Despite advancements in colorectal cancer (CRC) treatment, the prognosis remains unfavorable for patients with distant liver metastasis. Fluorescence molecular imaging with specific probes is increasingly used to guide CRC surgical resection in real-time and treatment planning. Here, we demonstrate the targeted imaging capacity of an MPA-PEG(4)-N-3-Ang II probe labeled with near-infrared (NIR) fluorescent dye targeting the angiotensin II (Ang II) type 1 receptor (AGTR1) that is significantly upregulated in CRC. MPA-PEG(4)-N-3-Ang II was highly selective and specific to in vitro tumor cells and in vivo tumors in a mouse CRC xenograft model. The favorable ex vivo imaging and in vivo biodistribution of MPA-PEG(4)-N-3-Ang II afforded tumor-specific accumulation with low background and >10 contrast tumor-to-colorectal values in multiple subcutaneous CRC models at 8 h following injection. Biodistribution analysis confirmed the probe's high uptake in HT29 and HCT116 orthotopic and liver metastatic models of CRC with signal-to-noise ratio (SNR) values of tumor-to-colorectal and -liver fluorescence of 5.8 +/- 0.6, 5.3 +/- 0.7, and 2.7 +/- 0.5, 2.6 +/- 0.5, respectively, enabling high-contrast intraoperative tumor visualization for surgical navigation. Given its rapid tumor targeting, precise tumor boundary delineation, durable tumor retention and docking study, MPA-PEG(4)-N-3-Ang II is a promising high-contrast imaging agent for the clinical detection of CRC.

Introduction:Osteoarthritis (OA) is the most common degenerative joint disorder. Prior studies revealed that activation of NLRP3 inflammasome could promote the activation and secretion of interleukin-1β (IL-1β), which has an adverse effect on the progression of OA. Betulinic acid (BA) is a compound extract of birch, whether it can protect against OA and the mechanisms involved are still unknown.Materials and Methods:In vivo experiments, using gait analysis, ELISA, micro-CT, and scanning electron microscopy (SEM), histological staining, immunohistological (IHC) and immunofluorescence (IF) staining, and atomic force microscopy (AFM) to assess OA progression after intraperitoneal injection of 5 and 15 mg/kg BA in an OA mouse model. In vitro experiments, caspase-1, IL-1β, and the N-terminal fragment of gasdermin D (GSDMD-NT) were measured in bone marrow-derived macrophages (BMDMs) by using ELISA, western blot, and immunofluorescence staining.Results:We demonstrated that OA progression can be postponed with intraperitoneal injection of 5 and 15 mg/kg BA in an OA mouse model. Specifically, BA postponed DMM-induced cartilage deterioration, alleviated subchondral bone sclerosis, and relieved synovial inflammation. In vitro studies, the activated NLRP3 inflammasome produces mature IL-1β by facilitating the cleavage of pro-IL-1β, and BA could inhibit the activation of NLRP3 inflammasome in BMDMs.Conclusions:Taken together, our analyses revealed that BA attenuates OA via limiting NLRP3 inflammasome activation to decrease the IL-1β maturation and secretion.

Rheumatoid arthritis (RA) is an essential cause of labor loss and disability for people worldwide. Acanthopanax senticosus polysaccharide (ASPS) is one of the most important active components from A. senticosus , which exhibits various pharmacological activities such as antioxidation and immunomodulation. However, no studies have reported the application of ASPS in treating RA. This study aims to investigate the therapeutic effect of ASPS on RA and reveal its underlying mechanism. The potential therapeutic effect of ASPS against RA is initially verified in this study using the collagen‐induced arthritis model. Moreover, the protective benefits of ASPS are transmitted through the fecal microbiota and blocked by simultaneous antibiotic cocktail treatment, indicating that gut microbiota may be correlated with ASPS. The 16S rRNA sequencing using feces samples and untargeted UPLC‐MS metabolomics using serum samples further reveal that ASPS reprograms the arthritic progression triggered dysbiosis, enhances the expression of γ ‐glutamylcysteine (GGC) synthetase, and enriches the serum concentration of GGC. Furthermore, metabolites GGC is found to be able to effectively interrupt NLRP3 inflammasome activation via inhibiting ASC nucleation and therefore attenuate inflammatory arthritis. Taken together, this work highlights ASPS's therapeutic potential against RA, which mainly exhibits its effects via modulating gut microbiota and regulating GGC production.

