Cefazolin/BMP-2-Loaded Mesoporous Silica Nanoparticles for the Repair of Open Fractures with Bone Defects.

The study aimed to explore the feasibility of a nanodrug delivery system to treat open fractures with bone defects. We developed a cefazolin (Cef)/bone morphogenetic protein 2 (BMP-2)@mesoporous silica nanoparticle (MSN) delivery system; meanwhile, Cef/MBP-2@ poly(lactic-co-glycolic acid) (PLGA) was also developed as control. For the purpose of determining the osteogenic and anti-inflammatory actions of the nanodelivery system, we cultured bone marrow mesenchymal stem cells (BMSCs) and constructed a bone defect mouse model to evaluate its clinical efficacy. After physicochemical property testing, we determined that MSN had good stability and did not easily accumulate or precipitate and it could effectively prolong the Cef's half-life by nearly eight times. In BMSCs, we found that compared with the PLGA delivery system, MSNs better penetrated into the bone tissue, thus effectively increasing BMSCs' proliferation and migration ability to facilitate bone defect repair. Furthermore, the MSN delivery system could improve BMSCs' mineralization indexes (alkaline phosphatase [ALP], osteocalcin [OCN], and collagen I [Col I]) to effectively improve its osteogenic ability. Moreover, the MSN delivery system could inhibit inflammation in bone defect mice, which was mainly reflected in its ability to reduce the release of IL-1ß and IL-4 and increase IL-10 levels; it could also effectively reduce apoptosis of CD4+ and CD8+ T cells, thus improving their immune function. Furthermore, the percentage of new bones, bone mineral density, trabecular volume, and trabecular numbers in the fracture region were improved in mice treated with MSN, which allowed better repair of bone defects. Hence, Cef/BMP-2@MSN may be feasible for open fractures with bone defects.

Distal Humerus Morphological Analysis of Chinese Individuals: A Statistical Shape Modeling Approach.

OBJECTIVE: A detailed analysis of the morphology of distal humeral articulation can help in the creation of anatomic prostheses of hemiarthroplasty. This study used statistical shape modeling to evaluate the 3D morphology of the distal humerus in healthy Chinese individuals and to investigate the proper articular morphology differences. METHODS: A statistical shape model (SSM) of the distal humerus was created using CT scans of 106 survey-confirmed nonpathologic elbows. In addition, the articular components of each principal component (PC) were selected and fitted on the mean mode. The Euclidean point-to-mesh distance of articular modes was calculated as a measurement the proper change in the morphology of the articulation. RESULTS: The first seven PCs jointly accounted for 80.9% of the total variation (44.4%, 12.2%, 7.9%, 5.9%, 4.1%, 3.4% and 3%, respectively). In the mean model, the distance between the medial and lateral epicondyles was 57.4 mm, the width of the articulation was 42.1 mm, and the angle of the transepicondylar line (TEL) and C line was 4.8°. The articular surface differences of the first PC were significant (RMS: 1.43 mm in the -3 SD model and 2.38 mm in the +3 SD model), whereas under other conditions, the differences were not remarkable despite the maximum deformation not exceeding 1 mm. CONCLUSION: A novel method (SSM) was used to evaluate the 3D morphology of the distal humerus in healthy Chinese individuals and investigate the proper articular shape differences. We found the proper shape of articular surface basically transformed into one variation pattern which was relevant to the bone size, even though the morphology of distal humerus possessed complicated variation modes. The findings of this study can be helpful to design the next generation of elbow hemiarthroplasty in the future.

3D bioprinting of in situ vascularized tissue engineered bone for repairing large segmental bone defects.

