Kanto Nagai

Intra-articular administration of gelatin hydrogels incorporating rapamycin–micelles reduces the development of experimental osteoarthritis in a murine model

Autophagy is a cellular homeostasis mechanism that may have a protective role against osteoarthritis (OA). The present study investigated the therapeutic effect of local administration of rapamycin, a potent activator of autophagy, against OA. To achieve controlled intra-articular administration of rapamycin, gelatin hydrogels incorporating rapamycin-micelles were created and the release profile was evaluated in vitro. The therapeutic effects of gelatin hydrogels incorporating rapamycin-micelles were then tested in a murine OA model. Mice were divided into four groups: Group 1, gelatin hydrogels alone; Group 2, single injection of 1 μg rapamycin; and Groups 3 and 4, gelatin hydrogels incorporating 100 ng or 1 μg rapamycin-micelles, respectively. Immunohistochemical analysis revealed that autophagic marker-positive chondrocytes were increased in the rapamycin-treated mice at 10 weeks after surgery. The histologic score was better in Groups 3 and 4 than in Groups 1 and 2, and Group 2 had a better score than Group 1. Delayed OA progression was maintained even at 16 weeks after surgery in Group 4. Microarray and real-time polymerase chain reaction analysis indicated that OA mediator genes were downregulated in the rapamycin-treated mice. Our novel system for intra-articular administration of rapamycin could be a novel therapeutic approach for treating patients with OA.

Soft Tissue Balance Changes Depending on Joint Distraction Force in Total Knee Arthroplasty

The influence of joint distraction force on intraoperative soft tissue balance was evaluated using Offset Repo-Tensor® for 78 knees that underwent primary posterior-stabilized total knee arthroplasty. The joint center gap and varus ligament balance were measured between osteotomized surfaces using 20, 40 and 60 lbs of joint distraction force. These values were significantly increased at extension and flexion as the distraction force increased. Furthermore, lateral compartment stiffness was significantly lower than medial compartment stiffness. Thus, larger joint distraction forces led to larger varus ligament balance and joint center gap, because of the difference in soft tissue stiffness between lateral and medial compartments. These findings indicate the importance of the strength of joint distraction force in the assessment of soft tissue balance, especially when using gap-balancing technique.

Age-Dependent Healing Potential of Anterior Cruciate Ligament Remnant-Derived Cells

Background: The anterior cruciate ligament (ACL) does not heal spontaneously after injury, and ACL patients of different ages respond differently to treatment. Although ACL-derived CD34-positive cells contribute to bone-tendon healing after ACL reconstruction, the relationship between the healing potential of ACL-derived cells and a patient’s age is unknown. Hypothesis: ACL-derived cells from young patients will have a greater effect on the maturation of bone-tendon integration in an immunodeficient rat model of ACL reconstruction compared with cells derived from older patients. Study Design: Controlled laboratory study. Methods: Sixty 10-week-old female immunodeficient rats underwent ACL reconstruction (using the autologous flexor digitorum longus tendon as a graft) followed by intracapsular administration of ACL-derived cells from patients aged 10 to 19 years (younger group) or patients aged 30 to 39 years (older group), or they were given phosphate-buffered saline (PBS; PBS group). Histologic, radiographic, and biomechanical examinations were performed 2 to 8 weeks after surgery. In addition, intrinsic and human cell–derived angiogenesis and osteogenesis were examined by immunohistochemistry. Results: In the younger group, histologic assessment demonstrated early bone-tendon healing, which induced endochondral ossification-like integration. Micro–computed tomography showed a statistically significant reduction in the area of tibial bone tunnel in the younger group (week 4, 20.0% ± 11.2% reduction; week 8, 25.7% ± 5.6% reduction) compared with the older group (week 4, 1.8% ± 3.0% reduction; week 8, 4.0% ± 5.9% reduction) and the PBS group (week 4, –0.5% ± 3.2% reduction; week 8, 3.3% ± 5.2% reduction) (week 4, P < .05; week 8, P < .01). Failure loads during tensile testing demonstrated a significantly higher ultimate load to failure in the younger group (17.52 ± 4.01 N) compared with the older (8.05 ± 2.91 N) and PBS (7.01 ± 3.16 N) groups (P < .05), and isolectin B4 and rat osteocalcin immunostaining indicated enhanced intrinsic angiogenesis and osteogenesis in the younger group. There was no statistically significant difference in the results of radiographic and biomechanical examinations between the older and PBS groups. Double immunohistochemistry for human-specific endothelial cell and osteoblast markers demonstrated a greater ability of differentiation into endothelial cells and osteoblasts in the younger group. Conclusion: ACL-derived cells from younger patients enhanced early bone-tendon healing in an immunodeficient rat model of ACL reconstruction. Clinical Relevance: Surgeons should consider a patient’s age when performing ACL reconstruction with remnant preservation or ruptured tissue incorporation, as this can predict healing ability.

