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Aims: Bone marrow mononuclear cells (BM-MNCs) are a rich source of hematopoietic stem cells that have been widely used in experimental therapies for patients with various diseases, including fractures.Activation of angiogenesis is believed to be one of the major modes of action of BM-MNCs; however, the essential mechanism by which BM-MNCs activate angiogenesis remains elusive. This study aimed to demonstrate that BM-MNCs promote bone healing by enhancing angiogenesis through direct cell-to-cell interactions via gap junctions, in addition to a previously reported method., Methods: Using a murine fracture model, we aimed to elucidate the relationship between gap junction-mediated cell-to-cell interactions and enhanced fracture healing after BM-MNC transplantation. We evaluated the transfer of substances from BM-MNCs to vascular endothelial cells and osteoblasts in the tissues surrounding the fracture site and assessed the effects of BM-MNC transplantation on bone healing, angiogenesis, and osteogenesis., Results: BM-MNCs transferred substances to vascular endothelial cells and osteoblasts in the tissues surrounding the fracture site. Moreover, BM-MNC transplantation promoted bone healing via gap junction-mediated cell-to-cell interactions, accelerating both angiogenesis and osteogenesis., Conclusions: Our findings provide a novel understanding of fracture healing mechanisms and suggest that BM-MNC transplantation enhances bone healing through gap junction-mediated cell-to-cell interactions, contributing to the development of regenerative medicine strategies targeting bone repair., (© The Author(s) 2025. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: The study aimed to determine the impact of intraoperative lateral laxity at extension on clinical and functional outcomes 1 year after posterior-stabilised total knee arthroplasty (PS-TKA)., Methods: In total, 91 varus-type osteoarthritic knees that underwent PS-TKA using the medial preservation gap technique were included. After the femoral trial component placement and patellofemoral joint reduction, the soft-tissue balance was assessed using an offset-type tensor with a 40-lb joint-distraction force. Patients were divided into the following three groups according to the intraoperative lateral laxity at extension (i.e., varus ligament balance) using the mean ± 1 standard deviation: Groups A, ≤0°; B, 0-4°; and C, >4°. The 2011 Knee Society Score (KSS) and 3-m timed up-and-go test (TUG) time 1-year postoperatively, and their improvements were compared among the groups., Results: While significant improvements were observed in all subscales of the 2011 KSS and TUG post-TKA (p < 0.05), the improvement of functional activities and TUG time were significantly lower in Group C than in Group B (p < 0.05). However, no significant differences were observed in symptom improvement, patient satisfaction or patient expectation scores among the groups., Conclusion: An excessive lateral laxity (varus angle) >4° at extension was associated with lower improvement in functional ability 1-year postoperatively. Therefore, excessive intraoperative lateral laxity should be avoided in PS-TKA., Level of Evidence: Level IV., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Objective: The role of Krüppel-like zinc finger transcription factor 15 (KLF15) in endochondral ossification during fracture healing remains unexplored. In this study, we aimed to elucidate the impact of KLF15 in a mouse model of tibial transverse fracture., Methods: We created tamoxifen-inducible, cartilage-specific KLF15 knockout mice (KLF15 KO). KLF15 fl/fl Col2-CreERT mice from the same litters as the KLF15 KO mice, but not treated with 4-hydroxytamoxifen, were used as controls (CT). At 10 weeks, male KLF15 KO and CT mice underwent tibial fracture followed by intramedullary nailing. Both groups were administered tamoxifen at days 0, 3, and 7 after surgery. The tibiae were harvested on post-surgery days 7, 10, and 14 for radiological assessment using micro-computed tomography. Histological staining (Safranin-O) and immunohistochemistry for KLF15, SOX9, Indian hedgehog (IHH), RUNX2, and Osterix were performed. Additionally, cartilage from mouse fetus was cultured for qRT-PCR and western blot analyses of KLF15, SOX9, IHH, Col2, RUNX2, Osterix, TGF-β, SMAD3, and phosphor-SMAD3., Results: The radiological assessment revealed that immature callus formation was delayed in KLF15 KO, compared with that in CT, peaking on day 14 compared with that on day 10 in CT. KLF15 KO mice exhibited delayed fracture healing and reduced Safranin-O staining at days 7 and 10 post-surgery. The ratio of cells positive for KLF15 and SOX9 was significantly lower in KLF15 KO than in CT, whereas the ratios for IHH, RUNX2, and Osterix showed no significant difference. RT-PCR revealed reduced expression of KLF15, SOX9, and COL2, with no significant changes in IHH, Osterix, RUNX2, TGF-β, and SMAD3. Western blot analysis indicated decreased SMAD3 phosphorylation in KLF15 KO mice., Conclusion: KLF15 regulates SOX9 via the TGF-β-SMAD3-SOX9 pathway, independent of IHH, in endochondral ossification. The KLF15 deficiency decreases SOX9 expression through reduced SMAD3 phosphorylation, subsequently delaying fracture healing., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to compare leg length discrepancies (LLD) between simultaneous and staged bilateral total hip arthroplasty (BTHA)., Materials and Methods: This retrospective cohort study included 150 consecutive patients who underwent BTHA (60 simultaneous and 90 staged BTHA). To adjust for preoperative patient characteristics between groups, 1:1 propensity score matching was performed based on age, sex, body mass index, American Society of Anesthesiologists Physical Status, Tönnis classification, Crowe classification, preoperative range of motion (flexion and abduction), LLD, and Harris Hip Score (HHS). Finally, 66 patients (33 pairs) with comparable preoperative backgrounds were analyzed. Postoperative LLD and clinical outcomes, including HHS, range of motion (flexion and abduction), operative time, intraoperative blood loss, and complications, were compared between the simultaneous and staged BTHA groups., Results: The LLD in the simultaneous BTHA group was significantly smaller than that in the staged BTHA group (simultaneous BTHA, 3.5 ± 3.2 mm; staged BTHA, 6.2 ± 4.5 mm, p < 0.001). The rate of LLD ≤ 7 mm was significantly higher in simultaneous BTHA (84.8%) compared to staged BTHA (57.6%) (p = 0.028). Other outcomes, including the HHS, range of motion (flexion and abduction), operative time, intraoperative blood loss, and complication rates were similar between the groups., Conclusion: Simultaneous BTHA has the potential to provide smaller LLD than staged BTHA because simultaneous surgery enables intraoperative comparison of bilateral leg lengths based on both extra- and intra-articular measurements. This approach may be advantageous for postoperative patient satisfaction., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent for participation in the study was obtained from all participants. The study protocol was approved by our Institutional Review Board on September 8, 2011 (no. 1220), and the study was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. Consent for publication: Not applicable. Conflict of interest: All authors do not have any conflict of interest. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study emphasizes the importance of early detection of osteonecrosis of the femoral head (ONFH) in young patients on long-term glucocorticoid therapy, including those with acute lymphoblastic leukemia, lupus, and other diagnoses. While X-ray and magnetic resonance imaging (MRI) are standard imaging methods for staging ONFH, MRI can be costly and time-consuming. The research focuses on utilizing artificial intelligence (AI) to enhance the evaluation of radiographic images for ONFH detection. The study involved analyzing X-ray and MRI from 102 control hips and 104 ONFH-affected hips at Association Research Circulation Osseous (ARCO) Stage II and IIIa. We employed transfer learning with the YOLOv8 model for object detection, using 80% of the data for training and 20% for validation, then assessed detection accuracy through mean average precision (mAP) and a precision-recall curve. Additionally, AI generated synthetic MRI (sMRI) from X-ray images using a Generative Adversarial Network (GAN) and evaluated their similarity to original MRI. Results showed that the mAP for ONFH detection was 0.923 for the YOLOv8n model and 0.951 for YOLOv8x. The GAN-generated sMRI exhibited lower image quality compared with originals but maintained potential for lesion assessment. Intrarater reliability among evaluators was high. The findings indicate that AI techniques, particularly YOLOv8 for object detection and GAN for image generation, can effectively assist in ONFH screening, despite some limitations in the generated MRI quality., (© 2024 Orthopaedic Research Society.)

