Efficacy and Safety of Beta-Tricalcium Phosphate/Polylactic-Co-Glycolic Acid for Implantation of Bone Defects.

INTRODUCTION: Bone defects are often observed after surgery for fractures and bone tumors. Their treatment is technically difficult and sometimes results in negative clinical and economic outcomes. To repair bone defects, a bone graft is implanted by selecting a transplant material from an autologous or artificial bone. Each method has its advantages and disadvantages. Compared to the gold standard of autologous bone graft, bone graft substitutes are not limited by the amount of harvested graft and avoid complications at the donor site. ORB-03 is a new cotton-like bone graft substitute composed of beta-tricalcium phosphate (ß-TCP) and a bioabsorbable polymer, polylactic-co-glycolic acid (PLGA). ORB-03 is easy to mold and can fill various bone defect shapes, and its three-dimensional microfiber scaffold can enhance the differentiation of osteoblasts and promote osteogenesis. We investigated the efficacy, ease of handling, and safety of ORB-03 as a bone graft substitute. A multicenter, open-label, single-group study was conducted at six institutions. METHODS: Between July 2018 and August 2019, 60 patients with bone defects caused by fracture, benign tumors, or an iliac donor site from bone harvesting were enrolled in this study; 54 patients were finally included for the safety analysis and 48 patients for the image analysis. During surgery, ORB-03 was mixed with the patient's blood and molded into a bone defect. To evaluate the efficacy of ORB-03, radiography and computed tomography (CT) were performed at intervals until 24 weeks after surgery. RESULTS: The effective rate and its accurate bilateral 95% confidence interval (CI) were calculated based on the efficacy criteria at 24 weeks postoperatively. The ease with which ORB-03 could be handled in surgery was evaluated. Adverse events that occurred after surgery were evaluated, and those associated with ORB-03 were examined. Bone fusion was good in all cases, and the radiography and CT effective rates were 100.0% and 91.5%, respectively. Handling was easy in all cases. There were four adverse events, none of which were clinically problematic. CONCLUSIONS: ORB-03 was found to be easy to handle, safe, and effective as a bone graft substitute for bone defects.

Age-dependent differences in response to partial-thickness cartilage defects in a rat model as a measure to evaluate the efficacy of interventions for cartilage repair.

The objectives of this study are (1) to examine age-dependent longitudinal differences in histological responses after creation of partial-thickness articular cartilage defects (PTCDs) in rats and to use this model (2) to objectively evaluate the effectiveness of interventions for cartilage repair. Linear PTCDs were created at a depth of 100 µm in the weight-bearing region of the medial femoral condyle in rats of different ages (3 weeks, 6 weeks, 10 weeks and 14 weeks). One day, one week, two weeks, four weeks and twelve weeks after PTCD generation, spontaneous healing was evaluated histologically and immunohistochemically. Effects of interventions comprising mesenchymal stem cells (MSCs) or platelet-rich plasma (PRP) or both on 14-week-old PTCD rats were evaluated and compared with natural courses in rats of other ages. Younger rats exhibited better cartilage repair. Cartilage in 3-week-old and 6-week-old rats exhibited nearly normal restoration after 4-12 weeks. Cartilage in 14-week-old rats deteriorated over time and early signs of cartilage degeneration were observed. With injection of MCSs alone or MSCs + PRP, 14-week-old PTCD rats showed almost the same reparative cartilage as 6-week-old rats. With injection of PRP, 14-week-old PTCD rats showed almost the same reparative cartilage as 10-week-old rats. This model will be of great use to objectively compare the effects of interventions for small cartilage lesions and may help to advance the development of disease-modifying osteoarthritis drugs.

Comparative Analysis of Gene Expression between Cartilage and Menisci in Early-Phase Osteoarthritis of the Knee-An Animal Model Study.