Influence of Intraoperative Soft Tissue Balance on Postoperative Active Knee Extension in Posterior-Stabilized Total Knee Arthroplasty.

We evaluated the influence of intraoperative soft tissue balance on postoperative active knee extension using Offset Repo-Tensor® among 73 varus osteoarthritic knees underwent primary posterior-stabilized total knee arthroplasty. The joint center gap between osteotomized surfaces and the component gap after femoral trial component placement were measured using a joint distraction force of 40lb. The active knee extension angle was measured 4weeks after surgery. The postoperative extension angle was not correlated with the joint center gap at 0°, but positively correlated with the component gap at 0°, and the joint looseness at 0° which was calculated by subtracting insert thickness from the component gap. Thus, intraoperative soft tissue measurement with femoral trial component placement would be useful to predict the postoperative knee extension angle.

The Graft Bending Angle Can Affect Early Graft Healing After Anterior Cruciate Ligament Reconstruction: In Vivo Analysis With 2 Years’ Follow-up

Background: A high graft bending angle (GBA) after anterior cruciate ligament (ACL) reconstruction has been suggested to cause stress on the graft. Nevertheless, evidence about its effect on graft healing in vivo is limited. Hypothesis: The signal intensity on magnetic resonance imaging (MRI) would be higher in the proximal region of the ACL graft, and higher signals would be correlated to a higher GBA. Study Design: Descriptive laboratory study. Methods: Anatomic single-bundle ACL reconstruction was performed on 24 patients (mean age, 20 ± 4 years) using the transportal technique. A quadriceps tendon autograft with a bone plug was harvested. To evaluate graft healing, the signal/noise quotient (SNQ) was measured in 3 regions of interest (ROIs) of the proximal, midsubstance, and distal ACL graft using high-resolution MRI (0.45 × 0.45 × 0.70 mm), with decreased signals suggesting improved healing. Dynamic knee motion was examined during treadmill walking and running to assess the in vivo GBA. The GBA was calculated from the 3-dimensional angle between the graft and femoral tunnel vectors at each motion frame, based on tibiofemoral kinematics determined from dynamic stereo X-ray analysis. Graft healing and GBAs were assessed at 6 and 24 months postoperatively. Repeated-measures analysis of variance was used to compare the SNQ in the 3 ROIs at 2 time points. Pearson correlations were used to analyze the relationship between the SNQ and mean GBA during 0% to 15% of the gait cycle. Results: The SNQ of the ACL graft in the proximal region was significantly higher than in the midsubstance (P = .022) and distal regions (P < .001) at 6 months. The SNQ in the proximal region was highly correlated with the GBA during standing (R = 0.64, P < .001), walking (R = 0.65, P = .002), and running (R = 0.54, P = .015) but not in the other regions. At 24 months, signals in the proximal and midsubstance regions decreased significantly compared with 6 months (P < .001 and P = .008, respectively), with no difference across the graft area. Conclusion: The signal intensity was highest in the proximal region and lowest in the distal region of the reconstructed graft at 6 months postoperatively. A steep GBA was significantly correlated with high signal intensities of the proximal graft in this early period. A steep GBA may negatively affect proximal graft healing after ACL reconstruction.

