Bio-nanoparticles loaded with synovial-derived exosomes ameliorate osteoarthritis progression by modifying the oxidative microenvironment.

BACKGROUND AND AIMS: Osteoarthritis (OA) is a prevalent degenerative joint disorder, marked by the progressive degeneration of joint cartilage, synovial inflammation, and subchondral bone hyperplasia. The synovial tissue plays a pivotal role in cartilage regulation. Exosomes (EXOs), small membrane-bound vesicles released by cells into the extracellular space, are crucial in mediating intercellular communication and facilitating the exchange of information between tissues. Our study aimed to devise a hydrogel microsphere infused with SOD3-enriched exosomes (S-EXOs) to protect cartilage and introduce a novel, effective approach for OA treatment. MATERIALS AND METHODS: We analyzed single-cell sequencing data from 4247 cells obtained from the GEO database. Techniques such as PCR, Western Blot, immunofluorescence (IF), and assays to measure oxidative stress levels were employed to validate the cartilage-protective properties of the identified key protein, SOD3. In vivo, OA mice received intra-articular injections of S-EXOs bearing hydrogel microspheres, and the effectiveness was assessed using safranine O (S.O) staining and IF. RESULTS: Single-cell sequencing data analysis suggested that the synovium influences cartilage via the exocrine release of SOD3. Our findings revealed that purified S-EXOs enhanced antioxidant capacity of chondrocytes, and maintained extracellular matrix metabolism stability. The S-EXO group showed a significant reduction in mitoROS and ROS levels by 164.2% (P < 0.0001) and 142.7% (P < 0.0001), respectively, compared to the IL-1ß group. Furthermore, the S-EXO group exhibited increased COL II and ACAN levels, with increments of 2.1-fold (P < 0.0001) and 3.1-fold (P < 0.0001), respectively, over the IL-1ß group. Additionally, the S-EXO group showed a decrease in MMP13 and ADAMTS5 protein expression by 42.3% (P < 0.0001) and 44.4% (P < 0.0001), respectively. It was found that S-EXO-containing hydrogel microspheres could effectively deliver SOD3 to cartilage and significantly mitigate OA progression. The OARSI score in the S-EXO microsphere group markedly decreased (P < 0.0001) compared to the OA group. CONCLUSION: The study demonstrated that the S-EXOs secreted by synovial fibroblasts exert a protective effect on chondrocytes, and microspheres laden with S-EXOs offer a promising therapeutic alternative for OA treatment.

Proteomic comparison between physiological degeneration and needle puncture model of disc generation disease.

BACKGROUND: The completeness of the intervertebral disc proteome is fundamental to the integrity and functionality of the intervertebral disc. METHODS: The 20 experimental rats were placed into two groups randomly, normal group (NG) and acupuncture pathological degeneration group-2 weeks (APDG-2w). The ten 24-month-old rats were grouped into physiological degeneration group (PDG). Magnetic resonance imaging, X-ray examination, histological staining (hematoxylin & eosin, safranin-O cartilage, and alcian blue staining), and immunohistochemical examination were carried out for assessing the degree of disc degradation. Intervertebral disc was collected, and protein composition was determined by LC- MS, followed by bioinformatic analysis including significance analysis, subcellular localization prediction, protein domain prediction, GO function and KEGG pathway analysis, and protein interaction network construction. LC-PRM was done for protein quantification. RESULTS: Physiological degeneration and especially needle puncture decreased T2 signal intensity and intervertebral disc height. Results from hematoxylin & eosin, safranin-O, and alcian blue staining revealed that the annulus fibrosus apparently showed the wavy and collapsed fibrocartilage lamellas in APDG-2w and PDG groups. The contents of the nucleus pulposus were decreased in physiological degeneration group and APDG-2w group compared with NG. Results from immunohistochemical analysis suggested the degeneration of intervertebral disc and inflammation in APDG-2w and PDG groups. The protein composition and expression between needle puncture rat models and the physiological degeneration group showed significant difference. CONCLUSIONS: Our studies produced point-reference datasets of normal rats, physiological degeneration rats, and needle puncture rat models, which is beneficial to subsequent pathological studies. There is differential expression of protein expression in degenerative discs with aging and acupuncture, which may be used as a potential discriminating index for different intervertebral degenerations.

Should adjacent asymptomatic lumbar disc herniation of L5-S1 isthmic spondylolisthesis be simultaneously rectified? Evaluation of postoperative spino-pelvic sagittal balance and functional outcomes.

