Designing nanohesives for rapid, universal, and robust hydrogel adhesion.

Nanoparticles-based glues have recently been shown with substantial potential for hydrogel adhesion. Nevertheless, the transformative advance in hydrogel-based application places great challenges on the rapidity, robustness, and universality of achieving hydrogel adhesion, which are rarely accommodated by existing nanoparticles-based glues. Herein, we design a type of nanohesives based on the modulation of hydrogel mechanics and the surface chemical activation of nanoparticles. The nanohesives can form robust hydrogel adhesion in seconds, to the surface of arbitrary engineering solids and biological tissues without any surface pre-treatments. A representative application of hydrogel machine demonstrates the tough and compliant adhesion between dynamic tissues and sensors via nanohesives, guaranteeing accurate and stable blood flow monitoring in vivo. Combined with their biocompatibility and inherent antimicrobial properties, the nanohesives provide a promising strategy in the field of hydrogel based engineering.

[Progress in Application of Concentrated Growth Factor in Oral Tissue Regeneration].

Tissue regeneration is an important engineering method for the treatment of oral soft and hard tissue defects.Growth factors,as one of the three elements of tissue regeneration,are a necessary condition for tissue regeneration.Concentrated growth factor(CGF)is a new generation of blood extract prepared by changing the centrifugal speed on the basis of the preparation of platelet-rich plasma(PRP)and platelet-rich fibrin(PRF).It contains abundant growth factors and a fibrin matrix with a three-dimensional network structure,being capable of activating angiogenesis and promoting tissue regeneration and healing.CGF has been widely used in the repair and regeneration of oral soft and hard tissues.This paper introduces the preparation and composition of CGF and reviews the application of CGF in oral implantation and the regeneration of oral bone tissue,periodontal tissue,and dental pulp tissue.

A Study of Two Novel Techniques for One-stage Closure of Chronic Oroantral Fistula and Sinus Floor Lift.

PURPOSE: This study aimed to compare two novel techniques for chronic oroantral fistula (OAF) closure combined with maxillary sinus floor elevation. MATERIALS AND METHODS: Ten patients who had implant installation needs but suffered from a chronic OAF were enrolled in the study from January 2016 to June 2021. The technique applied involved OAF closure and simultaneous sinus floor elevation by either a transalveolar or lateral window approach. Bone graft material evaluation results, postoperative clinical symptoms and complications were compared between the two groups. Student's t -test and χ 2 test were used to analyze the results. RESULTS: In this study, 5 patients with a chronic OAF were treated with the transalveolar approach (group I), and 5 were treated with the lateral window approach (group II). The alveolar bone height was significantly higher in group II than in group I ( P ＜0.001). The pain at 1 day ( P =0.018) and 3 days ( P =0.029) postoperatively and facial swelling at 7 days ( P =0.016) postoperatively were obviously greater in group II than in group I. There were no severe complications in either group. CONCLUSIONS: The techniques combined OAF closure with sinus lifting to reduce surgical frequency and risks. The transalveolar approach resulted in milder postoperative reactions, but the lateral approach could provide more bone volume.

Rapid induction and long-term self-renewal of neural crest-derived ectodermal chondrogenic cells from hPSCs.

Articular cartilage is highly specific and has limited capacity for regeneration if damaged. Human pluripotent stem cells (hPSCs) have the potential to generate any cell type in the body. Here, we report the dual-phase induction of ectodermal chondrogenic cells (ECCs) from hPSCs through the neural crest (NC). ECCs were able to self-renew long-term (over numerous passages) in a cocktail of growth factors and small molecules. The cells stably expressed cranial neural crest-derived mandibular condylar cartilage markers, such as MSX1, FOXC1 and FOXC2. Compared with chondroprogenitors from iPSCs via the paraxial mesoderm, ECCs had single-cell transcriptome profiles similar to condylar chondrocytes. After the removal of the cocktail sustaining self-renewal, the cells stopped proliferating and differentiated into a homogenous chondrocyte population. Remarkably, after transplantation, this cell lineage was able to form cartilage-like structures resembling mandibular condylar cartilage in vivo. This finding provides a framework to generate self-renewing cranial chondrogenic progenitors, which could be useful for developing cell-based therapy for cranial cartilage injury.