Influence of intra-operative parameters on postoperative early recovery of active knee flexion in posterior-stabilized total knee arthroplasty

PurposeActive knee flexion is more important for daily activities than passive knee flexion. The hypothesis is that the intra-operative parameters such as osteotomized bone thickness and soft tissue balance affect the postoperative active flexion angle in total knee arthroplasty (TKA). Therefore, we evaluate the influence of intra-operative parameters on postoperative early recovery of active flexion after posterior-stabilized (PS) TKA.MethodsThe subjects were 45 osteoarthritic knees undergoing primary PS TKA with anterior-reference technique. Intra-operative soft tissue balance was measured using an offset type tensor, and each osteotomized bone thickness was also measured. Pre- and postoperative active knee flexion angles were measured using lateral radiographs. Liner regression analysis was used to determine the influence of these intra-operative parameters on postoperative active flexion angles or recovery of active flexion angles.ResultsPre-operative flexion angle was positively correlated with postoperative flexion angle (R = 0.52, P = 0.0002). Postoperative flexion angle was negatively correlated with the osteotomized bone thickness of femoral medial posterior condyle (R = −0.37, P = 0.012), and femoral lateral posterior condyle (R = −0.36, P = 0.015). Recovery of flexion angle was slightly negatively correlated with gap difference calculated by subtracting joint gap at extension from that at flexion between osteotomized surfaces (R = −0.30, P = 0.046).ConclusionsThe osteotomized bone thickness of the femoral posterior condyle is a significant independent factor of postoperative flexion angles. This indicates that the restoration of the posterior condyle offset may lead to larger postoperative active flexion angles in PS TKA.

Local Administration of Simvastatin Stimulates Healing of an Avascular Meniscus in a Rabbit Model of a Meniscal Defect

Background: Repair of an avascular meniscus is challenging because of its low capacity for healing. Several reports have shown that simvastatin stimulates the anabolic activity of intervertebral fibrochondrocytes, suggesting that simvastatin may be used for the treatment of meniscal defects. Purpose: To test whether the local administration of simvastatin stimulates healing of an avascular meniscus in rabbits. Study Design: Controlled laboratory study. Methods: In 30 Japanese White rabbits, a cylindrical defect (1.5-mm diameter) was introduced into the avascular zone of the anterior part of the medial meniscus in bilateral knees. Either a gelatin hydrogel (control group) or simvastatin-conjugated gelatin hydrogel (simvastatin group) was implanted into the defect. Histological assessments were performed using qualitative scoring systems, and immunohistochemical analysis was performed at 12 weeks after surgery. The occupation ratio (OR) and safranin O staining occupation ratio (SOR) were evaluated quantitatively at each time point. Stiffness of the regenerated tissue was analyzed biomechanically at 12 weeks after surgery. Rabbit meniscal cells were cultured in the presence or absence of 0.5 μM simvastatin, and then real-time polymerase chain reaction was performed to evaluate gene expression. Results: The qualitative score was significantly higher in the simvastatin group after 8 and 12 weeks (P = .031 and .035, respectively). The mean OR and SOR were also significantly higher in the simvastatin group (OR at 8 weeks: 0.396 ± 0.019 [control] vs 0.564 ± 0.123 [simvastatin], P = .008; OR at 12 weeks: 0.451 ± 0.864 [control] vs 0.864 ± 0.035 [simvastatin], P = .001; SOR at 8 weeks: 0.071 ± 0.211 [control] vs 0.487 ± 0.430 [simvastatin], P = .009; SOR at 12 weeks: 0.093 ± 0.088 [control] vs 0.821 ± 0.051 [simvastatin], P = .006). Immunohistochemical analysis showed that at 12 weeks, the reparative tissue was more strongly positive for type I collagen (COL1), type II collagen (COL2), bone morphogenetic protein 2 (BMP-2), and BMP-7 in the simvastatin group than in the control group. Biomechanical analysis showed significantly higher stiffness in the simvastatin group (2.417 ± 1.593 N/ms [control] vs 5.172 ± 1.078 N/ms [simvastatin]; P = .005). In rabbit meniscal cells, BMP-2 and BMP-7 were upregulated after 4 and 8 hours and after 7 and 14 days, whereas COL1A1 and COL2A1 were significantly upregulated by simvastatin after 7 and 14 days. Conclusion: The local administration of simvastatin promotes the regeneration of an avascular meniscus in the rabbit model of a meniscal defect. The mechanism may involve the upregulation of BMPs and the subsequent upregulation of COL1 and COL2. Clinical Relevance: This study suggests that simvastatin stimulated intrinsic healing of an avascular meniscus. The local administration of simvastatin is safe and inexpensive and seems to be a promising treatment of meniscal injuries.