BACKGROUND: This study aimed to analyze the efficacy of the simultaneous rectification of adjacent asymptomatic lumbar disc herniation (asLDH) of L5-S1 isthmic spondylolisthesis (IS). METHODS: One hundred and forty-eight patients with L5-S1 IS, and simultaneous L4-5 asLDH, were recruited between January 2012 and December 2017, for this study. Group A: seventy-two patients received PLIF at L5-S1. Group B: seventy-six patients received PLIF at L4-S1. The radiographic outcomes were assessed via the lumbar lordosis (LL), segmental lordosis (SL), sacral slope (SS), pelvic incidence (PI), pelvic tilt (PT), PI-LL and slip degree (SD). The functional outcomes were evaluated via the visual analog scale (VAS), Oswestry disability index (ODI), and reoperation rate. The potential risk hazards for reoperation were identified using both uni- and multivariate logistic regression analyses. RESULTS: The postoperative LL, SL, PT, SS, SD, VAS, and ODI exhibited vast improvements (P < 0.05). Relative to Group A, Group B exhibited markedly better LL, SL, PT, PI-LL,VAS and ODI scores at the final follow-up (P < 0.05). Group B also achieved better SD values post surgery than Group A (P < 0.05). The reoperation rate was remarkably elevated in Group A, compared to Group B (P < 0.05). The multivariate logistic regression analysis showed the L4-5 asLDH grade was a stand-alone risk hazard for reoperation, whereas, pre-SL and pre-LL offered protection against reoperation (P < 0.05). CONCLUSIONS: L4-S1 PLIF is recommended to correct asLDH in L5-S1 IS patients, with high-grade disc herniation and abnormal sagittal alignment.

Study on the influence of balloon dilation mode on the intravertebral cleft of osteoporotic fracture.

BACKGROUND: Intravertebral cleft is common in osteoporotic vertebral compression fracture, and the bone sclerosis around the fissure brings difficulties to the surgical treatment. It is not known whether the balloon dilatation mode of percutaneous kyphoplasty affects the distribution of bone cement in the fracture vertebral body and further affects the surgical effect. The purpose of this study was to discuss the effect of balloon dilatation mode on percutaneous kyphoplasty in the treatment of osteoporotic vertebral fractures with intravertebral cleft. METHODS: According to the inclusion criteria and exclusion criteria, a retrospective analysis of patients with osteoporotic vertebral fracture combined with intravertebral cleft treated by percutaneous kyphoplasty in our hospital was conducted. All patients were divided into two groups based on way of balloon dilation. The mode of balloon dilatation, imaging changes of vertebral body, VAS score, ODI score, bone cement distribution and postoperative complications were analyzed. RESULTS: A total of 96 patients with osteoporotic vertebral fracture combined with intravertebral cleft were included in the study, including 51 patients treated with single balloon bilateral alternating dilatation technique and 45 patients treated with double balloon bilateral dilatation technique. The vertebral height, Cobb's angle of kyphosis, VAS score and ODI score were significantly improved in both groups after operation (P < 0.05). The postoperative vertebral height and Cobb's angle of kyphosis in the double balloon bilateral dilatation group were better than those in single balloon bilateral alternating dilatation group (P < 0.05). The distribution of bone cement in the single balloon bilateral alternating dilatation group was more inclined to insert filling, while the double balloon bilateral dilatation group was more inclined to fissure filling. The VAS score and ODI score at the final follow-up in the single balloon bilateral alternating dilatation group were lower than those in the double balloon bilateral dilatation group (P < 0.05). CONCLUSION: Double balloon bilateral dilatation technique can better restore the injured vertebral height in patients with osteoporotic vertebral fracture combined with intravertebral cleft. However, the distribution of injured vertebral cement in patients with single balloon bilateral alternating dilatation technique is more likely to be inserted and filled, and the long-term analgesia and lumbar function of patients are better.

Comparison of Clinical Outcomes Following Anterior Cervical Discectomy and Fusion with Zero-Profile Anchored Spacer-ROI-C-Fixation and Combined Intervertebral Cage and Anterior Cervical Discectomy and Fusion: A Retrospective Study from a Single Center.

