Comparison of tissue pharmacokinetics of esflurbiprofen plaster with flurbiprofen tablets in patients with knee osteoarthritis: A multicenter randomized controlled trial.

This open-label, multicenter, prospective, randomized controlled trial aimed to determine the effectiveness of esflurbiprofen plaster (SFPP) and flurbiprofen tablets (FPTs) on knee osteoarthritis in patients scheduled for total knee arthroplasty by comparing the transfer of esflurbiprofen and flurbiprofen to tissues and fluids. Thirty-eight patients were randomly assigned in a 1:1 ratio to receive SFPP or FPT. Both groups were then divided into four subgroups, according to whether they received the final dose of SFPP or FPT at 2, 7, 12, or 24 h before planned surgery. The primary endpoints were the esflurbiprofen concentrations in synovium, synovial fluid, and plasma. Areas under concentration-time curves (AUC0-24 h ) of esflurbiprofen were calculated for each group. Pain was assessed using a numeric rating scale (NRS) 7 days before and immediately before surgery. The AUC0-24 h in the synovium were 4401.24 and 4862.70 ng·h/g in the SFPP and FPT groups, respectively. Maximum esflurbiprofen concentrations were observed in the synovium, synovial fluids, and plasma after SFPP application for 12 h. The NRS results indicated a long-lasting effect of SFPP. The AUC of the synovial esflurbiprofen concentration of SFPP indicated that the SFPP is transferred to the synovium and synovial fluid in high concentration. The efficient deep-tissue transfer of esflurbiprofen suggests that its pharmacokinetic characteristics differ from those of conventional topical NSAIDs. This study was prospectively registered in the Japan Registry of Clinical Trials (registration number: jRCTs031180228).

Effect of posterolateral bundle graft fixation angles on graft tension curves and load sharing in double-bundle anterior cruciate ligament reconstruction using a transtibial drilling technique.

PURPOSE: To evaluate the effect of posterolateral bundle (PLB) graft fixation angles on graft tension curves and load sharing between the anteromedial bundle (AMB) and the PLB in double-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: Twenty-four patients who underwent double-bundle ACL reconstruction were included in this study. AMB and PLB were provisionally fixed to a graft tensioning system during surgery. The graft fixation settings were as follows: (1) AMB at 20° and PLB at 0° (A20P0), (2) AMB at 20° and PLB at 20° (A20P20), and (3) AMB at 20° and PLB at 45° (A20P45). Bundle tension was recorded during knee flexion-extension and in response to anterior or rotatory loads. A pivot-shift test, as well as factors affecting the residual pivot-shift, was also evaluated. RESULTS: A20P45 created reciprocal tension curves and load sharing, in which the tension in both bundles was equivalent during flexion-extension and during each loading test at 30°. In A20P0, the tension of the AMB was constantly higher than that of the PLB. Seven patients showed grade 1 pivot-shift phenomenon in A20P0, whereas no patient showed a positive pivot-shift at other settings. Larger tension reduction of the PLB between 0° and 30° and smaller load sharing of the PLB were significant factors affecting residual pivot-shift. CONCLUSIONS: In double-bundle ACL reconstruction, fixation of the AMB at 20° and the PLB at 45° created reciprocal tension curves and load sharing between the bundles. Fixation of the AMB at 20° and the PLB at 0° led to insufficient tension in the PLB, resulting in a residual pivot-shift phenomenon in 7 of 24 patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

The kinematic analysis of female subjects after double-bundle anterior cruciate ligament reconstruction during single-leg squatting.

