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Abstract Active artificial bone substitutes are crucial in bone repair and reconstruction. Calcium phosphate bone cement (CPC) is known for its biocompatibility, degradability, and ability to fill various shaped bone defects. However, its low osteoinductive capacity limits bone regeneration applications. Effectively integrating osteoinductive magnesium ions with CPC remains a challenge. Herein, we developed magnesium malate-modified CPC (MCPC). Incorporating 5% magnesium malate significantly enhances the compressive strength of CPC to (6.18 ± 0.49) MPa, reduces setting time and improves disintegration resistance. In vitro, MCPC steadily releases magnesium ions, promoting the proliferation of MC3T3-E1 cells without causing significant apoptosis, proving its biocompatibility. Molecularly, magnesium malate prompts macrophages to release prostaglandin E2 (PGE2) and synergistically stimulates dorsal root ganglion (DRG) neurons to synthesize and release calcitonin gene-related peptide (CGRP). The CGRP released by DRG neurons enhances the expression of the key osteogenic transcription factor Runt-related transcription factor-2 (RUNX2) in MC3T3-E1 cells, promoting osteogenesis. In vivo experiments using minipig vertebral bone defect model showed MCPC significantly increases the bone volume fraction, bone density, new bone formation, and proportion of mature bone in the defect area compared to CPC. Additionally, MCPC group exhibited significantly higher levels of osteogenesis and angiogenesis markers compared to CPC group, with no inflammation or necrosis observed in the hearts, livers, or kidneys, indicating its good biocompatibility. In conclusion, MCPC participates in the repair of bone defects in the complex post-fracture microenvironment through interactions among macrophages, DRG neurons, and osteoblasts. This demonstrates its significant potential for clinical application in bone defect repair.

The occurrence of bone metastasis is a grave medical concern that substantially impacts the quality of life in patients with cancer. The precise mechanisms underlying bone metastasis remain unclear despite extensive research efforts, and efficacious therapeutic interventions are currently lacking. The ability of osteoclasts to degrade the bone matrix makes them a crucial factor in the development of bone metastasis. Osteoclasts are implicated in several aspects of bone metastasis, encompassing the formation of premetastatic microenvironment, suppression of the immune system, and reactivation of quiescent tumor cells. Contemporary clinical interventions targeting osteoclasts have proven effective in mitigating bone-related symptoms in patients with cancer. This review comprehensively analyzes the mechanistic involvement of osteoclasts in bone metastasis, delineates potential therapeutic targets associated with osteoclasts, and explores clinical evidence regarding interventions targeting osteoclasts.

Mineralized collagen scaffold is one of the best choices for bone defects treatment, but weak mechanical strength is the main factor restricting its development. Recent studies demonstrated that despite being a fundamental form of mechanical stimulation in human activities, the impact of cyclic compressive stress on collagen mineralization remains unclear, with even less known about the dynamic mechanical mechanism. This study employed cyclic compressive stress to investigate its effect on collagen mineralization. The findings revealed that cyclic compressive strain promotes collagen mineralization by facilitating increased mineral penetration into the collagen and altering mineral morphology on the collagen surface. As the mineral volume fraction of mineralized collagen rises, its elastic modulus also increases. Additionally, the finite element simulation results proved that cyclic compressive stress can impact mineral distribution by affecting their transport and deposition, consequently influencing the stress distribution and regulating mechanical properties of mineralized collagen. Alterations in mechanical properties provide feedback on internal stress distribution, subsequently impacting mineral mineralization. This study achieves a closed-loop study on the mechanical regulated collagen mineralization, offers insight into the mechanism of collagen mineralization, paving the way for further exploration of biomineralization mechanisms and potentially inspiring novel approaches for the fabrication of mineralized collagen scaffolds.