Improved Muscle Regeneration into a Joint Prosthesis with Mechano-Growth Factor Loaded within Mesoporous Silica Combined with Carbon Nanotubes on a Porous Titanium Alloy.

Total joint replacement (TJR) is widely applied as a promising treatment for the reconstruction of serious joint diseases but is usually characterized by critical loss of skeletal muscle attachment to metal joint prostheses, resulting in fibrous scar tissue formation and subsequent motor dysfunction. Tissue engineering technology may provide a potential strategy for skeletal muscle regeneration into metal joint prostheses. Here, a porous titanium (Ti) alloy scaffold coated with carbon nanotubes (CNTs) and mesoporous silica nanoparticles (MSNs) through electrophoretic deposition (EPD) was designed as a mechano-growth factor (MGF) carrier. This two-layered coating exhibits a nanostructured topology, excellent MGF loading, and prolonged release performance via covalent bonding to improve myoblast adhesion, proliferation and myogenic differentiation in porous Ti alloy scaffolds without cytotoxicity. The Akt/mTOR signaling pathway plays a key role in this process. Furthermore, in vivo studies show that the scaffold promotes the growth of muscle, rather than fibrotic tissue, into the porous Ti alloy structure and improves muscle-derived mechanical properties, the migration of satellite cells, and possibly immunomodulation. In summary, this nanomaterial-coated scaffold provides a practical biomaterial platform to regenerate periprosthetic muscle tissue and restore comparable motor function to that of the natural joint.

[Effect of rat allogeneic BMSCs-Bio-Oss-bFGF compound on tooth extraction healing: a micro-CT study].

PRUPOSE: To investigate the effect of a compound of BMSCs-Bio-Oss-bFGF on microstructure of extraction sockets in rats. METHODS: Bone mesenchymal stem cells (BMSCs) were isolated from bone marrow of 3-week SD rats by adherent method. Maxillary posterior teeth of 36 6-week SD rats were extracted and materials were implanted into sockets according to grouping. The rats were divided into 4 groups: compound group with implanting BMSCs-Bio-Oss-bFGF compound, powder group with implanting Bio-Oss, BMSCs group with implanting BMSCs, and control group without implanting any materials. The sockets were scanned by micro-CT 4 weeks, 12 weeks and 24 weeks after implantation. Two-way ANOVA was used to assess whether there was significant difference between groups with GraphPad Prism 6.0 software package. RESULTS: There was no significant difference among groups in bone mineral density (BMD), trabecular separation(Tb.Sp), trabecular thickness(Tb.Th), degree of anisotropy(DA), and trabecular number(Tb.N) 4 weeks after implantation. By 12 weeks, BMD of compound group was significantly greater than those of BMSCs group, powder group and control group (P＜0.05), and significantly greater than those of powder group and control group at 24 weeks (P＜0.05). Tb.Th of compound group was significantly greater than that of BMSCs group at 12 and 24 weeks(P＜0.05). DA had no significant difference among groups at 4, 12, and 24 weeks (P＞0.05). Tb.Sp of compound group was significantly smaller than those of powder group, BMSCs group and control group at 24 weeks(P＜0.05). Tb.N of compound group was significantly greater than those of BMSCs group and control group(P＜0.05). CONCLUSIONS: The compound of rat allogeneic BMSCs-Bio-Oss-bFGF improves socket healing.

Experts' consensus on perioperative management of tooth extractions in patients receiving oral antithrombotic treatment.

Thromboembolic diseases, which comprise venous thromboembolic diseases and arterial thromboembolic diseases, have become the number one cause of death worldwide. To prevent or treat thrombosis, patients with thromboembolic diseases need to take antithrombotic drugs, which would increase the risk of bleeding during and after surgery. Tooth extraction is the most common operation in oral and maxillofacial surgery clinics. Although patients given oral antithrombotic drugs do not need to undergo drug withdrawal, the perioperative management of such patients remains confusing to most clinicians. Moreover, the potential risk factors for bleeding warrant further study. To improve the clinicians' knowledge of perioperative management for patients subjected to tooth extractions with oral antithrombotic drugs, experts have drafted this consensus focusing on preoperative bleeding risk assessment, intraoperative operating norms, and postoperative care to summarize the points needing attention.