BACKGROUND: The kinematic characteristics of female anterior cruciate ligament (ACL)-injured subjects were recognized in our previous study using an electromagnetic device comparing both female control groups and male ACL-injured subjects during single-leg squatting. OBJECTIVE: To assess the kinematic characteristics of female subjects after double-bundle ACL reconstruction during single-leg squatting. METHODS: Three-dimensional motion analysis was performed for single-leg squatting in female subjects after ACL reconstruction. We evaluated the relative angles between the pelvis, thigh, and lower leg using an electromagnetic device during single-leg squatting in 28 female subjects with ACL reconstruction. All patients included in this study restored their sports performance level to 90 % or higher. RESULTS: Comparing the involved leg to the uninjured leg of female subjects after ACL reconstruction, the involved leg demonstrated significantly more hip adduction and less knee varus than the uninjured leg. Comparing the anterior cruciate ligament-reconstructed female subjects to the healthy female controls, the involved leg after ACL reconstruction demonstrated significantly less hip flexion, more hip external rotation, more hip adduction, and more knee flexion than the dominant leg of the control group. CONCLUSION: This kinematic study exhibited kinematic characteristics of ACL-reconstructed knees of female subjects. Double-bundle anterior cruciate ligament reconstruction could not quite restore the normal kinematics of female-involved legs compared with both uninjured legs of female subjects and healthy female controls. In future studies, restoring the correct alignment of ACL reconstructed knee during single-leg squatting would be expected to reduce ACL re-injury and to assist a safe return to sport activities.

Remnant volume of anterior cruciate ligament correlates preoperative patients' status and postoperative outcome.

PURPOSE: A cohort study was conducted to evaluate the correlation of anterior cruciate ligament (ACL) remnant volume with preoperative status and postoperative outcome of the patients after a remnant-preserving double-bundle (DB) ACL reconstruction. METHODS: Eighty-eight patients of 105 unilateral DB anatomic ACL reconstructions performed between 2006 and 2008 were followed up for 24 months or more. They were evaluated with regard to preoperative knee laxity data under anaesthesia. Postoperative outcome was evaluated based on knee extension and flexion strength, manual laxity tests, KT measurements, etc. Overall knee condition and sports performance were evaluated with Lysholm knee score and subjective rating scale. Overall correlation of the remnant volume with the preoperative and postoperative evaluation was assessed. Then, the patients were divided into three subgroups based on the remnant volume (remnant volume: ≤ 30, 35-55 and ≤ 60 %). The evaluation was performed and analysed statistically among the three subgroups. RESULTS: Generally, preoperative laxity tests showed a weak correlation with the ACL remnant volume. Postoperative knee stability also indicated a weak correlation with the ACL remnant volume. Statistical analyses revealed that there were significant differences among the three groups regarding age at surgery, preoperative period, number of giving-way and preoperative KT measurements. Postoperatively, there were significant differences in Lachman test, KT measurements, Lysholm knee scale, subjective and sports performance recovery scores. As the clinical relevance, the study suggests that the remnant volume will be important as a background of preoperative condition and a predictor of operative outcome for each patient and that a remnant preserving surgery may not be simply better than a non-preserving technique with regard to subjective evaluation and sports performance recovery. CONCLUSION: The preoperative condition of patients with ACL injury was different depending upon the remnant volume. The remnant volume was also weakly correlated with the postoperative outcome regarding objective stability and subjective recovery.

Osteopontin level in synovial fluid is associated with the severity of joint pain and cartilage degradation after anterior cruciate ligament rupture.

OBJECTIVE: To explore the molecular function of Osteopontin (OPN) in the pathogenesis of human OA, we compared the expression levels of OPN in synovial fluid with clinical parameters such as arthroscopic observation of cartilage damage and joint pain after joint injury. METHODS: Synovial fluid was obtained from patients who underwent anterior cruciate ligament (ACL) reconstruction surgery from 2009 through 2011 in our university hospital. The amounts of intact OPN (OPN Full) and it's N-terminal fragment (OPN N-half) in synovial fluid from each patient were quantified by ELISA and compared with clinical parameters such as severity of articular cartilage damage (TMDU cartilage score) and severity of joint pain (Visual Analogue Scale and Lysholm score). RESULTS: Within a month after ACL rupture, both OPN Full and N-half levels in patient synovial fluid were positively correlated with the severity of joint pain. In contrast, patients with ACL injuries greater than one month ago felt less pain if they had higher amounts of OPN N-half in synovial fluid. OPN Full levels were positively correlated with articular cartilage damage in lateral tibial plateau. CONCLUSION: Our data suggest that OPN Full and N-half have distinct functions in articular cartilage homeostasis and in human joint pain.

