A xonotlite nanofiber bioactive 3D-printed hydrogel scaffold based on osteo-/angiogenesis and osteoimmune microenvironment remodeling accelerates vascularized bone regeneration.

BACKGROUND: Coordination between osteo-/angiogenesis and the osteoimmune microenvironment is essential for effective bone repair with biomaterials. As a highly personalized and precise biomaterial suitable for repairing complex bone defects in clinical practice, it is essential to endow 3D-printed scaffold the above key capabilities. RESULTS: Herein, by introducing xonotlite nanofiber (Ca6(Si6O17) (OH)2, CS) into the 3D-printed silk fibroin/gelatin basal scaffold, a novel bone repair system named SGC was fabricated. It was noted that the incorporation of CS could greatly enhance the chemical and mechanical properties of the scaffold to match the needs of bone regeneration. Besides, benefiting from the addition of CS, SGC scaffolds could accelerate osteo-/angiogenic differentiation of bone mesenchymal stem cells (BMSCs) and meanwhile reprogram macrophages to establish a favorable osteoimmune microenvironment. In vivo experiments further demonstrated that SGC scaffolds could efficiently stimulate bone repair and create a regeneration-friendly osteoimmune microenvironment. Mechanistically, we discovered that SGC scaffolds may achieve immune reprogramming in macrophages through a decrease in the expression of Smad6 and Smad7, both of which participate in the transforming growth factor-ß (TGF-ß) signaling pathway. CONCLUSION: Overall, this study demonstrated the clinical potential of the SGC scaffold due to its favorable pro-osteo-/angiogenic and osteoimmunomodulatory properties. In addition, it is a promising strategy to develop novel bone repair biomaterials by taking osteoinduction and osteoimmune microenvironment remodeling functions into account.

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway.

BACKGROUND: Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS: In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION: In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.

Pharmacokinetics and tissue distribution study of 15 ingredients of Polygonum chinense Linn extract in rats by UHPLC-MS/MS.

A rapid and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of 15 bioactive ingredients in rat plasma and tissues after oral administration of Polygonum chinense Linn extract (PCE). After addition of internal standards (ISs; rutin and danshensu), plasma and tissue samples were pre-treated by protein precipitation with acetonitrile-ethanol. The chromatographic separation was performed on an Agilent ZORBAX RRHD Eclipse Plus C18 column with gradient elution using a mobile phase composed of methanol and water (containing 0.2% acetic acid) at a flow rate of 0.3 mL min-1 . Mass spectrometric detection was carried out using a mass spectrometer in both positive and negative ion electrospray ionization modes by multiple reaction monitoring. The method provided excellent linearity, and the lower limit of quantification range 0.5-30 ng mL-1 for all analytes. The intra- and inter-day precision were less than 9.12% and the accuracy ranged from -4.02% to 6.32%, respectively. The mean extraction recovery and matrix effect of analytes and ISs ranged from 83.65% to 109.20%. The method was successfully applied to the pharmacokinetics and tissue distribution study of 15 ingredients of PCE in rats.

An ultra high performance liquid chromatography with tandem mass spectrometry method for simultaneous determination of thirteen components extracted from Radix Puerariae in rat plasma and tissues: Application to pharmacokinetic and tissue distribution study.

A rapid and sensitive ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for simultaneous determination of thirteen bioactive components (gallic acid, protocatechuic acid, puerarin, p-hydroxycinnamic acid, daidzin, ononin, daidzein, naringenin, genistein, apigenin, formononetin, biochanin A, and ß-sitosterol) of Radix Puerariae extract in rat plasma and tissues. The plasma and tissues samples were pretreated by protein precipitation extraction, and umbelliferone and rutin were used as internal standards. Sample separation was performed on a ZORBAX RRHD Eclipse plus C18 column (2.1 mm × 50 mm, 1.8 µm, Agilent) with a mobile phase consisting of methanol-water (containing 0.1% formic acid). The mass spectrometry analysis was conducted in positive and negative ionization modes with multiple reaction monitoring. The lower limit of quantitation range for the 13 analytes was 0.2-35 ng/mL. The intra- and inter-day precision of all the analytes were less than 10.92%, with an accuracy ranging from -13.10 to 11.96%. Both the recovery and matrix effect were within acceptable limits. This method was successfully applied to pharmacokinetic and tissue distribution study of the 13 bioactive components in rats after oral administration of R. Puerariae extract.

