Oxysophocarpine attenuates inflammatory osteolysis by modulating the NF-κb pathway and the reactive oxygen species-related Nrf2 signaling pathway.

BACKGROUND AND AIM: Inflammatory diseases often result in bone loss due to persistent inflammation, which activates osteoclasts and increases bone resorption. Oxysophocarpine (OSC), a bioalkaloid extracted from the roots of Sophora japonica and other leguminous plants, has neuroprotective and anti-tumor properties. However, it is still uncertain whether OSC can effectively inhibit the differentiation of osteoclasts and bone resorption. Therefore, this study explored the potential role of OSC in osteoclast formation and inflammatory osteolysis and its underlying mechanisms. EXPERIMENTAL PROCEDURE: This study involved inducing primary mouse bone marrow macrophages (BMMs) into osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) and examined the effects of OSC on osteoclast (OC) differentiation, function, and intracellular reactive oxygen species (ROS) production. The impact of OSC on the expression of osteoclast-specific genes and inflammation-related factors was assessed using real-time quantitative PCR. Additionally, changes in oxidative stress-related factors, NF-κB, and MAPK signaling pathways were examined using western blotting. Finally, this study investigated the influence of OSC on a mouse cranial bone resorption model induced by titanium (Ti) particles in vivo. RESULTS: OSC inhibited OC differentiation and resorption and reduces intracellular ROS levels. Moreover, OSC suppressed IL-1ß, TNF-α, IL-6, and osteoclast-specific gene transcription while increasing Nrf2 and HO-1 protein expression. Furthermore, OSC inhibited the expression and autoregulation of the NFATc1 gene, ultimately leading to a reduction in Ti particle-induced bone resorption in mice. CONCLUSION: OSC could be regarded as an innovative medication for the treatment of osteoclast-associated inflammatory osteolytic diseases.

A New Method to Predict Postoperative Stem Anteversion in Total Hip Arthroplasty for Developmental Dysplasia of the Hip.

BACKGROUND: Preoperative evaluation of femoral anteversion to predict postoperative stem anteversion aids the selection of an appropriate prosthesis and optimizes the combined anteversion in total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH). The conventional prediction methods are based on the femoral anteversion measurement at the location of the femoral head and/or neck. However, varied differences between femoral anteversion and postoperative stem anteversion were demonstrated. This study investigated the predictive role of a new method based on the principle of sagittal three-point fixation. METHODS: From January 2017 to December 2018, a total of 133 DDH hips that underwent THA were retrospectively analyzed. There were 76 Crowe type I, 27 type II, and 30 type III hips. The single-wedge stem was used in 49 hips, and the double-wedge stem was used in 84 hips. Preoperative native femoral anteversion at the femoral head-neck junction, anterior cortex anteversion at 2 levels of the lesser trochanter, posterior cortex anteversion at 5 levels of the femoral neck, and postoperative stem anteversion were measured using two-dimensional computed tomography. Predictive anteversion by the new method was calculated as the average anteversion formed by the anterior cortex at the lesser trochanter and the posterior cortex at the femoral neck. RESULTS: For hips with different neck heights, different Crowe types, different stem types, or different femoral anteversions, native femoral anteversion showed widely varied differences and correlations with stem anteversion, with differences ranging from -1.27 ± 8.33° to -13.67 ± 9.47° and correlations ranging from 0.122 (p = 0.705, no correlation) to 0.813. Predictive anteversion formed by the anterior cortex at the lesser trochanter proximal base and posterior cortex 10 mm above the lesser trochanter proximal base showed no significant difference with stem anteversion, with less varied differences (0.92 ± 7.52°) and good to excellent correlations (r = 0.826). CONCLUSION: Adopting our new method, predictive anteversion, measured as the average anteversion of the anterior cortex at the lesser trochanter proximal base and posterior cortex 10 mm above the lesser trochanter proximal base, predicted postoperative stem anteversion more reliably than native femoral anteversion.

Ubiquitin-proteasome system-mediated ubiquitination modification patterns and characterization of tumor microenvironment infiltration, stemness and cellular senescence in low-grade glioma.

