Mesenchymal Stem Cells-Derived Apoptotic Extracellular Vesicles (ApoEVs): Mechanism and Application in Tissue Regeneration.

Mesenchymal stem cells (MSCs) are commonly used as a source for cellular therapy owing to their strong immunosuppressive and regenerative effects. However, MSCs undergo extensive apoptosis within a short period after transplantation. During apoptosis, MSCs generate several apoptotic extracellular vesicles (MSCs-ApoEVs). MSCs-ApoEVs are rich in miRNomes, metabolites, and proteomes. They are critical intercellular communication mediators that can exert different regulatory effects on recipient cells. MSCs-ApoEVs have been shown to promote regeneration in the skin, hair, bone, muscle, and vascular system, etc. This review describes the production, release, isolation, and functionality of ApoEVs in detail. Furthermore, we summarize the existing mechanisms of MSCs-ApoEVs used for tissue regeneration and evaluate the possible strategies for their clinical application.

Inhibition of Adipocyte Necroptosis Alleviates Fat Necrosis and Fibrosis After Grafting in a Murine Model.

BACKGROUND: Because of the delicate structure of the adipose tissue, fat necrosis accounts for 43.7% of all complications after autologous fat grafting; however, its regulation remains unclear. OBJECTIVES: The purpose of this study was to examine the role of necroptosis in fat graft remodeling after grafting. METHODS: Clinical fat graft necrosis samples were collected, and the expression levels of the necroptosis marker phosphorylated(p)-MLKL were analyzed. Transcriptome analysis was performed on fat grafts before and 1 week after transplantation in C57BL/6 mouse fat grafting models. Additionally, the in vivo effects of RIPK1 inhibitor Nec-1s or RIPK3 inhibitor GSK'872 on the fat grafting complications, including fat necrosis and fibrosis, were investigated. RESULTS: Necroptosis markers were observed and associated with higher occurrence of fibrosis in clinical fat graft necrosis samples compared to normal fat tissue. Amplification and RNA-Seq were conducted on RNA isolated from fat grafts before and after grafting. MLKL, RIPK1, and RIPK3's expression levels were significantly upregulated in comparison to controls. Higher expression levels of necroptotic RNAs were associated with higher levels of DAMPs, including Cxcl2, HMGB1, S100a8, S100a9, Nlrp3, and IL33, and activated proinflammatory signaling pathways, including the TNF, NF-kappa B, and chemokine signaling pathways. Necroptotic inhibitor Nec-1s and GSK'872 robustly suppressed the p-MLKL expression level and significantly inhibited necroptotic cell death, especially in adipocytes. Moreover, administration of Nec-1s and GSK'872 significantly alleviated fat necrosis and subsequent fibrosis in fat grafts. CONCLUSIONS: Collectively, our study findings highlight the potential therapeutic applications of necroptosis inhibitors in preventing fat necrosis and fibrosis after grafting.

Delocalizing Excitation for Highly-Active Organic Photovoltaic Catalysts.

Localized excitation in traditional organic photocatalysts typically prevents the generation and extraction of photo-induced free charge carriers, limiting their activity enhancement under illumination. Here, we enhance delocalized photoexcitation of small molecular photovoltaic catalysts by weakening their electron-phonon coupling via rational fluoro-substitution. The optimized 2FBP-4F catalyst we develop here exhibits a minimized Huang-Rhys factor of 0.35 in solution, high dielectric constant and strong crystallization in the solid state. As a result, the energy barrier for exciton dissociation is decreased, and more importantly, polarons are unusually observed in 2FBP-4F nanoparticles (NPs). With the increased hole transfer efficiency and prolonged charge carrier lifetime highly related to enhanced exciton delocalization, the PM6 : 2FBP-4F heterojunction NPs at varied concentration exhibit much higher optimized photocatalytic activity (207.6-561.8 mmol h-1 g-1) for hydrogen evolution than the control PM6 : BP-4F and PM6 : 2FBP-6F NPs, as well as other reported photocatalysts under simulated solar light (AM 1.5G, 100 mW cm-2).

Suppressing Exciton-Vibration Coupling to Prolong Exciton Lifetime of Nonfullerene Acceptors Enables High-Efficiency Organic Solar Cells.