Large bone defects remain an unsolved clinical challenge because of the lack of effective vascularization in newly formed bone tissue. 3D bioprinting is a fabrication technology with the potential to create vascularized bone grafts with biological activity for repairing bone defects. In this study, vascular endothelial cells laden with thermosensitive bio-ink were bioprinted in situ on the inner surfaces of interconnected tubular channels of bone mesenchymal stem cell-laden 3D-bioprinted scaffolds. Endothelial cells exhibited a more uniform distribution and greater seeding efficiency throughout the channels. In vitro, the in situ bioprinted endothelial cells can form a vascular network through proliferation and migration. The in situ vascularized tissue-engineered bone also resulted in a coupling effect between angiogenesis and osteogenesis. Moreover, RNA sequencing analysis revealed that the expression of genes related to osteogenesis and angiogenesis is upregulated in biological processes. The in vivo 3D-bioprinted in situ vascularized scaffolds exhibited excellent performance in promoting new bone formation in rat calvarial critical-sized defect models. Consequently, in situ vascularized tissue-engineered bones constructed using 3D bioprinting technology have a potential of being used as bone grafts for repairing large bone defects, with a possible clinical application in the future.

Evaluating the cardioprotective effect of metformin on myocardial ischemia-reperfusion injury using dynamic 18F-FDG micro-PET/CT imaging.

BACKGROUND: The molecular mechanisms of protective effect of metformin (Met) on ischemic myocardium have not been fully understood. This study aims to evaluate the cardioprotective effect of metformin on myocardial ischemia-reperfusion injury (MIRI) in rat models at different time points using dynamic 18F-FDG micro-PET/CT imaging. METHODS: The I/R injury model in SD rats was established by ligation of left anterior descending coronary artery near the pulmonary arch root for 30 min. SD rats (n = 12) were randomly divided into 2 groups: Control group (n = 6) without any intervention and Met group (n = 6) with oral administration of metformin (50 mg/kg) twice a day. Gated 18F-FDG (40Mbq) micro-PET/CT imaging was performed for 10 min at different time points (day 1st, day 7th, day 14th and day 30th after operation). Volumes of interest were drawn to identify different myocardium regions (ischemia center, peri-ischemia area and remote area). Standardized uptake values (SUVs) (SUVmean and SUVmax) were analyzed to evaluate the FDG uptake activity, and then the center/remote ratio was calculated. In addition, the left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV) and LV ejection fraction (LVEF) were obtained. On the 30th day, all rats were scarified and myocardial ischemia was analyzed by HE staining and confirmed by pathology. RESULTS: In the Control group, the center/remote ratio showed no obvious change trend at each time point after reperfusion, while the LV EDV increased gradually over time, and they were significantly negatively correlated (r = - 0.507, p < 0.05). In the Met group, the center/remote ratio gradually increased with time, there was no significant correlation between center/remote ratio and LV EDV (r = - 0.078, p > 0.05). On the 30th day, the center/remote ratio of the Met group was significantly higher than that of the Control group (0.81 ± 0.06 vs. 0.65 ± 0.09, p < 0.05), while LV EDV in Met group was significantly lower than in Control group (358.21 ± 22.62 vs. 457.53 ± 29.91, p < 0.05). There was no significant difference of LVEF between Met group and Control group at different time points after reperfusion (p < 0.05). HE staining showed that the myocardial infarction and fibrosis in ischemic center area of the Control group was more serious than that of the Met group. CONCLUSIONS: Met could attenuate the severity of MIRI, delay and prevent the progress of LV remodeling. The cardioprotective progress could be dynamically assessed by 18F-FDG micro-PET/CT imaging.

bFGF-Loaded Mesoporous Silica Nanoparticles Promote Bone Regeneration Through the Wnt/ß-Catenin Signalling Pathway.

Background: Bone defects remain an unsolved clinical problem due to the lack of effective osteogenic induction protocols. Nanomaterials play an important role in bone defect repair by stimulating osteogenesis. However, constructing an effective bioactive nanomaterial remains a substantial challenge. Methods: In this study, mesoporous silica nanoparticles (MSNs) were prepared and used as nanocarriers for basic fibroblast growth factor (bFGF). The characteristics and biological properties of the synthetic bFGF@MSNs were tested. The osteogenic effects of the particles on the behavior of MC3T3-E1 cells were investigated in vitro. In addition, the differentially expressed genes during induction of osteogenesis were analyzed by transcriptomic sequencing. Radiological and histological observations were carried out to determine bone regeneration capability in a distal femur defect model. Results: Achieving bFGF sustained release, bFGF@MSNs had uniform spherical morphology and good biocompatibility. In vitro osteogenesis induction experiments showed that bFGF@MSNs exhibited excellent osteogenesis performance, with upregulation of osteogenesis-related genes (RUNX2, OCN, Osterix, ALP). Transcriptomic sequencing revealed that the Wnt/ß-catenin signalling pathway could be activated in regulation of biological processes. In vivo, bone defect repair experiments showed enhanced bone regeneration, as indicated by radiological and histological analysis, after the application of bFGF@MSNs. Conclusion: bFGF@MSNs can promote bone regeneration by activating the Wnt/ß-catenin signalling pathway. These particles are expected to become a potential therapeutic bioactive material for clinical application in repairing bone defects in the future.