Hyaluronan injection therapy for athletic patients with patellar tendinopathy.

BACKGROUND: Patellar tendinopathy produces activity-related pain and focal tenderness at the attachment of the patellar tendon at the lower pole of the patella. It frequently causes a reduction in athletic ability. An injection of hyaluronan was found to be useful for patellar tendinopathy, provided the indication is appropriate, based on the authors' pilot cases. The purpose of this study was to summarize the clinical experience of and to describe the appropriate indication for this injection therapy. METHODS: Fifty patients were treated from January 1999 to December 2006. The observation period averaged 25.7 months (range 6-88). All patients were graded stage 2 or 3 by Blazina's classification. Each treatment was counted separately for 9 patients (10 knees) who had more than one treatment period with 3 months or more between the injections. There were 4 bilaterally injected patients. Patellar tendinopathy was classified into 4 types according to the degree of tenderness and the regions that are tender. Hyaluronan was injected into the interface between the patellar tendon and the infrapatellar fat pad at the proximal insertion, or into the region of maximum tenderness. RESULTS: The total number of injections was 135, and there were an average of 2.0 injections per case (range 1-11). Following treatment, 54 % of the cases were rated in excellent condition, as they were able to return to their previous athletic activities with little difficulty, while 40 % of the cases were rated in good condition-these patients were able to return to their previous sporting activities with some degree of limitation. CONCLUSIONS: Hyaluronan injection therapy for athletic patients with patellar tendinopathy is an optional but effective treatment.

Surgical management of grade 3 medial knee injuries combined with cruciate ligament injuries.

PURPOSE: Although various surgical procedures have attempted to restore valgus stability in medial knee injuries, so far none has achieved satisfactory results. The purpose of this study was to assess clinical outcome for patients with grade 3 valgus instability who were treated according to our surgical management strategy. METHODS: Eighteen patients with both acute and chronic grade 3 medial knee injuries, all of which had combined cruciate ligament injuries, were treated with a proximal advancement of both the superficial medial collateral ligament (MCL) and posterior oblique ligament together with underlying deep MCL and joint capsule, in conjunction with cruciate ligament reconstructions in chronic phase. Augmentation with doubled semitendinosus tendon was added in 7 patients whose medial knee stability had been considered to be insufficient with only the proximal advancement procedure. They were evaluated preoperatively and at final follow-up. RESULTS: Manual valgus laxities at 0° and 30°, as well as side-to-side difference in medial joint opening in stress radiograph, were significantly improved at final follow-up. The Lysholm knee scale was also significantly improved. Median values of the subjective evaluations of the patients' satisfaction, stability and sports performance level measured with visual analogue scale at final follow-up were 82 (60-100), 94 (71-100) and 88 (60-100), respectively. CONCLUSIONS: Clinical outcomes of our surgical management strategy were reasonable in terms of restoring medial knee stability. This treatment protocol can help determine the surgical management of grade 3 medial knee injuries combined with cruciate ligament injuries. LEVEL OF EVIDENCE: Retrospective case series, Level IV.

High-flex posterior cruciate-retaining vs posterior cruciate-substituting designs in simultaneous bilateral total knee arthroplasty: a prospective, randomized study.

The superiority between the posterior cruciate-retaining and the posterior cruciate-substituting designs still remains controversial. We performed a prospective, randomized control study for evaluation of the superiority of these designs. This study investigated 58 knees in 29 patients with simultaneous bilateral total knee arthroplasty, in which the high-flex CR design was randomly implanted in one knee and the high-flex PS design was implanted in the other knee. The follow-up duration averaged 5.0 years, with a minimum duration of 3 years. Postoperatively, Knee Score and pain points in Knee Score resulted in no significant differences between the 2 designs. However, postoperative arc of range of motion, patient satisfaction, and posterior knee pain at passive flexion in the PS design were significantly superior to that of the CR design.