The Ubiquitin-proteasome system (UPS) performs a crucial role in immune activation and tumorigenesis. Nevertheless, the comprehensive role of the ubiquitin-proteasome system in the low-grade glioma (LGG) tumor microenvironment (TME) remains unknown. Ubiquitination modification patterns in LGG patients and corresponding characteristics of tumor immune traits, CSC stemness, and cellular senescence were evaluated via a comprehensive analysis of 20 ubiquitination modification regulators. For quantification of the ubiquitination modification status of individual patients, the UM-score was constructed and associated with TME characteristics, clinical features, cancer stem cell stemness, cellular senescence, prognosis, and immunotherapy efficacy. We identified that alterations in multiple ubiquitination regulators are linked to patient survival and the shaping of the tumor microenvironment. We found two different styles of ubiquitination modification in patients with low-grade glioma (immune-inflamed differentiation and immune-exclude dedifferentiation), characterized by high and low UM-score, and the two regulatory patterns of ubiquitination modification on immunity, stemness feature, and cellular senescence. We demonstrate that the UM-score could forecast the subtype of LGG, the immunologic infiltration traits, the biological process, the stemness feature, and the cellular senescence trait. Notably, the UM-score was related to immunotherapeutic efficacy, implying that modifying ubiquitination modification patterns by targeting ubiquitination modification regulators or ubiquitination modification pattern signature genes to reverse unfavorable TME properties will provide new insights into cancer immunotherapy. This research indicated that the ubiquitin-proteasome system is crucial in the formation of TME complexity and multiformity. The UM-score can determine ubiquitination modification status in individual patients, bringing about more personalized and effective immunotherapeutic tactics.

Dual "Unlocking" Strategy to Overcome Inefficient Nanomedicine Delivery and Tumor Hypoxia for Enhanced Photodynamic-Immunotherapy.

Lacking blood vessels is one of the main characteristics of most solid tumors due to their rapid and unrestricted growth, which thus causes the inefficient delivery efficiency of nanomedicine and tumor hypoxia. Herein, a dual "unlocking" strategy to overcome these obstacles is proposed by combining engineered hybrid nanoparticles (named ZnPc@FOM-Pt) with dexamethasone (DXM). It is verified that pretreatment of tumors with DXM can increase intratumorally micro-vessel density (delivery "unlocking") to enhance the tumor delivery efficiency of ZnPc@FOM-Pt and decrease HIF-1α expression. Correspondingly, more Pt can catalyze tumor-overexpressed H2 O2 to produce oxygen to further cause hypoxia "unlocking," ultimately achieving boosted ZnPc-based photodynamic therapy in vivo (tumor inhibition rate: 99.1%). Moreover, the immunosuppressive tumor microenvironment is efficiently reversed and the therapeutic effect of anti-PD-L1-based immunotherapy is promoted by this newly designed nanomedicine. This dual "unlocking" strategy provides an innovative paradigm on simultaneously enhancing nanomedicine delivery efficacy and hypoxia relief for tumor therapy.

Use of a Gigli Saw as a Substitute Osteotomy Tool When Oscillating Saw Malfunctions Occur During Hip Arthroplasty.

OBJECTIVE: The oscillating saw has some inherent disadvantages, such as notch formation and blood splash. The objective is to introduce the Gigli saw as a substitute osteotomy tool when oscillating saw malfunctions occur during surgery. METHODS: During our retrospective study, 120 patients (120 hips) who underwent primary total hip arthroplasty (THA) because of femoral neck fracture, femoral head necrosis, developmental hip dysplasia (Crowe I), or primary osteoarthritis between October 2017 and April 2020 at our institute were included. Sixty patients (26 men and 34 women) with a mean age of 67.3 years (±15.1 years) underwent femoral neck osteotomy using a Gigli saw. The other 60 patients (32 men and 28 women) with a mean age of 64.4 years (±18.8 years) underwent femoral neck osteotomy using an oscillating saw. Intraoperative evaluations, including osteotomy time, osteotomy height, number of notch formations, and blood splash generation, were performed. Routine anteroposterior views of the pelvis and proximal femur were obtained for all patients after surgery. RESULTS: The mean osteotomy times were 26.60 ± 14.80 s and 31.80 ± 14.20 s with the oscillating saw and Gigli saw, respectively (t = 1.964, P = 0.0519). The mean osteotomy heights were 1.26 ± 0.22 cm and 1.20 ± 0.14 cm with the oscillating saw and Gigli saw, respectively (t = 1.782, P = 0.0773). The use of a Gigli saw did not result in bone notch formation or blood splash generation when multiple blood splashes were generated in the oscillating saw group. Postoperative radiographs showed no prostheses malposition in the Gigli saw and oscillating saw groups. CONCLUSION: The Gigli saw has various advantages and can be a substitute tool for femoral neck osteotomy during THA when oscillating saw malfunctions occur.