A single-cell interactome of human tooth germ from growing third molar elucidates signaling networks regulating dental development.

BACKGROUND: Development of dental tissue is regulated by extensive cell crosstalk based on various signaling molecules, such as bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) pathways. However, an intact network of the intercellular regulation is still lacking. RESULT: To gain an unbiased and comprehensive view of this dental cell interactome, we applied single-cell RNA-seq on immature human tooth germ of the growing third molar, discovered refined cell subtypes, and applied multiple network analysis to identify the central signaling pathways. We found that immune cells made up over 80% of all tooth germ cells, which exhibited profound regulation on dental cells via Transforming growth factor-ß, Tumor necrosis factor (TNF) and Interleukin-1. During osteoblast differentiation, expression of genes related to extracellular matrix and mineralization was continuously elevated by signals from BMP and FGF family. As for the self-renewal of apical papilla stem cell, BMP-FGFR1-MSX1 pathway directly regulated the G0-to-S cell cycle transition. We also confirmed that Colony Stimulating Factor 1 secreted from pericyte and TNF Superfamily Member 11 secreted from osteoblast regulated a large proportion of genes related to osteoclast transformation from macrophage and monocyte. CONCLUSIONS: We constructed the intercellular signaling networks that regulated the essential developmental process of human tooth, which served as a foundation for future dental regeneration engineering and the understanding of oral pathology.

Upregulation of ETV2 Expression Promotes Endothelial Differentiation of Human Dental Pulp Stem Cells.

The lack of vasculogenesis often hampers the survivability and integration of newly engineered tissue grafts within the host. Autologous endothelial cells (ECs) are an ideal cell source for neovascularization, but they are limited by their scarcity, lack of proliferative capacity, and donor site morbidity upon isolation. The objective of this study was to determine whether differentiation of human dental pulp stem cells (DPSCs) into the endothelial lineage can be enhanced by recombinant ETV2 overexpression. DPSCs were extracted from fresh dental pulp tissues. ETV2 overexpression in DPSCs was achieved by lentiviral infection and cellular morphological changes were evaluated. The mRNA and protein expression levels of endothelial-specific markers were assessed through quantitative real-time polymerase chain reaction, western blot, immunofluorescence staining, and flow cytometry. The tube formation assay and Matrigel plug assay were also performed to evaluate the angiogenic potential of the ETV2-transduced cells in vitro and in vivo, respectively. Additionally, proteomic analysis was performed to analyze global changes in protein expression following ETV2 overexpression. After lentiviral infection, ETV2-overexpressing DPSCs showed endothelial-like morphology. Compared with control DPSCs, significantly higher mRNA and protein expression levels of endothelial-specific genes, including CD31, VE-Cadherin, VEGFR1, and VEGFR2, were detected in ETV2-overexpressing DPSCs. Moreover, ETV2 overexpression enhanced capillary-like tube formation on Matrigel in vitro, as well as neovascularization in vivo. In addition, comparative proteomic profiling showed that ETV2 overexpression upregulated the expression of vascular endothelial growth factor (VEGF) receptors, which was indicative of increased VEGF signaling. Taken together, our results indicate that ETV2 overexpression significantly enhanced the endothelial differentiation of DPSCs. Thus, this study shows that DPSCs can be a promising candidate cell source for tissue engineering applications.

Timing of force application on buccal tooth movement into bone-grafted alveolar defects: A pilot study in dogs.

