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Nacre of Pinctada maxima is a natural biomineralized matrix, appeared 7 million years before hominins. In this study, we converted nacre into a self-setting particle bound with multiple calcium orthophosphates that reassemble mammals’ bone mineral matrices for induction of bone regeneration. The nacre-based calcium orthophosphates composite (NCOC) exhibited a compression strength of 10 MPa, which is superior to human trabecular bone. In vitro bioactivity tests revealed the formation of apatite with nano-porous flake-like crystals on the composite surface that mimic HA structure of a human bone matrix. NCOC demonstrated efficient attachment and proliferation of osteoblast cells, promoting osteogenic differentiation by increasing expressions of RUNX2 and OPN. In vivo studies using rabbit back fascia demonstrated that NCOC displays better bone healing and biocompatibility than conventional bone substitute apatite in critical bone defect models. The degradation of calcium carbonate crystal in vivo does not compromise structural integrity of NCOC. Overall, our data showed that NCOC produced through self-setting reactions, presents advantages such as accelerated biodegradation and osteostimulative properties, making it a promising bone substitute for effective bone regeneration.

Background: Tendons are the force transferring tissue that enable joint movement. Excessive mechanical loading is commonly considered as a primary factor causing tendinopathy, however, an increasing body of evidence supports the hypothesis that overloading creates microdamage of collagen fibers resulting in a localized decreased loading on the cell population within the damaged site. Heterotopic ossification is a complication of late stage tendinopathy, which can significantly affect the mechanical properties and homeostasis of the tendon. Here, we the examine the effect of mechanical underloading on tendon ossification and investigate its underlying molecular mechanism. Method: Rabbit Achilles tendons were dissected and cultured in an underloading environment (3% cyclic tensile stain,0.25 ​Hz, 8 ​h/day) for either 10, 15 or 20 days. Using isolated tendon-derived stem cells (TDSCs) 3D constructs were generated, cultured and subjected to an underloading environment for 6 days. Histological assessments were performed to evaluate the structure of the 3D constructs; qPCR and immunohistochemistry were employed to study TDSC differentiation and the β-catenin signal pathway was investigated by Western blotting. Mechanical testing was used to determine ability of the tendon to withstand force generation. Result: Tendons cultured for extended times in an environment of underloading showed progressive heterotopic ossification and a reduction in biomechanical strength. qPCR revealed that 3D TDSCs constructs cultured in an underloading environment exhibited increased expression of several osteogenic genes: these include RUNX2, ALP and osteocalcin in comparison to tenogenic differentiation markers (scleraxis and tenomodulin). Immunohistochemical analysis further confirmed high osteocalcin production in 3D TDSCs constructs subject to underloading. Western blotting of TDSC constructs revealed that β-catenin accumulation and translocation were associated with an increase in phosphorylation at Ser552 and decrease phosphorylation at Ser33. Conclusion: These findings unveil a potential mechanism for heterotopic ossification in tendinopathy due to the underloading of TDSCs at the damage sites, and also that β-catenin could be a potential target for treating heterotopic ossification in tendons. The Translational potential: Tendon heterotopic ossification detrimentally affect quality of life especially for those who has atheletic career. This study reveals the possible mechanism of heterotpic ossification in tendon related to mechanical loading. This study provided the possible to develop a mechanical stimulation protocol for preventive and therapeutic purpose for tendon heterotopic ossification.