One-pot fabrication of a polydopamine-based nanoplatform for GSH triggered trimodal ROS-amplification for cancer therapy.

Reactive oxygen species (ROS) based nanoplatforms have been considered as attractive and feasible candidates for cancer therapy. However, the activated endogenous antioxidant defense of cancer cells in response to the ROS attack greatly hinders their therapeutic efficacy. Although cancer-specific ROS amplification strategies have been widely explored, most of them suffer from tedious synthesis procedures and complex components, which will bring about undesired side effects and unsatisfactory results. Herein, we design a cancer-specific oxidative stress amplification nanomedicine (CA-Cu-PDA), which is simply fabricated through integrating the glutathione (GSH) responsive/depleting nanocarrier of copper-polydopamine (Cu-PDA) nanoparticles with a ROS-generating drug cinnamaldehyde (CA) via a facile one-pot polymerization route. It is verified that GSH could trigger the breakage of CA-Cu-PDA networks and the subsequent release of both copper ions and CA in cancer cells. The released copper ions efficiently oxidize GSH, thereby weakening the antioxidant system of cancer cells and increasing the ROS levels. On the other hand, extra ROS are generated by the reduced copper ions through a Fenton reaction, so that a synergistic ROS therapy with CA is achieved. Consequently, oxidative stress is specifically increased within cancer cells, leading to efficient cancer cell apoptosis, significant tumor suppression and minimized side effects. Such an ingenious structure realizes the interlocking cooperation and full utilization of each component's function, presenting promising perspectives for nanomedicine design.

LY450139 Inhibited Ti-Particle-Induced Bone Dissolution via Suppressing Notch and NF-κB Signaling Pathways.

Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat peri-prosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mice skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1, and the downstream target gene Hes1 in Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for the treatment of peri-prosthetic osteolysis and other osteolytic disease associated with overactive osteoclasts.

Reliability and validity test of a novel three-dimensional acetabular bone defect classification system aided with additive manufacturing.

BACKGROUND: Accurate assessment of acetabular defects and designing precise and feasible surgical plans are essential for positive outcomes of hip revision arthroplasty. Additive manufacturing (AM) is a novel technique to print physical object models. We propose a three-dimensional acetabular bone defect classification system aided with AM model, and further assess its reliability and validity under blinded conditions. METHODS: We reviewed 104 consecutive patients who underwent hip revision arthroplasty at our department between January 2014 and December 2019, of whom 45 had AM models and were included in the reliability and validity tests. Three orthopedic surgeons retrospectively evaluated the bone defects of these 45 patients with our proposed classification, made surgical plans, and repeated the process after 2 weeks. The reliability and validity of the classification results and corresponding surgical plans were assessed using the intra-class correlation coefficient or kappa correlation coefficient. RESULTS: The reliability and validity of the classification results were excellent. The mean initial intra-class correlation coefficient for inter-observer reliability was 0.947, which increased to 0.972 when tested a second time. The intra-observer reliability ranged from 0.958 to 0.980. Validity of the classification results also showed a high kappa correlation coefficient of 0.951-0.967. When considering corresponding surgical plans, the reliability and validity were also excellent, with intra-class correlation coefficients and kappa correlation coefficients measuring all over 0.9. CONCLUSIONS: This three-dimensional acetabular defect classification has excellent reliability and validity. Using this classification system and AM models, accurate assessment of bone defect and reliable surgical plans could be achieved. This classification aided with AM is a promising tool for surgeons for preoperative evaluation.

Application of a novel osteotomy instrumentation as a substitute tool in total hip arthroplasty.