The effect of graft fixation angles on anteroposterior and rotational knee laxity in double-bundle anterior cruciate ligament reconstruction: evaluation using computerized navigation.

BACKGROUND: One of the main differences affecting outcome between single-bundle and double-bundle anterior cruciate ligament (ACL) reconstructions may be graft fixation angles and initial force settings; however, there has been little research to investigate these effects in either technique. HYPOTHESIS: Anteroposterior and rotational knee laxities will be less in double-bundle ACL reconstructions than single-bundle reconstructions, and different graft fixation angles affect knee kinematics and pivot-shift phenomenon in double-bundle ACL reconstructions. STUDY DESIGN: Controlled laboratory study. METHODS: Eleven patients who underwent double-bundle ACL reconstruction were included in this study. The anteromedial bundle (AMB) and the posterolateral bundle (PLB) were provisionally fixed to a graft tensioning system during surgery. The graft fixation settings were as follows: (1) AMB only at 20° (A20), (2) PLB only at 20° (P20), (3) AMB at 20° and PLB at 0° (A20P0), (4) AMB at 20° and PLB at 20° (A20P20), and (5) AMB at 20° and PLB at 45° (A20P45). All the grafts were tensioned at a constant stress level. Anterior tibial translation (ATT), internal rotation (IR), and external rotation (ER) at 30° and 90° of knee flexion applied with manual maximum load were measured before graft insertion and in each setting using a navigation system. A pivot-shift test was also evaluated manually with modified International Knee Documentation Committee criteria in each setting. RESULTS: A20 was less constrained than A20P20 and A20P45 in ATT at 30° and less constrained than A20P45 in IR at 30°. P20 was less constrained than any other settings in ATT at 30° and less constrained than A20P45 in IR at 30°. A20P0 was less constrained than A20P45 in IR at 30° and in ER at 30°. Grade 1 pivot-shift phenomenon persisted in 8 cases in P20, in 4 cases in A20, and in 3 cases in A20P0, whereas no case showed a positive pivot-shift result in A20P20 and A20P45. CONCLUSION: In this in vivo laboratory model, double-bundle ACL reconstruction with fixation of AMB at 20° and PLB at 20° or 45° restored better stability than single AMB or single PLB reconstruction in which the graft was of smaller size. CLINICAL RELEVANCE: In double-bundle ACL reconstruction, fixation of the PLB at 0° might be looser and function worse compared with that of PLB at 20° or 45° when the AMB is fixed at 20°, with the individual variability that should lead to caution until it can be better assessed by surgeons.

Effects of different initial bundle tensioning strategies on the outcome of double-bundle ACL reconstruction: a cohort study.

BACKGROUND: This study was performed to investigate the effects of different strategies and initial tension applied to each one of the bundles, antero-medial (AM) and postero-lateral (PL), on clinical outcome in double bundle (DB) ACL reconstruction. METHODS: One hundred fifty-one primary unilateral DB ACL reconstructions performed by a single surgeon from 1994 through 2002 were included in the study with a follow-up of at least 24 months. They were divided in the following 3 groups: Group I - Higher initial tension applied manually in the AM bundle compared to PL. II - Higher tension applied in the PL bundle compared to AM. III - The 2 bundles were attempted to be equally tensioned. All fixations were performed in 30 degrees of flexion. Group I = 59 patients, group II = 53 patients and group III = 39 patients. The groups had no statistical differences concerning demographic distribution. Clinical outcome was retrospectively evaluated by use of knee range of motion, manual knee laxity tests, KT-1000, Lysholm knee scale, subjective recovery scale and sports performance recovery scale. The differences of data were analyzed among the three groups. RESULTS: Group I showed a significant extension deficit compared with groups II and III. ANOVA revealed a significant difference of anterior laxity measured by the KT-1000 (average KT difference of 2.1, 2.1 and 1.2 mm in Group I, II and III, respectively). A statistical difference was found among the three groups regarding subjective and sports performance recovery scales with Group II showing higher scores in recovery than Group I. CONCLUSIONS: The current clinical study does not recommend manual maximum of initial tension applied to the anteromedial or posterolateral bundles with graft tension imbalance at 30 degrees of flexion in double-bundle ACL reconstruction to achieve a better clinical outcome.