Cartilage degeneration is believed to be the primary event in the development of osteoarthritis (OA). On the other hand, meniscal degeneration is observed with high prevalence, and some researchers have pointed out that pathological changes in menisci precede that of cartilage. The purpose of the present study is to investigate comprehensive gene expression pattern of cartilage and menisci in the initial phase of surgically induced OA and to compare them. Secondary OA was surgically induced in 10-week-old male Wistar rats by anterior cruciate ligament transection (ACLT). Articular cartilage and menisci were separately dissected from six ACLT- and six sham-operated rats. Each specimen was analyzed by microarray, histological, and immunohistochemical analysis 3 weeks after surgery. Of the 36,685 transcripts detectable by microarray, the number of upregulated transcripts in ACLT menisci was >2.5-fold compared with that in ACLT menisci in any given threshold. Cluster analysis using the Database for Annotation Visualization and Integrated Discovery (DAVID) showed genes related to OA, such as response to stimulus, angiogenesis, and apoptosis, which were predominantly found in menisci in ACLT rats. Representative proteases including Adamts2, 4, Mmp2, 12, 13, 14, 16, extracellular matrix genes including versican (Vcan), lumican (Lum), syndecan1 (Sdc1), and Prostaglandin endoperoxide synthase2 (Ptgs2) were up-regulated in menisci, but were not up-regulated in cartilage. Our results indicated that the molecular changes that occurred in menisci preceded those occurred in cartilage in the very early phase of surgically induced OA models.

Safety and Efficacy of Intra-articular Injection of Platelet-Rich Plasma in Patients With Ankle Osteoarthritis.

BACKGROUND: An intra-articular injection of platelet-rich plasma (PRP) may be an effective treatment for osteoarthritis (OA). However, its efficacy in ankle OA has not been investigated yet. The purpose of this study was to assess the safety and efficacy of an intra-articular injection of PRP in patients with ankle OA during a 24-week period. METHODS: Twenty ankles of 20 patients with varus-type ankle OA who received intra-articular injections of PRP were evaluated. PRP was extracted from whole blood by using the double-spin technique. Three injections of 2-mL PRP were administered to the ankle at an interval of 2 weeks under ultrasonographic guidance. Adverse events and efficacy were assessed at 4, 12, and 24 weeks after the last injection. Clinical outcomes were assessed by using the visual analog scale (VAS) for pain, the Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot scale, and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). RESULTS: No serious adverse effects were observed during the follow-up period. The VAS and JSSF scale scores significantly decreased from baseline to 4, 12, and 24 weeks after treatment ( P < .001). The mean score in the pain-related subscale of the SAFE-Q significantly improved from baseline to 12 weeks after treatment ( P = .04). Overall, the amount of pain reduction was maximal at 12 weeks after the last injection, and the effect was reduced at 24 weeks. The patients with late-stage OA had worse scores in all outcomes than those with early-stage OA. CONCLUSION: Intra-articular injections of PRP resulted in no serious adverse effects and significantly reduced pain in the patients with ankle OA. PRP treatment can be safe and effective and may be an option in the treatment of ankle OA. LEVEL OF EVIDENCE: Level IV, case series.

Quantitative US Elastography Can Be Used to Quantify Mechanical and Histologic Tendon Healing in a Rabbit Model of Achilles Tendon Transection.

Purpose To determine the time-dependent change in strain ratios (SRs) at the healing site of an Achilles tendon rupture in a rabbit model of tendon transection and to assess the correlation between SRs and the mechanical and histologic properties of the healing tissue. Materials and Methods Experimental methods were approved by the institutional animal care and use committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected. The SRs of Achilles tendons were calculated by using compression-based quantitative ultrasonographic elastography measurements obtained 2, 4, 8, and 12 weeks after transection. After in vivo elastography, the left Achilles tendon was harvested for mechanical testing of ultimate load, ultimate stress, elastic modulus, and linear stiffness, and the right tendons were harvested for tissue histologic analysis with the Bonar scale. Time-dependent changes in SRs, mechanical parameters, and Bonar scale scores were evaluated by using repeated-measures analysis of variance. The correlation between SRs and each measured variable was evaluated by using the Spearman rank correlation coefficient. Results Mean SRs and Bonar scale values decreased as a function of time after transection, whereas mechanical parameters increased (P < .001). SR correlated with ultimate stress (ρ = 0.68, P <.001,) elastic modulus (ρ = 0.74, P <.001), and the Bonar scale (ρ = 0.87, P <.001). Conclusion Quantitative elastography could be a useful method with which to evaluate mechanical and histologic properties of the healing tendon. © RSNA, 2017 Online supplemental material is available for this article.

