Tomohiro Mimura

Chondroitin sulfate for the treatment of hip and knee osteoarthritis: current status and future trends.

AIMS Osteoarthritis (OA) is a common joint disorder and a major socio-economic burden. Chondroitin sulfate (CS), which has chondroprotective properties, is a promising candidate for the therapeutic treatment of OA. Here, we summarize current knowledge as well as future trends of CS for the treatment of hip and knee OA. MAIN METHODS We retrospectively reviewed pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of CS for the treatment of OA. KEY FINDINGS The safety and tolerability of CS are confirmed. CS is effective, at least in part, for the treatment of OA, and its therapeutic benefits occur through three main mechanisms: 1) stimulation of extracellular matrix production by chondrocytes; 2) suppression of inflammatory mediators; and 3) inhibition of cartilage degeneration. SIGNIFICANCE CS is a safe and tolerable therapeutic agent for the management of OA. Its effects include benefits that are not achieved by current medicines and include chondroprotection and the prevention of joint space narrowing. Such positive effects of CS represent a breakthrough in the treatment of hip and knee OA.

A novel exogenous concentration-gradient collagen scaffold augments full-thickness articular cartilage repair

OBJECTIVES A collagen scaffold has been long used in order to enhance the regeneration of articular cartilage. In the present study, we investigate the effectiveness of a concentration-gradient (CG) collagen that is designed to recruit efficiently the mesenchymal stem cells (MSCs) to the central region of the full-thickness cartilage defects via haptotaxis. METHODS The present study used Cellmatrix (0.3% type I collagen; Nitta gelatin, Osaka, Japan) as the collagen material. We prepared 33%CG collagen gel and 50%CG collagen gel. No gradient collagen gel served as negative control. Full-thickness cartilage defects were created at the patella groove of the rabbit knee, to which the three different collagen gels were transplanted. Bromodeoxyuridine (BrdU) positive, proliferating cells were enumerated and localized, whereas the histological grading score for cartilage regeneration was counted. The expression of type I and type II collagens was evaluated by immunohistochemistry. We also confirmed that the MSCs migrate toward the collagen substrate of higher concentration in a stringently in vitro haptotactic manner. RESULTS Enumeration of the BrdU-positive cells demonstrated that 33%CG collagen gel recruited a significantly larger number of proliferating cells to the central region of the cartilage defect. The histological grading score for the regenerated cartilage treated with 33%CG collagen gel was superior to the other groups. CONCLUSIONS CG collagen scaffold recruits effectively the MSCs to the center of full-thickness cartilage defect and enhances regeneration of the full-thickness cartilage defect.

Prevalence, distribution, and morphology of thoracic ossification of the yellow ligament in Japanese: results of CT-based cross-sectional study.

Study Design. A cross-sectional study. Objective. To gain an insight for the prevalence, morphology, and distribution of thoracic ossification of the yellow ligament (OYL) by computed tomography (CT) and review of the literature. Summary of Background Data. The epidemiology and etiology of OYL remains obscure. To date, to the best of our knowledge, there is no study that comprehensively evaluated thoracic spine by CT to assess the prevalence, distribution, and morphology of OYL in a large enough sample size with wide age distribution. Methods. The participants of this study were the patients who have undergone chest CT for the examination of pulmonary diseases in our institute. The patients with previous thoracic spine surgery and younger than 15 years were excluded. Prevalence, distribution, and morphology of thoracic OYL were reviewed. Results. A total of 3013 patients (1261 females and 1752 males) with the mean age of 65 years were recruited. The CT-based evidence of OYL was noted in 1094 (428 females and 666 males) individuals (36%). Single-level involvement was noted in 532 cases, whereas 562 individuals presented multilevel involvement. Statistical analyses revealed that OYL was noted at a significantly higher rate among the males (P = 0.022). Of a total of 2051 OYLs, 779 central type OYLs, a mushroom-shaped ossification localized at the center of laminae, and 1272 noncentral type OYLs were noted. Distribution of the thoracic OYL formed 2 peaks with the highest and second highest peak found at T10–T11 and T4–T5, respectively. Interestingly, OYL is noted at consistent rates after the age of 30; however, its size increased in age-dependent manners. Conclusion. The prevalence of thoracic OYL in Japanese was 36%. A further study disclosing the association between clinical manifestations and size and/or morphology of OYL is warranted. Level of Evidence: N/A

Closed reduction for traumatic posterior dislocation of the shoulder using the 'lever principle': two case reports and a review of the literature

Traumatic posterior dislocation of the shoulder is frequently missed because of its rarity and the absence of characteristic symptoms. Several signs should be emphasised: an overlap of the humeral head and glenoid rim in a true anteroposterior view and the light-bulb sign in the anteroposterior view. To make an accurate and early diagnosis, use of multidirectional radiographs combined with computed tomography is recommended. Closed reduction was successfully performed under general anaesthesia using the DePalma method with slight modification—the lever principle—by pushing the medial side of the upper arm laterally to adduct the shoulder as far as possible. The dynamics of the lever principle make it a safer and more effective method of achieving a closed reduction of a posterior dislocation of the shoulder than the conventional method of solely pushing the humeral head anteriorly, especially in patients with locking of the glenohumeral joint and impression fractures.