The limited exciton lifetime (τ, generally <1 ns) leads to short exciton diffusion length (LD ) of organic semiconductors, which is the bottleneck issue impeding the further improvement of power conversion efficiencies (PCEs) for organic solar cells (OSCs). However, efficient strategies to prolong intrinsic τ are rare and vague. Herein, we propose a facile method to efficiently reduce vibrational frequency of molecular skeleton and suppress exciton-vibration coupling to decrease non-radiative decay rate and thus prolong τ via deuterating nonfullerene acceptors. The τ remarkably increases from 0.90 ns (non-deuterated L8-BO) to 1.35 ns (deuterated L8-BO-D), which is the record for organic photovoltaic materials. Besides, the inhibited molecular vibration improves molecular planarity of L8-BO-D for enhanced exciton diffusion coefficient. Consequently, the LD increases from 7.9 nm (L8-BO) to 10.7 nm (L8-BO-D). The prolonged LD of L8-BO-D enables PM6 : L8-BO-D-based bulk heterojunction OSCs to acquire higher PCEs of 18.5 % with more efficient exciton dissociation and weaker charge carrier recombination than PM6 : L8-BO-based counterparts. Moreover, benefiting from the prolonged LD , D18/L8-BO-D-based pseudo-planar heterojunction OSCs achieve an impressive PCE of 19.3 %, which is among the highest values. This work provides an efficient strategy to increase the τ and thus LD of organic semiconductors, boosting PCEs of OSCs.

LncRNA34977 promotes the proliferation, migration, and invasion and inhibits the apoptosis of canine mammary tumors by regulating the expression of miR-8881/ELAVL4.

Long-stranded noncoding RNAs (lncRNAs) play different roles in various diseases. lncRNA34977 has been shown to play a relevant role the development of canine mammary tumors (CMTs). However, the mechanism of lncRNA34977 in canine mammary tumors has not been fully investigated. The aim of this study was to investigate the effects of lncRNA34977 on the proliferation, migration, invasion, and apoptosis of canine mammary tumor (CMT) cells through the regulation of miR-8881/ELAVL4 expression. The apoptosis was detected by an in situ fluorescence assay and flow cytometry. The expression levels were analyzed by RT-qPCR. CCK-8, colony formation, wound healing, and Transwell assays were used to assess the proliferation, migration, and invasion. The expression of protein was detected by western blot. The siRNA-induced silencing of lncRNA34977 promoted the apoptosis of CHMp cells, and in overexpression of lncRNA34977, the result is the opposite. LncRNA34977 has a direct targeting relationship with miR-8881 and that miR-8881 is correlated with ELAVL4. Transfection of miR-8881 mimics inhibited the proliferation, migration, invasion, and promoted the apoptosis of CHMp cells of CHMp cells. In the transfection with miR-8881 inhibitors, the result is the opposite. Co-transfected with lncRNA34977, miR-8881, or ELAVL4, we found that lncRNA34977 could regulate the expression of miR-8881 or ELAVL4. Our study shows that lncRNA34977 promotes the proliferation, migration, and invasion and suppresses the apoptosis of CMT cells by regulating the expression of miR-8881/ELAVL4.

Mild Photothermal-Stimulation Based on Injectable and Photocurable Hydrogels Orchestrates Immunomodulation and Osteogenesis for High-Performance Bone Regeneration.

A photoactivated bone scaffold integrated with minimally invasive implantation and mild thermal-stimulation capability shows great promise in the repair and regeneration of irregularly damaged bone tissues. Developing multifunctional photothermal biomaterials that can simultaneously serve as both controllable thermal stimulators and biodegradable engineering scaffolds for integrated immunomodulation, infection therapy, and impaired bone repair remains an enormous challenge. Herein, an injectable and photocurable hydrogel therapeutic platform (AMAD/MP) based on alginate methacrylate, alginate-graft-dopamine, and polydopamine (PDA)-functionalized Ti3C2 MXene (MXene@PDA) nanosheets is rationally designed for near-infrared (NIR)-mediated bone regeneration synergistic immunomodulation, osteogenesis, and bacterial elimination. The optimized AMAD/MP hydrogel exhibits favorable biocompatibility, osteogenic activity, and immunomodulatory functions in vitro. The proper immune microenvironment provided by AMAD/MP could further modulate the balance of M1/M2 phenotypes of macrophages, thereby suppressing reactive oxygen species-induced inflammatory status. Significantly, this multifunctional hydrogel platform with mild thermal stimulation efficiently attenuates local immune reactions and further promotes new bone formation without the addition of exogenous cells, cytokines, or growth factors. This work highlights the potential application of an advanced multifunctional hydrogel providing photoactivated on-demand thermal cues for bone tissue engineering and regenerative medicine.