The highly conserved MicroRNA-9 (miR-9) family consists of three members. We discovered that miR-9-1 deletion reduced mature miR-9 expression, causing 43% of the mice to display smaller size and postweaning lethality. MiR-9-1-deficient mice with growth defects experienced severe lymphopenia, but other blood cells were unaffected. The lymphopenia wasn’t due to defects in hematopoietic progenitors, as mutant bone marrow (BM) cells underwent normal lymphopoiesis after transplantation into wild-type recipients. Additionally, miR-9-1-deficient mice exhibited impaired osteoblastic bone formation, as mutant mesenchymal stem cells (MSCs) failed to differentiate into osteoblastic cells (OBs). RNA sequencing revealed reduced expression of master transcription factors for osteoblastic differentiation, Runt-related transcription factor 2 (Runx2) and Osterix (Osx), and genes related to collagen formation, extracellular matrix organization, and cell adhesion, in miR-9-1-deficient MSCs. Follistatin (Fst), an antagonist of bone morphogenetic proteins (BMPs), was found to be a direct target of miR-9-1. Its deficiency led to the up-regulation of Fst, inhibiting BMP signaling in MSCs, and reducing IL-7 and IGF-1. Thus, miR-9-1 controls osteoblastic regulation of lymphopoiesis by targeting the Fst/BMP/Smad signaling axis.

Abstract Background Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis. Methods A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by Micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, Enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis. Results C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits (P < 0.001), higher level of bone volume to tissue volume (BV/TV, P < 0.001), bone mineral density (BMD, P < 0.001), and a lower total porosity (P < 0.001). C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleation-induced oligomerization, suppressing the cleavage of caspase-1 (P < 0.05) and IL-1β (P < 0.05) stimulated by CoCrMo alloy particles. C3 and C4 also inhibited the generation of Gasdermin D-N-terminal fragment (GSDMD-NT) to regulate pyroptosis. Besides, C3 and C4 have a negative impact on osteoclast differentiation (P < 0.05) and its function (P < 0.05), affecting the podosome arrangement and morphologically normal podosome belts formation. Conclusion Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.

Abstract Background Aseptic Loosening (AL) following periprosthetic osteolysis is the main long-term complication after total joint arthroplasty (TJA). However, there is rare effective treatment except for revision surgery, which is costly and painful to the patients. In recent years, the ketone body β-hydroxybutyrate (BHB) has attracted much attention and has been proved to be beneficial in many chronic diseases. With respect to the studies on the ketone body β-hydroxybutyrate (BHB), its anti-inflammatory ability has been widely investigated. Although the ketone body β-hydroxybutyrate has been applied in many inflammatory diseases and has achieved considerable therapeutic efficacy, its effect on wear particles induced osteolysis is still unknown. Results In this work, we confirmed that the anti-inflammatory action of β-hydroxybutyrate (BHB) could be reappeared in CoCrMo alloy particles induced osteolysis. Mechanistically, the ketone body β-hydroxybutyrate (BHB) deactivated the activation of NLRP3 inflammasome triggered by CoCrMo alloy particles. Of note, this inhibitory action was independent of Gpr109a receptor as well as histone deacetylase (HDAC) suppression. Furthermore, given that butyrate, one kind of short chain fatty acid (SCFA) structurally related to β-hydroxybutyrate (BHB), has been reported to be an inhibitor of osteoclast, thus we also investigate the effect of β-hydroxybutyrate (BHB) on osteoclast, which was contributed to bone resorption. It was found that β-hydroxybutyrate (BHB) did not only affect osteoclast differentiation, but also inhibit its function. Unlike the inflammasome, the effect of β-hydroxybutyrate (BHB) on osteoclast may mainly rely on histone deacetylase (HDAC) suppression. Conclusions In general, our study showed that the alleviation of osteolysis may owe to the effect of β-hydroxybutyrate (BHB) on inflammasome deactivation and osteoclast. Graphical Abstract