BACKGROUND The aim of this study was to compare the outcomes following anterior cervical discectomy and fusion with zero-profile anchored spacer-ROI-C-fixation (ROI-C) vs combined intervertebral cage and anterior cervical discectomy and fusion (ACDF). MATERIAL AND METHODS We retrospectively analyzed 87 patients who underwent operations between January 2015 and January 2019, including 42 patients that underwent ROI-C treatment (group A) and 45 that were treated by the ACDF approach (group B). Operative duration, blood loss, dysphagia, Neck Disability Index scores (NDI), Japanese Orthopaedic Association scores (JOA), and other complications were compared between these groups. In addition, implant settlement, fusion, and cervical Cobb angle were assessed via imaging analyses. RESULTS Patients in group A and group B were followed for 22.6±3.3 months and 27.1±3.5 months, respectively (range: 13-30 months). Relative to preoperative values, JOA scores were increased and NDI scores were reduced in both groups following treatment (P<0.05), with comparable outcomes between groups (P>0.05). However, operative duration, intraoperative blood loss, and postoperative complications did differ significantly between these groups (P<0.05). Specifically, rates of short-term dysphagia were lower and recovery time was faster in group A relative to group B (P<0.05). CONCLUSIONS The findings from this study showed that ROI-C fixation achieved satisfactory outcomes, improved cervical curvature, restored intervertebral height, and was associated with shorter operative duration, reduced blood loss, and less dysphagia.

Clinical efficacy and safety of bone cement combined with radiofrequency ablation in the treatment of spinal metastases.

BACKGROUND: To investigate the clinical efficacy and safety of bone cement combined with radiofrequency ablation (RFA) in the treatment of spinal metastases. METHODS: The medical records of patients with spinal metastatic tumor admitted to our hospital from January 2016 to December 2018 were retrospectively analyzed. Based on different surgical methods, the patients were divided into groups A (treated with RFA combined with bone cement) and B (treated with bone cement only). Group A included 35 patients with 47 segments of diseased vertebral bodies. Group B consisted of 52 patients with 78 vertebral segments. Pain, quality of life score, vertebra height, bone cement leakage, postoperative tumor recurrence, and complications were assessed 3 days and 1 and 6 months after surgery. RESULTS: All the patients had smooth operation without paraplegia, spinal cord injury, and perioperative death. Visual analogue scales (VAS) and Oswestry Disability Index (ODI) scores of the two groups significantly improved 3 days and 1 month after surgery compared with those before surgery (P < 0.05), but no significant difference was observed between the two groups (P > 0.05). Six months after surgery, the VAS and ODI scores of patients in group A were lower than those in group B, with statistically significant differences (P < 0.05). The postoperative vertebral body height of the two groups significantly increased compared with that before surgery, and the difference was statistically significant (P < 0.05). Meanwhile, no significant difference was observed between the two groups (P > 0.05). Postoperative bone cement permeability in group A was 6.4%, and postoperative tumor recurrence rate was 11.4%. The permeability of bone cement in group B was 20.5%, and the tumor recurrence rate was 30.8%. The bone cement permeability and tumor recurrence rate in group A were lower than those in group B, with statistically significant differences (P < 0.05). CONCLUSIONS: Bone cement combined with RFA for the treatment of spinal metastases can achieve good efficacy, desirable analgesic effect, low incidence of complications, small surgical trauma, and high safety. The proposed method has the value of clinical popularization and application.

Comparison of cervical disc arthroplasty and anterior cervical discectomy and fusion for the treatment of cervical disc degenerative diseases on the basis of more than 60 months of follow-up: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis was designed to investigate the long-term efficacy and safety between cervical disc arthroplasty (CDA) and anterior cervical discectomy and fusion (ACDF) in treating cervical disc degenerative diseases (CDDDs). METHODS: Literature search was performed on Pubmed, Embase, Cochrane Library, and Web of Science before Jan 2019. Surgical details, clinical outcomes, range of motion (ROM), complications, and reoperation rates between CDA and ACDF groups were compared and analyzed. A fixed- or random-effects model was applied based on different heterogeneity. STATA (Version 11.0) software was used to perform data analysis. RESULTS: A total of 13 randomized controlled trial studies with more than 60 months of follow-up (mean 83.1 months) were enrolled in this meta-analysis. Pool results indicated that the CDA group exhibited significantly better outcomes in clinical scores (odds ratio [OR] = 1.54, 95% confidence interval [CI]: 1.15-2.08, p = 0.004) and preservation of ROM (mean difference = 1.77, 95% CI: 1.60-1.95, p < 0.001) than the ACDF group. Meanwhile, the incidence of adjacent segment disease (ASD) (OR = 0.51, 95% CI: 0.35-0.76, p = 0.001) and occurrence of reoperation (OR = 0.41, 95% CI: 0.25-0.69, p = 0.001) were lower in the CDA group than in the ACDF group. CONCLUSIONS: At long-term follow-up, CDA showed better efficacy in terms of clinical outcomes, ROM, ASD, and reoperation than ACDF for treating CDDDs. However, our results require further validation in large-sample and high-quality studies.