Identification of genes required for the spontaneous repair of partial-thickness cartilage defects in immature rats.

PURPOSE: Our previous study showed that partial-thickness articular cartilage defects (PTCDs) created in immature rats spontaneously healed to resemble normal hyaline cartilage, but that of mature rats did not. To identify molecules involved in the spontaneous cartilage repair observed in this model, gene expression was compared between PTCD and sham-operated cartilage of immature and mature rats. MATERIALS AND METHODS: Six sets of gene comparisons were made at 12, 24, and 48 hours after the creation of PTCDs in immature and mature rats using microarrays. All the genes upregulated in immature cartilage at 12 hours were selected for further analysis if their expression pattern was not irregular such that diminished at 24 hours and re-upregulated at 48 hours. Relationships among genes selected through the above steps were analyzed using Ingenuity Pathway Analysis (IPA) software. After deriving networks, important molecules were further narrowed down by location within a network. Genes were regarded as central if they had relationships with more than 10 molecules in a network. Protein localization in tissues was confirmed by immunohistochemistry. RESULTS: Five networks were identified. Their functional annotations were gene expression, cell cycle, growth and proliferation, and cell signaling. Transforming growth factor-beta (TGF-ß) was centrally located in the network with the highest IPA score and mothers against decapentaplegic homolog-3 (Smad3) were centrally located in the second highest ranking network. Phosphorylated Smad3 was detected in the nuclei of chondrocytes in immature cartilage. CONCLUSIONS: Our data suggest the possible importance of Smad3 in the TGF-ß signaling in the spontaneous healing of PTCDs in immature rats.

Ultrasound for Treating Meniscocapsular Separation Together With Arthroscopy.

Magnetic resonance imaging (MRI) can be used to identify most types of meniscal tears; however, meniscocapsular separation of the medial meniscus can be difficult to identify with MRI. Here we present a technical note on the intrasurgical use of ultrasonography for the detection of meniscocapsular separation and confirmation of the beneficial effect of suturing on the stability of this lesion in a representative case of meniscocapsular separation that could be diagnosed with ultrasonography but not MRI preoperatively. Ultrasonography can detect meniscocapsular separation as a vertical low echoic area and be performed together with arthroscopy using the picture-in-picture function of the ultrasonography machine. Ultrasonography is an effective tool for diagnosing meniscocapsular separation and is helpful during arthroscopic surgery.

Quantitative Ultrasound Elastography With an Acoustic Coupler for Achilles Tendon Elasticity: Measurement Repeatability and Normative Values.

OBJECTIVES: The purposes of this study were to measure intraobserver and interobserver repeatability of quantitative elastography using an acoustic coupler for the Achilles tendon, to compare elastographic values among different age groups, and to assess the correlation between quantitative and conventional qualitative measurements. METHODS: One hundred asymptomatic Achilles tendons of 50 volunteers were examined. For quantitative elastography, the strain value of the tendon was divided by that of the acoustic coupler with a known Young modulus, and the strain ratio was calculated. B-mode image assessment and qualitative elastography were also performed. Intraobserver repeatability and interobserver repeatability of strain ratio measurements were calculated. The strain ratios were compared among age groups by the Kruskal-Wallis test. Additionally, strain ratios for each B-mode grade and qualitative elastographic grade were compared by the Wilcoxon signed rank test. RESULTS: Intraobserver repeatability intraclass correlation coefficient (1, 3) values were 0.87 and 0.93, respectively. The correlation coefficient between the observers' measurements was 0.61. The strain ratio for the 30s age group was 0.27, which was significantly lower than the values for the other age groups (P < .001). Although 97 of 100 tendons were normal on B-mode evaluations, 36 of the 97 tendons were degenerated on qualitative elastography and also had higher strain ratio values than normal tendons. CONCLUSIONS: Quantitative elastography using an acoustic coupler is a reproducible technique for measuring the elasticity of the Achilles tendon. It may detect early tendon degeneration that is not depicted on B-mode imaging.