Background: In patients with traumatic brain injury (TBI) combined with long bone fracture, the fracture healing is always faster than that of patients with single fracture, which is characterized by more callus growth at the fracture site and even ectopic ossification. Exosomes are nanoscale membrane vesicles secreted by cells, which contain cell-specific proteins, miRNAs, and mRNAs. Methods: In this study, we used exosomes as the entry point to explore the mechanism of brain trauma promoting fracture healing. We established a model of tibia fracture with TBI in mice to observe the callus growth and expression of osteogenic factors at the fracture site. Blood samples of model mice were further collected, exosomes in plasma were extracted by ultra-centrifugation method, and then identified and acted on osteoblasts cultured in vitro. The effects of exosomes on osteoblast differentiation at the cell, protein and gene levels were investigated by Western Blot and q-PCR, respectively. Furthermore, miRNA sequencing of exosomes was performed to identify a pattern of miRNAs that were present at increased or decreased levels. Results: The results suggested that plasma exosomes after TBI had the ability to promote the proliferation and differentiation of osteoblasts, which might be due to the increased expression of osteoblast-related miRNA in exosomes. They were transmitted to the osteoblasts at the fracture site, so as to achieve the role of promoting osteogenic differentiation. Conclusion: The TBI-derived exosomes may have potential applications for promoting fracture healing in future. The Translational Potential of this Article: Plasma exosomes early after TBI have the ability to promote osteoblast proliferation and differentiation. The mechanism may be achieved by miRNA in exosomes. Plasma exosomes may be used as breakthrough clinical treatment for delayed or non-union fractures.

Rheumatoid arthritis (RA) is an autoimmune disease that progresses from inflammation to cartilage destruction. Inspired by the similar characteristics of inflammatory granulation tissue to those of tumors, the newly emerged tumor therapy called thermochemotherapy is proposed to treat RA. Meanwhile, the repair of cartilage injury via tissue engineering is paid attention simultaneously. A first‐line antirheumatic drug (MTX; methotrexate) and transforming growth factor β1 (TGF‐β1) are loaded in nano‐Fe 3 O 4 composite chitosan‐polyolefin to construct a multifunctional hydrogel (DN‐Fe‐MTX‐TGFβ1). The mechanical properties of the hydrogel are equivalent to that of articular cartilage to guarantee its role as a scaffold. A long‐term release ability and the magnetocaloric properties of the hydrogel assure its effect to provide sustained local thermochemotherapy. The effective ability of the hydrogel for both anti‐inflammation and cartilage repair is demonstrated. This work indicates a promising way to combine thermochemotherapy and tissue engineering for the effective treatment of RA for the first time.

Background Inflammatory osteolysis after total joint replacement (TJR) may cause implant failure, periprosthetic fractures, and be a severe threat to global public health. Our previous studies demonstrated that melatonin had a therapeutic effect on wear-particles induced osteolysis. Gut microbiota is closely related to bone homeostasis, and has been proven to be affected by melatonin. However, whether melatonin could play its anti-osteolysis effects through reprogramming gut microbiota remains elusive. Results Here, we demonstrated that melatonin could alleviate Ti-particles induced osteolysis, while this therapeutic effect was blocked by antibiotic cocktail treatment. Interestingly, transplantation of fecal microbiota from mice treated with melatonin reappeared the same beneficial effect. Analysis of the 16S rRNA revealed that melatonin could reverse dysbacteriosis triggered by osteolysis, and elevate the relative abundance of some short chain fatty acid (SCFA) producing bacteria. Moreover, butyrate was enriched by exogenous melatonin administration, while acetate and propionate did not show an evident difference. This was consistent with the results of the metagenomic approach (PICRUSt2) analysis, which revealed a general increase in the synthetic enzymes of butyrate. More importantly, direct supplementation of butyrate could also recapitulate the anti-osteolysis effect of melatonin. Further analysis identified that butyrate alleviated osteolysis via activating its receptor GPR109A, and thus to suppress the activation of NLRP3 inflammasome triggered by Ti-particles. Conclusions Taken together, our results suggested that the benefits of melatonin mainly depend on the ability of modulating gut microbiota and regulating butyrate production. Graphic Abstract