Objective: This study aimed to analyze the clinical efficacy of JAK inhibitors in difficult-to-treat rheumatoid arthritis (D2TRA) and non-D2TRA patients and evaluate the factors influencing their efficacy using real-world data., Method: Here, 159 JAK inhibitor-treated patients with rheumatoid arthritis were categorized into D2TRA and non-D2TRA groups. Data including the Clinical Disease Activity Index (CDAI) at initiation and 6 months after drug administration, drug retention months, and reason for discontinuation due to toxic adverse events were collected., Results: The retention rates at 6 months were 64.0% (D2TRA) and 78.4% (non-D2TRA) and were significantly different between the two groups (p = 0.030). The discontinuation rate owing to toxic adverse events significantly differed between the two groups (p = 0.030). The CDAI-low disease activity (LDA) rates differed significantly between the two groups (non-D2TRA, 62.3%; D2TRA, 34%; p < 0.001). CDAI-LDA achievement at 6 months after drug introduction was significantly associated with the number of times that biologic and/or targeted synthetic disease-modifying anti-rheumatic drugs were previously used and the CDAI at baseline in all patients treated with JAK inhibitors. However, no predictive factors were identified for D2TRA patients treated with JAK inhibitors., Conclusion: Compared to non-D2TRA patients, D2TRA patients demonstrated significantly lower drug retention rates, CDAI-LDA achievement rates, and safety of JAK inhibitors. No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients. Key Points • The retention of JAK inhibitors were significantly lower for the treatment of D2TRA patients in comparison with non-D2TRA patients. • The efficacy and safety of JAK inhibitors were significantly lower for the treatment of D2TRA patients. • Number of previous uses of b/tsDMARDs and CDAI at baseline were identified as the predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. • No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Introduction: Many patients who have undergone a periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH) have had jobs preoperatively. Postoperative return to work and work productivity are important for livelihood security and the social economy. However, there is a lack of evidence on work productivity after PAOs. Therefore, this study investigated the return to work rates and influence of workload, clinical, and radiographic parameters on work productivity after a curved PAO., Materials and Methods: In this study, the data of 68 hip joints among 48 participants who underwent curved PAO for symptomatic DDH were analyzed. Correlations between postoperative work productivity and clinical, radiographic, and workload parameters were assessed. Work productivity was evaluated using the Work Productivity and Activity Impairment (WPAI) questionnaire. Clinical factors were assessed using the modified Harris Hip Scores (mHHS) and University of California, Los Angeles Activity scores. Preoperative and postoperative radiographic parameters were compared with postoperative work productivity. The workload was categorized using the Reichsausschuß für Arbeitszeitermittlung (REFA)-classification system., Results: Of the participants, 98% returned to work and 87.5% returned to their original jobs. Work productivity was significantly improved in all workload categories at the 1-year postoperative follow-up. Multivariate analysis demonstrated that preoperative Tönnis and REFA classification grades were significantly associated with the postoperative WPAI., Conclusion: Curved PAOs can improve postoperative work productivity and return to work rates. Preoperative progression of osteoarthritis and heavy workload affect postoperative work productivity., Competing Interests: Declarations. Ethical approval and consent to Participate: The study protocol was approved by our Institutional Review Board on September 8, 2011 (No 1219), and the study was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. Informed consent for participation in the study was obtained from all participants. Competing interests: The authors declare that they have no competing interests. Conflict of interest: All authors do not have any conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction/objectives: JAK/STAT signaling inhibition exerts therapeutic effects on angiogenesis in rheumatoid arthritis (RA). However, whether the inhibitory effect differs among JAK inhibitors because of differing selectivity is unknown. Therefore, we compared the inhibitory effects of tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib on angiogenesis., Method: RA-derived fibroblast-like synoviocytes (RA-FLS) were seeded on type I collagen gel, and human umbilical vein endothelial cells (HUVECs) were directly added. The control and aforementioned JAK inhibitors were added to the medium, followed by stimulation with interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). Each JAK inhibitor's concentration was determined based on estimated blood concentrations. The vascular endothelial growth factor (VEGF) concentration was evaluated with an enzyme-linked immunosorbent assay using the medium from the first exchange. A migration assay was performed, and HUVEC migration was evaluated using CD31 fluorescence immunostaining., Results: Hematoxylin-eosin staining showed that compared with the non-JAKi treatment group, the JAKi treatment group markedly degenerated in the sub-lining and deep lining, with decreased lymphocyte infiltration and neovascularization [Rooney's score subscale, non-JAKi vs JAKi (median, 6.5 vs 2.5, p = 0.005)]. In vitro, IL-6 and sIL-6R administration increased VEGF production from RA-FLS and promoted neovascularization in HUVECs, and JAK-inhibitor administration, which decreased VEGF production from RA-FLS and suppressed HUVEC migration, inhibited neovascularization in RA-FLS and HUVEC co-cultures., Conclusions: The JAK inhibitors suppressed IL-6-induced angiogenesis via decreased VEGF production and HUVEC migration in RA-FLS and HUVEC co-cultures. No significant differences were observed among the JAK inhibitors, whose anti-angiogenic effect may be an important mechanism for RA treatment. Key Points • JAK inhibitors inhibit angiogenesis in RA by reducing VEGF production from RA-derived fibroblast-like synoviocytes. • Our study provides new insights into RA treatment by elucidating the anti-angiogenic effect of JAK inhibitors., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: The uncultured adipose-derived stromal vascular fraction (SVF), consisting of adipose-derived stromal cells (ADSCs), M2 macrophages (M2Φ) and others, has shown therapeutic potential against osteoarthritis (OA), however, the mechanisms underlying its therapeutic effects remain unclear. Therefore, this study investigated the effects of the SVF on OA in a human-immunodeficient rat xenotransplantation model., Methods: OA model was induced in the knees of female immunodeficient rats by destabilization of the medial meniscus. Immediately after the surgery, human SVF (1 × 10 5 ), ADSCs (1 × 10 4 ), or phosphate buffered saline as a control group were transplanted into the knees. At 4 and 8 weeks postoperatively, OA progression and synovitis were analyzed by macroscopic and histological analyses, and the expression of collagen II, SOX9, MMP-13, ADAMTS-5, F4/80, CD86 (M1), CD163 (M2), and human nuclear antigen (hNA) were evaluated immunohistochemically. In vitro, flow cytometry was performed to collect CD163-positive cells as M2Φ from the SVF. Chondrocyte pellets (1 × 10 5 ) were co-cultured with SVF (1 × 10 5 ), M2Φ (1 × 10 4 ), and ADSCs (1 × 10 4 ) or alone as a control group, and the pellet size was compared. TGF-β, IL-10 and MMP-13 concentrations in the medium were evaluated using enzyme-linked immunosorbent assay., Results: In comparison with the control and ADSC groups, the SVF group showed significantly slower OA progression and less synovitis with higher expression of collagen II and SOX9, lower expression of MMP-13 and ADAMTS-5, and lower F4/80 and M1/M2 ratio in the synovium. Only the SVF group showed partial expression of hNA-, CD163-, and F4/80-positive cells in the rat synovium. In vitro, the SVF, M2Φ, ADSC and control groups, in that order, showed larger pellet sizes, higher TGF-β and IL-10, and lower MMP-13 concentrations., Conclusions: The M2Φ in the transplanted SVF directly affected recipient tissue, enhancing the secretion of growth factors and chondrocyte-protecting cytokines, and partially improving chondrocytes and joint homeostasis. These findings indicate that the SVF is as an effective option for regenerative therapy for OA, with mechanisms different from those of ADSCs., (© 2024. The Author(s).)

Background: Both kinematically-aligned (KA) total knee arthroplasty (TKA) and bicruciate stabilized (BCS) TKA aim to reproduce the physiological knee kinematics. In this study, we compared the femoro-tibial component rotational mismatch between patients who underwent modified KA-TKA and those who received guided-motion BCS-TKA, and its influence on the clinical outcomes., Methods: In this retrospective study, 77 consecutive patients were included and divided into two groups: subjects who underwent modified KA-TKA with Persona (KA Group; n = 42) and those who received BCS-TKA with JOURNEY II (BCS group; n = 35). Range of motion, the 2011 Knee Society Score (KSS), the rotational alignment of the femoral and tibial components, and the correlations between the rotational mismatch and the 2011 KSS subscales were examined., Results: The postoperative objective knee indicators (P = 0.0157), patient satisfaction (P = 0.0039) and functional activity scores (P = 0.0013) in the KA group were significantly superior to those in the BCS group 1 year postoperatively. There was no significant difference between the two groups observed in the rotational mismatch. In the BCS group, significant negative correlations were identified between the rotational mismatch and objective indicators, patient satisfaction, and functional activity scores but not in the KA group., Conclusions: The short-term clinical results following KA-TKA showed superior objective knee indicators, patient satisfaction and functional activity scores. A negative correlation was observed between component rotational mismatch and the 2011 KSS subscales in the BCS group, compared to no relationship found between the two in the KA group. These findings suggested that KA-TKA has a relatively higher tolerance for rotational mismatch than BCS-TKA., (© 2024. The Author(s).)