Radiographic description of femoral tunnel placement expressed as intercondylar clock time in double-bundle anterior cruciate ligament reconstruction.

PURPOSE: The purpose of this study was to propose an objective description of femoral tunnel position expressed as time of the intercondylar clock in ACL reconstruction using a simple radiograph for the sake of objective discussion and technical improvement. The reproducibility of the method was evaluated in double-bundle (DB) reconstructions. METHODS: The first series of 54 knees in 54 patients who underwent primary "isometric" DB ACL reconstructions from 1995 to 2002 were randomly picked up. The second series of 48 knees in 48 patients with primary "anatomic" DB ACL reconstructions during 2007 were assessed as a recent femoral tunnel position with the same method. All DB reconstructions of ACL with the anteromedial (AM) and posterolateral (PL) bundles were performed with an arthroscopically assisted trans-tibial technique. The o'clock description of femoral tunnel placement was expressed using a weight-bearing posterior-anterior view at 45° of flexion (45° W/B PA view) of the knee. Assessment was undertaken with radiographs 1 year postoperatively. RESULTS: The o'clock descriptions of femoral tunnel placement resulted in noon 40 min (standard deviation (SD): 10 min) for the AM bundle and one o'clock 40 min (SD: 20 min) for the PL bundle on average in the "isometric" reconstruction. In the "anatomic" reconstruction, the time descriptions of femoral tunnel placement were one o'clock 20 min (SD: 10 min) for the AM bundle and two o'clock 20 min (SD: 20 min) for the PL bundle on average. With the intra-examiner reproducibility assessment in the "anatomic" reconstruction, the differences between first and second assessments averaged 10 min (SD: 7 min) for femoral tunnel placement of the AM bundle and 12 min (SD: 9 min) of the PL bundle. Regarding the inter-examiner reproducibility, the differences between two examiners averaged 9 min (SD: 6 min) for femoral tunnel placement of the AM bundle and 14 min (SD: 9 min) of the PL bundle. CONCLUSION: This simple radiographic assessment is reproducible and reliable for clinical use, and useful for the evaluation of ACL reconstructive procedures.

Hip acetabular dysplasia and joint laxity of female anterior cruciate ligament-injured patients.

BACKGROUND: It has been noted that some female anterior cruciate ligament-injured patients have complaints of both coxalgia and joint laxity. HYPOTHESIS: Female anterior cruciate ligament-injured patients tend to have both acetabular dysplasia and generalized joint laxity. STUDY DESIGN: Cohort study (prevalence); Level of evidence, 2. METHODS: Hip radiographs of 100 female anterior cruciate ligament-injured patients and 40 female athletes without any hip joint complaints or history of anterior cruciate ligament injury were evaluated by measuring their center-edge angle (CEA). In addition, generalized joint laxity tests using 8 items were performed for anterior cruciate ligament-injured patients. Anterior-posterior (A-P) tibiofemoral translation of the uninjured knee was measured using a KT-1000 knee arthrometer to evaluate joint laxity under anesthesia before anterior cruciate ligament reconstruction. RESULTS: The average (± standard deviation) CEA of female anterior cruciate ligament-injured patients was 25.5° ± 5.3° (uninjured side) and 25.8° ± 4.8° (injured side), and that of the control group was 28.2° ± 4.2° (right side) and 29.2° ± 5.7° (left side), both P < .05. Among the 100 patients with anterior cruciate ligament tears, both the generalized joint laxity score and A-P tibiofemoral translation of the group with acetabular dysplasia (CEA of <25°, n = 37) were significantly greater than that of the normal group (CEA of ≥25°, n = 63). There was a negative correlation between the CEA of female anterior cruciate ligament-injured patients and both the generalized joint laxity score and A-P tibiofemoral translation. CONCLUSION: The CEA of female anterior cruciate ligament-injured patients was significantly smaller than that of the control group. Statstical analysis showed a moderate negative correlation between the CEA and generalized joint laxity score. Female athletes with an anterior cruciate ligament injury had an increased prevalence of acetabular dysplasia and generalized joint laxity.