Zinc-energized dynamic hydrogel accelerates bone regeneration via potentiating the coupling of angiogenesis and osteogenesis.

Insufficient initial vascularization plays a pivotal role in the ineffectiveness of bone biomaterials for treating bone defects. Consequently, enhancing the angiogenic properties of bone repair biomaterials holds immense importance in augmenting the efficacy of bone regeneration. In this context, we have successfully engineered a composite hydrogel capable of promoting vascularization in the process of bone regeneration. To achieve this, the researchers first prepared an aminated bioactive glass containing zinc ions (AZnBg), and hyaluronic acid contains aldehyde groups (HA-CHO). The composite hydrogel was formed by combining AZnBg with gelatin methacryloyl (GelMA) and HA-CHO through Schiff base bonding. This composite hydrogel has good biocompatibility. In addition, the composite hydrogel exhibited significant osteoinductive activity, promoting the activity of ALP, the formation of calcium nodules, and the expression of osteogenic genes. Notably, the hydrogel also promoted umbilical vein endothelial cell migration as well as tube formation by releasing zinc ions. The results of in vivo study demonstrated that implantation of the composite hydrogel in the bone defect of the distal femur of rats could effectively stimulate bone generation and the development of new blood vessels, thus accelerating the bone healing process. In conclusion, the combining zinc-containing bioactive glass with hydrogels can effectively promote bone growth and angiogenesis, making it a viable option for the repair of critical-sized bone defects.

Effects of Cage Implantation Depth on Sagittal Parameters and Functional Outcomes in Posterior Lumbar Interbody Fusion for the Treatment of L4-L5 Lumbar Degenerative Spondylolisthesis.

OBJECTIVE: In the treatment of lumbar degenerative spondylolisthesis (LDS) with Posterior lumbar interbody fusion (PLIF) surgery, interbody fusion implants play a key role in supporting the vertebral body and facilitating fusion. The objective of this study was to assess the impact of implantation depth on sagittal parameters and functional outcomes in patients undergoing PLIF surgery. METHODS: This study reviewed 128 patients with L4-L5 LDS between January 2016 and August 2019. All patients underwent an open PLIF surgery that included intravertebral decompression, implantation of pedicle screws and cage. We grouped according to the position of the center of the cage relative to the L5 vertebral endplate. Patients with the center of the cage located at the anterior 1/2 of the upper end plate of the L5 vertebral body were divided into Anterior group, and located at the posterior 1/2 of the upper end plate of the L5 vertebral body were divided into Posterior group. The lumbar lordosis (LL), segmental lordosis (SL), sacral slope (SS), pelvic incidence (PI), pelvic tilt (PT) and slope degree (SD) was measured for radiographic outcomes. We used the visual analog scale (VAS) and the oswestry disability index (ODI) score to assess functional outcomes. Paired t-test was used to compare imaging and bedside data before and after surgery between the two groups, and independent sample t-test, χ2 test and Fisher exact test were used to compare the data between the two groups. RESULT: The mean follow-up of Anterior group was 44.13 ± 9.23 months, and Posterior group was 45.62 ± 10.29 months (P > 0.05). The LL, SL, PT, SS, SD and PI-LL after operation showed great improvements, relative to the corresponding preoperative values in both groups (P < 0.05). Compared to Posterior group, Anterior group exhibited far enhanced SL (15.49 ± 3.28 vs. 13.67 ± 2.53, P < 0.05), LL (53.47 ± 3.21 vs. 52.08 ± 3.15, P < 0.05) outcomes and showed depressed PI-LL (8.87 ± 5.05 vs. 10.73 ± 5.39, P < 0.05) outcomes at the final follow-up. Meanwhile, the SL in Anterior group (16.18 ± 3.99) 1 months after operation were also higher than in Posterior group (14.12 ± 3.57) (P < 0.05). We found that VAS and ODI at the final follow-up in Anterior group (3.62 ± 0.96, 25.19 ± 5.25) were significantly lower than those in Posterior group (4.12 ± 0.98, 27.68 ± 5.13) (P < 0.05). CONCLUSIONS: For patients with LDS, the anteriorly placed cage may provide better improvement of SL after PLIF surgery. Meanwhile, the anteriorly placed cage may achieve better sagittal parameters of LL and PI-LL and functional outcomes at the final follow-up.

A sponge-like nanofiber melatonin-loaded scaffold accelerates vascularized bone regeneration via improving mitochondrial energy metabolism.