INTRODUCTION: The aim of this pilot study was to evaluate the effect of the timing of postoperative orthodontic force application on bone remodeling during tooth movement into surgical alveolar defects with bone grafts in beagle dogs. METHODS: Six beagle dogs underwent surgery for buccal dehiscence-type defects (width, 5 mm; height, 6 mm) on the distal root of maxillary second premolars bilaterally for 12 defects. After 1-month healing, bone-augmentation procedures were undertaken at the dehiscence defects. The second premolars were protracted buccally for 6 weeks into the surgical sites immediately (F-0), at 4 weeks (F-4), or 8 weeks (F-8) after grafting. Orthodontic tooth movement was monitored using digital models. Remodeling of alveolar bone was evaluated by histology, histomorphometry, immunohistochemistry, microcomputed tomography, and fluorescence microscopy. RESULTS: Group F-0 showed significant expansion (mean, 2.42 mm) and tipping (mean, 9.03°) after completing orthodontic tooth treatment. The vertical bone defect was significantly lower in groups F-4 and F-8 than that in group F-0 (mean, 2.1, 2.7, and 4.5 mm, respectively). In group F-4, the formation of new bone and mineralization were significantly greater than those in groups F-0 and F-8 (P <0.05). Group F-4 showed a minimal amount of bone-material remnants. Immunohistochemistry showed the highest expression of collagen-1 and osteopontin in group F-4, followed by group F-8 and group F-0, which demonstrated high osteoblast activity and enhanced bone remodeling in group F-4. CONCLUSIONS: Orthodontic force application at 4 weeks after an augmentation procedure provided the best functional stimulation for an alveolar bone graft. This strategy enhanced new-bone regeneration and degradation of bone substitutes and, eventually, promoted bone remodeling in the bone-grafted area.

A pH-responsive platform combining chemodynamic therapy with limotherapy for simultaneous bioimaging and synergistic cancer therapy.

Chemodynamic therapy (CDT) was widely exploited for cancer therapy and expected to replace traditional anticancer drug therapies. Generally, CDT needs to combine with extra therapeutic methods for obtaining the optimal therapeutic efficacy of cancer. Herein, a multifunctional theranostic platform combing CDT with limotherapy was developed via nanoselenium (nano-Se)-coated manganese carbonate-deposited iron oxide nanoparticle (MCDION-Se). MCDION-Se could release abundant of Mn2+ ions that catalyzed H2O2 into hydroxyl radicals (·OH) via a Fenton-like reaction, effectively inducing the apoptosis of cancer cells. Besides, nano-Se coated onto MCDION-Se also dramatically activated superoxide dismutase (SOD) and promoted the generation of superoxide anion radicals (SOARs) in tumor tissue. Subsequently, a high content of H2O2 was produced via SOD catalysis of SOARs, further enhancing CDT efficiency. Meanwhile, the nano-Se and Mn2+ ions inhibited the generation of adenosine triphosphate (ATP), thus starving cancer cells. In addition, in vitro and in vivo experiments showed that MCDION-Se could effectively enhance the contrast of tumor tissue and improve the quality of magnetic resonance imaging (MRI). Overall, this work provided a nanoplatform that combined CDT with limotherapy for cancer therapy and simultaneously utilized MRI for monitoring the treatment of tumors.

miRNA-21 promotes osteogenesis via the PTEN/PI3K/Akt/HIF-1α pathway and enhances bone regeneration in critical size defects.

BACKGROUND: Functional reconstruction of maxillofacial bone defects is a considerable clinical challenge. Many studies have emphasized the osteogenic and angiopoietic abilities of stem cells for tissue regeneration. We previously showed that microRNA-21 (miRNA-21) can promote angiogenesis in human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs). In the present study, the role of miRNA-21 in osteogenic differentiation of bone marrow-derived stem cells (BMSCs) was investigated. METHODS: Western blotting and qPCR were performed to investigate the influences of miRNA-21 on osteogenic differentiation of BMSCs. The effects of miRNA-21 on PTEN/PI3K/Akt/HIF-1α pathway were also assessed using western blotting. To further evaluate the roles of miRNA-21 in osteogenesis in vivo, we conducted animal experiments in rat and canine. New bone formation was assessed using micro-CT and histological methods. RESULTS: In the present study, we found that miRNA-21 promotes the migration and osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in vitro. Using gain- and loss-of-function studies, we found that miRNA-21 promoted the osteogenic ability of BMSCs by increasing P-Akt and HIF-1α activation. Finally, we verified the essential role of miRNA-21 in osteogenesis by implanting a miRNA-21-modified BMSCs/ß-tricalcium phosphate (ß-TCP) composite into critical size defects. Radiography, micro-CT, and histology revealed significantly greater volume of new bone formation in the miRNA-21 group than in the control group. CONCLUSION: In conclusion, our study demonstrated an essential role of miRNA-21 in promoting maxillofacial bone regeneration via the PTEN/PI3K/Akt/HIF-1α pathway.