Colorimetric enzymatic determination of glucose based on etching of gold nanorods by iodine and using carbon quantum dots as peroxidase mimics.

Carbon quantum dots (CQDs) with peroxidase-mimicking activity were successfully prepared from litchi rind. A colorimetric method for glucose determination was developed based on etching of gold nanorods (GNRs) using CQDs as peroxidase mimetic. The glucose oxidase-catalyzed oxidation of glucose leads to the generation of H2O2 which oxidizes added iodide under formation of elemental iodine under the catalytic action of CQDs. Iodine then etches the GNRs along the longitudinal direction due to the higher reaction activities at the tips of GNRs. This results in a stepwise decrease in the maximum absorption wavelength of the GNRs, from initially 953 nm to finally 645 nm. Under the optimized conditions, the shift in the maximum absorption wavelength decreases linearly in the 0.01-2.0 mM glucose concentration range, and the detection limit is 3.0 µM. Importantly, this method was applied to the determination of glucose in human serum. It is perceived that the CQDs are valuable peroxidase mimics due to their ease of preparation, low costs and stable catalytic activity. Graphical abstract Carbon quantum dots were prepared from litchi rind. They can induce the oxidation of gold nanorods in the presence of I- ions and H2O2. This finding was applied to design a colorimetric assay for glucose.

An off-on fluorescence method for acid phosphatase assay based on the inner filter effect of MnO2 nanosheets on vitamin B2.

Fluorescence analysis has attracted much attention due to its rapidity and sensitivity. The present work describes a novel fluorescence detection method for acid phosphatase (ACP) on the basis of inner-filter effect (IFE), where MnO2 nanosheets (MnO2 NSs) and vitamin B2 (VB2) are served as absorbers and fluorophores, respectively. In the absence of ACP, the absorption band of MnO2 NSs overlaps well with the excitation band of VB2, resulting in effective IFE and inhibition of VB2 fluorescence. In the presence of ACP, 2-phospho-L-ascorbic acid trisodium salt (AAP) is hydrolyzed to generate ascorbic acid (AA), which efficiently trigger the reduction of MnO2 NSs into Mn2+ ions, causing the weakening of the MnO2 NSs absorption band and the recovery of VB2 fluorescence. Further investigation indicates that the fluorescence recovery degree of VB2 increases with the increase of ACP concentration. Under selected experimental conditions, the proposed method can achieve sensitive detection of ACP in the ranges of 0.5-4.0 mU/mL and 4.0-15 mU/mL along with a limit of detection (LOD) as low as 0.14 mU/mL. Finally, this method was successfully applied for the detection of ACP in human serum samples with satisfactory recoveries in the range of 95.0 %-108 %.

Quercetin-Loaded Bioglass Injectable Hydrogel Promotes m6A Alteration of Per1 to Alleviate Oxidative Stress for Periodontal Bone Defects.

Periodontal disease ranks third among noncommunicable illnesses, behind cancer and cardiovascular disease, and is closely related to the occurrence and progression of various systemic diseases. However, elucidating the processes of periodontal disease and promoting periodontal bone regeneration remains a challenge. Here, quercetin is demonstrated to reduce the oxidative stress state of orofacial mesenchymal stem cells (OMSCs) in vitro and to affect the osteogenic growth of OMSCs through molecular mechanisms that mediate the m6A change in Per1. Nevertheless, the limited therapeutic efficacy of systemic medication and the limitations of local medication resulting from the small, moist, and highly dynamic periodontal environment make it challenging to treat periodontal tissues with medication. Herein, a biosafe injectable hydrogel drug-controlled delivery system is constructed as a bone-enhancing factory and loaded with quercetin to treat oxidative stress injury in periodontal tissues. This drug-carrying system made up of nanoscale bioglass microspheres and a light-cured injectable hydrogel, allows effective drug particle loading and cementation in the dynamic and moist periodontal environment. Furthermore, the system demonstrates the ability to stimulate OMSCs osteogenic differentiation in a Per1-dependent manner, which ultimately promotes periodontal bone repair, suggesting that this system has potential for clinical periodontal therapy.

A five-in-one novel MOF-modified injectable hydrogel with thermo-sensitive and adhesive properties for promoting alveolar bone repair in periodontitis: Antibacterial, hemostasis, immune reprogramming, pro-osteo-/angiogenesis and recruitment.