Electrospun nanofibers have been widely employed in bone tissue engineering for their ability to mimic the micro to nanometer scale network of the native bone extracellular matrix. However, the dense fibrous structure and limited mechanical support of these nanofibers pose challenges for the treatment of critical size bone defects. In this study, we propose a facile approach for creating a three-dimensional scaffold using interconnected electrospun nanofibers containing melatonin (Scaffold@MT). The hypothesis posited that the sponge-like Scaffold@MT could potentially enhance bone regeneration and angiogenesis by modulating mitochondrial energy metabolism. Melatonin-loaded gelatin and poly-lactic-acid nanofibers were fabricated using electrospinning, then fragmented into shorter fibers. The sponge-like Scaffold@MT was created through a process involving homogenization, low-temperature lyophilization, and chemical cross-linking, while maintaining the microstructure of the continuous nanofibers. The incorporation of short nanofibers led to a low release of melatonin and increased Young's modulus of the scaffold. Scaffold@MT demonstrated positive biocompatibility by promoting a 14.2 % increase in cell proliferation. In comparison to the control group, Scaffold@MT significantly enhanced matrix mineralization by 3.2-fold and upregulated the gene expression of osteoblast-specific markers, thereby facilitating osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). Significantly, Scaffold@MT led to a marked enhancement in the mitochondrial energy function of BMMSCs, evidenced by elevated adenosine triphosphate (ATP) production, mitochondrial membrane potential, and protein expression of respiratory chain factors. Furthermore, Scaffold@MT promoted the migration of human umbilical vein endothelial cells (HUVECs) and increased tube formation by 1.3 times compared to the control group, accompanied by an increase in vascular endothelial growth factor (VEGFA) expression. The results of in vivo experiments indicate that the implantation of Scaffold@MT significantly improved vascularized bone regeneration in a distal femur defect in rats. Micro-computed tomography analysis conducted 8 weeks post-surgery revealed that Scaffold@MT led to optimal development of new bone microarchitecture. Histological and immunohistochemical analyses demonstrated that Scaffold@MT facilitated bone matrix deposition and new blood vessel formation at the defect site. Overall, the utilization of melatonin-loaded nanofiber sponges exhibits significant promise as a scaffold that promotes bone growth and angiogenesis, making it a viable option for the repair of critical-sized bone defects.

Cascaded controlled delivering growth factors to build vascularized and osteogenic microenvironment for bone regeneration.

The process of bone regeneration is intricately regulated by various cytokines at distinct stages. The establishment of early and efficient vascularization, along with the maintenance of a sustained osteoinductive microenvironment, plays a crucial role in the successful utilization of bone repair materials. This study aimed to develop a composite hydrogel that would facilitate the creation of an osteogenic microenvironment for bone repair. This was achieved by incorporating an early rapid release of VEGF and a sustained slow release of BMP-2. Herein, the Schiff base was formed between VEGF and the composite hydrogel, and VEGF could be rapidly released to promote vascularization in response to the early acidic bone injury microenvironment. Furthermore, the encapsulation of BMP-2 within mesoporous silica nanoparticles enabled a controlled and sustained release, thereby facilitating the process of bone repair. Our developed composite hydrogel released more than 80% of VEGF and BMP-2 in the acidic medium, which was significantly higher than that in the neutral medium (about 60%). Moreover, the composite hydrogel demonstrated a significant improvement in the migratory capacity and tube formation ability of human umbilical vein endothelial cells (HUVECs). Furthermore, the composite hydrogel exhibited an augmented ability for osteogenesis, as confirmed by the utilization of ALP staining, alizarin red staining, and the upregulation of osteogenesis-related genes. Notably, the composite hydrogel displayed substantial osteoinductive properties, compared with other groups, the skull defect in the composite hydrogels combined with BMP-2 and VEGF was full of new bone, basically completely repaired, and the BV/TV value was greater than 80%. The outcomes of animal experiments demonstrated that the composite hydrogel effectively promoted bone regeneration in cranial defects of rats by leveraging the synergistic effect of an early rapid release of VEGF and a sustained slow release of BMP-2, thereby facilitating vascularized bone regeneration. In conclusion, our composite hydrogel has demonstrated promising potential for vascularized bone repair through the enhancement of angiogenesis and osteogenic microenvironment.

Irisin-loaded electrospun core-shell nanofibers as calvarial periosteum accelerate vascularized bone regeneration by activating the mitochondrial SIRT3 pathway.