BACKGROUND: Mechanical failure, power shortage, and inadvertent contamination of the oscillating saw occasionally occurs in actualizing femoral neck osteotomy during total hip arthroplasty (THA); however, no appropriate alternative solution is currently available. This study aimed to introduce a novel osteotomy instrumentation (fretsaw, jig, cable passer hook) as a substitute tool while the oscillating saw was unavailable during THA. METHODS: This study included 40 patients (40 hips) who underwent femoral neck osteotomy during primary THA using the new osteotomy instrumentation (n = 20) and the oscillating saw (n = 20). Clinical data and intraoperative findings of all patients were evaluated. RESULTS: The mean osteotomy time was 22.3 ± 3.1 s (range, 17-30 s) and 29.4 ± 3.7 s (range, 25-39 s) in the oscillating saw group and in the new osteotomy instrumentation group, respectively (P < 0.001). The Harris Hip Score (HHS) improved in both groups; the mean HSS was 82.3 ± 2.5 and 83.3 ± 3.5 in the oscillating saw group and new osteotomy instrumentation group at 6 months after surgery, respectively (P = 0.297). CONCLUSIONS: The original osteotomy instrumentation can be an ideal substitute tool for femoral neck osteotomy in THA, especially when the oscillating saw is unavailable or malfunctioning.

Positive Correlation Between the Femur Neck Shaft and Anteversion Angles: A Retrospective Computed Tomography Analysis in Patients With Developmental Dysplasia of the Hip.

BACKGROUND: This study aimed to explore the anatomical correlation between the femoral neck shaft angle (NSA) and femoral anteversion angle (AA) in patients with developmental dysplasia of the hip based on the Crowe classification and provide a novel method to estimate the femoral AA on anteroposterior pelvic radiographs. METHODS: A total of 208 patients with dysplastic hips who underwent total hip arthroplasty at our institution were retrospectively included. Preoperative physiological AA and NSA were determined via 3-dimensional computed tomography. Linear regressions and Pearson's coefficients were calculated to assess the correlation between the femoral NSA and femoral AA. RESULTS: A total of 416 hips were divided into 5 subgroups: 99 normal, 143 type I, 71 type II, 63 type III, and 40 type IV hips following the Crowe classification. Dysplastic femurs had significantly higher AAs than normal hips (25.2° vs 31.4° vs 33.3° vs 35.5° vs 41.7°). Significant positive correlations between the AA and NSA were observed in normal (r = 0.635), type I (r = 0.700), type II (r = 0.612), and type III (r = 0.638) hips (P < .001); however, no meaningful correlation was observed in type IV hips (r = 0.218, P = .176). CONCLUSION: The NSA and AA correlated positively and significantly in the normal and dysplastic Crowe type I-III hips. The relationship between the NSA and AA indicates torsion of the proximal femur and offers an opportunity for straightforward estimation of AA based on NSA.

Polydopamine-coated UiO-66 nanoparticles loaded with perfluorotributylamine/tirapazamine for hypoxia-activated osteosarcoma therapy.

BACKGROUND: Hypoxia is a characteristic of solid tumors that can lead to tumor angiogenesis and early metastasis, and addressing hypoxia presents tremendous challenges. In this work, a nanomedicine based on oxygen-absorbing perfluorotributylamine (PFA) and the bioreductive prodrug tirapazamine (TPZ) was prepared by using a polydopamine (PDA)-coated UiO-66 metal organic framework (MOF) as the drug carrier. RESULTS: The results showed that TPZ/PFA@UiO-66@PDA nanoparticles significantly enhanced hypoxia, induced cell apoptosis in vitro through the oxygen-dependent HIF-1α pathway and decreased oxygen levels in vivo after intratumoral injection. In addition, our study demonstrated that TPZ/PFA@UiO-66@PDA nanoparticles can accumulate in the tumor region after tail vein injection and effectively inhibit tumor growth when combined with photothermal therapy (PTT). TPZ/PFA@UiO-66@PDA nanoparticles increased HIF-1α expression while did not promote the expression of CD31 in vivo during the experiment. CONCLUSIONS: By using TPZ and PFA and the enhanced permeability and retention effect of nanoparticles, TPZ/PFA@UiO-66@PDA can target tumor tissues, enhance hypoxia in the tumor microenvironment, and activate TPZ. Combined with PTT, the growth of osteosarcoma xenografts can be effectively inhibited.

