Cationic Biopolymeric Scaffold of Chelating Nanohydroxyapatite Self-Regulates Intraoral Microenvironment for Periodontal Bone Regeneration.

Periodontal bone defect is a common but longstanding healthcare issue since traditional bone grafts have limited functionalities in regulating complex intraoral microenvironments. Here, a porous cationic biopolymeric scaffold (CSC-g-nHAp) with microenvironment self-regulating ability was synthesized by chitosan-catechol chelating the Ca2+ of nanohydroxyapatite and bonding type I collagen. Chitosan-catechol's inherent antibacterial and antioxidant abilities endowed this scaffold with desirable abilities to eliminate periodontal pathogen infection and maintain homeostatic balances between free radical generation and elimination. Meanwhile, this scaffold promoted rat bone marrow stromal cells' osteogenic differentiation and achieved significant ectopic mineralization after 4 weeks of subcutaneous implantation in nude mice. Moreover, after 8 weeks of implantation in the rat critical-sized periodontal bone defect model, CSC-g-nHAp conferred 5.5-fold greater alveolar bone regeneration than the untreated group. This cationic biopolymeric scaffold could regulate the local microenvironment through the synergistic effects of its antibacterial, antioxidant, and osteoconductive activities to promote solid periodontal bone regeneration.

Hydrogels for Exosome Delivery in Biomedical Applications.

Hydrogels, which are hydrophilic polymer networks, have attracted great attention, and significant advances in their biological and biomedical applications, such as for drug delivery, tissue engineering, and models for medical studies, have been made. Due to their similarity in physiological structure, hydrogels are highly compatible with extracellular matrices and biological tissues and can be used as both carriers and matrices to encapsulate cellular secretions. As small extracellular vesicles secreted by nearly all mammalian cells to mediate cell-cell interactions, exosomes play very important roles in therapeutic approaches and disease diagnosis. To maintain their biological activity and achieve controlled release, a strategy that embeds exosomes in hydrogels as a composite system has been focused on in recent studies. Therefore, this review aims to provide a thorough overview of the use of composite hydrogels for embedding exosomes in medical applications, including the resources for making hydrogels and the properties of hydrogels, and strategies for their combination with exosomes.

Anatomical limitations and factors influencing molar distalization.

OBJECTIVES: To analyze the anatomical limitations and characteristics of maxillary and mandibular retromolar regions affecting molar distalization using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: A total of 120 qualifying patients were classified into equal groups of skeletal Class II and Class III and stratified by vertical growth pattern, age, sex, and third molar presence. The available distance along the axis of distalization and cortical bone thickness (CBT) were measured in the maxillary and mandibular retromolar regions of Class II and Class III patients, respectively. One-way analysis of variance was used to examine the effects of the factors on the measured data. RESULTS: The minimum available distance of the Class II maxilla was observed at a level 3 mm from the cementoenamel junction (CEJ), while that of the Class III mandible was at a level 9 mm from the CEJ. The average available distance at the limit level was 4.06 ± 1.93 mm in the Class II maxilla, and the average corresponding CBT was 1.00 mm. The average available distance at the limit level in the Class III mandible was 2.80 ± 1.96 mm, and the corresponding CBT was 2.24 mm. In both skeletal Class II and Class III patients, hyperdivergent groups had the least available distance for molar distalization. CONCLUSIONS: The limit for available distance in the Class II maxilla is closer to the coronal level, while that of the Class III mandible is closer to the apical level. A hyperdivergent growth pattern in a patient is indicative of less potential for molar distalization. Axial slices of CBCT images provide valuable evaluation for molar distalization regarding limit levels.

Characterization of UDP-glycosyltransferase family members reveals how major flavonoid glycoside accumulates in the roots of Scutellaria baicalensis.