This study aimed to investigate the effect of the transverse sinus (TS) stenosis (TSS) position caused by arachnoid granulation on patients with venous pulsatile tinnitus (VPT) and to further identify the types of TSS that are of therapeutic significance for patients. Multiphysics interaction models of six patients with moderate TSS caused by arachnoid granulation and virtual stent placement in TSS were reconstructed, including three patients with TSS located in the middle segment of the TS (group 1) and three patients with TTS in the middle and proximal involvement segment of the TS (group 2). The transient multiphysics interaction simulation method was applied to elucidate the differences in biomechanical and acoustic parameters between the two groups. The results revealed that the blood flow pattern at the TS and sigmoid sinus junction was significantly changed depending on the stenosis position. Preoperative patients had increased blood flow in the TSS region and TSS downstream where the blood flow impacted the vessel wall. In group 1, the postoperative blood flow pattern, average wall pressure, vessel wall vibration, and sound pressure level of the three patients were comparable to the preoperative state. However, the postoperative blood flow velocity decreased in group 2. The postoperative average wall pressure, vessel wall vibration, and sound pressure level of the three patients were significantly improved compared with the preoperative state. Intravascular intervention therapy should be considered for patients with moderate TSS caused by arachnoid granulations in the middle and proximal involvement segment of the TS. TSS might not be considered the cause of VPT symptoms in patients with moderate TSS caused by arachnoid granulation in the middle segment of the TS.

Craniotomy is an invasive operation with great trauma and many complications, and patients undergoing craniotomy should enter the ICU for monitoring and treatment. Based on electronic medical records (EMR), the discovery of high-risk multi-biomarkers rather than a single biomarker that may affect the length of ICU stay (LoICUS) can provide better decision-making or intervention suggestions for clinicians in ICU to reduce the high medical expenses of these patients and the medical burden as much as possible. The multi-biomarkers or medical decision rules can be discovered according to some interpretable predictive models, such as tree-based methods. Our study aimed to develop an interpretable framework based on real-world EMRs to predict the LoICUS and discover some high-risk medical rules of patients undergoing craniotomy. The EMR datasets of patients undergoing craniotomy in ICU were separated into preoperative and postoperative features. The paper proposes a framework called Rules-TabNet (RTN) based on the datasets. RTN is a rule-based classification model. High-risk medical rules can be discovered from RTN, and a risk analysis process is implemented to validate the rules discovered by RTN. The performance of the postoperative model was considerably better than that of the preoperative model. The postoperative RTN model had a better performance compared with the baseline model and achieved an accuracy of 0.76 and an AUC of 0.85 for the task. Twenty-four key decision rules that may have impact on the LoICUS of patients undergoing craniotomy are discovered and validated by our framework. The proposed postoperative RTN model in our framework can precisely predict whether the patients undergoing craniotomy are hospitalized for too long (more than 15 days) in the ICU. We also discovered and validated some key medical decision rules from our framework.

Modified macroporous structures and active osteogenic substances are necessary to overcome the limited bone regeneration capacity and low degradability of self-curing calcium phosphate cement (CPC). Curcumin (CUR), which possesses strong osteogenic activity and poor aqueous solubility/bioavailability, esterifies the side chains in hyaluronic acid (HA) to form a water-soluble CUR-HA macromolecule. In this study, we incorporated the CUR-HA and glucose microparticles (GMPs) into the CPC powder to fabricate the CUR-HA/GMP/CPC composite, which not only retained the good injectability and mechanical strength of bone cements, but also significantly increased the cement porosity and sustained release property of CUR-HA in vitro. CUR-HA incorporation greatly improved the differentiation ability of bone marrow mesenchymal stem cells (BMSCs) to osteoblasts by activating the RUNX family transcription factor 2/fibroblast growth factor 18 (RUNX2/FGF18) signaling pathway, increasing the expression of osteocalcin and enhancing the alkaline phosphatase activity. In addition, in vivo implantation of CUR-HA/GMP/CPC into femoral condyle defects dramatically accelerated the degradation rate of cement and boosted local vascularization and osteopontin protein expression, and consequently promoted rapid bone regeneration. Therefore, macroporous CPC based composite cement with CUR-HA shows a remarkable ability to repair bone defects and is a promising translational application of modified CPC in clinical practice.