Periodontitis is a chronic inflammatory disease caused by plaque that destroys the alveolar bone tissues, resulting in tooth loss. Poor eradication of pathogenic microorganisms, persistent malignant inflammation and impaired osteo-/angiogenesis are currently the primary challenges to control disease progression and rebuild damaged alveolar bone. However, existing treatments for periodontitis fail to comprehensively address these issues. Herein, an injectable composite hydrogel (SFD/CS/ZIF-8@QCT) encapsulating quercetin-modified zeolitic imidazolate framework-8 (ZIF-8@QCT) is developed. This hydrogel possesses thermo-sensitive and adhesive properties, which can provide excellent flowability and post-injection stability, resist oral fluid washout as well as achieve effective tissue adhesion. Inspirationally, it is observed that SFD/CS/ZIF-8@QCT exhibits a rapid localized hemostatic effect following implantation, and then by virtue of the sustained release of zinc ions and quercetin exerts excellent collective functions including antibacterial, immunomodulation, pro-osteo-/angiogenesis and pro-recruitment, ultimately facilitating excellent alveolar bone regeneration. Notably, our study also demonstrates that the inhibition of osteo-/angiogenesis of PDLSCs under the periodontitis is due to the strong inhibition of energy metabolism as well as the powerful activation of oxidative stress and autophagy, whereas the synergistic effects of quercetin and zinc ions released by SFD/CS/ZIF-8@QCT are effective in reversing these biological processes. Overall, our study presents innovative insights into the advancement of biomaterials to regenerate alveolar bone in periodontitis.

A multifunctional quercetin/polycaprolactone electrospun fibrous membrane for periodontal bone regeneration.

Image 1.

CeO2-Co3O4 nanocomposite with oxidase-like activity for colorimetric detection of ascorbic acid.

A CeO2-Co3O4 nanocomposite (NC) was prepared and characterized by scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy and X-ray diffraction. The obtained CeO2-Co3O4 NC displayed biomimicking oxidase-like activity, which can catalytically oxidize the 3, 3', 5, 5'-tetramethylbenzidine (TMB) substrate from colorless to the blue oxidized TMB (ox-TMB) product with a characteristic absorption peak at 652 nm. When ascorbic acid (AA) was present, ox-TMB would be reduced, resulting in a lighter blue and lower absorbance. On the basis of these facts, a simple colorimetric method for detection of AA was established with a linear relationship ranging from 1.0 to 500 µM and a detection limit of 0.25 µM. When this method was used to detect AA in human serum and commercially available vitamin C tablet samples, a good recovery of 92.0% to 109.0% was obtained. Besides, the catalytic oxidation mechanism was investigated, and the possible catalytic mechanism of CeO2-Co3O4 NC can be described as follows. TMB is adsorbed on the CeO2-Co3O4 NC surface and provides lone-pair electrons to the CeO2-Co3O4 NC, leading to an increase in electron density of the CeO2-Co3O4 NC. An increased electron density can improve the electron transfer rate between TMB and the oxygen absorbed on its surface to generate O2˙- and ˙O2, which further oxidize TMB.

A novel sucrose phosphorylase from the metagenomes of sucrose-rich environment: isolation and characterization.

Sucrose phosphorylase, an important enzyme mainly involved in the generic starch and sucrose pathways, has now caught the attention of researchers due to its transglycosylation activity. A novel sucrose phosphorylase, unspase, has been isolated, and its transglycosylation properties were characterized. Compared with Bisp, the sucrose phosphorylase from Bifidobacterium adolescentis, unspase had two deleted regions in its C: -terminal. These deleted regions were probably equivalent to the important five-stranded anti-parallel ß-sheet domain in sucrose phosphorylase. Unspase has a k(m) of 21.12 mM, a V(max) of 69.24 µmol min(-1) mg(-1) and a k(cat) of 31.19 s(-1) with sucrose as substrate. In 3-(N-morpholino) propanesulfonic acid (MOPS) buffer, unspase transferred the glycosyl moiety to L-arabinose, D-fructose and L-sorbose. Much to our surprise, unspase can catalyze the transglycosylation in which a glycosyl moiety was transferred to L-arabinose in the presence of phosphate, which is an interesting exception to the generally accepted fact that transglycosylation can only occur under the condition of phosphate absence. The final yield of the transglycosylation product (37.9 %) in phosphate buffer was even higher than that (5.8 %) in MOPS buffer. This is a novel phenomenon that a sucrose phosphorylase can catalyze a transglycosylation reaction in the presence of phosphate.