Introduction: Postoperative osteoarthritis (OA) progression is a major determinant of failure after curved periacetabular osteotomy (CPO). A large postoperative combination angle, i.e., the combination of computed tomography-based anterior center edge and alpha angles, is associated with femoroacetabular impingement after CPO, but its association with postoperative OA progression is unclear. We aimed to identify the anatomical parameters that can lead to OA progression after CPO and the impact of the combination angle on the same., Materials and Methods: We included 90 hips that were subjected to CPO at our center between March 2013 and March 2018. Seventeen hips showed OA progression with an increase in the Tönnis classification after surgery; 73 hips showed no progression. Radiographic anatomical parameters, including the lateral and anterior center edge angles, femoral and acetabular anteversion, and combination angle, and clinical outcomes, including modified Harris Hip Scores (mHHSs), postoperative anterior impingement, and range of motion, were compared between the two groups. Statistical significance was set at P < 0.05., Results: Postoperative OA progression was significantly affected by preoperative OA evidence (P = 0.017), acetabular anteversion < 5.0° (P = 0.003), and a combination angle > 107.0° (P = 0.025). Patients with radiographic OA progression were associated with poor mHHSs (P = 0.017) and high frequencies of anterior impingement with a limited hip flexion and internal rotation angle., Conclusions: OA progression after CPO may be associated with preoperative evidence of OA and postoperative acetabular retroversion as well as a large combination angle. Surgeons should focus on the potential effects of preoperative OA grades, postoperative reduction in acetabular anteversion, and postoperative combination angle., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Bone maintenance after total hip arthroplasty (THA) is important for implant success. This study aimed to investigate the relationship between patient characteristics and periprosthetic bone maintenance after THA for better implant selection., Materials and Methods: This retrospective cohort study enrolled 112 consecutive patients who underwent THA using full hydroxyapatite (HA) compaction with short (n = 55) or short-tapered wedge (n = 61) stems. Periprosthetic bone mineral density (BMD) was compared between the two groups after propensity score matching, and the relationship between periprosthetic BMD changes and patient background was analyzed., Results: Both groups showed similar periprosthetic BMD changes after adjusting for patient background using propensity score matching. Canal flare index > 3.7 in patients that underwent THA using tapered-wedge stem (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3-7.9, p = 0.013) and baseline zone 1 BMD > 0.65 in patients that received with short HA compaction stems (OR, 430.0; 95% CI 1.3-1420, p = 0.040) were associated with proximal periprosthetic bone maintenance after THA., Conclusion: Considering their predictive value, canal flare index and zone 1 BMD assessment might be useful strategies for implant selection during THA., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The alignment philosophy in total knee arthroplasty (TKA) has tended to shift from the gold standard of mechanically aligned technique to personalized alignment, such as the kinematically aligned (KA) technique. However, the influences of different surgical techniques on lower limb alignment relative to the ground are not fully investigated. This study investigated the influence of the ankle and hindlimb alignment change after mechanically aligned TKA and KA-TKA. The varus osteoarthritic patients who underwent TKAs were divided into a mechanically aligned TKA group (group M, n  = 50) and a KA-TKA group (group K, n  = 50). Radiographic parameters (hip-knee-calcaneus [HKC] angle, hip-knee-ankle [HKA] angle, talar tilt angle [TTA], and tibiocalcaneal angle [TCA]) were investigated using full-length standing radiographs. The deviation angle (ΔTA; angle between the tibial mechanical axis [TMA] and the ground tibial mechanical axis [gTMA]) and the change of ΔTA (cΔTA) were also assessed. These parameters were compared between the two groups, along with the correlation between the preoperative HKA angle and other parameters. ΔTA, TTA, and TCA showed no differences between the groups pre- and postoperatively, and no significant changes were observed postoperatively. The preoperative HKA angle showed a significant negative correlation with cΔTA in both groups (group M: r  = -0.33, p  = 0.02; group K: r  = -0.29, p  = 0.04) although no correlation was observed the with preoperative TTA and TCA. Despite no change in ΔTA after surgery, the preoperative varus deformity was associated with a change in the deviation between gTMA and TMA after surgery. A severely varus knee may be inappropriate for ground KA-TKA., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: The indication for unicompartmental knee arthroplasty (UKA) has been extended to cases with some degree of preoperative knee flexion contracture recently. The purpose of this study was to clarify the effect of flexion contracture on component angles., Materials and Methods: Thirty-five fixed-bearing UKAs using the spacer block technique with preoperative flexion contracture (Group FC) and 35 UKAs using the same technique without preoperative flexion contracture (Group NC) were included. Using radiographs, the coronal femoral component angle, coronal tibial component angle, sagittal femoral component angle, and sagittal tibial component angle were determined. Also, extension and flexion angles of the knee as well as coronal Hip-Knee-Ankle (HKA) angles in long-leg standing radiographs were measured. The data about the thickness of the selected insert were also collected. The above results were compared between the two groups., Results: The femoral component tended to be placed in a more varus and flexed position in Group FC, while no significant difference was found about the tibial component angles. While there was no significant difference in pre- and postoperative knee flexion angles between the two groups, flexion contracture remained postoperatively in Group FC. Preoperative HKA angle was greater in Group FC while the difference was no longer significant postoperatively. Regarding the thickness of the selected insert, thicker inserts tended to be used in Group FC., Conclusions: In fixed-bearing UKA with the spacer block technique, the femoral component tended to be placed in a flexed and varus position in the knees with preoperative flexion contracture., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Introduction: Correct cup placement in total hip arthroplasty (THA) for patients with developmental dysplasia of the hip (DDH) is considerably difficult. This study aimed to analyze the orientation accuracy of cup insertion during THA using a portable navigation system in patients with DDH., Materials and Methods: In this retrospective cohort study, we analyzed data from 64 patients who underwent THA using infrared stereo camera-matching portable navigation. Patients underwent THA via the anterolateral approach in the lateral decubitus position. Navigation records for intraoperative cup angles, postoperative cup angles measured on computed tomography (CT) images, and cup angle measurement differences were measured and compared between patients with non-DDH/mild DDH and severe DDH. Furthermore, the predictive factors for outliers of accurate acetabular cup placement were analyzed., Results: The average measurement absolute abduction differences (postoperative CT-navigation record) were 3.9 ± 3.5° (severe DDH) and 3.3 ± 2.6° (non-DDH/ mild DDH), and the anteversion differences were 4.7 ± 3.4° (severe DDH) and 2.3 ± 2.1° (non-DDH/ mild DDH). The anteversion difference was different between the two groups. Multivariate analysis showed that the navigation difference (absolute difference in anteversion between postoperative CT and navigation records of > 5°) was significantly associated with severe DDH (odds ratio [OR]: 3.3; p = 0.049, 95% confidence interval [CI]: 1.0-11.1) and posterior pelvic tilt (OR: 1.1; p = 0.042, 95% CI: 1.0-1.27)., Conclusions: In patients with severe DDH, it is important to pay close attention during THA using portable navigation. However, the average difference was < 5º even in patients with severe DDH, and the accuracy may be acceptable in a clinical setting when the cost is considered., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Only a few reports have been published so far on factors that predict postoperative coronal alignment after unicompartmental knee arthroplasty (UKA). The purpose of this study is to clarify the relationship between the arithmetic hip-knee-ankle angle (aHKA) and postoperative coronal alignment after medial fixed-bearing UKA., Methods: One hundred and one consecutive patients (125 knees) who underwent medial fixed-bearing UKA were assessed. Pre- and postoperative coronal HKA angles, lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), and the thickness of the tibial and femoral bone cut were measured. aHKA was calculated as 180° - LDFA + MPTA. Correlations between postoperative HKA angle and aHKA, LDFA, and MPTA were investigated by single regression analysis. After the patients were divided into three groups according to the postoperative HKA angle, i.e., HKA angle > 180°, 175° < HKA angle ≤ 180°, and HKA angle ≤ 175°, aHKA, LDFA, MPTA, preoperative HKA angle, and the thickness of the distal femoral as well as tibial bone cut were compared among the three groups., Results: aHKA and MPTA were positively correlated with postoperative HKA angle, while no correlation was found between postoperative HKA angle and LDFA. Among the three groups classified by postoperative HKA angle, significant differences were found in aHKA, MPTA, and preoperative HKA angle, while no significant difference was found in LDFA and the amount of distal femoral and tibial osteotomies., Conclusions: aHKA was correlated with postoperative HKA angle after medial fixed-bearing UKA, which was probably due to the influence of MPTA., (© 2023. The Author(s).)

Background: Total knee arthroplasty (TKA) for Charcot arthropathy of the knee is considered controversial because of its higher complication rate compared with that of TKA for osteoarthritis. In this study, we investigated the clinical outcomes, survival rates, and complications of primary TKA for Charcot arthropathy., Methods: We conducted a retrospective analysis of nine patients (12 knees) with Charcot arthropathy who underwent TKA. The mean age of the patients was 63.9 ± 9.4 years (range, 52-83 years). The most frequent causative disease was diabetes mellitus (three patients). Patients' clinical outcomes, including the 2011 Knee Society Score and the range of motion, were compared between preoperative and the most recent postoperative data. The 5- and 10-year survival rates for aseptic revision, revision due to infection, and complications were examined. The mean follow-up period was 7.3 ± 3.9 years (range, 3-14 years)., Results: The 2011 Knee Society Score and the knee flexion angle significantly improved after TKA surgery ( P  < 0.05). The 5-year survival rates for aseptic revision, revision due to infection, and complications were 100%, 91.7%, and 83.3%, respectively; the 10-year survival rates for these parameters were the same. One patient underwent revision for insert replacement due to periprosthetic infection, and the other patient had varus/valgus instability due to soft tissue loosening., Conclusions: The mid- to long-term results of TKA for Charcot arthropathy were generally favorable. Our findings indicate that TKA may be a viable treatment option for Charcot arthropathy., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Indian Orthopaedics Association 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Aims: Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice., Methods: We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR)., Results: Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE. Bone resorption activity was decreased in both sexes. In vitro osteogenic and osteoclastic differentiation assays during inflammatory conditions did not reveal differences among the groups. Receptor activator of nuclear factor kappa Β ligand ( Rankl) gene expression by osteoblasts was significantly decreased only in males when treated with ODN., Conclusion: We demonstrated that NF-κB decoy ODN increased osteogenesis in male mice and decreased bone resorption activity in both sexes in preclinical models of chronic inflammation. NF-κB signalling could be a therapeutic target for chronic inflammatory diseases involving bone, especially in males., Competing Interests: The authors declare no conflicts of interest., (© 2024 Goodman et al.)

Nontraumatic osteonecrosis of the femoral head (ONFH) is a refractory condition that commonly results in femoral head collapse and degenerative arthritis of the hip. In the early stages, surgical procedures for hip preservation, including core decompression (CD), have been developed to prevent progressive collapse of the femoral head. Optimization of bone regeneration and biological augmentation may further enhance the therapeutic efficacy of CD for ONFH. Thus, combining CD with cell-based therapy has recently been proposed. In fact, patients treated with cell-based therapy using autologous bone marrow concentrate demonstrate improved survivorship of the femoral head, compared with conventional CD alone. Preclinical research studies to investigate adjunctive therapies for CD often utilize the rabbit model of corticosteroid-induced ONFH. Mesenchymal stem cells (MSCs) are known to promote osteogenesis and angiogenesis, and decrease inflammation in bone. Local drug delivery systems have the potential to achieve targeted therapeutic effects by precisely controlling the drug release rate. Scaffolds can provide an osteoconductive structural framework to facilitate the repair of osteonecrotic bone tissue. We focused on the combination of both cell-based and scaffold-based therapies for bone tissue regeneration in ONFH. We hypothesized that combining CD and osteoconductive scaffolds would provide mechanical strength and structural cell guidance; and that combining CD and genetically modified (GM) MSCs to express relevant cytokines, chemokines, and growth factors would promote bone tissue repair. We developed GM MSCs that overexpress the anti-inflammatory, pro-reconstructive cytokines platelet-derived growth factor-BB to provide MSCs with additional benefits and investigated the efficacy of combinations of these GM MSCs and scaffolds for treatment of ONFH in skeletally mature male New Zealand white rabbits. In the future, the long-term safety, efficacy, durability, and cost-effectiveness of these and other biological and mechanical treatments must be demonstrated for the patients affected by ONFH., (© 2023 Wiley Periodicals LLC.)

Local cell therapy has recently gained attention for the treatment of joint diseases and fractures. Mesenchymal stem cells (MSCs) are not only involved in osteogenesis and angiogenesis, but they also have immunomodulatory functions, such as inducing macrophage migration during bone regeneration via macrophage crosstalk. C-C motif chemokine ligand 2 (CCL2), a known inflammatory mediator, is associated with the migration of macrophages during inflammation. This study examined the utility of CCL2 as a therapeutic target for local cell therapy. Using lentiviral vectors for rabbit MSCs, genetically modified CCL2 overexpressing MSCs were generated. Osteogenic differentiation assays were performed using MSCs with or without macrophages in co-culture, and cell migration assays were also performed. Additionally, co-cultures were performed with endothelial cells (ECs), and angiogenesis was evaluated using a tube formation assay. Overexpression of CCL2 did not affect bone formation under monoculture conditions but promoted chemotaxis and osteogenesis when co-cultured with macrophages. Furthermore, CCL2 -overexpression promoted tube formation in co-culture with ECs. These results suggest that CCL2 induces macrophage chemotaxis and osteogenesis by promoting crosstalk between MSCs and macrophages; CCL2 also stimulates ECs to induce angiogenesis. These findings indicate that CCL2 may be a useful therapeutic target for local cell therapy in areas of bone loss.