BACKGROUND: Flavonoid glycosides extracted from roots of Scutellaria baicalensis exhibit strong pharmaceutical antitumor, antioxidative, anti-inflammatory, and antiviral activities. UDP glycosyltransferase (UGT) family members are responsible for the transfer of a glycosyl moiety from UDP sugars to a wide range of acceptor flavonoids. Baicalin is the major flavonoid glycoside found in S. baicalensis roots, and its aglycone baicalein is synthesized from a specially evolved pathway that has been elucidated. However, it is necessary to carry out a genome-wide study of genes involved in 7-O-glucuronidation, the final biosynthesis step of baicalin, which might elucidate the relationship between the enzymes and the metabolic accumulation patterns in this medicinal plant. RESULTS: We reported the phylogenetic analysis, tissue-specific expression, biochemical characterization and evolutionary analysis of glucosyltransferases (SbUGTs) and glucuronosyltransferases (SbUGATs) genes based on the recently released genome of S. baicalensis. A total of 124 UGTs were identified, and over one third of them were highly expressed in roots. In vitro enzyme assays showed that 6 SbUGTs could use UDP-glucose as a sugar donor and convert baicalein to oroxin A (baicalein 7-O-glucoside), while 4 SbUGATs used only UDP-glucuronic acid as the sugar donor and catalyzed baicalein to baicalin. SbUGAT4 and SbUGT2 are the most highly expressed SbUGAT and SbUGT genes in root tissues, respectively. Kinetic measurements revealed that SbUGAT4 had a lower Km value and higher Vmax/Km ratio to baicalein than those of SbUGT2. Furthermore, tandem duplication events were detected in SbUGTs and SbUGATs. CONCLUSIONS: This study demonstrated that glucosylation and glucuronidation are two major glycosylated decorations in the roots of S. baicalensis. Higher expression level and affinity to substrate of SbUGAT4, and expansion of this gene family contribute high accumulation of baicalin in the root of S. baicalensis.

High-Strength and Injectable Supramolecular Hydrogel Self-Assembled by Monomeric Nucleoside for Tooth-Extraction Wound Healing.

Hydrogels with high mechanical strength and injectability have attracted extensive attention in biomedical and tissue engineering. However, endowing a hydrogel with both properties is challenging because they are generally inversely related. In this work, by constructing a multi-hydrogen-bonding system, a high-strength and injectable supramolecular hydrogel is successfully fabricated. It is constructed by the self-assembly of a monomeric nucleoside molecular gelator (2-amino-2'-fluoro-2'-deoxyadenosine (2-FA)) with distilled water/phosphate buffered saline as solvent. Its storage modulus reaches 1 MPa at a concentration of 5.0 wt%, which is the strongest supramolecular hydrogel comprising an ultralow-molecular-weight (MW < 300) gelator. Furthermore, it exhibits excellent shear-thinning injectability, and completes the sol-gel transition in seconds after injection at 37 °C. The multi-hydrogen-bonding system is essentially based on the synergistic interactions between the double NH2 groups, water molecules, and 2'-F atoms. Furthermore, the 2-FA hydrogel exhibits excellent biocompatibility and antibacterial activity. When applied to rat molar extraction sockets, compared to natural healing and the commercial hemorrhage agent gelatin sponge, the 2-FA hydrogel exhibits faster degradation and induces less osteoclastic activity and inflammatory infiltration, resulting in more complete bone healing. In summary, this study provides ideas for proposing a multifunctional, high-strength, and injectable supramolecular hydrogel for various biomedical engineering applications.

RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia.

Fibrous dysplasia (FD) is a rare bone disease caused by GNAS mutation in skeletal stem cells, typically originating from and worsening in childhood. Till now, no cure for FD exists despite the well-recognized etiology. Studies have demonstrated that osteoclastogenesis hyperactivity is caused by elevated RANKL expression, making RANKL inhibition a potential therapy. Although a human monoclonal anti-RANKL antibody, denosumab, has been used in FD patients, the effects and mechanisms of RANKL inhibition for FD treatment require assessment. Denosumab is expensive and can only be injected. Therefore, formulating an oral-administered, cost-effective medicine is encouraged. In the current study, we evaluated the effects of a small-molecule RANKL inhibitor, AS2676293, on a transgenic FD mouse model. AS2676293 effectively suppressed osteoclastogenesis and halted FD progression. The pre-existing bone defects were primarily replaced by newly formed mineralized bone after two weeks of AS2676293 administration. The potent RANKL inhibitory effect and easier route of delivery make AS2676293 a promising target therapy of FD. Results from our study suggested that RANKL inhibition is effective in halting FD progression and promoting bone remineralization, which could benefit the patients with early onset of FD.