Fabrication and Effect of Strontium-Substituted Calcium Silicate/Silk Fibroin on Bone Regeneration In Vitro and In Vivo.

Achieving rapid osteogenesis and angiogenesis was the key factor for bone regeneration. In the present study, the strontium-substituted calcium silicate (SrCS)/silk fibroin (SF) composite materials have been constructed by combining the different functional component ratios of SrCS (12.5 wt%, 25 wt%) and SF. Then, the effects of SrCS/SF materials on proliferation, osteogenic differentiation, and angiogenic factor secretion of rat bone marrow-derived mesenchymal stromal cells (rBMSCs) were first evaluated in vitro. Moreover, the in vivo effect of osteogenesis was evaluated in a critical-sized rat calvarial defect model. In vitro studies showed that SrCS/SF significantly enhanced the cell proliferation, alkaline phosphatase (ALP) activity, and the expression of osteogenic and angiogenic factors of rBMSCs as compared with the SF and CS/SF, and the optimum proportion ratio was 25 wt%. Besides, the results also showed that CS/SF achieved enhanced effects on rBMSCs as compared with SF. The in vivo results showed that 25 wt% SrCS/SF could obviously promote new bone formation more than SF and CS/SF. The present study revealed that SrCS could significantly promote the osteogenic and angiogenic activities of SF, and SrCS/SF might be a good scaffold material for bone regeneration.

Bioactive natural compounds as potential medications for osteogenic effects in a molecular docking approach.

Bone defect repair and fracture healing are critical challenges in clinical treatments. Bioactive natural compounds are potential resources for medications for osteogenic effects. We have identified icariin, the effective ingredient of Epimedium pubescens, to promote osteogenic differentiation of bone mesenchymal stem cells (BMSCs) and repair bone defects. To explore more natural compounds with the potential modality for bone repair, in the present study, we employed an icariin-induced gene expression pattern as an osteogenic model and screened the Connectivity Map database for small molecules with gene expression signatures similar to this model. We verified the effectiveness of this molecule docking approach by introducing hydroxycholesterol, the second highest score of the similarity to icariin, into the osteoinductive experiments in vitro and demonstrated its excellent osteogenic effect on BMSCs compared with a BMP-2-positive control group. Based on the compatible result of hydroxycholesterol, subsequently, ginsenoside Rb1 was chosen as the most drug-like natural compound among the molecule docking results from icariin. Finally, ginsenoside Rb1 was demonstrated to promote the expression of osteoblastic genes and ALP activity in vitro and repair the calvarial defect of rats in vivo. The study aimed to provide diverse choices for clinical application in bone repair and functional regeneration.

Maxillary sinus floor elevation using BMP-2 and Nell-1 gene-modified bone marrow stromal cells and TCP in rabbits.

This study evaluated the synergistic osteogenic effect of bone morphogenetic protein-2 (BMP-2) and Nel-like molecule-1 (Nell-1) genes in a rabbit maxillary sinus floor elevation model. Bone marrow stromal cells (bMSCs) were cultured and transduced with AdEGFP, AdNell-1, AdBMP-2, or AdNell-1 + AdBMP-2 overexpression virus. These gene-modified autologous bMSCs were then combined with a ß-tricalcium phosphate (ß-TCP) granule scaffold and used to elevate the maxillary sinus floor in rabbits. bMSCs cotransduced with AdNell-1 + AdBMP-2 demonstrated a synergistic effect on osteogenic differentiation as detected by real-time PCR analysis on markers of runt-related transcription factor-2, osteocalcin, collagen type 1, alkaline phosphatase activity, and calcium deposits in vitro. As for maxillary sinus floor elevation in a rabbit model in vivo, AdNell-1 + AdBMP-2 gene-transduced autologeous bMSCs/ß-TCP complex had the largest bone area and most mature bone structure among the groups, as detected by HE staining and immunohistochemistry at weeks 2 and 8 after implantation. Our data suggested that the BMP-2 and Nell-1 genes possessed a synergistic effect on osteogenic differentiation of bMSCs, while bMSCs modified with the BMP-2 and Nell-1 genes could promote new bone formation and maturation in the rabbit maxillary sinus model.

Maxillary sinus floor elevation using a tissue-engineered bone with rhBMP-2-loaded porous calcium phosphate cement scaffold and bone marrow stromal cells in rabbits.

