Mechanical force regulates the paracrine functions of ADSCs to assist skin expansion in rats.

BACKGROUND: In the repair of massive tissue defects using expanded large skin flaps, the incidence of complications increases with the size of the expanded area. Currently, stem cell therapy has limitations to solve this problem. We hypothesized that conditioned medium of adipose-derived stem cells (ADSC-CM) collected following mechanical pretreatment can assist skin expansion. METHODS: Rat aortic endothelial cells and fibroblasts were cultured with ADSC-CM collected under 0%, 10%, 12%, and 15% stretching force. Ten-milliliter cylindrical soft tissue expanders were subcutaneously implanted into the backs of 36 Sprague-Dawley rats. The 0% and 10% stretch groups were injected with ADSC-CM collected under 0% and 10% stretching force, respectively, while the control group was not injected. After 3, 7, 14, and 30 days of expansion, expanded skin tissue was harvested for staining and qPCR analyses. RESULTS: Endothelial cells had the best lumen formation and highest migration rate, and fibroblasts secreted the most collagen upon culture with ADSC-CM collected under 10% stretching force. The skin expansion rate was significantly increased in the 10% stretch group. After 7 days of expansion, the number of blood vessels in the expanded area, expression of the angiogenesis-associated proteins vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor, and collagen deposition were significantly increased in the 10% stretch group. CONCLUSIONS: The optimal mechanical force upregulates specific paracrine proteins in ADSCs to increase angiogenesis and collagen secretion, and thereby promote skin regeneration and expansion. This study provides a new auxiliary method to expand large skin flaps.

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.

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).

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.

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.

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.

A Cu@ZIF-8 encapsulated antibacterial and angiogenic microneedle array for promoting wound healing.

Skin wounds caused by external injuries remain a serious challenge in clinical practice. Wound dressings that are antibacterial, pro-angiogenic, and have potent regeneration capacities are highly desirable for wound healing. In this study, a minimally invasive and wound-friendly Cu@ZIF-8 encapsulated PEGDA/CMCS microneedle (MN) array was fabricated using the molding method to promote wound healing. The MNs had good biocompatibility, excellent mechanical strength, as well as strong antibacterial properties and pro-angiogenic effects. When incubated with H2O2, Cu@ZIF-8 nanoparticles generated reactive oxygen species, which contributed to their antibacterial properties. Due to the oxidative stress of the cupric ions released from Cu@ZIF-8 and the anti-bacterial capability of the PEGDA/CMCS hydrogel scaffold, such an MN array presents excellent antibacterial activity. Moreover, with the continuous release of Cu ions from the scaffold, such MNs are effective in terms of promoting angiogenesis. With considerable biocompatibility and a minimally invasive approach, the degradable MN array composed of PEGDA/CMCS possessed superior capabilities to continuously and steadily release the loaded ingredients and avoid secondary damage to the wound. Benefiting from these features, the Cu@ZIF-8 encapsulated degradable MN array can dramatically accelerate epithelial regeneration and neovascularization. These results indicated that the combination of Cu@ZIF-8 and degradable MN arrays is valuable in promoting wound healing, which opened a new window for treatment of skin defection.

Evaluation of safety and efficacy of the bone marrow mesenchymal stem cell and gelatin-nano-hydroxyapatite combination in canine femoral defect repair.

Femoral shaft fracture is a common bone trauma in dogs. The limitation of mesenchymal stem cells in bone defect applications is that the cell suspension cannot be fixed to the bone defect site. In the study, our objective was to substantiate the combined application of canine bone marrow mesenchymal stem cells (cBMSCs) and gelatin-nano-hydroxyapatite (Gel-nHAP) and evaluate its therapeutic effect on bone defect diseases in dogs. Experiments were performed to evaluate the following: (1) the porosity of Gel-nHAP; (2) the adhesion of cBMSCs to Gel-nHAP; and (3) the effect of Gel-nHAP on cBMSC proliferation. The efficacy and safety of the combination of cBMSC and Gel-nHAP in the repair of femoral shaft defects were evaluated in animal experiments. The results showed that Gel-nHAP supported the attachment of cBMSCs and exhibited good biocompatibility. In the animal bone defect repair experiment, significant cortical bone growth was observed in the Gel-nHAP group at week 8 (p < 0.05) and in the cBMSCs-Gel-nHAP group at week 4 (p < 0.01). We demonstrated that Gel-nHAP could promote the repair of bone defects, and the effect of cBMSC-Gel-nHAP on the repair of bone defects was profound.

The marriage of immunomodulatory, angiogenic, and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scaffold for military medicine.