Effect of orthodontic treatment with premolar extractions on occlusal planes: A retrospective study.

OBJECTIVE: To figure out whether premolar extractions treatment would influence the cant of the occlusal planes and thus affect dentoskeletal patterns in patients with different types of malocclusions. MATERIALS AND METHODS: A total of 140 post-orthodontic treatment subjects (96 females, 44 males) were included in this study, and their lateral cephalograms and demographic information were collected and analysed. The patients were divided into extraction and non-extraction groups. The ANB, SNA, SNB, Wits, Facial Height Index (FHI), SN-MP, SN-AOP, SN-POP and AOP-POP angle were measured on the cephalograms. Other possible confounding factors were recorded. Data were analysed by univariate analysis, stratified analysis, multivariate analysis, and coefficient analysis. RESULTS: After treatment, the changes in the AOP-SN, POP-SN and AOP-POP angle were statistically different between the extraction and non-extraction groups. The results were consistent in different skeletal malocclusions and extent of crowding according to stratified analysis. After adjusting all confounding factors, the cant of the posterior occlusal plane was flattened further by 2.14 degrees in the extraction group than the non-extraction group after orthodontic treatment, and the AOP-SN and AOP-POP angle would further increase by 1.72 and 3.81 degrees, respectively. Although no significant differences were found between the two groups, the SNA, ANB, and Wits in the extraction group decreased more with increased counterclockwise rotation of the mandible. CONCLUSION: Compared to the non-extraction group, there were more increases in the AOP-SN and AOP-POP angle and more posterior flattening in patients with four premolar extractions despite different types of dentoskeletal malocclusion, which were correlated to the change of variables in sagittal and vertical dimensions such as Wits and FHI.

The Cell-Specific Role of SHP2 in Regulating Bone Homeostasis and Regeneration Niches.

Src homology-2 containing protein tyrosine phosphatase (SHP2), encoded by PTPN11, has been proven to participate in bone-related diseases, such as Noonan syndrome (NS), metachondromatosis and osteoarthritis. However, the mechanisms of SHP2 in bone remodeling and homeostasis maintenance are complex and undemonstrated. The abnormal expression of SHP2 can influence the differentiation and maturation of osteoblasts, osteoclasts and chondrocytes. Meanwhile, SHP2 mutations can act on the immune system, vasculature and nervous system, which in turn affect bone development and remodeling. Signaling pathways regulated by SHP2, such as mitogen-activated protein kinase (MAPK), Indian hedgehog (IHH) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT), are also involved in the proliferation, differentiation and migration of bone functioning cells. This review summarizes the recent advances of SHP2 on osteogenesis-related cells and niche cells in the bone marrow microenvironment. The phenotypic features of SHP2 conditional knockout mice and underlying mechanisms are discussed. The prospective applications of the current agonists or inhibitors that target SHP2 in bone-related diseases are also described. Full clarification of the role of SHP2 in bone remodeling will shed new light on potential treatment for bone related diseases.

Organic Photovoltaic Catalyst with Extended Exciton Diffusion for High-Performance Solar Hydrogen Evolution.

The short exciton diffusion length (LD) associated with most classical organic photocatalysts (5-10 nm) imposes severe limits on photocatalytic hydrogen evolution efficiency. Here, a photovoltaic molecule (F1) without electron-deficient units at the central building block was designed and synthesized to improve the photoluminescence quantum yield (PLQY). With the enhanced PLQY of 9.3% and a large integral spectral overlap of 3.32 × 1016 nm4 M-1 cm-1, the average LD of F1 film increases to 20 nm, nearly twice the length of the control photovoltaic molecule (Y6). Then, the single-component organic nanoparticles (SC-NPs) based on F1 show an optimized average hydrogen evolution rate (HER) of 152.60 mmol h-1 g-1 under AM 1.5G sunlight (100 mW cm-2) illumination for 10 h, which is among the best results for photocatalytic hydrogen evolution.

Plant Biomass and Soil Nutrients Mainly Explain the Variation of Soil Microbial Communities During Secondary Succession on the Loess Plateau.