Comparison of 3D Printing Rapid Prototyping Technology with Traditional Radiographs in Evaluating Acetabular Defects in Revision Hip Arthroplasty: A Prospective and Consecutive Study.

OBJECTIVE: To compare rapid prototyping technology (RP tech) in revision total hip arthroplasty (RTHA) with traditional examination methods and to see how they are different in evaluating acetabular anatomy and designing surgical procedure. METHODS: From February 2014 to March 2018, 43 RTHA patients with complex acetabulum defects were enrolled in this prospective study regardless of age or gender. Incomplete and unclear data were excluded. Three types of radiographic examination were performed on each patient before the revision surgery. Four groups of evaluations were designed: (i) X-ray; (ii) computed tomography (CT-scan); (iii) RP tech; and (iv) CT-aided RP tech. Discrepancies between preoperative radiographic analysis and intra-operative findings were separately compared by a team of surgeons. Premade surgical plans based on each evaluation method were compared with the final surgical procedure. The compliance of anatomic evaluation and surgical plan-design based on 3D RP tech and traditional radiographs were ranked manually by a of team surgeons into: (i) complete accordance; (ii) general accordance; and (iii) undetermined structure/procedure. The difference in ranks between RP tech and traditional radiographic methods were analyzed with a nonparametric Kruskal-Wallis test. P < 0.05 was considered significant. Multiple adjustments were taken for the statistical tests level according to the Bonferroni method. RESULTS: For anatomic analysis, the accordance in four groups of evaluating methods differed from each other (P < 0.05) except for the comparison of RP tech and CT-aided RP tech. RP tech displayed better anatomic evaluating accuracy than traditional methods (X-ray and CT) with the "complete accordance" rates of these groups being 88.37%, 4.65% and 27.91%, respectively. But CT-aided RP tech did not improve accuracy significantly compared with using RP tech individually, although the value seems high in the CT-aided RP group with the "complete accordance" rate of 95.35%. For surgery design, RP tech significantly showed better applicable surgical design compared with X-ray and CT (P < 0.05), and the "complete accordance" rates were 88.37%, 6.98% and 23.26%, but no significant difference was observed between RP tech and CT-aided RP tech, and the "complete accordance" rate of CT-aided RP tech group was 97.67%. RP tech showed remarkable improvement in bone defect assessment and surgical plan design. CONCLUSION: Using RP technology improved both sensibility and accuracy in acetabular defect evaluation with better locating and evaluating efficiency compared with X-ray and CT-scans. It also improved surgical schedule designing in complex acetabular defecting revision surgery. In particularly complex cases, CT aided RP tech may increase the accuracy of RP tech.

Verification and clinical translation of a newly designed "Skywalker" robot for total knee arthroplasty: A prospective clinical study.