The aim of this study was to evaluate the effects of maxillary sinus floor elevation by a tissue-engineered bone complex with recombinant human bone morphogenetic protein-2 (rhBMP-2)-loaded porous calcium phosphate cement (CPC) scaffold and bone marrow stromal cells (bMSCs) in rabbits. bMSCs were cultured and osteogenically induced. The osteoblastic differentiation of expanded bMSCs was detected by alkaline phosphatase activity, and calcium deposits in vitro. Thirty-six rabbits were randomly allocated into week 2, 4 and 8 observation groups. At each time point, 24 maxillary sinus floor elevation surgeries in 12 rabbits were performed bilaterally and randomly implanted by (1) CPC materials alone (group A, n = 6), (2) rhBMP-2/CPC composite materials alone (group B, n = 6), (3) CPC/bMSCs complex (group C, n = 6) and (4) rhBMP-2/CPC/bMSCs complex (group D, n = 6). As for maxillary sinus floor elevation, rhBMP-2-loaded CPC could promote new bone formation as compared to CPC, while addition of bMSCs could further enhance its new bone formation and maturity significantly, as detected by histological findings, and fluorochrome labeling. Our data suggested that rhBMP-2/CPC possessed excellent osteoinductive ability, while combining with bMSCs could further promote new bone formation and maturation in maxillary sinus elevation.

Application of rapid prototyping for temporomandibular joint reconstruction.

PURPOSE: To introduce the preliminary application of rapid prototyping (RP) for temporomandibular joint (TMJ) surgery. MATERIALS AND METHODS: This study included 11 consecutive patients (13 joints) seeking TMJ replacement. All patients had previously undergone 3-dimensional computed tomography (CT) scanning (0.625-mm slice thickness) of the craniofacial skeleton. The data from CT scanning in DICOM (Digital Imaging and Communications in Medicine) format were input into the interactive Simplant CMF software program (Materialise Medical, Leuven, Belgium). Preoperative planning included segmentation and osteotomies. The movements of the jaw bones were simulated by use of Simplant CMF. The affected mandible was reconstructed based on the contralateral side. Then, the titanium plate was shaped on the reconstructed model before surgery. The bone graft was transplanted by the shaped titanium plate during the operation to reconstruct the TMJ. Twenty-four patients who underwent traditional surgery were used as the control group. The operative time of the 2 groups was analyzed with the SPSS software package, version 13.0 (SPSS, Chicago, IL), with the Student t test. The data from CT scanning in the experimental group before and after surgery were compared by paired t test. RESULTS: All the incisions healed primarily without any complications. All patients were satisfied with the operation, because of their symmetric faces and good occlusion. Postoperative magnetic resonance imaging confirmed the position of the transplanted costochondral cartilage in the glenoid fossa. A group t test showed that the operative time was longer in the control group (mean, 7.09 hours) than that in the RP group (mean, 5.67 hours). Three parameters (condyle-incisor, condyle-mental foramen, and condyle-angle) from the postoperative CT scan were analyzed by paired t test, and there was no significant difference between the 2 sides. CONCLUSION: RP technology provides an advanced method for TMJ reconstruction that can make the TMJ reconstruction more accurate and symmetric, improve the mandible's function, and consequently, enhance the reconstructive effect.

Dual-signal uric acid sensing based on carbon quantum dots and o-phenylenediamine.

Fluorescent carbon quantum dots (CQDs), which showed excitation-dependent emission characteristics, were prepared using a facile hydrothermal method. The structure and optical properties of CQDs were characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, UV-Vis spectroscopy, and fluorescence spectroscopy. These CQDs also showed peroxidase-like activity and could catalyze the H2O2-mediated oxidation of o-phenylenediamine (OPD) to form 2,3-diaminophenazine (DAP) with an absorption peak at 420 nm. DAP exhibited an obvious fluorescence emission at 550 nm under the excitation of 360 nm. On the other hand, it decreased the fluorescence of CQDs at 450 nm via inner filter effect. The experimental results indicated that the H2O2 concentration affected the color of DAP and the fluorescence intensity of CQDs and DAP. Thus, a colorimetric and ratiometric fluorescence dual-signal method was established for measuring the concentrations of H2O2 and uric acid (UA). The effects of pH, incubation temperature, incubation time, and OPD concentration on the response were investigated. Under the conditions of pH 7.5, temperature 50 °C, incubation time 30 min, and OPD 1.5 mM, the absorbance and fluorescence intensity ratio responses were linearly dependent on UA concentration ranging from 5.0 µM to 100 µM. The limits of detection were 0.7 and 0.5 µM with a colorimetric method and ratiometric fluorescence method, respectively. More importantly, this dual responsive method has been applied to the determination of UA in urine samples with satisfactory results.