Abstract Background Botulinum toxin (Botox) injection is in widespread clinical use for the treatment of muscle spasms and tendinopathy but the mechanism of action is poorly understood. Hypothesis We hypothesised that the reduction of patellar-tendon mechanical-loading following intra-muscular injection of Botox results in tendon atrophy that is at least in part mediated by the induction of senescence of tendon-derived stem cells (TDSCs). Study design Controlled laboratory study Methods A total of 36 mice were randomly divided into 2 groups (18 Botox-injected and 18 vehicle-only control). Mice were injected into the right vastus lateralis of quadriceps muscles either with Botox (to induce mechanical stress deprivation of the patellar tendon) or with normal saline as a control. At 2 weeks post-injection, animals were euthanized prior to tissues being harvested for either evaluation of tendon morphology or in vitro studies. TDSCs were isolated by cell-sorting prior to determination of viability, differentiation capacity or the presence of senescence markers, as well as assessing their response to mechanical loading in a bioreactor. Finally, to examine the mechanism of tendon atrophy in vitro, the PTEN/AKT-mediated cell senescence pathway was evaluated in TDSCs from both groups. Results Two weeks after Botox injection, patellar tendons displayed several atrophic features including tissue volume reduction, collagen fibre misalignment and increased degradation. A colony formation assay revealed a significantly reduced number of colony forming units of TDSCs in the Botox-injected group compared to controls. Multipotent differentiation capacities of TDSCs were also diminished after Botox injection. To examine if mechanically deprived TDSC are capable of forming tendon tissue, we used an isolated bioreactor system to culture tendon constructs using TDSC. These results showed that TDSCs from the Botox-treated group failed to restore tenogenic differentiation after appropriate mechanical loading. Examination of the signalling pathway revealed that injection of Botox into quadriceps muscles causes PTEN/AKT-mediated cell senescence of TDSCs. Conclusion Intramuscular injection of Botox interferes with tendon homeostasis by inducing tendon atrophy and senescence of TDSCs. Botox injection may have long-term adverse consequences for the treatment of tendinopathy. Clinical relevance Intramuscular Botox injection for tendinopathy or tendon injury could result in adverse effects in human tendons and evaluation of its long-term efficacy is warranted.

Objectives: Residual hip dysplasia is the most common underlying condition leading to secondary osteoarthritis (OA) of the hip. Subchondral bone alterations in OA secondary to hip dysplasia (HD-OA) are poorly investigated. The aim of the present study was to analyse the microarchitecture, bone remodelling and pathological alterations of subchondral bone in femoral heads from patients with HD-OA. Methods: Subchondral bone specimens were extracted from both weight-bearing and non–weight-bearing regions of femoral heads from 20 patients with HD-OA and 20 patients with osteoporotic femoral neck fracture, during hip replacement surgery. Micro-CT and histological examination were performed to assess the microarchitecture and histopathological changes. Results: The weight-bearing subchondral bone showed significantly more sclerotic microarchitecture and higher bone remodelling level in HD-OA as compared with osteoporosis. In the non–weight-bearing region, the two diseases shared similar microarchitectural characteristics, but higher bone remodelling level was detected in HD-OA. Distinct regional differences were observed in HD-OA, whereas the two regions exhibited similar characteristics in osteoporosis. In addition, HD-OA displayed more serious pathological alterations, including subchondral bone cyst, metaplastic cartilaginous tissue, bone marrow oedema and fibrous tissue, especially in the weight-bearing region. Conclusions: Osteoarthritic deteriorations of subchondral bone induced by hip dysplasia spread throughout the whole joint, but exhibit region-dependent variations, with the weight-bearing region more seriously affected. Biomechanical stress might exert a pivotal impact on subchondral bone homeostasis in hip dysplasia. The translational potential of this article: The histomorphometric findings in the project indicate an early intervention for the development of hip dysplasia in clinic.

Summary: Obesity-related osteoarthritis (OA) is a complex, multifactorial condition that can cause significant impact on patients’ quality of life. Whilst chronic inflammation, adipocytokines and metabolic factors are considered to be important pathogenic factors in obesity related OA, there has been limited investigation into the biomechanical impact of obesity on OA development. This review aims to demonstrate that mechanical factors are the major pathological cause of obesity-related OA. The effect of obesity on pathological changes to the osteochondral unit and surrounding connective tissues in OA is summarized, as well as the impact of obesity-related excessive and abnormal joint loading, concomitant joint malalignment and muscle weakness. An integrated therapeutic strategy based on this multi-factorial presentation is presented, to assist in the management of obesity related OA. The translational potential of this article: Despite the high prevalence of obesity-related OA, there is no specific guideline available for obesity-related OA management. In this review, we demonstrated the pathological changes of obesity-related OA and summarized the impact of biomechanical factors by proposing a hypothetical model of obesity-related OA change. Therapeutic strategies based on adjusting abnormal mechanical effects are presented to assist in the management of obesity-related OA.