Changes in the frequency composition of the human electroencephalogram are associated with the transitions to epileptic seizures. Cross-frequency coupling (CFC) is a measure of neural oscillations in different frequency bands and brain areas, and specifically phase–amplitude coupling (PAC), a form of CFC, can be used to characterize these dynamic transitions. In this study, we propose a method for seizure detection and prediction based on frequency domain analysis and PAC combined with machine learning. We analyzed two databases, the Siena Scalp EEG database and the CHB-MIT database, and used the frequency features and modulation index (MI) for time-dependent quantification. The extracted features were fed to a random forest classifier for classification and prediction. The seizure prediction horizon (SPH) was also analyzed based on the highest-performing band to maximize the time for intervention and treatment while ensuring the accuracy of the prediction. Under comprehensive consideration, the results demonstrate that better performance could be achieved at an interval length of 5 min with an average accuracy of 85.71% and 95.87% for the Siena Scalp EEG database and the CHB-MIT database, respectively. As for the adult database, the combination of PAC analysis and classification can be of significant help for seizure detection and prediction. It suggests that the rarely used SPH also has a major impact on seizure detection and prediction and further explorations for the application of PAC are needed.

Objective: To explore the influence of the blood flow-diameter scaling laws of QαD3, QαD2.7 and QαD7╱3 on the numerical simulation of fraction flow reserve based on CTA images and to find the optimal exponents. Methods: 1) 26 patients with coronary artery disease were screened according to the inclusion criteria; 2) Microcirculation resistance (Rm) was calculated under the 3, 2.7 and 7/3 power of the flow-diameter scaling law, which were recorded as 3Rm, 2.7Rm and 7/3Rm, respectively; 3) 3Rm, 2.7Rm and 7/3Rm were used as exit boundary conditions to simulate FFRCT, quoted as 3FFRCT, 2.7FFRCT and 7/3FFRCT, respectively; 4) The correlation and diagnostic performance between three kinds of FFRCT and FFR were analyzed. Results: The p-values of comparing 3Rm, 2.7Rm and 7/3Rm with FFR were 0.004, 0.005 and 0.010, respectively; the r value between 7/3FFRCT and FFR (0.96) was better than that of 3FFRCT (0.95) and 2.7FFRCT (0.95); the 95% LoA between 7/3FFRCT and FFR (-0.08~0.11) was smaller than that of 3FFRCT (-0.10~0.12) and 2.7FFRCT (-0.09~0.11); the AUC and accuracy of 7/3FFRCT [0.962 (0.805-0.999), 96.15%] were the same as those of 2.7FFRCT [0.962 (0.805-0.999), 96.15%] and better than those of 3FFRCT [0.944 (0.777-0.996), 92.3%]. The prediction threshold of 7/3FFRCT (0.791) was closer to 0.8 than that of 3FFRCT (0.816) and 2.7FFRCT (0.787). Conclusion: The blood flow-diameter scaling law affects the FFRCT simulation by influencing the exit boundary condition Rm of the calculation. With QαD7╱3, FFRCT had the highest diagnostic performance. The blood flow-diameter scaling law provides theoretical support for the blood flow distribution in the bifurcated vessel and improves the FFRCT model.

Aortic valve disease (AVD) often coexists with coronary artery disease (CAD), but whether and how the two diseases are correlated remains poorly understood. In this study, a zero–three dimensional (0-3D) multi-scale modeling method was developed to integrate coronary artery hemodynamics, aortic valve dynamics, coronary flow autoregulation mechanism, and systemic hemodynamics into a unique model system, thereby yielding a mathematical tool for quantifying the influences of aortic valve stenosis (AS) and aortic valve regurgitation (AR) on hemodynamics in large coronary arteries. The model was applied to simulate blood flows in six patient-specific left anterior descending coronary arteries (LADs) under various aortic valve conditions (i.e., control (free of AVD), AS, and AR). Obtained results showed that the space-averaged oscillatory shear index (SA-OSI) was significantly higher under the AS condition but lower under the AR condition in comparison with the control condition. Relatively, the overall magnitude of wall shear stress was less affected by AVD. Further data analysis revealed that AS induced the increase in OSI in LADs mainly through its role in augmenting the low-frequency components of coronary flow waveform. These findings imply that AS might increase the risk or progression of CAD by deteriorating the hemodynamic environment in coronary arteries.