Soil microorganisms play an important role in the circulation of materials and nutrients between plants and soil ecosystems, but the drivers of microbial community composition and diversity remain uncertain in different vegetation restoration patterns. We studied soil physicochemical properties (i.e., soil moisture, bulk density, pH, soil nutrients, available nutrients), plant characteristics (i.e., Shannon index [HPlant] and Richness index [SPlant], litter biomass [LB], and fine root biomass [FRB]), and microbial variables (biomass, enzyme activity, diversity, and composition of bacterial and fungal communities) in different plant succession patterns (Robinia pseudoacacia [MF], Caragana korshinskii [SF], and grassland [GL]) on the Loess Plateau. The herb communities, soil microbial biomass, and enzyme activities were strongly affected by vegetation restoration, and soil bacterial and fungal communities were significantly different from each other at the sites. Correlation analysis showed that LB and FRB were significantly positively correlated with the Chao index of soil bacteria, soil microbial biomass, enzyme activities, Proteobacteria, Zygomycota, and Cercozoa, while negatively correlated with Actinobacteria and Basidiomycota. In addition, soil water content (SW), pH, and nutrients have important effects on the bacterial and fungal diversities, as well as Acidobacteria, Proteobacteria, Actinobacteria, Nitrospirae, Zygomycota, and microbial biomass. Furthermore, plant characteristics and soil properties modulated the composition and diversity of soil microorganisms, respectively. Overall, the relative contribution of vegetation and soil to the diversity and composition of soil bacterial and fungal communities illustrated that plant characteristics and soil properties may synergistically modulate soil microbial communities, and the composition and diversity of soil bacterial and fungal communities mainly depend on plant biomass and soil nutrients.

Elevation of miR-302b prevents multiple myeloma cell growth and bone destruction by blocking DKK1 secretion.

BACKGROUND: Myeloma bone disease (MBD) is a severe complication of multiple myeloma (MM) mainly due to an imbalance between enhanced osteoclast activity and reduced osteoblast function. Previous studies have demonstrated that miRNAs play a vital role in the osteogenic differentiation of mesenchymal stromal cells (MSCs) in MM. However, the value of miR­302b in MBD remains to be further elucidated. The aim of this study is to explore the role of miR­302b in the regulation of MBD osteogenic differentiation and evaluate the potential of a new therapeutic strategy for the clinical treatment of MBD. METHOD: Our previous research demonstrated that MiR-302b belongs to the miR-302 cluster and is able to inhibit tumor growth and osteolysis in an orthotopic osteosarcoma xenograft tumor mouse model. In this study, we first transfected miR-302b mimics, miR-302b inhibitor, and miR-302b NC into MM1.S and RPMI8226 MM cells to detect the correlation between miR-302b expression in the pathological specimens and the clinicopathological features by qPCR, the target correlation between miR-302b and DKK1 by immunohistochemistry, qPCR and Western blot, and the correlation between miR-302b and the Wnt/ß-catenin signaling pathway by Western blot. The effect of miR-302b on osteoblastogenesis was also studied in a subperiosteal tumorigenesis model of NOD/SCID nude mice. RESULTS: We found that increased miR-302b suppressed cell proliferation and induced cell apoptosis in RPMI 8226 and MM1.S cells. TargetScan online bioinformatic analysis predicted that miR-302b is able to bind to 3'UTR of DKK1 mRNA. Target binding of miR-302b to DKK1 was demonstrated by dual-luciferase reporter assay, qPCR, Western blot and immunohistochemistry, indicating that miR-302b is able to degrade DKK1 in RPMI 8226 and MM1.S cells. The model of co-culturing MM cells with preosteoblast MC3T3-E1 cells showed that miR-302b inhibits MM-induced suppression of osteoblast differentiation. Western blotting showed that miR-302b promotes the Wnt/ß-catenin signaling pathway in MM cells. Micro-CT and immunohistochemistry results showed that miR-302b suppresses myeloma bone destruction in vivo. CONCLUSION: miR-302b is able to target DKK1 and promote the Wnt/ß-catenin signaling pathway in MM.

Bioinspired soft-hard combined system with mild photothermal therapeutic activity promotes diabetic bone defect healing via synergetic effects of immune activation and angiogenesis.