The scarcity of native periosteum poses a significant clinical barrier in the repair of critical-sized bone defects. The challenge of enhancing regenerative potential in bone healing is further compounded by oxidative stress at the fracture site. However, the introduction of artificial periosteum has demonstrated its ability to promote bone regeneration through the provision of appropriate mechanical support and controlled release of pro-osteogenic factors. In this study, a poly (l-lactic acid) (PLLA)/hyaluronic acid (HA)-based nanofibrous membrane was fabricated using the coaxial electrospinning technique. The incorporation of irisin into the core-shell structure of PLLA/HA nanofibers (PLLA/HA@Irisin) achieved its sustained release. In vitro experiments demonstrated that the PLLA/HA@Irisin membranes exhibited favorable biocompatibility. The osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) was improved by PLLA/HA@Irisin, as evidenced by a significant increase in alkaline phosphatase activity and matrix mineralization. Mechanistically, PLLA/HA@Irisin significantly enhanced the mitochondrial function of BMMSCs via the activation of the sirtuin 3 antioxidant pathway. To assess the therapeutic effectiveness, PLLA/HA@Irisin membranes were implanted in situ into critical-sized calvarial defects in rats. The results at 4 and 8 weeks post-surgery indicated that the implantation of PLLA/HA@Irisin exhibited superior efficacy in promoting vascularized bone formation, as demonstrated by the enhancement of bone matrix synthesis and the development of new blood vessels. The results of our study indicate that the electrospun PLLA/HA@Irisin nanofibers possess characteristics of a biomimetic periosteum, showing potential for effectively treating critical-sized bone defects by improving the mitochondrial function and maintaining redox homeostasis of BMMSCs.

Melatonin-encapsuled silk fibroin electrospun nanofibers promote vascularized bone regeneration through regulation of osteogenesis-angiogenesis coupling.

The repair of critical-sized bone defects poses a significant challenge due to the absence of periosteum, which plays a crucial role in coordinating the processes of osteogenesis and vascularization during bone healing. Herein, we hypothesized that melatonin-encapsuled silk Fibronin electrospun nanofibers (SF@MT) could provide intrinsic induction of both osteogenesis and angiogenesis, thereby promoting vascularized bone regeneration. The sustained release of melatonin from the SF@MT nanofibers resulted in favorable biocompatibility and superior osteogenic induction of bone marrow mesenchymal stem cells (BMMSCs). Interestingly, melatonin promoted the migration and tube formation of human umbilical vein endothelial cells (HUVECs) in a BMMSC-dependent manner, potentially through the upregulation of vascular endothelial growth factor (VEGFA) expression in SF@MT-cultured BMMSCs. SF@MT nanofibers enhanced the BMMSC-mediated angiogenesis by activating the PI3K/Akt signaling pathway. In vivo experiments indicated that the implantation of SF@MT nanofibers into rat critical-sized calvarial defects significantly enhances the production of bone matrix and the development of new blood vessels, leading to an accelerated process of vascularized bone regeneration. Consequently, the utilization of melatonin-encapsulated silk Fibronin electrospun nanofibers shows great promise as a potential solution for artificial periosteum, with the potential to regulate the coupling of osteogenesis and angiogenesis in critical-sized bone defect repair.

Activation of NRF2 by celastrol increases antioxidant functions and prevents the progression of osteoarthritis in mice.

Excessive oxidative stress impairs cartilage matrix metabolism balance, significantly contributing to osteoarthritis (OA) development. Celastrol (CSL), a drug derived from Tripterygium wilfordii, has recognized applications in the treatment of cancer and immune system disorders, yet its antioxidative stress mechanisms in OA remain underexplored. This study aimed to substantiate CSL's chondroprotective effects and unravel its underlying mechanisms. We investigated CSL's impact on chondrocytes under both normal and inflammatory conditions. In vitro, CSL mitigated interleukin (IL)-1ß-induced activation of proteinases and promoted cartilage extracellular matrix (ECM) synthesis. In vivo, intra-articular injection of CSL ameliorated cartilage degeneration and mitigated subchondral bone lesions in OA mice. Mechanistically, it was found that inhibiting nuclear factor erythroid 2-related factor 2 (NRF2) abrogated CSL-mediated antioxidative functions and exacerbated the progression of OA. This study is the first to elucidate the role of CSL in the treatment of OA through the activation of NRF2, offering a novel therapeutic avenue for arthritis therapy.

Research progress of vascularization strategies of tissue-engineered bone.