OBJECTIVE: To evaluate accuracy of an innovative "Skywalker" system, a newly designed, robot-assisted operation system for orthopaedics via a clinical trial at knee joint. METHODS: We conducted a prospective analysis of the clinical data of 31 patients who underwent total knee arthroplasty assisted by the "Skywalker" robot (Microport, Suzhou, China) from June 2020 to January 2021. Five male patients and 26 female patients aged 69.68 â€‹± â€‹6.11 years (range: 57-79 years) were diagnosed with knee osteoarthritis and indicated for surgery. The "Skywalker" surgical robotic system was adopted to make a preoperative plan for knee arthroplasty. When the robotic arm reached the specified position during the operation, a single surgeon performed the osteotomy with a cutting saw through the cutting jig, and the difference between the actual and the expected resection thickness, and the preoperative and postoperative lower limb alignments were measured. RESULTS: The actual error of the resection thickness was the difference between the actual and the expected resection thickness. The absolute error of the resection thickness was the absolute value of the actual error of resection thickness. The absolute errors of the resection thickness of the medial and lateral condyle of the distal femur, the medial and lateral posterior condyle of the femur, and the medial and lateral sides of the tibial plateau were 0.87 â€‹± â€‹0.63 â€‹mm, 1.02 â€‹± â€‹0.67 â€‹mm, 0.74 â€‹± â€‹0.46 â€‹mm, 0.98 â€‹± â€‹0.81 â€‹mm, 0.92 â€‹± â€‹0.66 â€‹mm, and 1.04 â€‹± â€‹0.84 â€‹mm, respectively. The absolute angle errors between the actual postoperative angles and the preoperative planned angles of the lower limb alignment angles, coronal femoral component angles, and coronal tibial component angles were 1.46° â€‹± â€‹0.95°, 1.13° â€‹± â€‹1.01°, and 1.05° â€‹± â€‹0.73°, respectively. Besides, 100% of the absolute error of the HKA angles was within 3°. In addition, compared to the preoperative lower limb alignment angle, 90.32% of the postoperative lower limb alignment angles of 31 patients were closer to 180° after the operation. All 31 patients underwent a successful surgery, and no relevant complications occurred after the operation, such as surgical site infection, deep venous thrombosis, or vascular and nerve injury. CONCLUSION: The "Skywalker" system has good osteotomy accuracy, can achieve the planned angles well, and is expected to assist surgeons in performing accurate bone cuts and reconstructing planned lower limb alignments in the relevant clinical applications in future.

Bi-directional regulation functions of lanthanum-substituted layered double hydroxide nanohybrid scaffolds via activating osteogenesis and inhibiting osteoclastogenesis for osteoporotic bone regeneration.

Rationale: Osteoporotic patients suffer symptoms of excessive osteoclastogenesis and impaired osteogenesis, resulting in a great challenge to treat osteoporosis-related bone defects. Based on the positive effect of rare earth elements on bone metabolism and bone regeneration, we try to prove the hypothesis that the La3+ dopants in lanthanum-substituted MgAl layered double hydroxide (La-LDH) nanohybrid scaffolds simultaneously activate osteogenesis and inhibit osteoclastogenesis. Methods: A freeze-drying technology was employed to construct La-LDH nanohybrid scaffolds. The in vitro osteogenic and anti-osteoclastogenic activities of La-LDH nanohybrid scaffolds were evaluated by using ovariectomized rat bone marrow stromal cells (rBMSCs-OVX) and bone marrow-derived macrophages (BMMs) as cell models. The in vivo bone regeneration ability of the scaffolds was investigated by using critical-size calvarial bone defect model of OVX rats. Results: La-LDH nanohybrid scaffolds exhibited three-dimensional macroporous structure, and La-LDH nanoplates arranged perpendicularly on chitosan organic matrix. The La3+ dopants in the scaffolds promote proliferation and osteogenic differentiation of rBMSCs-OVX by activating Wnt/ß-catenin pathway, leading to high expression of ALP, Runx-2, COL-1 and OCN genes. Moreover, La-LDH scaffolds significantly suppressed RANKL-induced osteoclastogenesis by inhibiting NF-κB signaling pathway. As compared with the scaffolds without La3+ dopants, La-LDH scaffolds provided more favourable microenvironment to induce new bone in-growth along macroporous channels. Conclusion: La-LDH nanohybrid scaffolds possessed the bi-directional regulation functions on osteogenesis and osteoclastogenesis for osteoporotic bone regeneration. The modification of La3+ dopants in bone scaffolds provides a novel strategy for osteoporosis-related bone defect healing.

Graphene-modified CePO4 nanorods effectively treat breast cancer-induced bone metastases and regulate macrophage polarization to improve osteo-inductive ability.