Background: The comprehensive management of diabetic bone defects remains a substantial clinical challenge due to the hostile regenerative microenvironment characterized by aggravated inflammation, excessive reactive oxygen species (ROS), bacterial infection, impaired angiogenesis, and unbalanced bone homeostasis. Thus, an advanced multifunctional therapeutic platform capable of simultaneously achieving immune regulation, bacterial elimination, and tissue regeneration is urgently designed for augmented bone regeneration under diabetic pathological milieu. Methods and Results: Herein, a photoactivated soft-hard combined scaffold system (PGCZ) was engineered by introducing polydopamine-modified zeolitic imidazolate framework-8-loaded double-network hydrogel (soft matrix component) into 3D-printed poly(ε-caprolactone) (PCL) scaffold (hard matrix component). The versatile PGCZ scaffold based on double-network hydrogel and 3D-printed PCL was thus prepared and features highly extracellular matrix-mimicking microstructure, suitable biodegradability and mechanical properties, and excellent photothermal performance, allowing long-term structural stability and mechanical support for bone regeneration. Under periodic near-infrared (NIR) irradiation, the localized photothermal effect of PGCZ triggers the on-demand release of Zn2+, which, together with repeated mild hyperthermia, collectively accelerates the proliferation and osteogenic differentiation of preosteoblasts and potently inhibits bacterial growth and biofilm formation. Additionally, the photoactivated PGCZ system also presents outstanding immunomodulatory and ROS scavenging capacities, which regulate M2 polarization of macrophages and drive functional cytokine secretion, thus leading to a pro-regenerative microenvironment in situ with enhanced vascularization. In vivo experiments further demonstrated that the PGCZ platform in conjunction with mild photothermal therapeutic activity remarkably attenuated the local inflammatory cascade, initiated endogenous stem cell recruitment and neovascularization, and orchestrated the osteoblast/osteoclast balance, ultimately accelerating diabetic bone regeneration. Conclusions: This work highlights the potential application of a photoactivated soft-hard combined system that provides long-term biophysical (mild photothermal stimulation) and biochemical (on-demand ion delivery) cues for accelerated healing of diabetic bone defects.

Smart-Responsive Multifunctional Therapeutic System for Improved Regenerative Microenvironment and Accelerated Bone Regeneration via Mild Photothermal Therapy.

The treatment of bone defects remains a substantial clinical challenge due to the lack of spatiotemporal management of the immune microenvironment, revascularization, and osteogenic differentiation. Herein, deferoxamine (DFO)-loaded black phosphorus nanosheets decorated by polydopamine layer are prepared (BPPD) and compounded into gelatin methacrylate/sodium alginate methacrylate (GA) hybrid hydrogel as a smart-responsive therapeutic system (GA/BPPD) for accelerated bone regeneration. The BPPD nanocomposites served as bioactive components and near-infrared (NIR) photothermal agents, which conferred the hydrogel with excellent NIR/pH dual-responsive properties, realizing the stimuli-responsive release of DFO and PO4 3 - during bone regeneration. Under the action of NIR-triggered mild photothermal therapy, the GA/BPPD hydrogel exhibited a positive effect on promoting osteogenesis and angiogenesis, eliminating excessive reactive oxygen species, and inducing macrophage polarization to the M2 phenotype. More significantly, through macrophage M2 polarization-induced osteoimmune microenvironment, this hydrogel platform could also drive functional cytokine secretion for enhanced angiogenesis and osteogenesis. In vivo experiments further demonstrated that the GA/BPPD system could facilitate bone healing by attenuating the local inflammatory response, increasing the secretion of pro-healing factors, stimulating endogenous cell recruitment, and accelerating revascularization. Collectively, the proposed intelligent photothermal hydrogel platform provides a promising strategy to reshape the damaged tissue microenvironment for augmented bone regeneration.

Manipulating Vertical Phase Separation Enables Pseudoplanar Heterojunction Organic Solar Cells Over 19% Efficiency via Ternary Polymerization.

