived Whartons jelly (WJ)‐derived MSCs and 8 factors among 55 angiogenesis‐related factors were secreted at considerable levels. Two distinct WJ‐MSCs that had the lowest or the highest secretion of these eight factors showed corresponding proangiogenic activities in in vitro angiogenesis assays. When four additional different donor‐derived WJ‐MSCs were further examined, proangiogenic activities in migration and tube formation of endothelial cells and in in vivo Matrigel plug assay were highly consistent with secretion levels of four major factors (angiogenin, interleukin‐8, monocyte chemoattractant protein‐1, and vascular endothelial growth factor). Such correlation was also observed in vascular regenerative effect in a mouse hind limb ischemia model. Blocking of these four factors by neutralizing antibodies or knockdown of them by siRNA treatment resulted in significant inhibition of proangiogenic activities of not only WJ‐MSCs, but also bone marrow‐derived MSCs. These results suggest that these four factors may represent efficient biomarkers for predicting vascular regenerative efficacy of MSCs. Stem Cells 2019;37:77–88

Cartilage Regeneration Using a Fibrin and Autologous Cultured Chondrocytes Mixture in a Canine Model

Background: Various surgical methods have been designed to avoid the necessity of using periosteum, i.e. an operative weak point of autologous chondrocyte implantation (ACI) which is a representative method for treating articular cartilage injury. This study was performed in the attempt to develop a simple, injectable type of ACI to in order facilitate the surgical process. Methods: Seven of 10 dogs were used for the injectable type ACI using fibrin, while the remaining three dogs were used for implantation according to the previous surgical method using periosteum. The left knee of each dog was incised in order to expose the medial femoral condyle, and a circular defect was then made to 5mm in diameter on the articular cartilage of the exposed medial femoral condyle so that chondrocyte implantation using periosteum and the injectable chondrocyte implantation using fibrin glue could both be performed. At week 12 following surgery, the cartilage was observed and compared histologically with normal articular cartilage. Results: The surface of the cartilage newly generated at week 12 was very smooth and even, and it was also seen that the entire area was completely regenerated. Through the histological evaluation, IHC test, and electron microscope pictures, it was verified that collagen type II was normally expressed and that the ultrastructure of the regenerated tissue showed the normal cartilage properties. Conclusion: Gel-type ACI using fibrinfor articular cartilage defects of the knee, appears to be an effective method for the regeneration and growth of cartilage and also has many potential surgical advantages.

Enhancement of Healing of Long Tubular Bone Defects in Rabbits Using a Mixture of Atelocollagen Gel and Bone Marrow Aspirate Concentrate

We evaluated the bone-forming potential of a mixture of atelocollagen and bone marrow aspirate concentrate which was transplanted into bone defects. Radial shaft defects of about 10 mm in size were created in 30 New Zealand white rabbits. Ten rabbits in the control group were not treated further, 10 rabbits in the first experimental group (E1) received an atelocollagen injection, and 10 rabbits in the second experimental group (E2) received an injection of a mixture of atelocollagen and bone marrow aspirate concentrate. The groups were compared radiologically at 8 weeks. Osteogenesis in group E2 progressed more rapidly than that in the other groups, and osteogenesis in group E1 progressed faster than that in the control group. Thus, the administration of a mixture of atelocollagen and bone marrow aspirate concentrate in bone defects was found to enhance bone defect healing.