Intra-articular injections of bone morphogenetic protein-7 retard progression of existing cartilage degeneration.

We investigated the effect of weekly intra-articular injections of bone morphogenetic protein-7 (BMP-7) on prevention of progression of existing cartilage degeneration in an osteoarthritis model in rabbits. An anterior cruciate ligament transection (ACLT) model was used to create a progressive osteoarthritis model. BMP-7 was intra-articular injected weekly into the right knee and PBS into the left knee from 4 weeks after ACLT. Both sides of the knees were compared macroscopically, histologically, immunohistochemically, and by micro CT. Macroscopically, fibrillation in the femoral condyle was observed 4 weeks after ACLT. In the control knees, cartilage degeneration further progressed throughout the 12-week period. In the BMP-7 treated knee, osteoarthritis progression was milder than in the control knees. Histologically, safranin-O staining was decreased in the surgical knees at 4 weeks. Obvious erosions in both medial and lateral condyles were revealed in the control knees at 12 weeks, while cartilage matrix was predominantly retained in the BMP-7 treated knees. The macroscopic and microscopic OA score in the BMP-7 treated knee was better than that in the control in each rabbit. Immunohistochemical analysis demonstrated that both type II collagen and BMP-7 were more expressed in cartilage treated with BMP-7. Micro CT analysis showed that osteophytes were smaller in the BMP-7 treated knee compared to that of the control. Weekly intra-articular injections of BMP-7 inhibited progression of existing cartilage degeneration.

Analysis of human synovial and bone marrow mesenchymal stem cells in relation to heat-inactivation of autologous and fetal bovine serums.

BACKGROUND: Though sera are essential for Mesenchymal stem cells (MSCs), the effect of heat-inactivation remains unknown. Autologous human serum is recommended for clinical use; however, it is unclear whether differentiation potentials are maintained. To examine whether heat-inactivation of serum affected the proliferation and whether autologous human serum influenced their multipotentiality. METHODS: After whole blood collection, human synovium and bone marrow were harvested. Nucleated cells were expanded with autologous human serum and FBS. RESULTS: Heat-inactivation of autologous human serum enhanced proliferation of synovial MSCs. Heat-inactivation of each types of serum didn't affect calcification of synovial MSCs. The induction of calcification increased ALP activity, with the exception of bone marrow MSCs with autologous human serum. For adipogenesis of synovial MSCs, the Oil Red-O positive colony forming efficiency with autologous human serum was similar to or less than that with FBS. CONCLUSION: These clarified the processing of human autologous serum and the influence of different sera for differentiation of synovial and bone marrow MSCs.

Revision anterior cruciate ligament reconstruction by double-bundle technique using multi-strand semitendinosus tendon.