Controlling vertical phase separation of the active layer to enable efficient exciton dissociation and charge carrier transport is crucial to boost power conversion efficiencies (PCEs) of pseudoplanar heterojunction (PPHJ) organic solar cells (OSCs). However, how to optimize the vertical phase separation of PPHJ OSCs via molecule design is rarely reported yet. Herein, ternary polymerization strategy is employed to develop a series of polymer donors, DL1-DL4, and regulate their solubility, molecular aggregation, molecular orientation, and miscibility, thus efficiently manipulating vertical phase separation in PPHJ OSCs. Among them, DL1 not only has enhanced solubility, inhibited molecular aggregation and partial edge-on orientation to facilitate acceptor molecules, Y6, to permeate into polymer layer and increase donor/acceptor interfaces, but also sustains high crystallinity and appropriate miscibility with Y6 to acquire ordered molecular packing, thus achieving optimized vertical phase separation to well juggle exciton dissociation and charge transport in PPHJ devices. Therefore, DL1/Y6 based PPHJ OSCs gain the best exciton dissociation probability, highest charge carrier mobilities and weakest charge recombination, and thus afford an impressive PCE of 19.10%, which is the record value for terpolymer donors. It demonstrates that ternary polymerization is an efficient method to optimize vertical phase separation in PPHJ OSCs for high PCEs.

Bioorthogonal photocatalytic proximity labeling in primary living samples.

In situ profiling of subcellular proteomics in primary living systems, such as native tissues or clinic samples, is crucial for understanding life processes and diseases, yet challenging due to methodological obstacles. Here we report CAT-S, a bioorthogonal photocatalytic chemistry-enabled proximity labeling method, that expands proximity labeling to a wide range of primary living samples for in situ profiling of mitochondrial proteomes. Powered by our thioQM labeling warhead development and targeted bioorthogonal photocatalytic chemistry, CAT-S enables the labeling of mitochondrial proteins in living cells with high efficiency and specificity. We apply CAT-S to diverse cell cultures, dissociated mouse tissues as well as primary T cells from human blood, portraying the native-state mitochondrial proteomic characteristics, and unveiled hidden mitochondrial proteins (PTPN1, SLC35A4 uORF, and TRABD). Furthermore, CAT-S allows quantification of proteomic perturbations on dysfunctional tissues, exampled by diabetic mouse kidneys, revealing the alterations of lipid metabolism that may drive disease progression. Given the advantages of non-genetic operation, generality, and spatiotemporal resolution, CAT-S may open exciting avenues for subcellular proteomic investigations of primary samples that are otherwise inaccessible.

Effects of chemical boundary conditions on simulated O3 concentrations in China and their chemical mechanisms.

Chemical boundary conditions (BCs) are important inputs for regional chemical transport models. In this study, we use the brute-force method (BFM), process analysis (PA) and response surface model (RSM) to quantify the effects of BCs on simulated O3 concentrations in different regions of China by the weather research and forecasting with chemistry (WRF-Chem) model. We combine the model with an integrated gas-phase reaction rate (IRR) tool to further analyze the changes in the O3 chemical mechanisms. Our results show that the simulated O3 concentrations in western cities are significantly affected by the O3 in the BCs (BC-O3), which can increase the maximum simulated O3 concentration, such as in Lanzhou (36.6 µg/m3, 26.3 %), Wuhai (30.1 µg/m3, 25.5 %) and Urumqi (50.7 µg/m3, 41.2 %). In contrast, O3 generation in the eastern region is dominated by emissions. Subsequently, we compare the reaction rate changes in O3 generation and consumption under the effects of BC-O3 in the western city of Urumqi and the eastern city of Beijing. The results show that in Beijing, the O3 concentration and the related chemical reaction rates undergo little change, while in Urumqi, the concentration and reaction rates have significant differences. The BC-O3 significantly accelerates the O3 photochemical reaction process in Urumqi, resulting in increased O3 generation and consumption reaction rates; additionally, there may be a chemical reaction pathway for the formation of O3: BC-O3 + NO → NO2 + hv → O + O2 → O3. BC-O3 transmission is the main pathway of changes in the simulated O3 concentration in the study area, and the chemical reactions between BC-O3 and local pollutants are primarily characterized by O3 consumption. In conclusion, the study shows the importance of BCs for regional model simulation while providing supporting information for O3 formation in model studies.

Bioinspired Piezoelectric Periosteum to Augment Bone Regeneration via Synergistic Immunomodulation and Osteogenesis.