BACKGROUND: Breast cancer bone metastasis has become one of the most common complications; however, it may cause cancer recurrence and bone nonunion, as well as local bone defects. METHODS: Herein, In vitro, we verified the effect of bioscaffold materials on cell proliferation and apoptosis through a CCK8 trial, staining of live/dead cells, and flow cytometry. We used immunofluorescence technology and flow cytometry to verify whether bioscaffold materials regulate macrophage polarization, and we used ALP staining, alizarin red staining and PCR to verify whether bioscaffold material promotes bone regeneration. In vivo, we once again studied the effect of bioscaffold materials on tumors by measuring tumor volume in mice, Tunel staining, and caspase-3 immunofluorescence. We also constructed a mouse skull ultimate defect model to verify the effect on bone regeneration. RESULTS: Graphene oxide (GO) nanoparticles, hydrated CePO4 nanorods and bioactive chitosan (CS) are combined to form a bioactive multifunctional CePO4/CS/GO scaffold, with characteristics such as photothermal therapy to kill tumors, macrophage polarization to promote blood vessel formation, and induction of bone formation. CePO4/CS/GO scaffold activates the caspase-3 proteasein local tumor cells, thereby lysing the DNA between nucleosomes and causing apoptosis. On the one hand, the as-released Ce3+ ions promote M2 polarization of macrophages, which secretes vascular endothelial growth factor (VEGF) and Arginase-1 (Arg-1), which promotes angiogenesis. On the other hand, the as-released Ce3+ ions also activated the BMP-2/Smad signaling pathway which facilitated bone tissue regeneration. CONCLUSION: The multifunctional CePO4/CS/GO scaffolds may become a promising platform for therapy of breast cancer bone metastases.

Bifunctional, Copper-Doped, Mesoporous Silica Nanosphere-Modified, Bioceramic Scaffolds for Bone Tumor Therapy.

In the traditional surgical intervention procedure, residual tumor cells may potentially cause tumor recurrence. In addition, large bone defects caused by surgery are difficult to self-repair. Thus, it is necessary to design a bioactive scaffold that can not only kill residual tumor cells but also promote bone defect regeneration simultaneously. Here, we successfully developed Cu-containing mesoporous silica nanosphere-modified ß-tricalcium phosphate (Cu-MSN-TCP) scaffolds, with uniform and dense nanolayers with spherical morphology via 3D printing and spin coating. The scaffolds exhibited coating time- and laser power density-dependent photothermal performance, which favored the effective killing of tumor cells under near-infrared laser irradiation. Furthermore, the prepared scaffolds favored the proliferation and attachment of rabbit bone marrow-derived mesenchymal stem cells and stimulated the gene expression of osteogenic markers. Overall, Cu-MSN-TCP scaffolds can be considered for complete eradication of residual bone tumor cells and simultaneous healing of large bone defects, which may provide a novel and effective strategy for bone tumor therapy. In the future, such Cu-MSN-TCP scaffolds may function as carriers of anti-cancer drugs or immune checkpoint inhibitors in chemo-/photothermal or immune-/photothermal therapy of bone tumors, favoring for effective treatment.

The Recombinant Protein EphB4-Fc Changes the Ti Particle-Mediated Imbalance of OPG/RANKL via EphrinB2/EphB4 Signaling Pathway and Inhibits the Release of Proinflammatory Factors In Vivo.

Aseptic loosening caused by wear particles is one of the common complications after total hip arthroplasty. We investigated the effect of the recombinant protein ephB4-Fc (erythropoietin-producing human hepatocellular receptor 4) on wear particle-mediated inflammatory response. In vitro, ephrinB2 expression was analyzed using siRNA-NFATc1 (nuclear factor of activated T-cells 1) and siRNA-c-Fos. Additionally, we used Tartrate-resistant acid phosphatase (TRAP) staining, bone pit resorption, Enzyme-linked immunosorbent assay (ELISA), as well as ephrinB2 overexpression and knockdown experiments to verify the effect of ephB4-Fc on osteoclast differentiation and function. In vivo, a mouse skull model was constructed to test whether the ephB4-Fc inhibits osteolysis and inhibits inflammation by micro-CT, H&E staining, immunohistochemistry, and immunofluorescence. The gene expression of ephrinB2 was regulated by c-Fos/NFATc1. Titanium wear particles activated this signaling pathway to the promoted expression of the ephrinB2 gene. However, ephrinB2 protein can be activated by osteoblast membrane receptor ephB4 to inhibit osteoclast differentiation. In in vivo experiments, we found that ephB4 could regulate Ti particle-mediated imbalance of OPG/RANKL, and the most important finding was that ephB4 relieved the release of proinflammatory factors. The ephB4-Fc inhibits wear particle-mediated osteolysis and inflammatory response through the ephrinB2/EphB4 bidirectional signaling pathway, and ephrinB2 ligand is expected to become a new clinical drug therapeutic target.