Background: Endometriosis is an under-recognised and often misdiagnosed chronic disease that affects one in ten women. It occurs when cells similar to those that line a uterus grow in other parts of the body, usually around the pelvis. The current gold standard for diagnosis of endometriosis is direct visualisation by histological analysis which can only be achieved by an invasive laparoscopy. It is estimated 176 million women and girls around the world are living with endometriosis. The condition costs $7.7 billion a year in direct medical expenses and lost productivity in Australia alone. Aim: To analyse a series of plasma samples from patients with clinically diagnosed endometriosis, others with gynaecological symptoms without endometriosis and otherwise healthy controls to identify biomarkers to differentiate these groups and potentially aid in endometriosis diagnosis. Method: A standard proteomic discovery workflow was used to search for unique biomarkers of endometriosis. Initially, pooled plasma samples from three distinct groups of patients were tested. The first group had symptoms of endometriosis with a laparoscopic/histology confirmed diagnosis. The second group also had symptoms, but the laparoscopy confirmed no endometriosis or an alternate diagnosis. The third group were healthy matched controls. The pooled plasma samples were quantitatively profiled against each other with a triplicate experiment. A validation of the biomarkers identified as significant in the discovery phase, was then undertaken in a larger clinical cohort (n=902) using a targeted multiplex mass spectrometry assay using multiple reaction monitoring (MRM). Statistical analyses were caried out using Stata and logistical regression was used to evaluate associations of biomarkers with binary clinical outcomes. Results: Out of the 943 proteins identified with [Formula: see text] 2 significant peptides in the initial discovery workflow, 47 were determined as being differential biomarkers across the three clinical groups. The derived targeted MRM assay was tested on the clinical validation cohort, and a number of candidate biomarkers were significantly associated, thereby indicating their potential for use in the diagnosis of endometriosis.

Brushless direct current (BLDC) permanent magnet (PM) synchronous motors are in high demand for ventilator applications owing to their high speed, high efficiency, and other significant features. However, it has become an important problem in eddy current loss calculations with high-speed motors, which leads to low motor (ventilator) life and PM demagnetization. This paper focuses on the eddy current loss calculation and the structure improvement design for the two-pole 90 W, 47,000 r/min toothless BLDC motor. First, the influencing factors of eddy current loss are comprehensively investigated, and a multiparameter improvement methodology is proposed accordingly. Second, by finite element analysis (FEA), the effective winding length ratio and the number of parallel wires were mainly researched for the winding, and the influence on the eddy current loss and the efficiency was determined, providing a reference for BLDC high-speed motors. This study has resulted in a 34.75% reduction in the winding losses, and a 4.6% increase in the efficiency of the improved model compared with the original design. Third, the new rotor structure is proposed, saving PM volume 15% more than original. THD of gap flux density is decreased 20.97%; the eddy current loss in the new rotor is decreased 22% more than original. Furthermore, by coupling simulation of the magnetic–thermal field, the maximum temperature of winding of the improved model is 13.4% lower than that of the original model at the thermal steady state. Finally, the electromagnetic and thermal properties simulation results were verified by testing the prototype. It is of great significance to the structure design and efficiency improvement of the BLDC high-speed motor.

Diabetic neuropathy (DN) is one of the chronic complications of diabetes which can cause severe harm to patients. In order to determine the key genes and pathways related to the pathogenesis of DN, we downloaded the microarray data set GSE27382 from Gene Expression Omnibus (GEO) and adopted bioinformatics methods for comprehensive analysis, including functional enrichment, construction of PPI networks, central genes screening, TFs-target interaction analysis, and evaluation of immune infiltration characteristics. Finally, we examined quantitative real- time PCR (qPCR) to validate the expression of hub genes. A total of 318 differentially expressed genes (DEGs) were identified, among which 125 upregulated DEGs were enriched in the mitotic nuclear division, extracellular region, immunoglobulin receptor binding, and p53 signaling pathway, while 193 downregulated DEGs were enriched in ion transport, membrane, synapse, sodium channel activity, and retrograde endocannabinoid signaling. GSEA plots showed that condensed nuclear chromosome kinetochore were the most significant enriched gene set positively correlated with the DN group. Importantly, we identified five central genes (Birc5, Bub1, Cdk1, Ccnb2, and Ccnb1), and KEGG pathway analysis showed that the five hub genes were focused on progesterone-mediated oocyte maturation, cell cycle, and p53 signaling pathway. The proportion of immune cells from DN tissue and normal group showed significant individual differences. In DN samples, T cells CD4 memory resting and dendritic cells resting accounted for a higher proportion, and macrophage M2 accounted for a lower proportion. In addition, all five central genes showed consistent correlation with immune cell infiltration levels. qPCR showed the same expression trend of five central genes as in our analysis. Our research identified key genes related to differential genes and immune infiltration related to the pathogenesis of DN and provided new diagnostic and potential therapeutic targets for DN.