Physiologically personalized coronary blood flow model to improve the estimation of noninvasive fractional flow reserve.

PURPOSE: Coronary outlet resistance is influenced by the quantification and distribution of resting coronary blood flow. It is crucial for a more physiologically accurate estimation of fractional flow reserve (FFR) derived from computed tomography angiography (CTA), referred to as FFRCT. This study presents a physiologically personalized (PP)-based coronary blood flow model involving the outlet boundary condition (BC) and a standardized outlet truncation strategy to estimate the outlet resistance and FFRCT. METHODS: In this study, a total of 274 vessels were retrospectively collected from 221 patients who underwent coronary CTA and invasive FFR within 14 days. For FFRCT determination, we have employed a PP-based outlet BC model involving personalized physiological parameters and left ventricular mass (LVM) to quantify resting coronary blood flow. We evaluated the improvement achieved in the diagnostic performance of FFRCT by using the PP-based outlet BC model relative to the LVM-based model, with respect to the invasive FFR. Additionally, in order to evaluate the impact of the outlet truncation strategy on FFRCT, 68 vessels were randomly selected and analyzed independently by two operators, by using two different outlet truncation strategies at 1-month intervals. RESULTS: The per-vessel diagnostic performance of the PP-based outlet BC model was improved, based on invasive FFR as reference, compared to the LVM-based model: (i) accuracy/sensitivity/specificity: 91.2%/90.4%/91.8% versus 86.5%/84.6%/87.6%, for the entire dataset of 274 vessels, (ii) accuracy/sensitivity/specificity: 88.7%/82.4%/90.4% versus 82.4%/ 76.5%/84.0%, for moderately stenosis lesions. The standardized outlet truncation strategy showed good repeatability with the Kappa coefficient of 0.908. CONCLUSIONS: It has been shown that our PP-based outlet BC model and standardized outlet truncation strategy can improve the diagnostic performance and repeatability of FFRCT.

Echocardiographic changes in elderly patients with heart failure with reduced ejection fraction after sacubitril-valsartan treatment.

BACKGROUND: To observe the changes of cardiac structure and function in elderly patients with heart failure with reduced ejection fraction (HFrEF) after taking Sacubitril-Valsartan for 6 months. METHODS: Elderly patients with HFrEF hospitalized in Beijing Anzhen Hospital from May 2019 to May 2020 were enrolled continuously in the single-center, retrospective, cohort study. Patients' Echocardiographs were examined for the evaluation of their cardiac condition. The primary outcomes were changes in cardiac function and structure at the sixth month after discharge, including left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left atrial diameter (LAD), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT) and left ventricular mass index (LVMI). RESULTS: A total of 336 elderly patients with HFrEF were enrolled in this study, with an average age of 69.8 years, including 268 males (79.8%). Compared to the admission levels, the LVEF after taking Sacubitril-Valsartan for 6 months was markedly improved (48.49% vs. 39.07%, P<0.01), while the LVEDD (54.70 vs. 59.97 mm, P<0.01), LVESD (40.59 vs. 47.59 mm, P<0.01), LAD (48.59 vs. 52.45 mm, P<0.01) and LVMI (105.16 vs. 125.20 g/m2, P<0.01) decreased. Similar results were obtained in the subgroups of patients who were diagnosed with HFrEF on admission. In men, NHYA II and NHYA III subgroups, cardiac function improved significantly. CONCLUSIONS: Sacubitril-Valsartan can improve the cardiac function and structure of elderly patients with HFrEF.

Candidate symptomatic markers for predicting violence in schizophrenia: A cross-sectional study of 7711 patients in a Chinese population.