The bone defect caused by fracture, bone tumor, infection, and other causes is not only a problematic point in clinical treatment but also one of the hot issues in current research. The development of bone tissue engineering provides a new way to repair bone defects. Many animal experimental and rising clinical application studies have shown their excellent application prospects. The construction of rapid vascularization of tissue-engineered bone is the main bottleneck and critical factor in repairing bone defects. The rapid establishment of vascular networks early after biomaterial implantation can provide sufficient nutrients and transport metabolites. If the slow formation of the local vascular network results in a lack of blood supply, the osteogenesis process will be delayed or even unable to form new bone. The researchers modified the scaffold material by changing the physical and chemical properties of the scaffold material, loading the growth factor sustained release system, and combining it with trace elements so that it can promote early angiogenesis in the process of induced bone regeneration, which is beneficial to the whole process of bone regeneration. This article reviews the local vascular microenvironment in the process of bone defect repair and the current methods of improving scaffold materials and promoting vascularization.

The STING in Non-Alcoholic Fatty Liver Diseases: Potential Therapeutic Targets in Inflammation-Carcinogenesis Pathway.

Non-alcoholic fatty liver disease (NAFLD), an important chronic disease, is one of the major causes of high mortality and creates a substantial financial burden worldwide. The various immune cells in the liver, including macrophages, NK cells, dendritic cells, and the neutrophils involved in the innate immune response, trigger inflammation after recognizing the damage signaled from infection or injured cells and tissues. The stimulator of interferon genes (STING) is a critical molecule that binds to the cyclic dinucleotides (CDNs) generated by the cyclic GMP-AMP synthase (cGAS) to initiate the innate immune response against infection. Previous studies have demonstrated that the cGAS-STING pathway plays a critical role in inflammatory, auto-immune, and anti-viral immune responses. Recently, studies have focused on the role of STING in liver diseases, the results implying that alterations in its activity may be involved in the pathogenesis of liver disorders. Here, we summarize the function of STING in the development of NAFLD and present the current inhibitors and agonists targeting STING.

Effects of distribution of bone cement on clinical efficacy and secondary fracture after percutaneous kyphoplasty for osteoporotic vertebral compression fractures.

Objective: To investigate the effect of bilateral bone cement distribution on the clinical efficacy of percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral compression fracture (OVCF). Methods: According to strict inclusion and exclusion criteria, 109 cases of OVCF patients treated with bipedicular PKP were included in this study from August 2018 to July 2020. According to the distribution morphology of bilateral bone cement in vertebral body, patients were divided into 3 groups, including Group A (n = 44): bilateral diffuse type; Group B (n = 31): bilateral dense type; Group C (n = 34): mixed type. To assess the clinical and radiographic efficacy of the surgery, the visual analogue scale (VAS) score, Oswestry disability index (ODI) score, anterior vertebral height (AVH), anterior vertebral height ratio (AVHR) and local kyphotic angle (LKA) were recorded at preoperatively, 2 days after surgery and 1 year after surgery. Results: Compared with the preoperative recorded value, the VAS score, ODI score, AVH, AVHR and LKA of the three groups were significantly improved at 2 days after surgery and 1 year after surgery (p < 0.05). At 1 year after surgery, the VAS score of Group A was better than that of groups B and C (p < 0.05), and there were significantly differences in ODI score, AVH, and LKA between Group A and Group B (p < 0.05). Compared with other bone cement distribution patterns, the incidence of recompression in bilateral diffuse bone cement distribution pattern was lower (p < 0.05). Conclusion: In the mid-term follow-up of patients undergoing bipedicular PKP, diffuse and symmetrical distribution of bone cement can obtain better clinical improvement and lower the incidence of secondary compression.

Bone Cement and Pedicle Screw for the Treatment of Spinal Tumors with Spinal Cord Compression and Posterior Wall Defects.

OBJECTIVE: To compare the safety and efficacy of posterior internal fixation with open vertebroplasty (VP) and posterior internal fixation with open kyphoplasty (KP) in the treatment of metastatic epidural spinal cord compression (MESCC) with posterior wall destruction. METHODS: This retrospective study, conducted between January 2016 and May 2019, equally divided 60 patients with MESCC and posterior wall destruction into two groups based on the surgical method: open vertebroplasty with pedicle screw fixation (VP group) and open kyphoplasty with pedicle screw fixation (KP group). Visual analogue scale (VAS), SF-36 scores, middle vertebral height (MVH), and posterior vertebral height (PVH) were evaluated for the two groups preoperatively, postoperatively, and 1 year after surgery. Spinal Instability Neoplastic Score, Frankel grades and complications were recorded and evaluated. RESULTS: Five patients were excluded from the analysis, and our study cohort consisted of 55 adult patients who met the inclusion criteria. The VAS and SF-36 scores of these two groups of patients significantly improved, when compared with those before the surgery (P < 0.05). There were significant differences in total cost (8835 ± 1468 vs 9540 ± 053 USD) and cement volume (4.51 ± 0.96 ml vs 6.35 ± 1.09 ml) between two groups (P < 0.05). The MVH and PVH of these two groups of patients significantly improved, when compared with those before the surgery (P < 0.05). The MVH was significantly larger in the KP group than in the VP group postoperatively (20.15 ± 4.86 vs 17.70 ± 3.78, P < 0.05) and at the final follow-up (20.42 ± 5.59 vs 17.28 ± 3.23, P < 0.05). However, the PVH of the two groups did not significantly differ at the two postoperative follow-ups (P > 0.05). No significant differences were found in surgery time, time from surgery to discharge, blood loss and complications between both groups postoperatively (P > 0.05). CONCLUSION: In the short term, both approaches are effective and safe in patients with MESCC and posterior wall destruction. The posterior internal fixation with open VP may be a good choice of surgical method in patients with MESCC and posterior wall defects.