Enhanced Bactericidal Effect of Calcinated Mg-Fe Layered Double Hydroxide Films Driven by the Fenton Reaction.

Osteogenic and antibacterial abilities are the permanent pursuit of titanium (Ti)-based orthopedic implants. However, it is difficult to strike the right balance between these two properties. It has been proved that an appropriate alkaline microenvironment formed by Ti modified by magnesium-aluminum layered double hydroxides (Mg-Al LDHs) could achieve the selective killing of bacteria and promote osteogenesis. However, the existence of Al induces biosafety concerns. In this study, iron (Fe), an essential trace element in the human body, was used to substitute Al, and a calcinated Mg-Fe LDH film was constructed on Ti. The results showed that a proper local alkaline environment created by the constructed film could enhance the antibacterial and osteogenic properties of the material. In addition, the introduction of Fe promoted the Fenton reaction and could produce reactive oxygen species in the infection environment, which might further strengthen the in vivo bactericidal effect.

Orthodontic maximum anchorages in malocclusion treatment: A systematic review and network meta-analysis.

OBJECTIVE: We did a network meta-analysis and systematic review among patients seeking for maximum anchorage and provided a guidance of selecting certain systems in clinical practice. METHODS: Seven databases were searched, and randomized controlled trials (RCTs) published with no language restrictions from January 1994 to February 2021 comparing any of the following seven anchorage systems for maximum anchorage orthodontic treatment were selected(PROSPERO: CRD42019117995). A network meta-analysis (NMA) was then conducted to integrate direct evidence with indirect evidence based on logical inference to compare and rank treatments for maximum anchorages in the capacity of maintaining anchorage and duration of total treatment time. RESULTS: Nine publications with 522 participants were considered eligible and were taken into evaluation. According to the capacity of anchorage reinforcement, three skeleton anchorages including miniscrew implants, midpalate implants and Onplant midpalate implants were significantly more effective than conventional anchorages including headgears, TPAs and Nance buttons respectively. According to conventional anchorages, headgears and Nance buttons were significantly more effective than TPA. The strategy ranking reflected the same results as above. However, miniscrew implants required the longest total treatment time. CONCLUSIONS: In general, miniscrew impants are most effective in reserving anchorage. Nance buttons require the least total treatment time. Total evidence is graded as moderate. Midpalatal implants might be the best choice when doing treatment planning because it has the most favorable balance between effectiveness and treatment time. But data analysis of the acceptability and acquisition cost of those anchorage systems must be done to make final decisions.

Mg-Fe layered double hydroxides modified titanium enhanced the adhesion of human gingival fibroblasts through regulation of local pH level.

The durability of dental implants is closely related to osseointegration and surrounding soft tissue sealing. Appropriate local pH favors fibroblasts adhesion and contributes to soft tissue sealing. Layered double hydroxides (LDHs) are characterized by adjustable alkalinity, offering a possibility to investigate the influence of pH on cellular behaviors. Herein, we fabricated MgFe LDHs modified titanium. During calcination, the local pH value of LDHs increase, without altering other physics and chemical properties via OH- exchange mechanism. In vitro studies showed that LDHs films calcined at 250 °C for 2 h provide a local pH of 10.17, which promote early adhesion, proliferation, and type I collagen expression of human gingival fibroblasts (hGFs) through the formation of focal adhesion complex and activation of focal adhesion kinase related signaling pathways. In conclusion, endowing the titanium surface with appropriate alkalinity by MgFe LDHs films enhances the adhesion of hGFs, providing a new strategy of designing multifunctional biomaterials for soft tissue sealing around dental implants.

Fabrication of an injectable iron (III) crosslinked alginate-hyaluronic acid hydrogel with shear-thinning and antimicrobial activities.

The combination of alginate, hyaluronic acid and multivalent ions have been reported to form alginate-hyaluronic acid ionic-crosslinking hydrogels for biomedical applications. However, injectable alginate-hyaluronic acid ionic-crosslinking hydrogels with satisfactory shear-thinning property have rarely been reported. In this study, we successfully developed an ionic-crosslinked alginate-hyaluronic acid hydrogel by simple assembly of alginate-hyaluronic acid mixture and Fe3+ complex. This hydrogel could fully recover within seconds after damaged, while displayed shear thinning behavior and good injectability which were contributed by the reversible and dynamic metal-ligand interactions formed via ferric ions and carboxyl groups of the polymers. Moreover, the local degradation of this hydrogel giving the hydrogel sustained ferric ions release property, of which led to potential long-term antibacterial activities against multiple types of bacteria including gram-negative Escherichia coli and gram-positive Staphylococcus aureus, as well as representative oral pathogenic bacteria Streptococcus mutans and Porphyromonas gingivalis.