Effect of dynamic compressive loading and its combination with a growth factor on the chondrocytic phenotype of 3-dimensional scaffold-embedded chondrocytes

Background and purpose Three-dimensionally (3D-) embedded chondrocytes have been suggested to maintain the chondrocytic phenotype. Furthermore, mechanical stress and growth factors have been found to be capable of enhancing cell proliferation and ECM synthesis. We investigated the effect of mechanical loading and growth factors on reactivation of the 3D-embedded chondrocytes. Methods Freshly isolated chondrocytes from rat articular cartilage were grown in monolayer cultures and then in collagen gel. Real-time RT-PCR and histological analysis for aggrecan and type II and type I collagen was performed to evaluate their chondrocytic activity. Then, the 3D-embedded chondrocytes were cultured under either mechanical loading alone or in combination with growth factor. The dynamic compression (5% compression, 0.33 Hz) was loaded for 4 durations: 0, 10, 60, and 120 min/day. The growth factor administered was either basic fibroblast growth factor (bFGF) or bone morphogenetic protein-2 (BMP-2). Results Mechanical loading statistically significantly reactivated the aggrecan and type II collagen expression with loading of 60 min/day as compared to the other durations. The presence of BMP-2 and bFGF clearly enhanced the aggrecan and type II collagen expression of 3D-embedded chondrocytes. Unlike previous reports using monolayer chondrocytes, however, BMP-2 or bFGF did not augment the chondrocytic phenotype when applied together with mechanical loading. Interpretation Dynamic compression effectively reactivated the dedifferentiated chondrocytes in 3D culture. However, the growth factors did not play any synergistic role when applied with dynamic compressive loading, suggesting that growth factors should be administered at different time points during regeneration of the transplantation-ready cartilage.

Prevalence, distribution, and morphology of thoracic ossification of the posterior longitudinal ligament in Japanese: results of CT-based cross-sectional study.

Study Design. A cross-sectional study. Objective. To gain an insight into the prevalence, morphology, and distribution of thoracic ossification of the posterior longitudinal ligament of the spine (T-OPLL) by computed tomography (CT) and review of the literature. Summary of Background Data. The epidemiology and cause of T-OPLL remains obscure. To date, to the best of our knowledge, there is no study that has comprehensively evaluated the thoracic spine by CT to assess the prevalence, distribution, and morphology of T-OPLL in a sufficiently large size of sample with wide distribution of age. Methods. The participants of this study were the patients who have undergone chest CT for the examination of pulmonary diseases in our institute. The patients with previous thoracic spine surgery and younger than 15 years were excluded. Prevalence, distribution, and morphology of T-OPLL were reviewed. Results. A total of 3013 patients (1261 females and 1752 males) with the mean age of 65 years were recruited. The CT-based evidence of T-OPLL was noted in 56 (38 females and 18 males) individuals (1.9%). Most frequently encountered type was liner type, followed by continuous cylindrical type and mixed type. Continuous waveform and beaked type were less frequently encountered. Statistical analyses revealed that T-OPLL was noted at a significantly higher rate among the females. The mean age of T-OPLL–positive males was significantly higher than that of T-OPLL–negative males. Furthermore, there was significant difference of body mass index between T-OPLL–positive and T-OPLL–negative individuals. Most of T-OPLLs were confirmed in higher or middle thoracic regions and the highest peak was found at T3–T4. T-OPLL was noted after the age of 40 years with the peak distribution found at the age of 60 years. Conclusion. The prevalence of T-OPLL in Japanese was 1.9%. Further studies that characterize definitive subtypes of T-OPLL on CT are warranted so as to establish possible association between clinical manifestations and size and/or subtypes of T-OPLL. Level of Evidence: N/A

Exogenous collagen-enhanced recruitment of mesenchymal stem cells during rabbit articular cartilage repair