Factors associated with the status of meniscal tears following meniscal repair concomitant with anterior cruciate ligament reconstruction

ABSTRACT Purpose: Anterior cruciate ligament (ACL) injuries are often accompanied by meniscal tears. Meniscal repair is typically performed during ACL reconstruction. However, retear of the meniscus after repair is frequent. The purpose of this study was to analyze the factors associated with meniscal healing after meniscal repair concomitant with ACL reconstruction. Materials and methods: Eighty-seven meniscal repairs in 87 patients who received meniscal repair combined with ACL reconstruction and received second-look arthroscopy at a mean of postoperatively 15.7 months were examined retrospectively. The menisci were divided into three groups (complete heal, incomplete heal, and retear), and factors thought to affect the healing status of repaired menisci were analyzed using multivariate logistic regression analysis. Results: Meniscal healing was judged to be complete in 49 knees (56%), incomplete in 19 knees, (22%), and retear in 19 knees (22%). There were no significant differences among the three groups in age, sex, time from injury to operation, mean Tegner activity scale, tear location, or mean postoperative anteroposterior tibial translation on KT-1000. The mean length of the tear was significantly higher in the retear group. Additionally, the proportion patients with complete tear and the proportion with postoperative positive pivot shift test were significantly higher in the retear group than in the other groups. Multivariate logistic regression analysis showed that complete tear and positive pivot shift test were associated with retear. Conclusions: These findings suggest that complete tears and residual instability are associated with retears after meniscal repair concomitant with ACL reconstruction.

Kinematic outcomes following ACL reconstruction

Anterior cruciate ligament (ACL) reconstruction aims to restore the translational and rotational motion to the knee joint that is lost after injury. However, despite technical advancements, clinical outcomes are less than ideal, particularly in return to previous activity level. A major issue is the inability to standardize treatment protocols due to variations in materials and approaches used to accomplish ACL reconstruction. These include surgical techniques such as the transtibial and anteromedial portal methods that are currently under use and the wide availability of graft types that will be used to reconstruct the ACL. In addition, concomitant soft tissue injuries to the menisci and capsule are frequently present after ACL injury and, if left unaddressed, can lead to persistent instability even after the ACL has been reconstructed. Advances in the field of biomechanics that help to objectively measure motion of the knee joint may provide more precise data than current subjective clinical measurements. These technologies include extra-articular motion capture systems that measure the movement of the tibia in relation to the femur. With data gathered from these devices, a threshold for satisfactory knee stability may be established in order to correctly identify a successful reconstruction following ACL injury.

Treatment of 50 Deep Infections After Total Knee Arthroplasty

The prevalence of infections caused by methicillin-resistant organisms has increased, causing difficulty in the treatment of prosthetic joint infection. A multicenter study was performed to review 50 patients with deep infections with or without a resistant organism, such as methicillin-resistant Staphylococcus aureus, at the site of total knee arthroplasty. A group of 13 patients with early deep infections and 4 patients with acute hematogenous infections underwent treatment with debridement, antibiotic therapy, and retention of the prosthesis with revision of the polyethylene insert. Thirty-three patients with late chronic infections were treated with challenging prosthesis retention for prostheses that had not loosened or 2-stage exchange arthroplasty for prostheses that had loosened. Mean duration of follow-up was 4.7±1.8 years. No significant differences in resultant functional knees and mean number of operations were observed between 7 patients with resistant early deep infections and 6 patients with nonresistant early deep infections. However, 24 patients with nonresistant chronic infections showed significant improvement in resultant functional knees (24 of 24; 100%) and fewer mean operations (2.8 times) compared with 9 patients with resistant chronic infections (1 of 9, 11%, and 4.3 times, respectively). The remaining 8 patients with resistant chronic infections (89%) had arthrodesis (3 patients) or underwent above-the-knee amputation (1 patient) or spacer arthroplasty (4 patients). Although patients with resistant early postoperative deep infections showed good results that were similar to those in patients with nonresistant early infections, those with resistant late chronic infections had a significantly inferior success rate compared with those who had nonresistant late chronic infections.