Bi-layered electrospun nanofibrous membrane with osteogenic and antibacterial properties for guided bone regeneration.

Guided bone regeneration (GBR) membranes have the potential to prevent the invasion of epithelial and connective tissues as well as to maintain a stable space for facilitating the ingrowth of regenerative bone tissue. However, the bioactivity and regeneration potential of currently available membranes still need to be improved. In this study, a novel bi-layered membrane with both osteogenic and antibacterial functions was developed for GBR applications. The loose layer (LL) of the membrane was composed of conjugated electrospun poly (lactic-co-glycolic acid) (PLGA)/gelatin nanofibers incorporating dexamethasone-loaded mesoporous silica nanoparticles (DEX@MSNs), while the dense layer (DL) of the membrane consisted of traditionally electrospun PLGA nanofibers loaded with the broad-spectrum antibiotic doxycycline hyclate (DCH). Morphological results showed that the LL (DEX@MSNs/PLGA/Gel) membrane exhibited a porous and loosely packed structure, which was beneficial for cell adhesion and infiltration, while the DL (DCH/PLGA) membrane remained dense enough to act as a barrier. In vitro drug release tests indicated that both DEX and DCH followed a favorable sustained release profile. The cell viability evaluation suggested that the electrospun membranes possessed good cytocompatibility. Furthermore, in vitro osteogenesis analyses demonstrated that the DEX@MSNs/PLGA/Gel composite membrane possessed an enhanced osteoinductive capacity for rat bone marrow stem cells (BMSCs), which was verified by the increased alkaline phosphatase (ALP) activity, the enhanced calcium deposition, and the upregulated osteocalcin (OCN) expression. In vitro antimicrobial experiments revealed the effective antibacterial potency of the DCH/PLGA membrane. In conclusion, the prepared nanocarrier-incorporated bi-layered composite membrane with combined osteogenic and antibacterial properties may be a promising candidate for GBR application.

A biodegradable MnSiO3@Fe3O4 nanoplatform for dual-mode magnetic resonance imaging guided combinatorial cancer therapy.

In this work, a tumor microenvironment (TME)-responsive biodegradable MnSiO3@Fe3O4 nanoplatform for dual-mode magnetic resonance imaging (MRI)-guided combinatorial cancer therapy was constructed. Fe3O4 nanoparticles decorated on the surface of MnSiO3 could effectively obstruct the pores of MnSiO3 and reduce the leakage of anticancer drugs under physiological conditions. The structure of the nanoplatform was broken under the weakly acidic and high-concentration glutathione conditions in the TME, resulting in the separation of the Fe3O4 nanoparticles from the nanoplatform and rapid drug release. In addition, the exfoliated Fe3O4 and released Mn2+ can help reduce the interference between their T1 and T2 contrast abilities, resulting in dual-mode MRI contrast enhancement. Furthermore, during the exfoliation process of the Fe3O4 nanocrystals, the catalytic activity of the Fe3O4 nanocrystals toward a Fenton-like reaction within cancer cells could be improved because of the increase in specific surface area, which led to the generation of highly toxic hydroxyl radicals and induced HeLa cell apoptosis. The nanoplatform also displayed excellent T1-T2 dual-mode MRI contrast enhancement and anticancer activity in vivo with reduced systemic toxicity. Thus, this multifunctional nanoplatform could be a potential nanotheranostic for dual-mode MRI-guided combinatorial cancer therapy.

Superhero Rictor promotes cellular differentiation of mouse embryonic stem cells.

Embryonic stem cells (ESCs) hold great promise for regenerative medicine. To harness the full therapeutic potential of ESCs, better understanding of the molecular mechanisms underlying the maintenance and differentiation of ESCs is required. Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that integrates growth factor receptor signaling with cellular growth and proliferation. Dysregulation of mTOR signaling has been linked to various human diseases including cancer and metabolic syndromes. However, little is known regarding the function of mTOR signaling in the regulation of ES cell differentiation. Here we report that Rictor, a key component of mTORC2, functions as a novel ES cell differentiation promoting factor. Mechanistically, Rictor is able to interact with Prkch and facilitate Prkch phosphorylation at Ser-642. Upon phosphorylation, Prkch promotes Klf4 phosphorylation and inhibits Klf4-dependent E-cadherin expression, thereafter leading to the ES cell differentiation. These findings reveal a novel Rictor-Prkch-Klf4 pathway that plays an important role in the regulation of ES cell differentiation.

Novel mutations identified in patients with tooth agenesis by whole-exome sequencing.

OBJECTIVES: To identify potentially pathogenic mutations for tooth agenesis by whole-exome sequencing. SUBJECTS AND METHODS: Ten Chinese families including five families with ectodermal dysplasia (syndromic tooth agenesis) and five families with selective tooth agenesis were included. Whole-exome sequencing was performed using genomic DNA. Potentially pathogenic mutations were identified after data filtering and screening. The pathogenicity of novel variants was investigated by segregation analysis, in silico analysis, and functional studies. RESULTS: One novel mutation (c.441_442insACTCT) and three reported mutations (c.252delT, c.463C>T, and c.1013C>T) in EDA were identified in families with ectodermal dysplasia. The novel EDA mutation was co-segregated with phenotype. A functional study revealed that NF-κB activation was compromised by the identified mutations. The secretion of active EDA was also compromised detection by western blotting. Novel Wnt10A mutations (c.521T>C and c.653T>G) and EVC2 mutation (c.1472C>T) were identified in families with selective tooth agenesis. The Wnt10A c.521T>C mutation and the EVC2 c.1472C>T mutation were considered as pathogenic for affecting highly conserved amino acids, co-segregated with phenotype and predicted to be disease-causing by SIFT and PolyPhen2. Moreover, several reported mutations in PAX9, Wnt10A, and FGFR3 were also detected. CONCLUSIONS: Our study expanded our knowledge on tooth agenesis spectrum by identifying novel variants.

Composite of Gadolinium-Labeled Dendrimer Nanocluster And Graphene Oxide Nanosheet for Highly Efficient Liver T1-Weighted Imaging Probe.

Magnetic resonance contrast agent employs the use of gadolinium chelates, which has many limitations for clinical use including a low contrast effect, a short diagnostic window, and a brief blood circulation time. On this basis, we designed a gadolinium-labeled dendrimer nanocluster (GdDN) loaded graphene oxide nanosheet (GO-GdDN) to boost T1 contrast ability for imaging in vivo and improve blood circulation time. GO-GdDN presented an ultrahigh r1 relaxivity up to 19.07 mM-1 s-1 in a 9.4 T MR scanner, and a bright contrast image in vitro experiment. In addition, GO-GdDN could be internalized by HepG2 cells and presented strong cell contrast enhancement and reduction of the T1 value in HepG2 cells. In vivo, the retention time of GO-GdDN was significantly improved, so that the accumulation of GO-GdDN in liver was enhanced. Moreover, compared to Gd-DTPA, systemic delivery of GO-GdDN dramatically enhanced the signal-to-noise ratio of liver images, which was helpful for accurate imaging of liver and detection of liver lesions in vivo. Thus, this study demonstrates the utility of a powerful diagnosis tool for liver tumor or lesions.

Effective pH-Activated Theranostic Platform for Synchronous Magnetic Resonance Imaging Diagnosis and Chemotherapy.

Current magnetic resonance imaging (MRI)-guided pH-switching therapeutic platforms have encountered problems such as low relaxation rates, poor pH-switching efficiencies, and a lag in the drug release behind the MRI. Herein, we designed a nanoplatform with tunable pore size, which could match the size of drug molecules for pH-switching MRI and chemotherapy via ultrasmall manganese oxide-capped mesoporous silica nanoparticles (USMO@MSNs). USMO@MSN could quickly dissolve under weakly acidic conditions and leach abundant Mn2+ ions (leaching ratio: 76%), enhancing the MR contrast. The longitudinal relaxation rate ( r1) of USMO@MSNs significantly increased from 0.65 to 5.61 mM-1 s-1 as the pH decreased from 7.4 to 4.5, showing an ultrahigh-efficiency pH-switching T1-weighted MR contrast ability for in vivo tumor. Meanwhile, the matching pore structure allowed effective loading of doxorubicin (DOX) on USMO@MSNs to form smart therapeutic system (USMO@MSNs-DOX). The DOX release rate was strongly proportional to the pH-switching MRI signal of USMO@MSNs-DOX, allowing the release of DOX to be efficiently monitored by MRI. Confocal observations indicated that USMO@MSNs-DOX could be effectively internalized by HSC3 cells, and the entire system showed a good pH-switching theranostic performance for HSC3 cells. Therefore, this simple pH-switching system provides a new avenue for timely cancer diagnosis and personalized therapy.

Functional reconstruction of critical-sized load-bearing bone defects using a Sclerostin-targeting miR-210-3p-based construct to enhance osteogenic activity.

A considerable amount of research has focused on improving regenerative therapy strategies for repairing defects in load-bearing bones. The enhancement of tissue regeneration with microRNAs (miRNAs) is being developed because miRNAs can simultaneously regulate multiple signaling pathways in an endogenous manner. In this study, we developed a miR-210-based bone repair strategy. We identified a miRNA (miR-210-3p) that can simultaneously up-regulate the expression of multiple key osteogenic genes in vitro. This process resulted in enhanced bone formation in a subcutaneous mouse model with a miR-210-3p/poly-l-lactic acid (PLLA)/bone marrow-derived stem cell (BMSC) construct. Furthermore, we constructed a model of critical-sized load-bearing bone defects and implanted a miR-210-3p/ß-tricalcium phosphate (ß-TCP)/bone mesenchymal stem cell (BMSC) construct into the defect. We found that the load-bearing defect was almost fully repaired using the miR-210-3p construct. We also identified a new mechanism by which miR-210-3p regulates Sclerostin protein levels. This miRNA-based strategy may yield novel therapeutic methods for the treatment of regenerative defects in vital load-bearing bones by utilizing miRNA therapy for tissue engineering. STATEMENT OF SIGNIFICANCE: The destroyed maxillofacial bone reconstruction is still a real challenge for maxillofacial surgeon, due to that functional bone reconstruction involved load-bearing. Base on the above problem, this paper developed a novel miR-210-3p/ß-tricalcium phosphate (TCP)/bone marrow-derived stem cell (BMSC) construct (miR-210-3p/ß-TCP/BMSCs), which lead to functional reconstruction of critical-size mandible bone defect. We found that the load-bearing defect was almost fully repaired using the miR-210-3p construct. In addition, we also found the mechanism of how the delivered microRNA activated the signaling pathways of endogenous stem cells, leading to the defect regeneration. This miRNA-based strategy can be used to regenerate defects in vital load-bearing bones, thus addressing a critical challenge in regenerative medicine by utilizing miRNA therapy for tissue engineering.

A tailored nanosheet decorated with a metallized dendrimer for angiography and magnetic resonance imaging-guided combined chemotherapy.

Considering the chemical exchange between gadolinium centers and water protons, nanosystems comprising gadolinium conjugated with high specific area nanocarriers might serve as more robust clinical tools for diagnosis and imaging-guided therapy. Herein, a pH-responsive nanosystem containing graphene oxide conjugated with a folic acid- and gadolinium-labeled dendrimer (FA-GCGLD) to boost its T1 contrast ability was developed, and doxorubicin (DOX) and colchicine (COLC) were efficiently loaded onto this nanosystem (FA-GCGLD-DOX/COLC). This nanosystem showed a prominent T1 contrast with an ultrahigh relaxivity of up to 11.6 mM-1 s-1 and pH-responsive drug release behavior. HepG2 cells treated with FA-GCGLD-DOX/COLC were efficiently inhibited, and the cell contrast was enhanced. In vivo, the tumor accumulation of FA-GCGLD-DOX/COLC significantly increased, thereby facilitating the systemic delivery of particles and exerting tumor growth inhibition and an enhanced tumor contrast effect. Moreover, compared to free drugs, FA-GCGLD-DOX/COLC effectively decreased the drug resistance of the tumor, thereby improving the cancer chemotherapeutic efficacy. In addition, injecting rats with FA-GCGLD afforded excellent magnetic resonance angiography (MRA) images with high-resolution vascular structures because of the long blood circulation time of FA-GCGLD. Thus, this study provides a powerful tool for diverse applications in the biomedical field, including accurate diagnosis and chemotherapy of tumors and the detection of cardiovascular diseases.