BACKGROUND Distal femoral and proximal tibial fractures often lead to nonunion and post-traumatic osteoarthritis, and total knee arthroplasty (TKA) has emerged as an effective alternative for older patients. This report includes 3 cases of successful TKA treatment. The cases involve a 42-year-old man and a 62-year-old man with Hoffa coronal fractures of the distal femur, and a 50-year-old man with a proximal tibial fracture. These patients underwent multiple osteosynthesis procedures before receiving TKA. CASE REPORT Case 1: A 42-year-old man with a displaced Hoffa's fracture had persistent knee pain. Nonunion post-initial fixation led to reoperation with iliac bone grafting and plate fixation. TKA using a Posterior Stabilized (PS)-type implant resulted in improved motion and function after 3 years. Case 2: A 62-year-old man suffered lateral condyle and ligament injuries from a displaced Hoffa's fracture. Despite plate fixation, dislocation occurred, requiring conversion. TKA with long-stem hinge-type implant, using augmentation block, led to enhanced stability and outcomes at 2 years. Case 3: A 50-year-old man's tibial nonunion, treated with plate fixation, resulted in infection and bone fusion. TKA using a constrained PS-type implant insert addressed the lateral tibial adhesions via iliotibial band (ITB) release and treated severe tibial plateau damage. Positive results were seen at 1 year. CONCLUSIONS The challenges of pseudarthrosis, like bone defects and compromised tissue, highlight the need for precise implant selection based on evaluations of bone quality, defects, knee stability, and hyperextension, rather than resorting to overly-constrained implants.

The aim of the study is to explore and compare the differences in trochlear shape and knee anatomy between four types of prostheses and preoperative native knee matched with preoperative computed tomography (CT). Thirty patients were scheduled for primary kinematically aligned total knee arthroplasty (TKA) for varus knee osteoarthritis at our hospital and the region between their pelvis to ankle joint was simulated using a CT-based three-dimensional planning software. The axial plane containing the transepicondylar axis was set as Slice A, and the 10-mm distal plane from Slice A was set as Slice B. The distances to the deepest trochlear groove between the native knee and each prosthesis and the medial and lateral facet heights were compared among the four groups. The deepest femoral trochlear groove of the prostheses was located 1.6 to 3.0 mm more medial than that of the native knee, and in the Persona group, it was significantly more medial than in the e-motion or Triathlon groups on both Slices A and B. The native knee and the medial and lateral facet heights of the four prostheses on both Slices A and B were significantly lower than those of preoperative native knees when femoral prostheses were set in the kinematically aligned (KA)-TKA position. The deepest point of the trochlear groove of the Persona group was the most medial among the four prostheses studied, and the deepest points differed depending on the prosthesis design in KA-TKA. Thus, surgeons should carefully select the type of prostheses used in KA-TKA., Competing Interests: None declared., (Thieme. All rights reserved.)

The stromal-vascular fraction (SVF), comprising heterogeneous cell populations and adipose-derived stromal cells (ADSCs), has therapeutic potential against osteoarthritis (OA); however, the underlying mechanism remains elusive. This study aimed to investigate the therapeutic effects of heterogeneous cells in rabbit SVF on rabbit chondrocytes. Rabbit SVF and ADSCs were autografted into knees at OA onset. The SVF (1 × 10 5 ) and low-dose ADSCs (lADSC; 1 × 10 4 ) groups adjusted for their stromal cell content were compared. Animals were euthanized 8 and 12 weeks after OA onset for macroscopic and histological analyses of OA progression and synovitis. Immunohistochemical and real-time polymerase chain reaction assessments were conducted. In vitro, immune-fluorescent double staining was performed for SVF to stain macrophages with F4/80, CD86(M1), and CD163(M2). OA progression was markedly suppressed, and synovitis was reduced in the SVF groups (OARSI histological score 8 W: 6.8 ± 0.75 vs. 3.8 ± 0.75, p = 0.001; 12 W: 8.8 ± 0.4 vs. 5.4 ± 0.49, p = 0.0002). The SVF groups had higher expression of collagen II and SOX9 in cartilage and TGF-β and IL-10 in the synovium, lower expression of MMP-13, and lower macrophage M1/M2 ratio than the lADSC groups. Immunofluorescent double staining revealed a markedly higher number of M2 than that of M1 macrophages in the SVF. The therapeutic effects of SVF on chondrocytes were superior than those of lADSCs, with enhanced anabolic and inhibited catabolic factors. Heterogeneous cells, mainly M2 macrophages in the SVF, enhanced growth factor secretion and chondrocyte-protective cytokines, thus benefiting chondrocytes and knee joint homeostasis. Overall, the SVF is a safe, relatively simple, and a useful treatment option for OA., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dysregulated inflammation is associated with many skeletal diseases and disorders, such as osteolysis, non-union of fractures, osteonecrosis, osteoarthritis and orthopaedic infections. We previously showed that continuous infusion of lipopolysaccharide (LPS) contaminated polyethylene particles (cPE) caused prolonged inflammation and impaired bone formation. However, the metabolic and bioenergetic processes associated with inflammation of bone are unknown. Mitochondria are highly dynamic organelles that modulate cell metabolism and orchestrate the inflammatory responses that involve both resident and recruited cells. Glycolytic reprogramming, the shift from oxidative phosphorylation (OXPHOS) to glycolysis causes inappropriate cell activation and function, resulting in dysfunctional cellular metabolism. We hypothesized that impaired immunoregulation and bone regeneration from inflammatory states are associated with glycolytic reprogramming and mitochondrial dysfunction in macrophages (Mφ) and mesenchymal stromal cells (MSCs)., Methods: We used the Seahorse XF96 analyzer and real-time qPCR to study the bioenergetics of Mφ and MSCs exposed to cPE. To understand the oxygen consumption rate (OCR), we used Seahorse XF Cell Mito Stress Test Kit with Seahorse XF96 analyzer. Similarly, Seahorse XF Glycolytic Rate Assay Kit was used to detect the extracellular acidification rate (ECAR) and Seahorse XF Real-Time ATP Rate Assay kit was used to detect the real-time ATP production rates from OXPHOS and glycolysis. Real-time qPCR was performed to analyze the gene expression of key enzymes in glycolysis and mitochondrial biogenesis. We further detected the gene expression of proinflammatory cytokines in Mφ and genes related to cell differentiation in MSC during the challenge of cPE., Results: Our results demonstrated that the oxidative phosphorylation of Mφ exposed to cPE was significantly decreased when compared with the control group. We found reduced basal, maximal and ATP-production coupled respiration rates, and decreased proton leak in Mφ during challenge with cPE. Meanwhile, Mφ showed increased basal glycolysis and proton efflux rates (PER) when exposed to cPE. The percentage (%) of PER from glycolysis was higher in Mφ exposed to cPE, indicating that the contribution of the glycolytic pathway to total extracellular acidification was elevated during the challenge of cPE. In line with the results of OCR and ECAR, we found Mφ during cPE challenge showed higher glycolytic ATP (glycoATP) production rates and lower mitochondrial ATP (mitoATP) production rates which is mainly from OXPHOS. Interestingly, MSCs showed enhanced glycolysis during challenge with cPE, but no significant changes in oxygen consumption rates (OCR). In accordance, seahorse assay of real-time ATP revealed glycoATP rates were elevated while mitoATP rates showed no significant differences in MSC during challenge with cPE. Furthermore, Mφ and MSCs exposed to cPE showed upregulated gene expression levels of glycolytic regulators and Mφ exposed to cPE expressed higher levels of pro-inflammatory cytokines., Conclusion: This study demonstrated the dysfunctional bioenergetic activity of bone marrow-derived Mφ and MSCs exposed to cPE, which could impair the immunoregulatory properties of cells in the bone niche. The underlying molecular defect related to disordered mitochondrial function could represent a potential therapeutic target during the resolution of inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Shen, Zhang, Teissier, Huang, Gao, Tsubosaka, Toya, Kushioka, Maduka, Contag, Chow, Zhang and Goodman.)

Core decompression (CD) with mesenchymal stromal cells (MSCs) is an effective therapy for early-stage osteonecrosis of the femoral head (ONFH). Preconditioning of MSCs, using inflammatory mediators, is widely used in immunology and various cell therapies. We developed a three-dimensional printed functionally graded scaffold (FGS), made of β-TCP and PCL, for cell delivery at a specific location. The present study examined the efficacy of CD treatments with genetically modified (GM) MSCs over-expressing PDGF-BB (PDGF-MSCs) or GM MSCs co-over-expressing IL-4 and PDGF-BB and preconditioned for three days of exposure to lipopolysaccharide and tumor necrosis factor-alpha (IL-4-PDGF-pMSCs) using the FGS for treating steroid-induced ONFH in rabbits. We compared CD without cell-therapy, with IL-4-PDGF-pMSCs alone, and with FGS loaded with PDGF-MSCs or IL-4-PDGF-pMSCs. For the area inside the CD, the bone volume in the CD alone was higher than in both FGS groups. The IL-4-PDGF-pMSCs alone and FGS + PDGF-MSCs reduced the occurrence of empty lacunae and improved osteoclastogenesis. There was no significant difference in angiogenesis among the four groups. The combined effect of GM MSCs or pMSCs and the FGS was not superior to the effect of each alone. To establish an important adjunctive therapy for CD for early ONFH in the future, it is necessary and essential to develop an FGS that delivers biologics appropriately and provides structural and mechanical support., (© 2023 Wiley Periodicals LLC.)