Sigmoid sinus wall dehiscence (SSWD) is an important etiology of venous pulsatile tinnitus (VPT) and is treated by sigmoid sinus wall reconstruction (SSWR). This study aimed to investigate the therapeutic effects of the different degrees of SSWR and the prognostic effect in patients with VPT. Personalized models of three patients with SSWD (control), 3/4SSWD, 1/2SSWD, 1/4SSWD, and 0SSWD were reconstructed. A multiphysics interaction approach was applied to elucidate the biomechanical and acoustic changes. Results revealed that after SSWR, the average pressure of venous vessel on the SSWD region reduced by 33.70 ± 12.53%, 35.86 ± 12.39%, and 39.70 ± 12.45% (mean ± SD) in three patients with 3/4SSWD, 1/2SSWD, and 1/4SSWD. The maximum displacement of the SSWR region reduced by 25.91 ± 30.20%, 37.20 ± 31.47%, 52.60 ± 34.66%, and 79.35 ± 18.13% (mean ± SD) in three patients with 3/4SSWD, 1/2SSWD, 1/4SSWD, and 0SSWD, with a magnitude approximately 10−3 times that of the venous vessel in the SSWD region. The sound pressure level at the tympanum reduced by 23.72 ± 1.91%, 31.03 ± 14.40%, 45.62 ± 19.11%, and 128.46 ± 15.46% (mean ± SD). The SSWR region was still loaded with high stress in comparison to the surrounding region. The SSWR region of the temporal bone effectively shielded the high wall pressure and blocked the transmission of venous vessel vibration to the inner ear. Patients with inadequate SSWR still had residual VPT symptoms despite the remission of VPT symptoms. Complete SSWR could completely solve VPT issues. High-stress distribution of the SSWR region may be the cause of the recurrence of VPT symptoms.

Objective: After coronary artery bypass grafting (CABG) surgery, the main causes of poor instant patency of left internal mammary arteries (LIMAs) are competitive flow and anastomotic stenosis, but how to determine the cause of LIMA non-patency without interfering with the native coronary artery is still a difficult problem to be solved urgently.Methods: In this study, a 0D-3D coupled multiscaled CABG model of anastomotic stenosis and competitive flow was constructed. After calculation, the flow waveform of the LIMA was extracted, and the waveform shape, common clinical parameters (average flow, PI, and DF), and graft flow FFT ratio results (F0/H1 and F0/H2) were analyzed.Results: For LIMA, these three common clinical parameters did not differ significantly between the anastomotic stenosis group and competitive flow group. However, the waveform shape and FFT ratio (especially F0/H2) of the competitive flow group were significantly different from those of the anastomotic stenosis group. When the cause was competitive flow, there was systolic backflow, and F0/H2 was too high (>14.89). When the cause was anastomotic stenosis, the waveform maintained a bimodal state and F0/H2 was in a normal state (about 1.17).Conclusion: When poor instant patency of the LIMA is found after CABG, the causes can be determined by graft flow waveform shape and F0/H2.