An Acid-Sensitive Bone Targeting Delivery System Carrying Acacetin Prevents Osteoporosis in Ovariectomized Mice.

One effective treatment for postmenopausal osteoporosis is to inhibit osteoclasts and subsequent bone resorption. In our study, we demonstrated that acacetin, a flavone with potential therapeutic effects in infections, cancers, and several metabolic disorders, inhibited osteoclast differentiation and bone resorption in vitro. For improving the efficacy of acacetin in vivo, we developed an acid-sensitive bone-targeting delivery system composed of an acid-sensitive linker (N-ε-maleimidocaproic acid hydrazide, EMCH) for ensuring an effective release of acacetin at the site of action and a hydrophilic aspartic acid hexapeptide ((Asp)6, D6) as the effective bone targeting agent. Our results revealed that Acacetin-EMCH-D6 specifically bound to the bone surface once administrated in vivo, prolonged the retention time in bone and released acacetin at the osteoclastic bone resorption sites where the acidity is higher. We further demonstrated that, in ovariectomy-induced osteoporosis mice, treatment with Acacetin-EMCH-D6 inhibited osteoclast formation and increased trabecular bone mass. On the contrary, neither acacetin nor EMCH-D6 with the same dosage alone showed significant anti-osteoporosis effects in vivo. Mechanistically, targeted delivery of acacetin to the bone resorption sites by Acacetin-EMCH-D6 inhibited autophagy through activating PI3K/AKT/mTOR pathway in osteoclasts, while the activation of autophagy by rapamycin partially reversed the inhibitory effects of acacetin in vitro and in vivo. In summary, our study, for the first time, showed that the acid-sensitive bone-targeting delivery system carrying acacetin was effective for the treatment of postmenopausal osteoporosis. Thus, targeted delivery of acacetin using Acacetin-EMCH-D6 to bone resorption sites is a promising therapy for osteoporosis.

A retrospective study on the efficacy and safety of bone cement in the treatment of endplate fractures.

Background: Endplate fractures is an important factor affecting the curative effect of percutaneous kyphoplasty for spinal fracture. The purpose of this study is to investigate the effect of sealing endplate fracture with bone cement on minimally invasive treatment of spinal fracture. Methods: A total of 98 patients with osteoporotic vertebral fractures combined with endplate fractures treated with bone cement surgery in our hospital were retrospectively analyzed. They were grouped according to whether bone cement was involved in the endplate fractures. Group A: bone cement was not only distributed in the fractured vertebral body, but also dispersed into the endplate fractures. Group B: bone cement was confined to the fractured vertebra but did not diffuse into the cracks of the endplate. The basic information, imaging changes of the fractured vertebral body, VAS score, ODI score, bone cement distribution and postoperative complications of the two groups were analyzed and compared. Results: The height of the injured vertebra and the kyphotic Cobb angle in the two groups were significantly improved after surgery, but the anterior height of the vertebra in group B was lower than that in group A and the kyphotic Cobb angle was higher than that in group A at the last follow-up (P < 0.05). VAS score and ODI score in 2 groups were significantly improved after operation (P < 0.05), but the VAS score and ODI score in group A were lower than those in group B at the last follow-up (P < 0.05). The incidence of bone cement leakage and adjacent vertebral fracture in group A was higher than that in group B (P < 0.05). Conclusion: Diffusion of bone cement into the cracks of the endplate may also restore and maintain the height of the injured vertebra, relieve pain and restore lumbar function. However, diffusion of bone cement into the cracks of the endplate can increase the incidence of cement leakage and adjacent vertebral fractures.