Ideal periosteum materials are required to participate in a sequence of bone repair-related physiological events, including the initial immune response, endogenous stem cell recruitment, angiogenesis, and osteogenesis. However, conventional tissue-engineered periosteal materials have difficulty achieving these functions by simply mimicking the periosteum via structural design or by loading exogenous stem cells, cytokines, or growth factors. Herein, we present a novel biomimetic periosteum preparation strategy to comprehensively enhance the bone regeneration effect using functionalized piezoelectric materials. The resulting biomimetic periosteum possessing an excellent piezoelectric effect and improved physicochemical properties was prepared using a biocompatible and biodegradable poly(3-hydroxybutyric acid-co-3-hydrovaleric acid) (PHBV) polymer matrix, antioxidized polydopamine-modified hydroxyapatite (PHA), and barium titanate (PBT), which were further incorporated into the polymer matrix to fabricate a multifunctional piezoelectric periosteum by a simple one-step spin-coating method. The addition of PHA and PBT dramatically enhanced the physicochemical properties and biological functions of the piezoelectric periosteum, resulting in improved surface hydrophilicity and roughness, enhanced mechanical performance, tunable degradation behavior, and stable and desired endogenous electrical stimulations, which is conducive to accelerating bone regeneration. Benefiting from endogenous piezoelectric stimulation and bioactive components, the as-fabricated biomimetic periosteum demonstrated favorable biocompatibility, osteogenic activity, and immunomodulatory functions in vitro, which not only promoted adhesion, proliferation, and spreading as well as osteogenesis of mesenchymal stem cells (MSCs) but also effectively induced M2 macrophage polarization, thereby suppressing reactive oxygen species (ROS)-induced inflammatory reactions. Through in vivo experiments, the biomimetic periosteum with endogenous piezoelectric stimulation synergistically accelerated the formation of new bone in a rat critical-sized cranial defect model. The whole defect was almost completely covered by new bone at 8 weeks post treatment, with a thickness close to that of the host bone. Collectively, with its favorable immunomodulatory and osteogenic properties, the biomimetic periosteum developed here represents a novel method to rapidly regenerate bone tissue using piezoelectric stimulation.

Association between the severity of hypodontia and the characteristics of craniofacial morphology in a Chinese population: A cross-sectional study.

Objective: To investigate craniofacial differences in individuals with hypodontia and explore the relationship between craniofacial features and the number of congenitally missing teeth. Methods: A cross-sectional study was conducted among 261 Chinese patients (males, 124; females, 137; age, 7-24 years), divided into four groups (without hypodontia: no teeth missing, mild: one or two missing teeth, moderate: three to five missing teeth, severe: six or more missing teeth) according to the number of congenitally missing teeth. Differences in cephalometric measurements among the groups were analyzed. Further, multivariate linear regression and smooth curve fitting were performed to evaluate the relationship between the number of congenitally missing teeth and the cephalometric measurements. Results: In patients with hypodontia, SNA, NA-AP, FH-NA, ANB, Wits, ANS-Me/N-Me, GoGn-SN, UL-EP, and LL-EP significantly decreased, while Pog-NB, AB-NP, N-ANS, and S-Go/N-Me significantly increased. In multivariate linear regression analysis, SNB, Pog-NB, and S-Go/N-Me were positively related to the number of congenitally missing teeth. In contrast, NA-AP, FH-NA, ANB, Wits, N-Me, ANS-Me, ANS-Me/N-Me, GoGn-SN, SGn-FH (Y-axis), UL-EP, and LL-EP were negatively related, with absolute values of regression coefficients ranging from 0.147 to 0.357. Further, NA-AP, Pog-NB, S-Go/N-Me, and GoGn-SN showed the same tendency in both sexes, whereas UL-EP and LL-EP were different. Conclusions: Compared with controls, patients with hypodontia tend toward a Class III skeletal relationship, reduced lower anterior face height, flatter mandibular plane, and more retrusive lips. The number of congenitally missing teeth had a greater effect on certain characteristics of craniofacial morphology in males than in females.

Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity. Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities. However, the underlying molecular mechanism of these discrepancies remains unclear. The potential role of mechanotransduction in tumorigenicity is of particular interest. To this end, we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo. We utilized a sphere culture model, a soft agar assay, and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells. Additionally, we quantified the expression of sensor proteins, including four kinases and seven cytoskeletal proteins, in OS cell lines. The upstream core transcription factors of rigidity-sensing proteins were further investigated. We detected anoikis resistance in transformed OS cells. The mechanosensing function of transformed OS cells was also impaired, with general downregulation of rigidity-sensing components. We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells. We further uncovered a novel TP53 mutation (R156P) in transformed OS cells, which acquired gain of function to inhibit rigidity sensing, thus sustaining transformed growth. Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment. In addition, the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.