Novel minimally invasive strategies are needed to obtain robust bone healing in complex fractures and bone defects in the elderly population. Local cell therapy is one potential option for future treatment. Mesenchymal stromal cells (MSCs) are not only involved in osteogenesis but also help direct the recruitment of macrophages during bone regeneration via MSC-macrophage crosstalk. The C-C motif chemokine ligand 2 (CCL2) is an inflammatory chemokine that is associated with the migration of macrophages and MSCs during inflammation. This study investigated the use of CCL2 as a therapeutic target for local cell therapy. MSCs and macrophages were isolated from 10 to 12 week-old BALB/c male mice. Genetically modified CCL2 over-expressing MSCs were produced using murine CCL2-secreting pCDH-CMV-mCCL2-copGFP expressing lentivirus vector. Osteogenic differentiation assays were performed using MSCs with or without macrophages in co-culture. Cell migration assays were also performed. MSCs transfected with murine CCL2-secreting pCDH-CMV-mCCL2-copGFP expressing lentivirus vector showed higher levels of CCL2 secretion compared to unaltered MSCs ( p < 0.05). Genetic manipulation did not affect cell proliferation. CCL2 did not affect the osteogenic ability of MSCs alone. However, acute (1 day) but not sustained (7 days) stimulation with CCL2 increased the alizarin red-positive area when MSCs were co-cultured with macrophages ( p < 0.001). Both recombinant CCL2 ( p < 0.05) and CCL2 released from MSCs ( p < 0.05) facilitated macrophage migration. We demonstrated that acute CCL2 stimulation promoted subsequent osteogenesis in co-culture of MSCs and macrophages. Acute CCL2 stimulation potentially facilitates osteogenesis during the acute inflammatory phase of bone healing by directing local macrophage migration, fostering macrophage-MSC crosstalk, and subsequently, by activating or licensing of MSCs by macrophage pro-inflammatory cytokines. The combination of CCL2, MSCs, and macrophages could be a potential strategy for local cell therapy in compromised bone healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Toya, Zhang, Tsubosaka, Kushioka, Gao, Li, Chow and Goodman.)

Introduction: Currently, studies on adipose-derived stromal vascular fraction (SVF) cells are attracting increasing attention because they have the potential to differentiate into a subset of cell types, such as bone marrow-derived mesenchymal stromal cells (MSCs), and are easier to harvest than MSCs, thus making them easier to apply clinically. This study evaluated the short-term clinical outcomes of SVF cell therapy for hip osteoarthritis (OA)., Methods: Forty-two patients were enrolled in this study; these patients received a single injection comprising an average of 3.8 (standard deviation [SD], ±1.3) × 10 7 SVF cells into the hip joint. All patients were followed-up for at least 6 months. The mean age of the patients was 60.2 years (SD, ±9.4 years). Kellgren-Lawrence (KL) grades II, III, and IV based on radiography were 13, 13, and 16 patients, respectively. SVF cells were obtained from the subcutaneous fat of the abdomen or breech using a Celution® 800/CRS system. The average cell viability of SVF cells was 90.8% (SD, ±2.8%). Clinical assessments were performed using the Harris Hip Score (HHS), Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ) score, and visual analog scale (VAS) score to evaluate pain. Images were evaluated using radiography, and T2 mapping values were obtained using a 1.5-T magnetic resonance imaging system. These clinical and imaging assessments were followed from preoperatively to 6 months postoperatively., Results: The HHS, JHEQ score, and VAS score improved significantly from 22.5 (SD, ±16.6), 26.6 (SD, ±11.3), and 75.5 (SD, ±15.8) preoperatively to 46.8 (SD, ±27.2), 39.4 (SD, ±19.7), and 46.5 (SD, ±27.9), respectively, at 6 months postoperatively. KL grade II showed significant improvement in clinical outcome from preoperative to postoperative, while KL grade IV showed slight or little improvement. The center edge angle, acetabular head index on the radiographs, and T2 mapping values did not change significantly from preoperatively to 6 months postoperatively., Conclusions: SVF cell injection in the hip joint showed good short-term clinical efficacy for reducing hip OA symptoms. SVF cell therapy is thus an innovative and effective treatment for hip OA., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Aging of the global population increases the incidence of osteoporosis and associated fragility fractures, significantly impacting patient quality of life and healthcare costs. The acute inflammatory reaction is essential to initiate healing after injury. However, aging is associated with "inflammaging", referring to the presence of systemic low-level chronic inflammation. Chronic inflammation impairs the initiation of bone regeneration in elderly patients. This review examines current knowledge of the bone regeneration process and potential immunomodulatory therapies to facilitate bone healing in inflammaging.Aged macrophages show increased sensitivity and responsiveness to inflammatory signals. While M1 macrophages are activated during the acute inflammatory response, proper resolution of the inflammatory phase involves repolarizing pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype associated with tissue regeneration. In aging, persistent chronic inflammation resulting from the failure of M1 to M2 repolarization leads to increased osteoclast activation and decreased osteoblast formation, thus increasing bone resorption and decreasing bone formation during healing.Inflammaging can impair the ability of stem cells to support bone regeneration and contributes to the decline in bone mass and strength that occurs with aging. Therefore, modulating inflammaging is a promising approach for improving bone health in the aging population. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that may benefit bone regeneration in inflammation. Preconditioning MSCs with pro-inflammatory cytokines affects MSCs' secretory profile and osteogenic ability. MSCs cultured under hypoxic conditions show increased proliferation rates and secretion of growth factors. Resolution of inflammation via local delivery of anti-inflammatory cytokines is also a potential therapy for bone regeneration in inflammaging. Scaffolds containing anti-inflammatory cytokines, unaltered MSCs, and genetically modified MSCs can also have therapeutic potential. MSC exosomes can increase the migration of MSCs to the fracture site and enhance osteogenic differentiation and angiogenesis.In conclusion, inflammaging can impair the proper initiation of bone regeneration in the elderly. Modulating inflammaging is a promising approach for improving compromised bone healing in the aging population., (© 2023. The Author(s).)

The number of total joint replacements is increasing, especially in elderly patients, and so too are implant-related complications such as prosthesis loosening. Wear particles from the prosthesis induce a chronic inflammatory reaction and subsequent osteolysis, leading to the need for revision surgery. This study investigated the therapeutic effect of NF-ĸB decoy oligodeoxynucleotides (ODN), mesenchymal stem cells (MSCs), and genetically-modified NF-ĸB sensing interleukin-4 over-secreting MSCs (IL4-MSCs) on chronic inflammation in aged mice. The model was generated by continuous infusion of contaminated polyethylene particles into the intramedullary space of the distal femur of aged mice (15-17 months old) for 6 weeks. Local delivery of ODN showed increased bone mineral density (BMD), decreased osteoclast-like cells, increased alkaline phosphatase (ALP)-positive area, and increased M2/M1 macrophage ratio. Local injection of MSCs and IL4-MSCs significantly decreased osteoclast-like cells and increased the M2/M1 ratio, with a greater trend for IL4-MSCs than MSCs. MSCs significantly increased ALP-positive area and BMD values compared with the control. The IL4-MSCs demonstrated higher values for both ALP-positive area and BMD. These findings demonstrated the therapeutic effects of ODN, MSCs, and IL4-MSCs on chronic inflammatory osteolysis in aged mice. The two MSC-based therapies were more effective than ODN in increasing the M2/M1 macrophage ratio, reducing bone resorption, and increasing bone formation. Specifically, MSCs were more effective in increasing bone formation, and IL4-MSCs were more effective in mitigating inflammation. This study suggests potential therapeutic strategies for treating wear particle-associated inflammatory osteolysis after arthroplasty in the elderly., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Rationale: Efficient labeling methods for mesenchymal stem cells (MSCs) are crucial for tracking and understanding their behavior in regenerative medicine applications, particularly in cartilage defects. MegaPro nanoparticles have emerged as a potential alternative to ferumoxytol nanoparticles for this purpose. Methods: In this study, we employed mechanoporation to develop an efficient labeling method for MSCs using MegaPro nanoparticles and compared their effectiveness with ferumoxytol nanoparticles in tracking MSCs and chondrogenic pellets. Pig MSCs were labeled with both nanoparticles using a custom-made microfluidic device, and their characteristics were analyzed using various imaging and spectroscopy techniques. The viability and differentiation capacity of labeled MSCs were also assessed. Labeled MSCs and chondrogenic pellets were implanted into pig knee joints and monitored using MRI and histological analysis. Results: MegaPro-labeled MSCs demonstrated shorter T2 relaxation times, higher iron content, and greater nanoparticle uptake compared to ferumoxytol-labeled MSCs, without significantly affecting their viability and differentiation capacity. Post-implantation, MegaPro-labeled MSCs and chondrogenic pellets displayed a strong hypointense signal on MRI with considerably shorter T2* relaxation times compared to adjacent cartilage. The hypointense signal of both MegaPro- and ferumoxytol-labeled chondrogenic pellets decreased over time. Histological evaluations showed regenerated defect areas and proteoglycan formation with no significant differences between the labeled groups. Conclusion: Our study demonstrates that mechanoporation with MegaPro nanoparticles enables efficient MSC labeling without affecting viability or differentiation. MegaPro-labeled cells show enhanced MRI tracking compared to ferumoxytol-labeled cells, emphasizing their potential in clinical stem cell therapies for cartilage defects., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Continuous cross talk between MSCs and macrophages is integral to acute and chronic inflammation resulting from contaminated polyethylene particles (cPE); however, the effect of this inflammatory microenvironment on mitochondrial metabolism has not been fully elucidated. We hypothesized that (a) exposure to cPE leads to impaired mitochondrial metabolism and glycolytic reprogramming and (b) macrophages play a key role in this pathway., Methods: We cultured MSCs with/without uncommitted M0 macrophages, with/without cPE in 3-dimensional gelatin methacrylate (3D GelMA) constructs/scaffolds. We evaluated mitochondrial function (membrane potential and reactive oxygen species-ROS production), metabolic pathways for adenosine triphosphate (ATP) production (glycolysis or oxidative phosphorylation) and response to stress mechanisms. We also studied macrophage polarization toward the pro-inflammatory M1 or the anti-inflammatory M2 phenotype and the osteogenic differentiation of MSCs., Results: Exposure to cPE impaired mitochondrial metabolism of MSCs; addition of M0 macrophages restored healthy mitochondrial function. Macrophages exposed to cPE-induced glycolytic reprogramming, but also initiated a response to this stress to restore mitochondrial biogenesis and homeostatic oxidative phosphorylation. Uncommitted M0 macrophages in coculture with MSC polarized to both M1 and M2 phenotypes. Osteogenesis was comparable among groups after 21 days., Conclusion: This work confirmed that cPE exposure triggers impaired mitochondrial metabolism and glycolytic reprogramming in a 3D coculture model of MSCs and macrophages and demonstrated that macrophages cocultured with MSCs undergo metabolic changes to maintain energy production and restore homeostatic metabolism., (© 2023. The Author(s).)

BACKGROUND Periprosthetic joint infection is a difficult complication, especially in patients with rheumatoid arthritis. Life-threatening septic shock due to periprosthetic joint infection caused by group G streptococcus is rare, and there have been few reports about its treatment. We describe a successful case of sudden onset septic shock due to group G Streptococcus infection after revision total knee arthroplasty. CASE REPORT A 61-year-old woman with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs for about 12 years presented with acute right knee pain and shock 6 months after revision total knee arthroplasty. Periprosthetic joint infection caused by group G Streptococcus was diagnosed. She was admitted to the Intensive Care Unit, treated with respiratory support and dialysis, and underwent irrigation, debridement, and polyethylene liner exchange as the first surgery. At 9 days after the first surgery, she underwent the second surgery, consisting of implant removal and antibiotic spacer placement due to failure. It took approximately 7 weeks to normalize the levels of systemic markers of inflammation with intravenous antibiotics and then oral antibiotics for further 12 weeks, but re-revision total knee arthroplasty was successfully performed 1.5 years later. At a 1-year follow-up from the final surgery, she was able to walk with a cane and had no symptoms of infection. CONCLUSIONS In such cases with sudden onset of septic shock due to periprosthetic joint infection, appropriate and prompt surgical treatment should be performed to save the infected limb as well as the patient's life.

The aim of the article is to compare the clinical and radiological outcomes between single and double stromal vascular fraction (SVF) cell injections in patients with knee osteoarthritis (OA). We included 54 patients treated for varus knee OA with intra-articular SVF cell injection. They were divided into two groups: those who received one injection and those who received two. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, knee range of motion, and knee muscle force were assessed at baseline and 3, 6, 12, and 24 months after the first injection. The preoperative hip-knee-ankle (HKA) angle was evaluated using plain radiographs, and T2 mapping values were assessed. The total WOMAC score improved significantly in the single injection group from 3 to 24 months, but the total WOMAC score in the double injection group improved significantly at 24 months. The T2 mapping values in both the groups improved, with a significant difference at 12 months. The preoperative mean HKA angle and the correlation coefficients between the HKA angle and the total WOMAC score and between the HKA angle and the T2 mapping value of the medial femur were significant. In conclusion, double injections may provide more satisfactory treatment outcomes in patients with severe varus knee alignment. This clinical trial is registered in the Japanese Ministry of Health, Labour and Welfare (URL: https://saiseiiryo.mhlw.go.jp/published&#95;plan/index/2) with the registration name "Cell transplantation therapy for osteoarthritis using autologous subcutaneous adipose tissue-derived regenerative (stem) cells (ADRCs)," and the registration number was "PB5160012."

Novel medial preserving gap technique (MPGT) focuses on medial compartment stability and allows lateral physiological laxity. This study aimed to compare the MPGT with the measured resection technique (MRT) to determine which provides better postoperative knee stability after posterior-stabilized total knee arthroplasty (PS-TKA). Primary PS-TKA, using either MPGT ( n  = 65) or MRT ( n  = 65), was performed in 130 patients with varus knee osteoarthritis. Postoperative knee stabilities at extension and flexion were assessed using varus-valgus stress radiographs and stress epicondylar view, respectively (at 1 month, 6 months, 1 year, and 3 years postoperatively). The distance between the femoral prosthesis and polyethylene insert was measured on each medial and lateral side, defined as the medial joint opening (MJO) and lateral joint opening (LJO), respectively. Decreasing MJO or LJO translated to increasing postoperative stability. The femoral external rotation angle was compared between the two surgical techniques; postoperative knee stability was also compared between the medial and lateral compartments, as well as the surgical techniques. A significant difference was found in the femoral external rotation angle between MPGT (4.2 ± 0.2 degrees) and MRT (3.6 ± 0.1 degrees, p  < 0.01). Postoperative MJOs both at extension and flexion were significantly smaller than LJOs using MPGT and MRT at all time points ( p  < 0.05). MJOs and LJOs at extension using MPGT were significantly smaller than those when using MRT, at 1 and 3 years postoperatively ( p  < 0.05). Furthermore, MJOs at flexion using MPGT were significantly smaller than those when using MRT at 6 months, 1 year, and 3 years postoperatively ( p  < 0.05). MPGT provided higher postoperative medial knee stability than MRT both at extension and flexion, even at 3 years after PS-TKA. This suggests that this newly developed surgical technique is a more feasible option than MRT for the preservation of postoperative medial knee stability., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Endochondral ossification is a complex biological phenomenon involving a variety of factors and cells. Cyclin-dependent kinase inhibitor 1 (p21) inhibits cell cycle progression and is affected by external stress. We recently reported that embryonic endochondral ossification is unaffected by endogenous p21 deficiency. In this study, we evaluated whether p21 expression affects endochondral ossification during fracture healing., Methods: Tibial fractures were introduced into p21 knockout (p21 -/- ) (n = 24) and wild-type C57BL/6 (p21 +/+ ) (n = 24) mice at age 10 weeks. Fracture healing was evaluated using radiological, histological, and immunohistochemical (IHC) analyses. The effect of p21 small interfering RNA (siRNA) on ATDC5 cells was assessed in vitro., Results: The Allen score for fracture healing was lower in p21 -/- mice than in p21 +/+ mice. In addition, p21 -/- mice exhibited larger calluses and lower bone mineral density. IHC analyses showed that p21 -/- mice exhibited delayed endochondral ossification via the Ihh-Runx2-Osterix pathway in vivo. Down-regulation of p21 expression in ATDC5 cells delayed endochondral ossification in vitro., Conclusions: p21 deficiency leads to delayed endochondral ossification by attenuating the Ihh-Runx2-Osterix pathway in vivo, and p21 deficiency in hypertrophic chondrocytes causes delayed differentiation of hypertrophic chondrocytes in vitro. p21 plays a role in endochondral ossification during fracture healing., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The presence of tibiofemoral subluxation (TFS) in patients with unicompartmental arthritis, a potential contraindication to unicompartmental knee arthroplasty (UKA), remains controversial and is not commonly discussed. This study aimed to determine the predictability of postoperative TFS before surgery and the effect of TFS on clinical outcomes after fixed-bearing UKA., Materials and Methods: In total, 70 patients with anteromedial osteoarthritis and osteonecrosis of the knee who underwent fixed-bearing UKA from January 2015 to January 2017 were included. The preoperative TFS was assessed using plain anteroposterior and valgus stress radiographs. The patients were classified into three groups as follows: group A (acceptable TFS, n = 36) comprising patients with preoperative TFS less than 5.0 mm; group C (correctable TFS, n = 17) comprising patients with preoperative TFS of more than 5.0 mm but corrected to less than 5.0 mm under valgus stress; and group U (uncorrectable TFS, n = 17) comprising patients with preoperative TFS of more than 5.0 mm under valgus stress. Patient-derived clinical scores were assessed with the 2011 Knee Society Score preoperatively and 2 years postoperatively. The results were compared among the three groups using analysis of variance., Results: Group U showed significantly higher postoperative TFS than groups A and C. Improvements in "symptoms" and "patient satisfaction" scores 2 years after surgery were significantly higher in groups A and C than in group U., Conclusion: Preoperative assessment of TFS under valgus stress could be a predictor of postoperative TFS. Furthermore, preoperative uncorrectable TFS could increase pain and decrease patient satisfaction 2 years after undergoing fixed-bearing UKA., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Lateral compartment osteoarthritis progression (LOP) is a major complication after Oxford mobile-bearing unicompartmental knee arthroplasty (OUKA). This study aimed to identify the association between tibiofemoral subluxation (TFS) and LOP after OUKA. Patients whose TFS was uncorrectable according to preoperative stress radiographs were hypothesised to develop residual TFS even after surgery, and thought to be more likely to develop LOP., Methods: The study included 201 patients who underwent medial OUKA. Fifteen patients showed increases in LOP of at least two Kellgren-Lawrence grades after surgery [progression (P) group], while the others had no progression (N group, n = 186). TFS was measured on preoperative full leg weight-bearing radiographs, valgus stress radiographs and postoperative plain radiographs. Valgus stress radiographs were obtained using a firm manual valgus force with the knee flexed at 20°. Leg alignment, Oxford knee score (OKS), and revision rates were assessed., Results: The P group had significantly higher TFS values on preoperative valgus stress (6.8° ± 2.2° vs. 4.5° ± 2.0°; P < 0.001) and postoperative radiographs (6.6° ± 2.3° vs. 4.6° ± 2.9°; P < 0.001) than the N group. Patients with postoperative residual TFS and postoperative valgus alignment were more likely to have LOP, but 9 of the 15 LOP patients did not show postoperative valgus alignment. The P group had significantly poorer postoperative OKS (33.0 ± 10.2 vs. 37.4 ± 6.5, P = 0.017) and a higher rate of revision (6/15 vs 6/186; odds ratio = 19.16; 95% CI = 4.98-76.05, P < 0.001)., Conclusion: OA progression in the lateral compartment after medial OUKA might be associated with postoperative residual TFS, but does not always coexist with postoperative valgus alignment. Preoperative assessment of TFS with valgus stress could be a potential predictor of postoperative residual TFS and LOP., Level of Evidence: Level III., (© 2021. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Posterior tibial slope (PTS) has been known to contribute to anterior-posterior knee stability and play an essential biomechanical role in knee kinematics. This study aimed to investigate the effect of PTS on single-leg standing sagittal knee alignment of the intact knee. This study included 100 patients with unilateral ACL injury knee (ACL injury group, 53 patients) or with the normal knee (control group, 47 patients). The single-leg standing sagittal alignment of the unaffected knees of the ACL injury group and normal knees of the control group were assessed radiographically with the following parameters: knee extension angle (EXT), PTS, PTS to the horizontal line (PTS-H), femoral shaft anterior tilt to the vertical axis (FAT), and tibial shaft anterior tilt to the vertical axis (TAT). PTS was negatively correlated with EXT and positively correlated with TAT. EXT was significantly larger in the ACL injury group, whereas TAT was smaller in the ACL injury group. Patients with larger PTS tend to stand with a higher knee flexion angle by tilting the tibia anteriorly, possibly reducing tibial shear force. Patients with ACL injury tend to stand with larger EXT, i.e., there is less preventive alignment to minimize the tibial shear force., (© 2022. The Author(s).)

Wear particles from joint arthroplasties induce chronic inflammation associated with prolonged upregulation of nuclear factor kappa-B (NF-κB) signaling in macrophages and osteoclasts, which leads to osteolysis and implant loosening. Mesenchymal stromal cell (MSC)-based therapy showed great potential for immunomodulation and mitigation of osteolysis in vivo , especially in the chronic phase of inflammation. We previously generated genetically modified MSCs that secrete the anti-inflammatory cytokine interleukin 4 (IL-4) in response to NF-κB activation (NFκB-IL-4 MSCs). However, whether the impact of sexual difference in the internal environment can alter the therapeutic effects of IL-4 over-secreting MSCs that simultaneously mitigate prolonged inflammation and enhance bone formation remains unknown. This study investigated the therapeutic effects of unaltered MSCs versus NFκB-IL-4 MSCs in mitigating chronic inflammation and enhancing bone formation in male and female mice. The murine model was established by continuous infusion of polyethylene particles contaminated with lipopolysaccharide (cPE) into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation. Unaltered MSCs or NFκB-IL-4 MSCs were infused into the femoral intramedullary cavity in sex-matched groups beginning 3 weeks after primary surgery. Femurs were harvested at 6 weeks, and bone marrow density was measured with micro-computational tomography. Numbers of osteoclast-like cells, osteoblasts, and macrophages were evaluated with histochemical and immunofluorescence staining. cPE infusion resulted in severe bone loss at the surgery site, increased tartrate-resistant acid phosphatase positive osteoclasts and M1 pro-inflammatory macrophages, and decreased alkaline phosphatase expression. MSC-based therapy effectively decreased local bone loss and polarized M1 macrophages into an M2 anti-inflammatory phenotype. In females, unaltered MSCs demonstrated a larger impact in enhancing the osteogenesis, but they demonstrated similar anti-inflammatory effects compared to NFκB-IL-4 MSCs. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments in a sexually dimorphic manner, which could be an efficacious therapeutic strategy for treatment of periprosthetic osteolysis in both genders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Kushioka, Toya, Utsunomiya, Hirata, Huang, Tsubosaka, Gao, Li, Teissier, Zhang and Goodman.)

Kinematically aligned total knee arthroplasty (TKA) has gained interest for achieving more favorable clinical outcomes than mechanically aligned TKA. The present study aimed to compare the clinical outcomes of kinematically aligned TKAs using single-radius (SR) or multi-radius (MR) prostheses. Sixty modified kinematically aligned cruciate-retaining TKAs (30 SR and 30 MR type prostheses) were performed in patients with varus-type osteoarthritis using a navigation system. Intraoperative and postoperative patellar tracking were compared between the two groups. Trochlea shape was also compared between the prostheses and preoperative native anatomy using three-dimensional simulation software. Total 2 years postoperatively, the range of motion and 2011 Knee Society Scores (KSS) were compared between the two groups. There were no differences in patellar maltracking including patellar lateral shift and tilt between the two groups; however, the ratio of intraoperative lateral retinacular release for adjusting patellar tracking was significantly higher in the MR group than in the SR group. Lateral and medial facet heights in both prostheses were understuffed compared with native knee anatomy, while the deepest point of the trochlear groove was significantly more medial in the MR group. The postoperative clinical outcomes showed no significant differences between the two groups. In conclusion, modified kinematically aligned TKAs using a SR or MR prosthesis showed no significant differences in clinical outcomes or patellar tracking when appropriate lateral retinacular release was performed., Competing Interests: None declared., (Thieme. All rights reserved.)

The relationship between patellofemoral joint (PFJ) degeneration and clinical outcomes following lateral unicompartmental knee arthroplasty (UKA) has not been well described thus far. This study aimed to investigate the relationship between the preoperative PFJ condition and postoperative outcomes and the changes in lower-limb and PFJ alignment after lateral UKA. This was a retrospective study including 54 patients (mean age 72.9 years) who underwent lateral UKA for isolated lateral knee osteoarthritis at our institution between March 2013 and January 2019. The Oxford Knee Score (OKS), the Knee Society Score-Knee (KSSK), and Knee Society Score-Function (KSSF), the degree of degeneration, tilting angle and lateral shift of the PFJ, and the hip-knee-ankle angle (HKA) were evaluated pre- and postoperatively. The average follow-up period was 2.8 (range 1-6.1) years. There was a significant improvement in the OKS, KSSK, and KSSF after lateral UKA. Preoperative degeneration of the PFJ did not correlate with the recovery of clinical scores. The degeneration, tilting angle, and lateral shift of the PFJ did not significantly progress following lateral UKA. The HKA was improved after lateral UKA, and there was no correlation between the HKA change and PFJ condition. Postoperative severe valgus knee alignment was associated with a greater tilting angle. Preoperative degeneration of the PFJ did not have a negative impact on postoperative outcomes, and no short-term changes in the degeneration, tilting angle, and lateral shift of the PFJ were observed. Correction of knee-joint alignment did not have a negative impact on the condition of the PFJ., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Patient-reported outcome measures (PROMs) are important aspects of evaluating clinical outcomes after total knee arthroplasty (TKA). The patient-satisfaction score in the 2011 Knee Society Score (KSS) is one of the most frequently used questionnaires; however, patient satisfaction is a subjective assessment and is affected by multiple factors. Therefore, we evaluated correlations between the patient-satisfaction score in the 2011 KSS and that of other categories of the 2011 KSS as well as other PROMs. Furthermore, the ceiling effects of each PROMS were also investigated., Methods: We enrolled 85 patients aged ≥65 years who underwent cruciate retaining TKA. Patients completed various questionnaires, including the 2011 KSS, Forgotten Joint Score-12 (FJS-12), EuroQol 5 Dimension (EQ-5D), and Geriatric Locomotive Function Scale (GLFS-25), one year after TKA. Simple linear regression analysis was used to evaluate correlations between each PROM and the patient-satisfaction score in the 2011 KSS. Ceiling effects of the patient-satisfaction score in the 2011 KSS, FJS-12, EQ-5D and GLFS-25 were evaluated by comparing the number of patients categorized into the top 10% with each PROM., Results: All scores were significantly correlated (p < 0.001) with the patient-satisfaction score in the 2011 KSS (symptoms: r = 0.69, functional activities: r = 0.69, patient expectations: r = 0.73, FJS-12: r = 0.72, EQ-5D: r = 0.67, GLFS-25: r = -0.74). The patient-satisfaction score in the 2011 KSS and GLFS-25 showed a ceiling effect. On the other hand, this effect was not observed in the results of the FJS-12 and EQ-5D., Conclusions: The patient-satisfaction score in the 2011 KSS correlated with other PROMs, and the indicated level of satisfaction was consistent. The results of the FJS-12 and EQ-5D had good positive correlation to patient satisfaction without ceiling effect., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: A discoid medial meniscus is rare in comparison with a discoid lateral meniscus. We encountered a new type of incomplete discoid with an oversized posterior segment. Therefore, this study aimed to report cases of medial meniscus with an oversized posterior segment and analyze the morphological characteristics by comparing them to cases with a discoid medial meniscus and normal medial meniscus., Methods: Four patients with an oversized posterior segment medial meniscus (oversize group, mean age: 25.3 ± 12.0 years) and seven patients with a discoid medial meniscus (discoid group, mean age: 34.4 ± 19.6) were identified using magnetic resonance imaging (MRI) and diagnosed by arthroscopic findings in our hospital. Fifty patients without medial meniscal injury were retrospectively selected as the normal group (normal group, mean age: 24.0 ± 11.3 years). The clinical symptoms were examined. The anteroposterior (AP) length of both the anterior and posterior segments, AP length ratio of the posterior segment to the AP length of the medial tibial plateau, and mediolateral (ML) width of the mid-body of the medial meniscus were also evaluated using MRI and compared among the three groups., Results: All patients in the oversize group complained of medial knee pain during deep knee flexion. In sagittal MRI, posteriorly deviated indentations were also observed at the medial tibial plateau in all cases in the oversize group. There was a significant difference in the AP length of the posterior segment between the normal and oversize groups (14.3 ± 2.8 vs. 23.6 ± 2.8 mm, P < 0.001), whereas there was no significant difference in the AP length of the anterior segment (9.1 ± 2.1 vs. 9.5 ± 1.9 mm, P = 0.869). The ML width of the mid-body in the normal, oversize, and discoid groups was 9.3 ± 1.8, 19.9 ± 2.6, and 25.8 ± 1.9 mm, respectively (normal vs. oversize group: P < 0.001, oversize vs discoid group: P = 0.01, normal vs. discoid group: P < 0.001)., Conclusions: Oversized posterior and normal anterior segments characterize this new type of incomplete discoid medial meniscus as a morphological abnormality., (© 2022. The Author(s).)