BACKGROUND: Most bone-related injuries to grassroots troops are caused by training or accidental injuries. To establish preventive measures to reduce all kinds of trauma and improve the combat effectiveness of grassroots troops, it is imperative to develop new strategies and scaffolds to promote bone regeneration. METHODS: In this study, a porous piezoelectric hydrogel bone scaffold was fabricated by incorporating polydopamine (PDA)-modified ceramic hydroxyapatite (PDA-hydroxyapatite, PHA) and PDA-modified barium titanate (PDA-BaTiO3, PBT) nanoparticles into a chitosan/gelatin (Cs/Gel) matrix. The physical and chemical properties of the Cs/Gel/PHA scaffold with 0-10 wt% PBT were analyzed. Cell and animal experiments were performed to characterize the immunomodulatory, angiogenic, and osteogenic capabilities of the piezoelectric hydrogel scaffold in vitro and in vivo. RESULTS: The incorporation of BaTiO3 into the scaffold improved its mechanical properties and increased self-generated electricity. Due to their endogenous piezoelectric stimulation and bioactive constituents, the as-prepared Cs/Gel/PHA/PBT hydrogels exhibited cytocompatibility as well as immunomodulatory, angiogenic, and osteogenic capabilities; they not only effectively induced macrophage polarization to M2 phenotype but also promoted the migration, tube formation, and angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) and facilitated the migration, osteo-differentiation, and extracellular matrix (ECM) mineralization of MC3T3-E1 cells. The in vivo evaluations showed that these piezoelectric hydrogels with versatile capabilities significantly facilitated new bone formation in a rat large-sized cranial injury model. The underlying molecular mechanism can be partly attributed to the immunomodulation of the Cs/Gel/PHA/PBT hydrogels as shown via transcriptome sequencing analysis, and the PI3K/Akt signaling axis plays an important role in regulating macrophage M2 polarization. CONCLUSION: The piezoelectric Cs/Gel/PHA/PBT hydrogels developed here with favorable immunomodulation, angiogenesis, and osteogenesis functions may be used as a substitute in periosteum injuries, thereby offering the novel strategy of applying piezoelectric stimulation in bone tissue engineering for the enhancement of combat effectiveness in grassroots troops.

Updating and evaluating the NH3 gas-phase chemical mechanism of MOZART-4 in the WRF-Chem model.

The accuracy of determining atmospheric chemical mechanisms is a key factor in air pollution prediction, pollution-cause analysis and the development of control schemes based on air quality model simulations. However, the reaction of NH3 and OH to generate NH2 and its subsequent reactions are often ignored in the MOZART-4 chemical mechanism. To solve this problem, the gas-phase chemical mechanism of NH3 was updated in this study. Response surface methodology (RSM), integrated gas-phase reaction rate (IRR) diagnosis and process analysis (PA) were used to quantify the influence of the updated NH3 chemical mechanism on the O3 simulated concentration, the nonlinear response relationship of O3 and its precursors, the chemical reaction rate of O3 generation and the meteorological transport process. The results show that the updated NH3 chemical mechanism can reduce the error between the simulated and observed O3 concentrations and better simulate the O3 concentration. Compared with the Base scenario (original chemical mechanism simulated), the first-order term of NH3 in the Updated scenario (updated NH3 chemical mechanism simulated) in RSM passed the significance test (p < 0.05), indicating that NH3 emissions have an influence on the O3 simulation, and the effects of the updated NH3 chemical mechanism on NOx-VOC-O3 in different cities are different. In addition, the analysis of chemical reaction rate changes showed that NH3 can affect the generation of O3 by affecting the NOx concentration and NOx circulation with radicals of OH and HO2 in the Updated scenario, and the change of pollutant concentration in the atmosphere leads to the change of meteorological transmission, eventually leading to the reduction of O3 concentration in Beijing. In conclusion, this study highlights the importance of atmospheric chemistry for air quality models to model atmospheric pollutants and should attract more research focus.

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.

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.

[Effects of Short-term Nitrogen Addition on Soil Organic Carbon Components in Robinia pseudoacacia L. Plantation].

Nitrogen (N) deposition in the context of human activities continuously affects the carbon cycle of ecosystems. The effect of N deposition on soil organic carbon is related to the differential responses of different carbon fractions. To investigate the changes in soil organic carbon fraction and its influencing factors in the context of short-term N deposition, four N addition gradients:0 (CK), 1.5 (N1), 3 (N2), and 6 (N3) g·(m2·a)-1 were set up in acacia plantations based on field N addition experiments, and the soil physicochemical properties, microbial biomass, and enzyme activities were measured in June and September. The results showed that:① exogenous N input reduced soil pH, promoted the increase in soluble organic carbon content, and increased soil nitrogen effectiveness. ② Short-term N addition significantly reduced soil organic carbon content, and the response of each component of organic carbon to N addition was different. Among them, the content of easily oxidized organic carbon was significantly reduced and reached the lowest value under the N2 treatment, with 54.4% and 48.2% reduction compared with that of the control, respectively, and the content of inert organic carbon increased, although the increase was not significant. Nitrogen addition reduced the soil carbon pool activity and improved the stability of the soil carbon pool. Soil carbon pool activity reached its lowest under the N3 and N2 treatments, with a decrease of 53.3% and 52.80%, respectively, compared to that of the control. ③Random forest modeling indicated that the soil microbial biomass stoichiometry ratio, microbial biomass carbon, and AP were the key factors driving the changes in soil organic carbon activity under short-term N addition, explaining 65.96% and 66.68% of the changes in oxidizable organic carbon and inert organic carbon, respectively. Structural equation modeling validated the results of the random forest modeling, and soil microbial biomass stoichiometric ratios significantly influenced carbon pool activity. Short-term nitrogen addition changed soil microbial biomass and its stoichiometric ratio in the acacia plantation forest mainly through two pathways, i.e., increasing soil nitrogen effectiveness and promoting soil acidification and inhibiting extracellular carbon hydrolase activity, thus changing the soil carbon fraction ratio and participating in the soil organic carbon cycling process.

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.

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.

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.

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.