Background The clavicular hook plate is an accepted surgical procedure for distal clavicle fractures. The relationship of the characteristics of the hook plate, acromioclavicular joint and acromion morphology, and clinical outcome has remained poorly understood. We reviewed the clinical records of patients who had distal clavicle fractures with different lateral acromion angles treated using a clavicle hook plate and evaluated their clinical outcomes with respect to shoulder pain and acromial morphology. Methods We retrospectively reviewed 102 patients with distal clavicle fractures treated with hook plates at our institution from 2010 to 2017. They were divided into four groups according to lateral acromion angle on shoulder AP view X-rays. The angle was defined as the incline angle between the superior surface of distal clavicle and the inferior facet of acromion on coronal plane. We reviewed their clinical features, including Neer’s impingement sign, MRI findings, and outcomes using Japanese Orthopaedic Association Scores. The mean follow-up was 25.5 months (range, 24 to 28 months). Results All patients in group D (large lateral acromion angle (α) > 40°, acromion coronal angle (β) < 60°) complained of postoperative symptoms. Compared to those with common lateral acromion angle, the incidence of postoperative impingement in group D was undoubtedly much higher (100%). Japanese Orthopaedic Association (JOA) scores in group D were worse at 3 months post-surgery, 3 months post plate removal, and at the last follow-up despite a slightly earlier removal in this group. Conclusion Lateral acromion angle appears to be an important factor in the development of postoperative pain and worse outcomes (JOA scores) in patients treated with the hook plate. The incidence of subacromial impingement and rotator cuff lesion (RCL) increased with the α angle. Early limited mobility and removal of the implant may improve the prognosis and resolve the postoperative shoulder pain. Study design Retrospective review, level of evidence IV.

Objective Hemorrhagic arthritis (HA) is a common disease of the musculoskeletal system caused by hemorrhage in the joints, leading to damages in the synovium and cartilage. Pure platelet-rich plasma (P-PRP) has been recently demonstrated to have anti-inflammatory and regenerative potential attributed to the various cytokines and growth factors that it contains. The aim of this study was to investigate the efficacy of P-PRP for the treatment of patients with mild and severe HA. Methods Autologous blood was withdrawn from the New Zealand rabbits and injected into their left and right knees to establish the HA models. The injection was performed once a week and repeated for 8 weeks to establish the mild HA models and for 16 weeks to establish the severe HA models. One hundred microliters of P-PRP was injected into the left HA knees, and the same volume of sterile 0.9% saline was injected into the corresponding right knees. MRI examination, H&E staining, and toluidine blue staining were respectively performed to evaluate the histological difference of synovium and cartilage between the P-PRP treated and untreated mild and severe groups. Normal knees were set as the control group. Results Pathological changes including tissue color, joint effusion, and synovium inflammation in the mild treated group were less severe compared to the other three experimental groups based on gross observation. The difference of joint cavity diameter between the mild treated and untreated groups was 2.67 ± 0.75 mm (95%CI, 1.20–4.14 mm), which was significantly larger than that between the severe treated and untreated groups (1.50 mm ± 0.48, 95%CI, 0.56–2.44 mm) (mean difference in joint cavity, 1.17 ± 0.32 mm; 95%CI, 0.49–1.85 mm; P < 0.01). MRI examination showed the synovitis and bone marrow edema were less severe in the treated groups compared to the corresponding untreated groups. H&E staining of the synovium suggested that the inflammation was much less and the cell number was much smaller in the treated than in the untreated HA knees in regard to both the mild and severe groups. The mean difference of cell number between the mild treated and untreated groups was 307.40 ± 14.23 (95%CI, 241.54–343.26; P < 0.001), which was 699.20 ± 82.80 (95%CI, 508.26–890.14; P < 0.001) between the severe treated and untreated groups. H&E staining and toluidine blue staining of the cartilage exhibited an obvious amelioration of inflammation and cartilage matrix loss after being treated with P-PRP for both groups, especially the mild group. Conclusions P-PRP was effective for the treatment of HA by inhibiting the development of synovitis and cartilage matrix loss in the affected joints, which was particularly obvious in the early-stage HA. This study supports the view that there is a great potential of P-PRP to be considered and used as a non-operative treatment for hemorrhagic arthritis at its early stage.