Light stimulus responsive nanomedicine in the treatment of oral squamous cell carcinoma.

Light stimulus responsive therapies are based on a variety of low-toxic therapeutic agents and produce anti-tumor effects only under external light stimulation, thus greatly reducing system toxicity and improving the specificity of treatment. Moreover, light stimulus responsive drug delivery system (DDS) can combine various theranostics molecules to exert synergistic therapeutic effects of various treatments, which has played an important role in cancer treatment. In this review, we introduced the light stimulus responsive cancer therapies including photodynamic therapy (PDT), photothermal therapy (PTT) and light-triggered DDS applied in the treatment of OSCC, described considerable photosensitizers (PSs) and nanomaterials used for oral cancers, which will hope to better the clinic outcome of OSCC patients.

Advances in molecular biology of Paeonia L.

Molecular biology can serve as a tool to solve the limitations of traditional breeding and cultivation techniques related to flower patterns, the improvement of flower color, and the regulation of flowering and stress resistance. These characteristics of molecular biology ensured its significant role in improving the efficiency of breeding and germplasm amelioration of Paeonia. This review describes the advances in molecular biology of Paeonia, including: (1) the application of molecular markers; (2) genomics, transcriptomics, proteomics, metabolomics, and microRNA studies; (3) studies of functional genes; and (4) molecular biology techniques. This review also points out select limitations in current molecular biology, analyzes the direction of Paeonia molecular biology research, and provides advice for future research objectives.

Graphene quantum dots (GQDs)-based nanomaterials for improving photodynamic therapy in cancer treatment.

Graphene quantum dots (GQDs) as novel nanomaterials, have received significant interest in the field of biomedical applications. It is worth noting that a large amount of research is devoted to GQDs-based nanocomposites for cancer treatment, especially for photodynamic therapy (PDT), in that they can act not only as more favorable photosensitizers (PSs) but also nanoplatforms for delivering PSs. In this review, the biological behavior and physicochemical properties of GQDs for PDT are described in detail, and the application of GQDs-based nanocomposites in improved PDT and PDT-based combination therapies is analyzed, which may provide a new strategy for designing efficient PDT systems for cancer treatment.

Incorporating Local Adaptation Into Species Distribution Modeling of Paeonia mairei, an Endemic Plant to China.

Paeonia (Paeoniaceae), a culturally and economically important plant genus, has an isolated taxonomy while the evolution of this genus is unclear. A plant species endemic to southwest China, Paeonia mairei is precious germplasm for evolution-related research and cultivar improvement, and its conservation is urgent. However, little is known about its patterns of habitat distribution and responses to climate change. Using 98 occurrence sites and data of 19 bioclimatic variables, we conducted principal component analysis and hierarchical cluster analysis to delineate different climatic populations. Maximum entropy algorithm (MaxEnt) was applied to each population to evaluate the importance of environmental variables in shaping their distribution, and to identify distribution shifts under different climate change scenarios. We also applied MaxEnt to all of the P. mairei presence sites (P_Whole) to evaluate the need to construct separate species distribution models for separate populations rather than a common approach by treating them as a whole. Our results show that local adaptation exists within the distribution range of P. mairei and that all presence sites were clustered into a western population (P_West) and an eastern population (P_East). Two variables (precipitation of the driest month and temperature seasonality) are important when shaping the distribution of P_West, and another two variables (mean diurnal range and mean temperature of the wettest quarter) are important for P_East. Both populations are likely to shift upward under climate change, while P_East may lose most current suitable areas while P_West may not. P_Whole produced a narrower area compared to the combination of P_West and P_East but a suitable area (south Chongqing) may have been missed in the prediction. Accordingly, a population-based approach in constructing a species distribution model is needed to provide a detailed appreciation of the distribution of P. mairei, allowing for a population-based conservation strategy. In this case, it could include assisted migration to new and suitable distribution areas for P_West and in situ conservation in high elevation regions for P_East. The results of our study could be a useful reference for implementing the long-term conservation and further research of P. mairei.