Background: The underuse of invasive fraction flow reserve (FFR) in clinical practice has motivated research towards its non-invasive prediction. The early attempts relied on solving the incompressible three-dimensional Navier–Stokes equations in segmented coronary arteries. However, transient boundary condition has a high resource intensity in terms of computational time. Herein, a method for calculating FFR based on steady-state geometric multiscale (FFRSS) is proposed.Methods: A total of 154 moderately stenotic vessels (40–80% diameter stenosis) from 136 patients with stable angina were included in this study to validate the clinical diagnostic performance of FFRSS. The method was based on the coronary artery model segmented from the patient’s coronary CTA image. The average pressure was used as the boundary condition for the inlet, and the microcirculation resistance calculated by the coronary flow was used as the boundary condition for the outlet to calculate the patient-specific coronary hyperemia. Then, the flow velocity and pressure distribution and the FFRss of each coronary artery branch were calculated to evaluate the degree of myocardial ischemia caused by coronary stenosis. Also, the FFRSS and FFRCT of all patients were calculated, and the clinically measured FFR was used as the “gold standard” to verify the diagnostic performance of FFRSS and to compare the correlation between FFRSS and FFRCT.Results: According to the FFRSS calculation results of all patients, FFRSS and FFR have a good correlation (r = 0.68, p < 0.001). Similarly, the correlation of FFRSS and FFRCT demonstrated an r of 0.75 (95%CI: 0.67–0.72) (p < 0.001). On receiver-operating characteristic analysis, the optimal FFRSS cut point for FFR≤0.80 was 0.80 (AUC:0.85 [95% confidence interval: 0.79 to 0.90]; overall accuracy:88.3%). The overall sensitivity, specificity, PPV, and NPV for FFRSS ≤0.80 versus FFR ≤0.80 was 68.18% (95% CI: 52.4–81.4), 93.64% (95% CI: 87.3–97.4), 82.9%, and 91.1%, respectively.Conclusion: FFRSS is a reliable diagnostic index for myocardial ischemia. This method was similar to the closed-loop geometric multiscale calculation of FFR accuracy but improved the calculation efficiency. It also improved the clinical applicability of the non-invasive computational FFR model, helped the clinicians diagnose myocardial ischemia, and guided percutaneous coronary intervention.

Bone has a special structure that is both stiff and elastic, and the composition of bone confers it with an exceptional mechanical property. However, bone substitute materials that are made of the same hydroxyapatite (HA) and collagen do not offer the same mechanical properties. It is important for bionic bone preparation to understand the structure of bone and the mineralization process and factors. In this paper, the research on the mineralization of collagen is reviewed in terms of the mechanical properties in recent years. Firstly, the structure and mechanical properties of bone are analyzed, and the differences of bone in different parts are described. Then, different scaffolds for bone repair are suggested considering bone repair sites. Mineralized collagen seems to be a better option for new composite scaffolds. Last, the paper introduces the most common method to prepare mineralized collagen and summarizes the factors influencing collagen mineralization and methods to analyze its mechanical properties. In conclusion, mineralized collagen is thought to be an ideal bone substitute material because it promotes faster development. Among the factors that promote collagen mineralization, more attention should be given to the mechanical loading factors of bone.

In this paper, we study the dynamic behavior of a stochastic tungiasis model for public health education. First, the existence and uniqueness of global positive solution of stochastic models are proved. Secondly, by constructing Lyapunov function and using Ito^ formula, sufficient conditions for disease extinction and persistence in the stochastic model are proved. Thirdly, under the condition of disease persistence, the existence and uniqueness of an ergodic stationary distribution of the model is obtained. Finally, the importance of public health education in preventing the spread of tungiasis is illustrated through the combination of theoretical results and numerical simulation.

Mineralized collagen is the basic unit in hierarchically organized natural bone with different structures. Polyacrylic acid (PAA) and periodic fluid shear stress (FSS) are the most common chemical and physical means to induce intrafibrillar mineralization. In the present study, non-mineralized collagen, extrafibrillar mineralized (EM) collagen, intrafibrillar mineralized (IM) collagen, and hierarchical intrafibrillar mineralized (HIM) collagen induced by PAA and FSS were prepared, respectively. The physical and chemical properties of these mineralized collagens with different microstructures were systematically investigated afterwards. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) showed that mineralized collagen with different microstructures was prepared successfully. The pore density of the mineralized collagen scaffold is higher under the action of periodic FSS. Fourier transform infrared spectroscopy (FTIR) analysis showed the formation of the hydroxyapatite (HA) crystal. A significant improvement in the pore density, hydrophilicity, enzymatic stability, and thermal stability of the mineralized collagen indicated that the IM collagen under the action of periodic FSS was beneficial for maintaining collagen activity. HIM collagen fibers, which are prepared under the co-action of periodic FSS and sodium tripolyphosphate (TPP), may pave the way for new bone substitute material applications.