Medical Leadership: Experiences in the Use of Shared and Parental Leadership to Improve Academic Performance in the Management of a National Plastic Surgery Unit in China.

BACKGROUND: Effective leadership is an integral component for optimal academic performance of surgical units. As one of the leading plastic surgery academic medical centers in China, the authors would like to share their experiences of using the combined parental and shared leadership approach in managing their surgical staff within the department. It has taken into account the essence of Eastern moral philosophies and Western leadership theories. METHODS: The authors performed a review of the academic development of their staff and changes in the academic productivity of the department between 1999 and 2018. The difference between the first 10 years (1999 to 2008) and second 10 years (2009 to 2018) was analyzed to assess the effectiveness of the authors' leadership approach. RESULTS: There is an increase in the number of Science Citation Index articles published in the past decade with a higher impact factor and more articles published in international journals. The timing to promotion was on average 8.4 years. The average age of promotion to consultants has increased, likely because of a later start in the training. With similar average age, prior education, and gender ratio of surgeons in the unit, the department also received 14 times more in research funding and four times more in national key topic research topic. CONCLUSIONS: The effective application of this combined leadership approach has significantly improved the academic productivity and quality of the authors' residents and surgeons and the academic advancement of the unit.

Bone marrow stromal cells stimulated by strontium-substituted calcium silicate ceramics: release of exosomal miR-146a regulates osteogenesis and angiogenesis.

Dual-functional regulation for angiogenesis and osteogenesis is crucial for desired bone regeneration especially in large-sized bone defects. Exosomes have been demonstrated to facilitate bone regeneration through enhanced osteogenesis and angiogenesis. Moreover, functional stimulation to mesenchymal stromal cells (MSCs) was reported to further boost the pro-angiogenic ability of exosomes secreted. However, whether the stimulation by bioactive trace elements of biomaterials could enhance pro-angiogenic capability of bone marrow stromal cells (BMSCs)-derived exosomes and consequently promote in vivo vascularized bone regeneration has not been investigated. In this study, strontium-substituted calcium silicate (Sr-CS) was chosen and the biological function of BMSCs-derived exosomes after Sr-CS stimulation (Sr-CS-Exo) was systemically investigated. The results showed that Sr-CS-Exo could significantly promote in vitro angiogenesis of human umbilical vein endothelial cells (HUVECs), which might be attributed to elevated pro-angiogenic miR-146a cargos and inhibition of Smad4 and NF2 proteins. Moreover, the in vivo study confirmed that Sr-CS-Exo possessed superior pro-angiogenic ability, which contributed to the accelerated developmental vascularization in zebrafish along with the neovascularization and bone regeneration in rat distal femur defects. Our findings may provide new insights into the mechanisms underlying Sr-containing biomaterials-induced angiogenesis, and for the first time, proposed that Sr-CS-Exo may serve as the candidate engineered-exosomes with dual-functional regulation for angiogenesis and osteogenesis in vascularized bone regeneration.

Effect of quercetin on chondrocyte phenotype and extracellular matrix expression.

Due to the poor repair ability of cartilage tissue, regenerative medicine still faces great challenges in the repair of large articular cartilage defects. Quercetin is widely applied as a traditional Chinese medicine in tissue regeneration including liver, bone and skin tissues. However, the evidence for its effects and internal mechanisms for cartilage regeneration are limited. In the present study, the effects of quercetin on chondrocyte function were systematically evaluated by CCK8 assay, PCR assay, cartilaginous matrix staining assays, immunofluorescence assay, and western blotting. The results showed that quercetin significantly up-regulated the expression of chondrogenesis genes and stimulated the secretion of GAG (glycosaminoglycan) through activating the ERK, P38 and AKT signalling pathways in a dose-dependent manner. Furthermore, in vivo experiments revealed that quercetin-loaded silk protein scaffolds dramatically stimulated the formation of new cartilage-like tissue with higher histological scores in rat femoral cartilage defects. These data suggest that quercetin can effectively stimulate chondrogenesis in vitro and in vivo, demonstrating the potential application of quercetin in the regeneration of cartilage defects.