OBJECTIVE: Violent behaviour is an alarming problem among schizophrenia patients. The effects of historical, clinical, and pathological risk factors for violence have been investigated by multiple studies, but consensus has not been achieved. As psychotic symptoms are more direct and intuitive indicators for violence, identifying robustly associated symptoms is a crucial part of the future prediction and precise management of violent patients in clinics. This study aims to identify the psychotic symptoms correlated with violence among schizophrenia patients in a Chinese population. METHODS: In this cross-sectional study, the medical records of 7711 schizophrenia patients (4711 in the discovery set and 3000 in the validation set) were collected from 1998 to 2010. Their psychotic symptoms were extracted, and the patients were divided into violent and non-violent groups. Multivariate logistic analysis was applied to identify symptoms associated with violence in the discovery set. RESULTS: Eight psychotic symptoms were found to be significantly correlated with violence in schizophrenia. "Destruction of property", "verbal aggression" and "insomnia" increased the risk of violence, while "flat affect", "delusion of persecution", "auditory hallucination", "vagueness of thought" and "poverty of thought" decreased the risk of violence. The regression model was evaluated by receiver operating characteristic (ROC) analysis for its discriminatory performance, achieving area under curve (AUC) values of 0.887 in the discovery sample set and 0.824 in the validation sample set. CONCLUSIONS: The correlated symptoms identified by this study can serve as future candidate predictors for violence in schizophrenia, paving the way for precise management of schizophrenia patients in clinics.

An investigation of calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) in schizophrenia.

Evidence indicates that abnormal phospholipase A2 (PLA2) levels and niacin insensitivity are present in individuals with schizophrenia. This study was designed to determine whether differences in plasma calcium-independent phospholipase A2 (iPLA2) and cytosolic phospholipase A2 (cPLA2) exist between those with schizophrenia and healthy controls, and to explore the correlation between PLA2s and the niacin skin reaction in schizophrenic patients. We performed ELISA experiments to measure the concentrations of plasma iPLA2 and cPLA2 and we conducted a series of niacin skin tests on schizophrenic patients from the Chinese Han population. In addition, a meta-analysis of the relationship between PLA2 and schizophrenia was conducted. The plasma concentration of iPLA2 in patients with schizophrenia was significantly higher than that in healthy controls while the plasma concentration of cPLA2 did not differ. The meta-analysis also revealed that the activity level of iPLA2 in individuals with schizophrenia was higher than that in healthy controls, whereas that of cPLA2 was not. Furthermore, a significant positive correlation was found between the concentration of iPLA2 and the score for the skin flushing response within 20 min. The abnormal plasma iPLA2 concentration and its relationship with the niacin skin test in schizophrenic patients has contributed to a deeper understanding of the pathology of schizophrenia, which may in turn provide new insights into the clinical diagnoses and treatment of schizophrenia.

Leukocyte Proteomic Profiling in First-Episode Schizophrenia Patients: Does Oxidative Stress Play Central Roles in the Pathophysiology Network of Schizophrenia?

Although several underlying etiologic implications for schizophrenia (SZ) have been proposed, the cross talk between them is rarely explored systematically. The aim of the present study was to illustrate the pathogenic mechanism of SZ through describing a systematical pathophysiology network using proteomic signatures in first-episode SZ patients. A total of 3152 proteins were identified in leukocytes, and 475 of these proteins were significantly altered in SZ. Functional analysis revealed that cell redox homeostasis was dramatically disrupted, demonstrated as upregulated glycolysis, mitochondrial oxidative phosphorylation, and thioredoxin-centered antioxidant system. We also identified an activated complement system and caspase-independent apoptosis. In addition, increased pyruvate and lactate levels and decreased lactate-to-pyruvate ratios were observed in plasma of SZ patients. The results here lead to the hypothesis that increased oxidative stress is caused by metabolic upregulation and complement activation, which induces protein damage and cell apoptosis, thus contributing to the development of SZ. Antioxid. Redox Signal. 31, 579-588.

Preclinical Study of Anticoagulation Regimens in Sheep After Implantation of CH-VAD Blood Pump.