目的:研究青少年L5滑脱患者的脊柱-骨盆矢状面形态,分析不同类型滑脱的矢状面参数特征及临床意义.方法:回顾性分析2010年1月～2019年12月在我院就诊的资料完整的青少年L5滑脱患者36例,男、女各18例,平均年龄14.1±2.5岁(10～18岁);按照Wiltse滑脱分型分为峡部裂组28例和发育不良组8例;按照Meyerding分度标准分为轻度滑脱组32例(Ⅰ度29例、Ⅱ度3例)和重度滑脱组4例(Ⅲ度2例、Ⅳ度2例).在站立位全长脊柱侧位片上测量脊柱-骨盆矢状面参数.其中滑移参数包括:滑脱率(slip rate,SR)、滑脱角(slip angle,SA);骨盆矢状面参数包括:骨盆入射角(pelvic incidence,PI)、骨盆倾斜角(pelvic tilt,PT)、腰骶角(lumbosacral angle,LSA)、骶骨平台角(sacral table angle,STA);脊柱矢状面参数包括:胸椎后凸角(thoracic kyphosis,TK)、腰椎前凸角(lumbar lordosis,LL)和矢状垂直偏距(sagittal vertical axis,SVA).对比研究峡部裂组和发育不良组以及轻度和重度滑脱患者的脊柱-骨盆矢状面参数特点和相关临床意义.结果:峡部裂组SR=(13.7±8.1)％,PT=15.7°±8.3°,LSA=105.9°±11.8°,STA=102.8°±6.5°;发育不良组SR=(42.4±27.8)％,PT=34.2°±9.6°,LSA=78.7°±11.2°,STA=76.4°±9.5°;两组相比具有显著的统计学差异(P.＜0.05).轻度滑脱组SR=(14.4±7.8)％,PT=18.1°±10.4°,LSA=102.1°±15.5°,STA=99.9°±10.8°;重度滑脱组SR=(65.0±19.6)％,PT=33.9°±11.1°,LSA=77.4°±6.7°,STA=77.7°±8.8°,两组相比具有显著的统计学差异(P＜0.05).峡部裂组SA=2.6°±13.1°,PI=54.6°±9.0°,TK =23.5°±15.5°,LL=-53.0°±18.3°;发育不良组SA=1 1.2°±10.5°,PI=60.8°±14.5°,TK=21.5°±14.3°,LL=-45.3°±15.9°;两组相比无统计学差异(P＞0.05).轻度滑脱组SA=3.3°±12.6°,PI=55.3°±10.4°,TK=24.0°±13.1°,LL=-52.7°±17.4°;重度滑脱组SA=14.5°±12.8°,PI=61.0°±12.2°,TK=14.8°±3.7°,LL=-40.0°±20.0°,两组相比无统计学差异(P＞0.05).结论:青少年L5滑脱中,发育不良性多为重度滑脱,而峡部裂性多为轻度滑脱.发育不良性重度滑脱容易出现矢状面失衡和滑脱进展,其脊柱-骨盆矢状面呈现躯干前倾,骶骨垂直和骨盆后倾的形态.