Background: Despite the high incidence of fractures and pseudoarthrosis in the aged population, a potential role for the use of mesenchymal stem cells (MSCs) in the treatment of bone defects in elderly patients has not been elucidated. Inflammation and the innate immune system, including macrophages, play crucial roles in the differentiation and activation of MSCs. We have developed lentivirus-transduced interleukin 4 (IL4) over-expressing MSCs (IL4-MSCs) to polarize macrophages to an M2 phenotype to promote bone healing in an established young murine critical size bone defect model. In the current study, we explore the potential of IL4-MSCs in aged mice., Methods: A 2 mm femoral diaphyseal bone defect was created and fixed with an external fixation device in 15- to 17-month-old male and female BALB/c mice. Microribbon (µRB) scaffolds (Sc) with or without encapsulation of MSCs were implanted in the defect sites. Accordingly, the mice were divided into three treatment groups: Sc-only, Sc + MSCs, and Sc + IL4-MSCs. Mice were euthanized six weeks after the surgery; subsequently, MicroCT (µCT), histochemical and immunohistochemical analyses were performed., Results: µCT analysis revealed that bone formation was markedly enhanced in the IL4-MSC group. Compared with the Sc-only, the amount of new bone increased in the Sc + MSCs and Sc + IL4-MSC groups. However, no bridging of bone was observed in all groups. H&E staining showed fibrous tissue within the defect in all groups. Alkaline phosphatase (ALP) staining was increased in the Sc + IL4-MSC group. The Sc + IL4-MSCs group showed a decrease in the number of M1 macrophages and an increase in the number of M2 macrophages, with a significant increase in the M2/M1 ratio., Discussion: IL4 promotes macrophage polarization to an M2 phenotype, facilitating osteogenesis and vasculogenesis. The addition of IL4-MSCs in the µRB scaffold polarized macrophages to an M2 phenotype and increased bone formation; however, complete bone bridging was not observed in any specimens. These results suggest that IL4-MSCs are insufficient to heal a critical size bone defect in aged mice, as opposed to younger animals. Additional therapeutic strategies are needed in this challenging clinical scenario., (© 2022. The Author(s).)

The use of genetically modified (GM) mesenchymal stromal cells (MSCs) and preconditioned MSCs (pMSCs) may provide further opportunities to improve the outcome of core decompression (CD) for the treatment of early-stage osteonecrosis of the femoral head (ONFH). GM interleukin-4 (IL4) over-expressing MSCs (IL4-MSCs), platelet-derived growth factor (PDGF)-BB over-expressing MSCs (PDGF-BB-MSCs), and IL4-PDGF-BB co-over-expressing MSCs (IL4-PDGF-BB-MSCs) and their respective pMSCs were used in this in vitro study and compared with respect to cell proliferation and osteogenic differentiation. IL4-MSCs, PDGF-BB-MSCs, IL4-PDGF-BB-MSCs, and each pMSC treatment significantly increased cell proliferation compared to the MSC group alone. The percentage of Alizarin red-stained area in the IL4-MSC and IL4-pMSC groups was significantly lower than in the MSC group. However, the percentage of Alizarin red-stained area in the PDGF-BB-MSC group was significantly higher than in the MSC and PDGF-BB-pMSC groups. The percentage of Alizarin red-stained area in the IL4-PDGF-BB-pMSC was significantly higher than in the IL4-PDGF-BB-MSC group. There were no significant differences in the percentage of Alizarin red-stained area between the MSC and IL4-PDGF-BB-pMSC groups. The use of PDGF-BB-MSCs or IL4-PDGF-BB-pMSCs increased cell proliferation. Furthermore, PDGF-BB-MSCs promoted osteogenic differentiation. The addition of GM MSCs may provide a useful supplementary cell-based therapy to CD for treatment of ONFH.

Since a hindfoot alignment is not included in the conventional mechanical axis (hip-ankle [HA] line), a mechanical axis including the calcaneus (hip-calcaneus [HC] line) has recently attracted attention as an alternative weight-bearing line. However, there are few reports on unicompartmental knee arthroplasty (UKA) regarding the HC line. Therefore, this study aimed to compare postoperative alignments after UKA between the HA line and the HC line. Postoperatively, HC radiographs were taken in 88 consecutive patients who underwent medial UKA. The hip-knee-ankle (HKA) and hip-knee-calcaneus (HKC) angles were compared in the same patient. Regarding tibial inclination, the conventional tibial component-ankle (TCA) angle was compared with reference to the HC line (tibial component-calcaneus [TCC] angle). The mean postoperative HKA and HKC angles were 2.8 ± 2.7 and 2.0 ± 2.5 degree, respectively. The mean postoperative TCA and TCC angles were 87.7 ± 2.1 and 88.5 ± 2.1 degree, respectively. There were significant differences between the two groups in both lower limb alignment and tibial component angle. The present study indicated that the HKC and the TCC angles significantly decreased the varus alignment by approximately 1 degree compared with the HKA and TCA angles. Neutral in the HA line corresponds to valgus in reference to the HC line, which may result in overcorrection. Surgeons should consider evaluating the HC line in place of the HA line, which may affect preoperative planning and postoperative outcome during UKA. This is a Level II, diagnostic study., Competing Interests: Dr. Kuroda reports grants from Stryker Japan KK, Zimmer Biomet, Smith & Nephew KK, Astellas Pharm Inc., Chugai Pharmaceutical Co. Ltd., Taisyo Toyama Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Asahi Kasei Pharma Corporation.Dr. Kuroda reports personal fees from Medacta International, Arthrex, Inc. and Hirosaki Life Science Innovation, Inc. for consultancy, and personal fees from Daiichi Sankyo Company Limited, Taisyo Toyama Pharmaceutical Co. Ltd., Hisamitsu Pharmaceutical Co. Inc., and Stryker Japan KK for lectures., (Thieme. All rights reserved.)

Several studies have reported better clinical outcomes following kinematically aligned total knee arthroplasty (KA-TKA) than mechanically aligned TKA. Consistent reproduction of a KA-TKA is aided by accurate tibial bone resections using computer navigation systems. This study compares an accelerometer-based portable navigation system with a conventional navigation system on tibial bone resection and clinical outcomes in KA-TKA. This study included 60 knees of patients who underwent primary KA-TKA between May 2015 and September 2017. They were randomly assigned to the OrthoPilot and iASSIST groups. A tibial bone cut was performed with 3 degree varus and 7 degree posterior slope in relation to the mechanical axis in all cases. The tibial component angle (TCA) and posterior slope angle (PSA) were evaluated by postoperative radiography, and those that deviated more than 2 degree were set as outliers. The clinical outcomes were the knee range of motion (ROM) and 2011 Knee Society Score (KSS) evaluated at 1 year postoperation. The groups were compared in terms of the TCA, PSA, number of outliers, ROM, and 2011 KSS ( p  < 0.05). No significant difference was observed between the groups in terms of the mean TCA, PSA, number of outliers, ROM, and categories of the 2011 KSS (objective knee indicators, symptoms, satisfaction, expectations, and functional activities). Although tibial bone cuts were performed with 3 degree varus and 7 degree posterior slope, no significant difference was observed between the OrthoPilot and iASSIST groups in terms of the accuracy of cuts or postoperative clinical result. The iASSIST was found to be a simple and useful navigation system for KA-TKA., Competing Interests: None declared., (Thieme. All rights reserved.)

We recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21 -/- ) (n = 16) and wild type C57BL/6 (p21 +/+ ) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1β stimulation was determined in vitro. Arthritis scores were higher in p21 -/- mice than in p21 +/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21 -/- mice compared to p21 +/+ mice. p21 -/- mice expressed higher levels of IL-1β, TNF-α, F4/80, CD86, p-IKKα/β, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/β and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1β, IL-6, and TNF-α.

Background: Lateral unicompartmental knee arthroplasty (UKA) leads to good clinical outcomes for isolated lateral osteoarthritis. However, the impact of the tibial component position on postoperative outcomes in lateral UKA is yet to be determined., Purpose: This study investigated the influence of tibial component malposition on clinical outcomes in lateral UKA., Materials: This was a retrospective study of 50 knees (mean age 73.5 years) who underwent lateral UKA between September 2013 and January 2019. The Oxford Knee Score (OKS), Knee Society Score - Knee (KSSK), and Knee Society Score - Function (KSSF) were evaluated. The coronal alignment, posterior slope of tibial component, tibial component rotation relative to Akagi's line (angle α), and femoral anteroposterior (AP) axis (angle β) were measured postoperatively. The average follow up period was 2.3 (range, 1-4.9) years., Results: Clinical scores were significantly improved after lateral UKA. The mean coronal alignment was 0.9° ± 3.2° varus (range, 9.1° varus to 5.5° valgus), the mean posterior slope was 6.8° ± 3.8° (range, 0.8° to 14.8°). The mean α and β angles, were 4.1° ± 5.8° (range, -9.7° to 16.5°) and 6.7° ± 7.1° (range, -7.0° to 20.5°) external rotation. The angle α had significant negative correlations with postoperative OKS (r = -0.36), KSSK (r = -0.28), and KSSF (r = -0.39), and angle β had significant negative correlations with postoperative OKS (r = -0.34) and KSSK (r = -0.46)., Conclusion: Excessive external rotation of the tibial component could negatively influence the postoperative outcomes of lateral UKA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Lower extremity alignment is very important after total knee arthroplasty (TKA). This study aimed to compare the plantar pressure distribution while walking and the overall limb alignment, including the hindfoot, between kinematically (KA) and mechanically aligned (MA) TKA. The plantar pressure distribution was investigated using a pressure plate during walking and one-leg standing among four groups: patients one year after KA-TKA (KA group; n = 25), patients one year after MA-TKA (MA group, n = 25), patients with osteoarthritis (OA) undergoing non-surgical care (OA group, n = 25), and healthy controls (Healthy group; n = 25). Conventional and true mechanical axes (the line from the femoral head to the lowest point of the calcaneus) were evaluated on unipedal standing long-leg radiographs in the KA, MA, and OA groups. Results were compared using analysis of variance. The OA group showed a lateral loading pattern in the mid- and rearfoot, while the MA group showed a medial rearfoot loading pattern during walking. On the contrary, the KA and Healthy groups showed an almost equal pressure distribution between the medial and lateral rearfoot. Moreover, although both mechanical axes in the KA group passed through the knee more medially, a more neutral alignment was achieved in the true mechanical axis compared to that in the MA group. KA-TKA results in more neutral weight-bearing through the true mechanical axis and allows patients to walk while maintaining medial and lateral rearfoot pressure more evenly than MA-TKA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)