PURPOSE: The purpose of the study was to compare the outcome of revision anterior cruciate ligament (ACL) reconstruction by the double-bundle (DB) technique using multi-strand semitendinosus tendon with that of primary reconstruction by use of the same technique. METHODS: The study included 21 patients who underwent revision ACL reconstruction (mean follow-up, 40 months) with the semitendinosus tendon DB technique between 1995 and 2006 and 86 unilateral primary DB ACL reconstructions (mean follow-up, 33 months) between 2000 and 2004. The outcome of both groups was compared based on differences between operated and unoperated limbs and modified International Knee Documentation Committee grades. Both the overall and sports-related subjective scores were evaluated between the 2 groups. RESULTS: The KT measurements (MEDmetric, San Diego, CA) averaged 1.7 mm (SD, 1.8 mm) in the revision group and 1.5 mm (SD, 1.6 mm) in the primary group. There was no significant difference in KT measurements between the 2 groups. The Lachman test was negative in 83% of revision cases and 87% of primary cases; the anterior drawer test was negative in 83% and 91%, respectively, and the pivot-shift test was negative in 78% and 90%, respectively. There was a tendency for a positive pivot-shift test in the revision group being higher. The Lysholm score and subjective recovery score were significantly lower in the revision group. CONCLUSIONS: The semitendinosus tendon DB revision procedure provided range of motion and anterior stability comparable to those after primary DB surgery and a comparable return to athletic activities. However, the patients tended to have positive pivot-shift test results. The revision cases were also inferior in terms of the general evaluation of recovery of knee condition. The outcome scores were lower overall in the revision group. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Ketoprofen absorption by muscle and tendon after topical or oral administration in patients undergoing anterior cruciate ligament reconstruction.

Topical ketoprofen patches are widely used in the treatment of musculoskeletal pain, but the pharmacokinetics of ketoprofen following topical application remain unclear. This open-label, single-dose pharmacokinetic study was designed to determine the concentrations of ketoprofen in the semitendinosus muscle/tendon and plasma after topical application or oral administration to patients scheduled for anterior cruciate ligament reconstruction. Two ketoprofen patches (20 mg each) were applied over the semitendinosus muscle/tendon for 1, 6, 14, or 20 h before surgery in 21 patients, while one sustained-release 150 mg ketoprofen capsule was administered to six patients 14 h before surgery. Ten untreated patients served as the control group. The main outcome measures were the semitendinosus muscle/tendon and plasma concentrations of ketoprofen at 1, 6, 14, and 20 h. Ketoprofen was detected in the semitendinosus muscle/tendon from about 1 h after topical application. The peak concentration was reached at 6 h, and it decreased gradually until 20 h, although the concentration at 20 h was still higher than that at 1 h. Unlike the tissue concentration, the plasma concentration of ketoprofen increased gradually after topical application. At 14 h, there was no significant difference of the tissue concentration between the topical and oral groups, although the plasma concentration was about 17-fold higher in the oral group than in the topical group. In conclusion, following topical application in a patch, ketoprofen shows rapid and sustained delivery to the underlying tissues without a significant increase of the plasma drug concentration.

Revascularization in the tendon graft following anterior cruciate ligament reconstruction of the knee: its mechanisms and regulation.

In anterior cruciate ligament (ACL) reconstruction, slow graft maturation may result in graft failure or elongation during the postoperative rehabilitation period. Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis. The findings of recent studies suggest that VEGF application is a potential strategy to accelerate angiogenesis in the graft after ACL reconstruction. However, the biomechanical results indicate that exogenous VEGF application decreases the stiffness of the grafted tendon at least temporarily. Therefore, we should take into account this adverse effect of exogenous VEGF application on the mechanical characteristics of the grafted tendon.

Periodic knee injections of BMP-7 delay cartilage degeneration induced by excessive running in rats.