Background: Discoid lateral meniscus (DLM) has long been observed and diagnosed in clinic, whereas its etiology and pathology remain unclear. The aim of this study is to investigate the difference of ultrastructure as regard to cell function and protein expression profile between DLM and normal-shaped lateral meniscus (NLM). Methods and Results: By using the iIsobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was performed to detect the difference of protein profiling between DLM and NLM. Expression of the representative differentially expressed proteins (DEPs) was validated by western blotting and immunohistochemistry (IHC) assays. Gene ontology (GO) enrichment analysis and predicted interaction network were conducted to investigate the biological processes involved. Meanwhile, meniscus cells were isolated from DLM and NLM tissues and processed for proliferation assay and gene expression analysis. Findings: 1314 proteins in total were identified in the inner 2/3 part of DLM and normal-shaped lateral meniscus (NLM) specimens. 21 of them were up-regulated while 4 were down-regulated in the DLM group. Western blotting and IHC assays validated increased Expression expression of fibronectin (FN), periostin (POSTN) and, type IV collagenase (MMP-2) and while decreased expression of hemoglobin subunit beta (HBB) were validated byin DLM compared to those in NLM. western blotting and immunohistochemistry (IHC) assays. Gene ontology (GO) enrichment analysis and predicted interaction network of the differentially expressed proteins (DEPs) indicated that the DEPs were primarily involved in the molecular function of "binding" and "transporting", mediating biological processes such as extracellular matrix (ECM) remolding, response to stimulus and angiogenesis. Proliferation potential Meniscus cells fromof DLM cells was demonstrated to be higher proliferation potential than those fromthat of NLM cells. Compared to mRNA expression in NLM cells, eExpression level of collagen I and aggrecan mRNAs were higher while expressionthat of collagen II and osteocalcin (OC) mRNAs were lower in DLM cells than in NLM cells. No significant difference of mRNA expression of FN, integrin V, integrin 1, POSTN, MMP-2 and HBB was observed between two groups. Interpretation: Ultrastructure of DLM was quite different from that of NLM. Cell proliferation potential and mRNA expression of aggrecan and collagen I were increased in DLM, synthesis of DEPs such as FN, POSTN and MMP-2 were increased while HBB was decreased. In addition, biological processes such as ECM remolding, response to stimulus and angiogenesis had been abnormally activated in DLM.Funding Statement: This study was supported by the National Natural Science Foundations of China (81501852, 81472046, 81271942, 81802200, 81472045), by the Distinguished Youth Foundation of Peking Union Medical College Hospital (JQ201506), by the Beijing nova program (2016), by the Central Level Public Interest Program for Scientific Research Institute (No.13, 2015), by the Basic Scientific Research Business Project of Central Public-interest Scientific Institution of Chinese Academy of Medical Sciences (2015PT320013), and by the National Key R&D program of China (2018YFF0301105). Declaration of Interests: All the authors declare no conflicts of interests.Ethics Approval Statement: Written informed consents were received from all the patients prior to their participation in the study. This study was approved by the Ethical Committee of Clinical Investigation of PUMCH.

Department of Orthopaedic Surgery, Peking Union Medical College and Chinese A Shuaifuyuan, Beijing 100730, China. E-ma 126.com; Tel: +86-10-6915-2800; +86-10-69 Key Laboratory for Biomechanics and Me School of Biological Science and Medical 100191, China Department of Orthopaedic Surgery, Th University, Suzhou, Jiangsu, China Central Laboratory, Peking Union Medical College and Chinese Academy of Medica 100730, China Beijing Key Laboratory for Genetic Resea Shuaifuyuan, Beijing 100730, China Cite this: RSC Adv., 2017, 7, 4253

This study provides a promising approach to improve angiogenesis and osteogenesis in an ischemic environment.

Being beneficial in restoring stability and stiffness of osteoporotic vertebraes, cement augmentation techniques including vertebroplasty (VP) and kyphoplasty (KP) have been demonstrated to be effective for the treatment of patients with osteoporotic vertebral compressive fractures (OVCFs). However, it is unclear the influence of cement augmentation on the dynamics of pathologic and adjacent vertebraes under vibration condition. In this study, we developed a three-dimensional (3D) finite-element (FE) model of the spinal T12-Pelvis segment by using CT scan data of lumbar spine of an adult woman with no physical abnormalities. By modulating model parameters we further simulated osteoporotic conditions of the T12-Pelvis FE model with or without polymethyl methacrylate (PMMA) augmentation. Dynamic characteristics of the osteoporotic T12-Pelvis model were detected at the first order of vertical resonant frequencies (FOVRFs) under vertical vibration, which included vertical axial displacements, anteroposterior (AP) displacements and rotational angles of each vertebrae and intervertebral disc (IVD). The results showed that axial and AP displacements of both vertebraes and IVDs decreased in some point after PMMA augmentation. Axial displacements of the L4-L5 motion segment decreased most significantly and the changing ratios ranged from 20% to 30%. AP displacements of L5, D1-2 (the IVD between vertebraes L1 and L2) and D3-4 reduced most obviously after 1, 2 or 3 levels PMMA augmentation. No significant difference of axial or AP displacements of each vertebrae and IVD was observed between one-level and multilevel PMMA augmentation. Thus, we demonstrated that PMMA augmentation could reduce vertical axial and AP deformations of the osteoporotic lumbar motion segments under vertical vibration, especially for the inferior adjacent motion segments. However, the influence of the number of vertebraes with PMMA augmentation on the dynamics of osteoporotic lumbar spine was indistinctive.

Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration.