TNF-α-licensed exosome-integrated titaniumaccelerated T2D osseointegration by promoting autophagy-regulated M2 macrophage polarization.

Type 2 diabetes (T2D) is on a notable rise worldwide, which leads to unfavorable outcomes during implant treatments. Surface modification of implants and exosome treatment have been utilized to enhance osseointegration. However, there has been insufficient approach to improve adverse osseointegration in T2D conditions. In this study, we successfully loaded TNF-α-treated mesenchymal stem cell (MSC)-derived exosomes onto micro/nano-network titanium (Ti) surfaces. TNF-α-licensed exosome-integrated titanium (TNF-exo-Ti) effectively enhanced M2 macrophage polarization in hyperglycemic conditions, with increased secretion of anti-inflammatory cytokines and decreased secretion of pro-inflammatory cytokines. In addition, TNF-exo-Ti pretreated macrophage further enhanced angiogenesis and osteogenesis of endothelial cells and bone marrow MSCs. More importantly, TNF-exo-Ti markedly promoted osseointegration in T2D mice. Mechanistically, TNF-exo-Ti activated macrophage autophagy to promote M2 polarization through inhibition of the PI3K/AKT/mTOR pathway, which could be abolished by PI3K agonist. Thus, this study established TNF-α-licensed exosome-immobilized titanium surfaces that could rectify macrophage immune states and accelerate osseointegration in T2D conditions.

Mesenchymal stem cell-derived apoptotic vesicles ameliorate impaired ovarian folliculogenesis in polycystic ovary syndrome and ovarian aging by targeting WNT signaling.

Rationale: It has been emergingly recognized that apoptosis generates plenty of heterogeneous apoptotic vesicles (apoVs), which play a pivotal role in the maintenance of organ and tissue homeostasis. However, it is unknown whether apoVs influence postnatal ovarian folliculogenesis. Methods: Apoptotic pathway deficient mice including Fas mutant (Fasmut ) and Fas ligand mutant (FasLmut ) mice were used with apoV replenishment to evaluate the biological function of apoVs during ovarian folliculogenesis. Ovarian function was characterized by morphological analysis, biochemical examination and cellular assays. Mechanistical studies were assessed by combinations of transcriptomic and proteomic analysis as well as molecular assays. CYP17A1-Cre; Axin1fl /fl mice was established to verify the role of WNT signaling during ovarian folliculogenesis. Polycystic ovarian syndrome (PCOS) mice and 15-month-old mice were used with apoV replenishment to further validate the therapeutic effects of apoVs based on WNT signaling regulation. Results: We show that systemic administration of mesenchymal stem cell (MSC)-derived apoptotic vesicles (MSC-apoVs) can ameliorate impaired ovarian folliculogenesis, PCOS phenotype, and reduced birth rate in Fasmut and FasLmut mice. Mechanistically, transcriptome analysis results revealed that MSC-apoVs downregulated a number of aberrant gene expression in Fasmut mice, which were enriched by kyoto encyclopedia of genes and genomes (KEGG) pathway analysis in WNT signaling and sex hormone biosynthesis. Furthermore, we found that apoptotic deficiency resulted in aberrant WNT/ß-catenin activation in theca and mural granulosa cells, leading to responsive action of dickkopf1 (DKK1) in the cumulus cell and oocyte zone, which downregulated WNT/ß-catenin expression in oocytes and, therefore, impaired ovarian folliculogenesis via NPPC/cGMP/PDE3A/cAMP cascade. When WNT/ß-catenin was specially activated in theca cells of CYP17A1-Cre; Axin1fl /fl mice, the same ovarian impairment phenotypes observed in apoptosis-deficient mice were established, confirming that aberrant activation of WNT/ß-catenin in theca cells caused the impairment of ovarian folliculogenesis. We firstly revealed that apoVs delivered WNT membrane receptor inhibitor protein RNF43 to ovarian theca cells to balance follicle homeostasis through vesicle-cell membrane integration. Systemically infused RNF43-apoVs down-regulated aberrantly activated WNT/ß-catenin signaling in theca cells, contributing to ovarian functional maintenance. Since aging mice have down-regulated expression of WNT/ß-catenin in oocytes, we used MSC-apoVs to treat 15-month-old mice and found that MSC-apoVs effectively ameliorated the ovarian function and fertility capacity of these aging mice through rescuing WNT/ß-catenin expression in oocytes. Conclusion: Our studies reveal a previously unknown association between apoVs and ovarian folliculogenesis and suggest an apoV-based therapeutic approach to improve oocyte function and birth rates in PCOS and aging.

Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.

Insights into the toxicological effects of nanomaterials on atherosclerosis: mechanisms involved and influence factors.

Atherosclerosis is one of the most common types of cardiovascular disease and is driven by lipid accumulation and chronic inflammation in the arteries, which leads to stenosis and thrombosis. Researchers have been working to design multifunctional nanomedicines with the ability to target, diagnose, and treat atherosclerosis, but recent studies have also identified that nanomaterials can cause atherosclerosis. Therefore, this review aims to outline the molecular mechanisms and physicochemical properties of nanomaterials that promote atherosclerosis. By analyzing the toxicological effects of nanomaterials on cells involved in the pathogenesis of atherosclerosis such as vascular endothelial cells, vascular smooth muscle cells and immune cells, we aim to provide new perspectives for the prevention and treatment of atherosclerosis, and raise awareness of nanotoxicology to advance the clinical translation and sustainable development of nanomaterials.

Use of an occlusal ramp for rehabilitation after a mandibulectomy and its effects on mastication.

STATEMENT OF PROBLEM: Patients with a mandibular defect can develop mandibular deviation, resulting in a loss of or reduction in occlusal contact and ultimately loss of function. The occlusal ramp is a prosthesis used to help restore the masticatory function of such patients and is used particularly in the maxillofacial rehabilitation of patients with masticatory dysfunction resulting from mandibular deviation. The occlusal ramp is usually attached to a mandibular denture or worn as an independent device placed on the palate corresponding to the mandible that produces the offset. However, evidence of the effects of its use is sparse. PURPOSE: The purpose of this clinical study was to investigate the effects of occlusal ramp use in functional rehabilitation. MATERIALS AND METHODS: This study included 10 patients who had received mandibulectomies (5 men and 5 women; mean age 76.7 years, range 67 to 90 years) with deviation of the mandible. An occlusal ramp was fabricated for each participant as part of their maxillofacial prosthetic treatment. Masticatory performance was evaluated before and after the treatment by measuring glucose extraction while masticating a piece of gummy jelly. The Wilcoxon signed-rank test was used for statistical analysis (α=.05). RESULTS: The median masticatory performance score, represented as glucose concentration (mg/dL), was 82.45 before treatment and 115.45 after treatment, with an overall improvement of 33.00. Scores differed significantly before and after treatment (P=.005). Masticatory performance for each participant improved in the range of 17.7 to 103.3, highlighting the role that the occlusal ramp played in mastication, although with differing effects in each participant. CONCLUSIONS: Masticatory performance in participants with mandibular deviation after a mandibulectomy was significantly improved with an occlusal ramp. This suggests the effectiveness of using occlusal ramps in maxillofacial prosthetic treatment for the recovery of masticatory function in patients with mandibular deviation.

Three-dimensional evaluation of the dental arch in cleft lip and palate after prosthetic treatment.

PURPOSE: This study aimed to evaluate the stability of the surface of the maxillary teeth and mucosa in cleft lip and palate (CLP) patients with a maxilla defect or tissue deficiency according to the duration of observation and cleft type. METHODS: Pairs of maxillary casts taken from 18 patients at different time points after prosthodontic treatment were investigated in this study. All 36 casts were scanned with an intraoral scanner, and the acquired images were saved in standard tesselation language (STL) files. The two STL files for each patient were then superimposed using three-dimensional (3D) evaluation software, with 3D deviations shown as a color map. Areas with a 3D deviation within ±0.100 mm were defined as stable. The influence of cleft type and duration of observation on the ratio of stable areas to the entire maxillary surface comprising the teeth and mucosa was investigated using multiple regression analysis. Statistical significance was set at p <0.05. RESULTS: Multiple regression analysis showed that the duration of observation was significantly associated with the stable area ratio (B = -23.463, P<.001), whereas cleft type was not (ß = 0.13, P = 0.301). CONCLUSIONS: The maxillary teeth and mucosa of CLP patients changed over time, with stable areas showing a negative correlation with the observation period. However, the stability of the dental arch was not significantly affected by the cleft type. 3D analysis of the casts of CLP patients allowed for measurements and to accurately assess relapse of the maxillary arch after prosthetic treatment.

Evaluating the Feasibility and Accuracy of Digitizing a Maxillary Defect Model Simulating Various Trismus Conditions.

PURPOSE: To compare the feasibility and accuracy of using intraoral scanners to digitize a maxillary defect model simulating various trismus conditions. MATERIALS AND METHODS: Four intraoral scanners were used to digitize a maxillary defect model simulating four different degrees of trismus (mouth opening = 10, 20, 30, and 40 mm), and the scanned areas were compared. The scans were also superimposed on each other for precision analysis and on reference data for trueness analysis using 3D evaluation software. Two-way ANOVA was used to compare area, precision, and trueness among scanners and among conditions. RESULTS: The surface area for which 3D data were obtained by the intraoral scanners ranged from 2,672 to 6,613 mm2. Significant differences were observed between the scanners (P < .001) and between the trismus conditions (P < .001), with a smaller scanned surface area in severe trismus (10 mm). Trueness ranged from 0.033 to 0.301 mm, and precision from 0.022 to 0.397 mm. Significant differences in trueness and precision values were found among the scanners (P = .001 and P = .001, respectively), but not the trismus conditions (P = .260 and P = .075, respectively). CONCLUSION: Although trueness and precision differed between intraoral scanners, digitization of the maxillectomy model simulating various trismus conditions appears to be feasible from the perspective of accuracy with all of the scanners used. The smaller scanned surface area in the severe trismus condition was due to lack of data on the defect site in that condition.

How Nanoparticles Open the Paracellular Route of Biological Barriers: Mechanisms, Applications, and Prospects.

Biological barriers are essential physiological protective systems and obstacles to drug delivery. Nanoparticles (NPs) can access the paracellular route of biological barriers, either causing adverse health impacts on humans or producing therapeutic opportunities. This Review introduces the structural and functional influences of NPs on the key components that govern the paracellular route, mainly tight junctions, adherens junctions, and cytoskeletons. Furthermore, we evaluate their interaction mechanisms and address the influencing factors that determine the ability of NPs to open the paracellular route, which provides a better knowledge of how NPs can open the paracellular route in a safer and more controllable way. Finally, we summarize limitations in the research models and methodologies of the existing research in the field and provide future research direction. This Review demonstrates the in-depth causes for the reversible opening or destruction of the integrity of barriers generated by NPs; more importantly, it contributes insights into the design of NP-based medications to boost paracellular drug delivery efficiency.

Feasibility of Intraoral Scanning for Data Acquisition of Maxillectomy Defects.

PURPOSE: To assess the feasibility of using an intraoral scanner for data acquisition of maxillectomy defects. MATERIALS AND METHODS: In 10 patients who had undergone a maxillectomy, the maxillectomy defects in dentate and edentulous maxillary arches were intraorally scanned. Intraoral photographs were also taken using a digital camera for comparison. RESULTS: Adequate scanning was achieved for the nondefect side of the maxilla and for residual teeth. In some cases, it was impossible to scan the maxillectomy defect, especially the deep sites. CONCLUSION: Improved intraoral scanning technology will increase the feasibility of its use in maxillofacial prosthetics.