Accuracy of high-resolution ultrasound in the detection of meniscal tears and determination of the visible area of menisci.

BACKGROUND: Imaging is of great importance in diagnosing meniscal tears. The aim of this study was to assess the accuracy of high-resolution ultrasound in the diagnosis of meniscal tears, with arthroscopic examination as the standard reference, after resolution was confirmed with a target-mounted reference phantom. An additional goal was to elucidate the area of the meniscus that could be visualized with the same ultrasound machine after placement of markers into the menisci of cadaveric knees. METHODS: Seventy patients were included for the assessment of the accuracy of a high-resolution ultrasound machine with a 14.0 to 6.0-MHz linear transducer. The preoperative ultrasound diagnosis, in terms of the presence and type of tear, was compared with that in the surgical reports. In the cadaveric studies, nine needles were placed in the peripheral zone of the menisci at regular intervals and the number of needles that could be observed with the system was recorded. RESULTS: The overall sensitivity, specificity, positive predictive value, and negative predictive value of ultrasound examination for meniscal tears were 88%, 85%, 85%, and 88%, respectively. These statistical parameters did not differ significantly between the medial and lateral menisci. The sensitivity for diagnosing horizontal, vertical, radial, flap, bucket-handle, and complex tears and for detecting discoid lateral menisci was 83%, 64%, 0%, 64%, 54%, 90%, and 80%, respectively. Ten percent of the lateral menisci could not be evaluated because of poor images. The cadaveric studies revealed that the ultrasound visualized the entire meniscus except for the anterior horn. CONCLUSIONS: The findings of this study suggest that ultrasound examination may be suitable for screening for meniscal tears. The fact that almost 10% of the lateral menisci could not be evaluated because of poor images appears to be a weakness of ultrasound.

Quantitative Assessment of Tendon Healing by Using MR T2 Mapping in a Rabbit Achilles Tendon Transection Model Treated with Platelet-rich Plasma.

PURPOSE: To determine if magnetic resonance (MR) imaging T2 mapping can be used to quantify histologic tendon healing by using a rabbit Achilles tendon transection model treated with platelet-rich plasma (PRP). MATERIALS AND METHODS: Experiments were approved by the Institutional Animal Care and Use Committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected, and PRP (in the test group) or saline (in the control group) was injected into the transection site. The rabbits were sacrificed 2, 4, 8, and 12 weeks after surgery. Thereafter, T2 mapping and histologic evaluations were performed by using the Bonar scale. A mixed-model multivariate analysis of variance was used to test the effects of time and PRP treatment on the T2 value and Bonar grade, respectively. The correlation between the T2 value and Bonar grade was also assessed by using the Spearman correlation coefficient. RESULTS: The Bonar scale values decreased in both groups during tendon healing. The T2 value also shortened over time (P < .001 for both groups). The T2 values were positively correlated with the Bonar grade (ρ = 0.78, P < .001). Both the T2 value and Bonar scale value were lower in the PRP group than in the control group at 4, 8, and 12 weeks; however, there was no significant effect of PRP treatment on the T2 value or Bonar grade. CONCLUSION: The T2 value changes reflected histologic tendon healing. While T2 and Bonar grade were lower at all time points in tendons treated with PRP, there was no significant difference between the treatment and control tendons.

Spontaneous repair of partial thickness linear cartilage injuries in immature rats.