Strenuous running of rats enhances mechanical stress on the knee, thereby inducing degeneration of articular cartilage. Bone morphogenetic protein-7 (BMP-7) has an inhibitory effect on cartilage degeneration, suggesting its usefulness for human osteoarthritis patients. However, its mode of administration should be investigated. We examined whether weekly knee injections of BMP-7 delayed the progression of cartilage degeneration. Wistar rats were forced to run 30 km in 6 weeks on a rodent treadmill, and BMP-7 was injected weekly into the knee. Macroscopically and histologically, this strenuous running regimen induced cartilage degeneration. Weekly injections of 250 ng BMP-7 delayed the progression of cartilage degeneration. Immunohistochemically, in the control knee, type II collagen expression decreased, while BMP-7 expression in chondrocytes slightly increased. Interestingly, weekly injection of BMP-7 increased BMP-7 expression even 9 days after the final injection. Disulfate disaccharide keratan sulfate in serum transiently increased in the control group, while it remained at a low level in the BMP-7 group. Weekly BMP-7 injection increased BMP-7 expression in chondrocytes and its effect seemed to last more than 7 days. The effect of BMP-7 could be monitored by serum keratan sulfate concentration. Periodical injections of BMP-7 delayed progression of cartilage degeneration induced by excessive running in rats.

Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament, and articular chondrocytes share similar gene expression profiles.

Mesenchymal stem cells (MSCs) can be obtained from various tissues, and contain common features. However, an increasing number of reports have described variant properties dependent of cell sources. We examined (1) whether MSCs existed in several intraarticular tissues, (2) whether gene expression profiles in intraarticular tissue MSCs closely resembled each other, and (3) whether identified genes were specific to intraarticular tissue MSCs. Human synovium, meniscus, intraarticular ligament, muscle, adipose tissue, and bone marrow were harvested, and colony-forming cells were analyzed. All these cells showed multipotentiality and surface markers typical of MSCs. Gene profiles of intraarticular tissue MSCs and chondrocytes were closer to each other than those of extraarticular tissues MSCs. Among three characteristic genes specific for intraarticular tissue MSCs, we focused on proline arginine-rich end leucine-rich repeat protein (PRELP). Higher expression of PRELP was confirmed in chondrocytes and intraarticular tissue MSCs among three elderly and three young donors. Synovium MSCs stably expressed PRELP, contrarily, bone marrow MSCs increased PRELP expression during in vitro chondrogenesis. In conclusion, MSCs could be isolated from various intraarticular tissues including meniscus and ligament, gene expression profiles of intraarticular tissue MSCs closely resembled each other, and the higher expression of PRELP was characteristic of intraarticular tissue MSCs.

Weekly intra-articular injections of bone morphogenetic protein-7 inhibits osteoarthritis progression.

INTRODUCTION: We investigated the ability of a weekly intra-articular injection of bone morphogenetic protein (BMP)-7 to prevent osteoarthritis in rabbits with anterior cruciate ligament transections. METHODS: First, 36 knee joints were randomly divided into four groups: 50, 500, 5,000 ng BMP-7, and control. Knee cartilage was evaluated at 4, 8, and 12 weeks. Then, in order to control for individual differences, 500 ng BMP-7 was injected into one knee and phosphate-buffered saline (PBS) into the other, and the two knees were compared at 4, 8, and 12 weeks (n = 5). For pharmacokinetic analysis, cartilage was harvested at 1 hour and 1, 2, 4, and 7 days after knee injection of 500 ng BMP-7 or PBS (n = 3). RESULTS: Histological scores in the 500 and 5,000 ng BMP-7 groups were significantly better than those in the other groups at 12 weeks. Matched pair analysis demonstrated that both macroscopic and histological scores in the 500 ng BMP-7 group were better than those in the control group. Immunohistochemical analysis revealed higher BMP-7 expression by chondrocytes in the BMP-7 injected knees. Histology of whole knee and quantitative micro computed tomography analysis showed that weekly injections of 500 ng BMP-7 did not induce synovial fibrosis, ectopic bone, or osteophyte formation. As detected by enzyme-linked immunosorbent assay, BMP-7 concentration in the cartilage tissue was still higher in the BMP-7 treated group 7 days after the injection. CONCLUSIONS: Weekly intra-articular injections of BMP-7 inhibited progression of osteoarthritis. Obvious adverse effects were not observed. BMP-7 concentration and expression in cartilage were still higher 7 days after injection.