Optimal Level of Femoral Neck for Predicting Postoperative Stem Anteversion in Total Hip Arthroplasty for Crowe Type I Dysplastic Hip.

OBJECTIVE: This study aimed to investigate the optimal level of femoral neck for measuring femoral anteversion to predict postoperative stem anteversion in Crowe type I developmental dysplasia of the hip. METHODS: This retrospective study analyzed 108 Crowe type I hips that underwent THA between January 2016 and December 2017, including 70 women and 19 men with a mean age of 63.08 ± 9.13 (range, 41-83) years. The single-wedge stem was used in 37 hips, the double-wedge stem was used in 71 hips. Computed tomography scans were performed pre- and post-operation. Femoral anteversion at six levels of the proximal femur were measured via preoperative two-dimensional computed tomography. Femoral anteversion at the level of the femoral neck osteotomy plane and postoperative stem anteversion were measured via three-dimensional reconstructed models. RESULTS: The mean follow-up period was 18.5 months (range, 12-27). The mean preoperative Harris Hip Score was 51.5 ± 8.7 and improved to 90.4 ± 7.8 (P < 0.001) by the last follow-up. There were no intraoperative fractures, and no infections occurred during the follow-up period. Two patients developed deep venous thrombosis. There was no sign of prosthetic loosening in all hips. No significant correlations were found between the height of the femoral neck osteotomy plane and postoperative stem anteversion (r = -0.119, P = 0.220). Femoral anteversion decreased gradually from 64.00° ± 10.51° at the center of lesser trochanter to 15.21° ± 13.31° at the head-neck junction, which was changed from more to less than stem anteversion (24.37° ± 13.86°). The femoral anteversion at femoral head-neck junction (15.21° ± 13.31°) was significantly less than postoperative stem anteversion (P = 0.000), with a difference of -9.16° ± 9.27°. The femoral anteversion at the level of the osteotomy plane (28.48° ± 15.34°) was significantly more than the postoperative stem anteversion (P = 0.000), with a difference of 4.11° ± 9.56°. Among all six levels and the level of osteotomy, femoral anteversion at the 10-mm level above the proximal base of lesser trochanter (22.65 ± 12.92) displayed the smallest difference (-1.72° ± 8.90°) and a good correlation (r = 0.764) with postoperative stem anteversion for all 108 hips, with a moderate correlation of 0.465 for single-wedge stem hips and an excellent correlation of 0.821 for double-wedge stem hips. CONCLUSION: For Crowe type I hips, femoral anteversion would be different if it was measured via different levels of the femoral neck. The 10-mm level above the proximal base of the lesser trochanter could be an optimum choice for measuring femoral anteversion to predict postoperative stem anteversion.

Quercetin inhibits macrophage polarization through the p-38α/ß signalling pathway and regulates OPG/RANKL balance in a mouse skull model.

Aseptic loosening caused by wear particles is a common complication after total hip arthroplasty. We investigated the effect of the quercetin on wear particle-mediated macrophage polarization, inflammatory response and osteolysis. In vitro, we verified that Ti particles promoted the differentiation of RAW264.7 cells into M1 macrophages through p-38α/ß signalling pathway by using flow cytometry, immunofluorescence assay and small interfering p-38α/ß RNA. We used enzyme-linked immunosorbent assays to confirm that the protein expression of M1 macrophages increased in the presence of Ti particles and that these pro-inflammatory factors further regulated the imbalance of OPG/RANKL and promoted the differentiation of osteoclasts. However, this could be suppressed, and the protein expression of M2 macrophages was increased by the presence of the quercetin. In vivo, we revealed similar results in the mouse skull by µ-CT, H&E staining, immunohistochemistry and immunofluorescence assay. We obtained samples from patients with osteolytic tissue. Immunofluorescence analysis indicated that most of the macrophages surrounding the wear particles were M1 macrophages and that pro-inflammatory factors were released. Titanium particle-mediated M1 macrophage polarization, which caused the release of pro-inflammatory factors through the p-38α/ß signalling pathway, regulated OPG/RANKL balance. Macrophage polarization is expected to become a new clinical drug therapeutic target.