Background Despite the well-known effect of type-I collagen in promoting cartilage repair, the mechanism still remains unknown. In this study we investigated this mechanism using a rabbit model of cartilage defects. Animals and methods 5-mm-diameter full-thickness defects were created on both patellar grooves of 53 Japanese white rabbits (approximately 13 weeks old). The left defect was filled with collagen gel and the right defect was left empty. The rabbits were killed and examined morphometrically until the twenty-fourth postoperative week, by (1) evaluation of matrix production, (2) enumeration of the total number of cells engaged in cartilage repair, (3) enumeration of the proliferating cells, (4) localization of mesenchymal stem cells, and (v) localization of apoptotic cells. Results We found that type-I collagen enhances cell recruitment, and thereby increases the number of proliferating cells. A considerable proportion of the proliferating cells were identified as bone marrow-derived mesenchymal stem cells. However, type-I collagen does not prevent the chondrocyte precursors from undergoing apoptotic disengagement from the chondrogenic lineage. Interpretation Type-I collagen promotes cartilage repair by enhancing recruitment of bone marrowderived mesenchymal stem cells. Additional use of agent(s) that sustain mesenchymal stem cells along the chondrogenic path of differentiation may constitute an appropriate environment for cartilage repair.

Improved quality of cartilage repair by bone marrow mesenchymal stem cells for treatment of an osteochondral defect in a cynomolgus macaque model

Background and purpose — Integration of repaired cartilage with surrounding native cartilage is a major challenge for successful tissue-engineering strategies of cartilage repair. We investigated whether incorporation of mesenchymal stem cells (MSCs) into the collagen scaffold improves integration and repair of cartilage defects in a cynomolgus macaque model. Methods — Cynomolgus macaque bone marrow-derived MSCs were isolated and incorporated into type-I collagen gel. Full-thickness osteochondral defects (3 mm in diameter, 5 mm in depth) were created in the patellar groove of 36 knees of 18 macaques and were either left untreated (null group, n = 12), had collagen gel alone inserted (gel group, n = 12), or had collagen gel incorporating MSCs inserted (MSC group, n = 12). After 6, 12, and 24 weeks, the cartilage integration and tissue response were evaluated macroscopically and histologically (4 null, 4 gel, and 4 MSC knees at each time point). Results — The gel group showed most cartilage-rich reparative tissue covering the defect, owing to formation of excessive cartilage extruding though the insufficient subchondral bone. Despite the fact that a lower amount of new cartilage was produced, the MSC group had better-quality cartilage with regular surface, seamless integration with neighboring naïve cartilage, and reconstruction of trabecular subchondral bone. Interpretation — Even with intensive investigation, MSC-based cell therapy has not yet been established in experimental cartilage repair. Our model using cynomolgus macaques had optimized conditions, and the method using MSCs is superior to other experimental settings, allowing the possibility that the procedure might be introduced to future clinical practice.

Spatiotemporal control of proliferation and differentiation of bone marrow–derived mesenchymal stem cells recruited using collagen hydrogel for repair of articular cartilage defects

Articular cartilage has a poor healing capacity, and cartilage regeneration is not always warranted to achieve healing. On the other hand, collagen scaffolds have been shown to support regeneration of articular cartilage defects in animal models, whereas bone morphogenetic protein-2 (BMP-2) is known to cause chondrogenic differentiation of marrow-derived mesenchymal stem cells (MSCs). The purpose of this study was to evaluate the effectiveness of intra-articular administration of BMP-2 into bone marrow-derived MSCs recruited to defects using original collagen hydrogel in rabbits at various time points. Full-thickness defects were created in both knees, then collagen hydrogels were transplanted, and BMP-2 was supplied for 1-week periods, as follows. BMP-2 was administered immediately after the operation for 1 week (BMP0-1 group), and BMP-2 was administered between weeks 1 and 2 after the operation (BMP1-2 group). BMP2 was administered between weeks 2 and 3 (BMP2-3 group). Specimens were then obtained, and bromodeoxyuridine (BrdU)-positive cells were enumerated and histologic grading was also performed. In addition, the gene expression analysis was performed using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) assays. Enumeration of BrdU-positive cells showed a significant increase in the BMP0-1 group compared with the other groups. Similarly, histologic scores in the BMP0-1 group were superior for up to 8 weeks. Finally, RT-PCR findings revealed that immediate BMP-2 administration enhanced chondrogenic differentiation.

Triple pelvic osteotomy: Report of our mid-term results and review of literature

A wide variety of pelvic osteotomies have been developed for the treatment of developmental dysplasia of the hip (DDH). In the present paper, we present a detailed review of previous studies of triple osteotomy as an alternative treatment for DDH. We also report our experience treating 6 adult cases of DDH by triple osteotomy in order to highlight the various aspects of this procedure.The mean age of our patients was 31.2 years with a mean follow-up period of 6 years. We assessed range of motion, center-edge angle, acetabular index angle, Sharp angle, acetabulum head index, head lateralization index, Japanese Orthopedic Association score, Harris hip score, patient satisfaction, and the difference between lower limb lengths before and after the procedure. At final follow-up, clinical scores were significantly improved and radiographic parameters also showed good correction of acetabulum.