Effective anticoagulation regimens are needed to reduce risks of thrombosis and bleeding in animal models of ventricular assist device to verify its hemocompatibility, biologic safety and reliability. This study is to develop a validated anticoagulation procedure for a sheep model to test the newly developed CH-VAD. CH-VAD models were established in six healthy sheep by constructing blood bypass of left ventricle → ventricular assist device → descending aorta. Heparin infusion was used during operation and in the prior 4 days to maintain activated clotting time 1.5-2.0 times the baseline. From the third day, proper dosage of warfarin was used orally to maintain international normalized ratio values within the range of 1.2-2.0. After termination, we examined whether there was thrombosis in the blood pump, grafts, and anastomotic stoma. Macroscopic and histopathologic examinations were performed in major organs to check for congestion and infarction. Bleeding complications were not found in any animals throughout the experiments. Activated clotting time values were 326 ± 33 s intraoperatively and 157 ± 28 s in the prior 4 days postoperatively. Activated partial thromboplastin time values increased slowly and reached the lower limit of the target range on the fourth day. Only in one of six cases was thrombus or fibrosis tissue found in the blood flow channel of the pump. Pathologic analysis showed no thrombosis, necrosis and microembolus in end-stage organs. Under the anticoagulation regimens, coagulation system could be well controlled to avoid thrombosis and bleeding complications in sheep models for CH-VAD.

Quantitative Evaluation of Coronary Plaque Progression by Computed Tomographic Angiography.

Understanding plaque formation in patients at risk for coronary artery disease-the leading cause of morbidity and death in the world-enables physicians to better determine whether and how to treat these individuals. We used computed tomographic angiography to quantitatively evaluate the progression of nonculprit coronary plaques along the full length of the right coronary artery in 21 patients with acute coronary syndrome. Each right coronary artery was analyzed in sequential, 3-mm-long segments, and the minimum luminal area, plaque burden, and plaque volume within each segment were evaluated at baseline and at 12-month follow-up. Serial remodeling of the right coronary artery was also evaluated. In total, 625 arterial segments were analyzed. At 12-month follow-up, the plaque burden had increased slightly by 0.34% (interquartile range [IQR], -4.32% to 6.35%; P=0.02), and the plaque volume was not significantly changed (0.33 mm3; IQR, -3.05 to 3.54; P=0.213). The minimum luminal area decreased 0.05 mm2 (IQR, -1.33 to 0.87 mm2; P=0.012), and this was accompanied by vessel reduction, as evidenced by negative remodeling in 43% of the 625 segments. We conclude that serial computed tomographic angiography can be used to quantitatively evaluate the morphologic progression of coronary plaques.

Prediction of coronary plaque progression using biomechanical factors and vascular characteristics based on computed tomography angiography.

OBJECTIVES: Coronary atherosclerotic plaques progress in a highly individual manner. Accurately predicting plaque progression will promote clinical management of atherosclerosis. The purpose of this study was to investigate the role of local biomechanics factors and vascular characteristics in coronary plaque progression and arterial remodeling. METHODS: Computed tomography angiography-based three-dimensional reconstruction of the native right coronary artery was performed in vivo in twelve patients with acute coronary syndrome at baseline and 12-month follow-up. The reconstructed arteries were divided into sequential 3-mm-long segments. Wall shear stress (WSS) and von Mises stress (VMS) were computed in all segments at baseline by applying fluid-structure interaction simulations. RESULTS: In total, 365 segments 3-mm long were analyzed. The decrease in minimal lumen area was independently predicted by low baseline VMS (-0.73 ± 0.13 mm2), increase in plaque burden was independently predicted by small minimal lumen area and low baseline WSS (6.28 ± 0.96%), and decrease in plaque volume was independently predicted by low baseline VMS (-0.99 ± 0.49 mm3). Negative remodeling was more likely to occur in low- (55%) and moderate-VMS (40%) segments, but expansive remodeling was more likely to occur in high-VMS (44%) segments. CONCLUSIONS: Local von Mises stress, wall shear stress, minimal lumen area, and plaque burden provide independent and additive prediction in identifying coronary plaque progression and arterial remodeling.