Partial thickness articular cartilage injuries (PTCIs) were not previously thought to heal spontaneously. Immature rats have the capacity for spontaneous repair of PTCIs, although it is a long-term process. Our aim has been to examine the spontaneous repair response mechanism in immature rats. Single linear PTCIs were created in 3-week-old and 12-week-old rats in the direction of joint motion. On day 1 and at 1, 2, and 4 weeks after PTCI, evaluations of histological changes and immunohistology at the injury site and in the surrounding cartilage were performed. Anti-CD105 and anti-CD166 antibodies (as stem cell markers to identify mesenchymal stem cells in reparative cartilage tissue) were used for immunohistological evaluations. To determine whether endogenous repair ability existed in articular cartilage, an ex vivo experiment was also carried out. Femoral condyles with PTCIs were incubated in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum for 1 day and for 1 and 2 weeks. Histological changes were subsequently examined. Immature cartilage showed a higher repair response than did mature cartilage, and the response occurred immediately after PTCI. In immature rats, CD105- and CD166-positive cells were found in the superficial and transitional zones of the articular cartilage. Few CD166-positive cells were identified in mature articular cartilage. No significant in vivo differences in the spontaneous repair responses to PTCIs were observed between mature and immature groups. Thus, the repair response to PTCIs seems to be associated not only with CD105- and CD166-positive cells, but also with other perichondral factors.

Intra-articular angioleiomyoma of the knee with an atypical finding on gadolinium-enhanced magnetic resonance imaging: a case report.

INTRODUCTION: Angioleiomyoma is a benign smooth muscle tumor. It originates in the tunica media of veins. In general, it arises from the dermis, subcutaneous fat and fascia of lower extremities in middle-aged women. The case of intra-articular occurrence is very rare. CASE PRESENTATION: This case report describes a 30-year-old Asian man with a 6-month history of recurrent pain localized in the lateral side of his left knee. Magnetic resonance imaging revealed an isolated intra-articular lesion. We performed a surgical excision of this lesion. On histological examination, the diagnosis of angioleiomyoma was confirmed. After the surgery, he recovered completely. Furthermore, no sign of recurrence was observed 1 year after surgery. CONCLUSIONS: In this study, we report a rare case of intra-articular angioleiomyoma of the knee. The mass showed atypical findings on magnetic resonance imaging including gadolinium-enhanced imaging in comparison to previously reported intra-articular lesions. This intra-articular tumor is difficult to diagnose prior to surgery due to paucity of information.

Effective knock down of matrix metalloproteinase-13 by an intra-articular injection of small interfering RNA (siRNA) in a murine surgically-induced osteoarthritis model.

This study investigated the effect of MMP-13 gene knock down on cartilage degradation by injecting small interfering RNA (siRNA) into knee joints in a mouse model of osteoarthritis (OA). OA was induced in male C57BL/6 mice by destabilization of medial meniscus (DMM) surgery. Change of Mmp13 expression over time was determined by qPCR analysis from 3 days to 6 weeks after surgery. Mmp13 and control chemically modified siRNA were injected into the knee joint 1 week after surgery and expression levels were assessed in synovium by qPCR 48 h later. Cartilage degradation was histologically assessed 8 weeks after DMM surgery according to OARSI recommendations. Mmp13 expression levels were elevated 1 week after surgery and peaked at 77 fold at 2 weeks compared to expression at 3 days. A 55% decrease of Mmp13 levels in cartilage was observed 48 h after injection of Mmp13 siRNA (p = 0.05). Significant reduction in the histological score at 8 weeks after surgery was observed in the Mmp13 siRNA-treated group compared to the control siRNA group (p < 0.001). Intra-articular injection of Mmp13 siRNA at the early phase of OA development resulted in effective knock down of Mmp13 expression and delay in cartilage degradation in vivo.

Remarkable thickening of right atrial wall in subjects with cardiac amyloidosis complicated with sick sinus syndrome.

We observed a 63-year old male with cardiac amyloidosis who presented with the clinical symptoms of sick sinus syndrome and dyspnea and abnormal thickening of the right atrial wall, which extended to the junction of the superior vena cava. This may explain the relationship of abnormal thickening of the right atrium which extends to the junction of the superior vena cava and right atrium with amyloid deposits in the sinus node and occurrence of sick sinus syndrome.