Initial In Vivo Evaluation of a Novel Left Ventricular Assist Device.

The aim of the study was to use the ovine model to evaluate the hemocompatibility and end-organ effects of a newly developed magnetic suspension centrifugal left ventricular assist device (LVAD) by CH Biomedical Inc., Jiangsu, China. The LVADs were implanted in 6 healthy sheep, where inflow was inserted into the left ventricular apex and outflow was anastomosed to the descending aorta. All sheep received anticoagulation and antiaggregation therapy during the study. Hematologic and biochemical tests were performed to evaluate anemia, hepatorenal function, and the extent of hemolysis. The experiments lasted for up to 30 days on the beating hearts. All sheep were humanely killed at the termination of the experiments, and the end-organs were examined macroscopically and histopathologically. Autopsy was performed in all animals and there was no thrombus formation observed inside the pump. The pump's inflow and outflow conduits were also free of thrombus. Hematologic and biochemical test results were within normal limits during the study period. Postmortem examination of the explanted organs revealed no evidence of ischemia or infarction. Based on the in vivo study, this LVAD is suitable for implantation and can provide efficient support with good biocompatibility. The encouraging results in this study suggest that it is feasible to evaluate the device's long-term durability and stability.

A new application of high-efficient silver salts-based photocatalyst under natural indoor weak light for wastewater cleaning.

As a high-quantum-efficiency photocatalyst, the serious photo-corrosion of silver phosphate (Ag3PO4), limits the practical applications in water purification and challenges us. Herein, Ag3PO4 is found to have a high stability under natural indoor weak light irradiation, suggesting that we can employ it by adopting a new application strategy. In our studies, rhodamine B (RhB, cationic dye), methyl orange (MO, anionic dye) and RhB-MO mixture aqueous solutions are used as the probing reaction for the degradation of organic wastewater. It is found that RhB, MO and RhB-MO can be completely degraded after 28 h under natural indoor weak light irradiation, indicating that multi-component organic contaminants can be efficiently degraded by Ag3PO4 under natural indoor weak light irradiation. The density of natural indoor weak light is measured to be 72cd, which is merely one-thousandth of 300 W xenon lamp (68.2 × 10(3)cd). Most importantly, Ag3PO4 shows a high stability under natural indoor weak light irradiation, demonstrated by the formation of fairly rare Ag. Furthermore, we also investigate the influence of inorganic ions on organic dyes degradation. It shows that the Cl(-) and Cr(6+) ions with high concentrations in wastewater have significantly decreased the degradation rate. From the viewpoint of energy saving and stability, this study shows us that we can utilize the Ag-containing photocatalysts under natural indoor weak light, which could be extended to indoor air cleaning process.

In vivo evaluation of an implantable magnetic suspending left ventricular assist device.

PURPOSE: The CH-VAD is an implantable, fully magnetically suspended ventricular assist device developed by the China Heart Biomedical Corporation (Suzhou, China) for full cardiac support. This study was performed to evaluate the reliability, hemocompatibility and end-organ effects of CH-VAD in a 35-day animal model trial. METHODS: The pump was implanted in 6 sheep. The pump inflow was inserted into the left ventricle and the outflow graft was anastomosed to the descending aorta. Data on pump function and the health condition of the animals, including hematologic and biochemical tests, were collected during the study period. When each study was determined to termination, the sheep were humanely euthanized and the end organs were examined macroscopically and histopathologically. Hemolysis was evaluated based on the amount of free hemoglobin in the plasma. RESULTS: Except for one device that stopped operation on postoperative day 25 because of thrombus formation, the devices functioned normally until the scheduled termination. Gross examination of the pump interiors, inflow and outflow, and of the arterial anastomosis sites showed no significant abnormalities. Hematologic and biochemical test results were within normal limits during the study period. Macroscopic and histopathologic examinations of the explanted organs revealed no evidence of ischemia or infarction associated with the device implantation, except for small foci of infarction in the kidneys of two sheep. The free hemoglobin level in plasma peaked at 9.5 mg/dl on postoperative day 5. CONCLUSIONS: The CH-VAD system demonstrated promising reliability and blood-handling characteristics without obvious damage to end organs during a 35-day implantation in sheep.