Esthetic evaluation of facial cheek volume: A study using 3D stereophotogrammetry.

OBJECTIVES: To investigate the influence of cheek volume on facial esthetics judged by orthodontists and non-specialists. MATERIALS AND METHODS: A 25-year-old female's natural and smiling face was captured by 3D stereophotogrammetry. Cheek volume of the 3D image was altered to different degrees three-dimensionally. For the natural and smiling face, seven groups of facial images were created: decreased grade I/II/III, increased grade I/II/III, and the original one. Thirty orthodontists and 30 nonspecialists were invited to perform esthetic evaluation of the original and transformed images using a questionnaire. Data were calculated with one-way analysis of variance (least significant difference test) and independent samples t test. RESULTS: Compared to nonspecialists, orthodontists gave lower esthetic scores to the decreased grade III facial images (maximum deformation degree: 7.500 mm and 7.327 mm in natural and smiling face-oriented image groups, respectively). The decreased grade III facial images also received the highest age ranks. However, the increased grade III facial images received the lowest scores and highest age ranks from nonspecialists (maximum deformation degree: 6.994 mm and 5.300 mm in natural and smiling face-oriented image groups, respectively) ( P < .01). CONCLUSIONS: Orthodontists and nonspecialists showed different esthetic evaluation of varied cheek volume. The influence of cheek volume in orthodontic diagnostic analysis needs further consideration.

Co-delivery of Doxorubicin and Interferon-γ by Thermosensitive Nanoparticles for Cancer Immunochemotherapy.

A dual-sensitive nanoparticle delivery system was constructed by incorporating an acid sensitive hydrazone linker into thermosensitive nanoparticles (TSNs) for co-encapsulating doxorubicin (DOX) and interferon γ (IFNγ) and to realize the co-delivery of chemotherapy and immunotherapy agents against melanoma. DOX, a chemotherapeutic drug, was conjugated to TSNs by a pH-sensitive chemical bond, and IFNγ, a potent immune-modulator, was absorbed into TSNs through the thermosensitivity and electrostatics of nanoparticles. Consequently, the dual sensitive drug-loaded TSN delivery systems were successfully built and showed an obvious core-shell structure, good encapsulation efficiency of drugs, sustained and sensitive drug release, prolonged circulation time, as well as excellent synergistic antitumor efficiency against B16F10 tumor bearing mice. Moreover, the combinational antitumor immune responses of hydrazone bearing DOX/IFNγ-TSN (hyd) were strengthened by activating Th1-type CD4+ T cells, cytotoxic T lymphocytes, and natural killer cells, downregulating the expression levels of immunosuppressive cytokines, such as IL10 and TGFß, and upregulating the secretion of IL2 and TNFα. Taken together, the multifunctional TSNs system provides a promising strategy for multiple drugs co-delivery with distinct properties.

Injectable self-crosslinking HA-SH/Col I blend hydrogels for in vitro construction of engineered cartilage.

The injectable self-crosslinking blend hydrogel by combination of collagen I and thiolated hyaluronic acid could alleviate collagen I contraction in vitro and overcome weak cell adhesive sites of hyaluronic acid. Five groups of injectable hydrogels with different ratios were prepared to investigate their gelation time, injection force, mechanical properties, swelling capacity and disintegration performance. These results indicated that Col7HA-SH3 hydrogel achieved the optimal controlled and injectable effect, the gelation time was just ten seconds with injection force at 3.5 N, and the storage modulus of hydrogel could reach 11 kPa with frequency at 10 Hz. Furthermore, the phenotype maintaining, biocompatibility and chondrocytes proliferation were administrated by CLSM, SEM, histological staining, immuohistochemical staining, MTT test and glycoaminoglycans quantification. Similarly, the Col7HA-SH3 blend hydrogel encapsulated chondrocytes presented most excellent proliferation potential, phenotype maintaining, biocompatibility and convenient operational characteristics. These findings might approach the underlying clinical application of blend hydrogel in cartilage repair.

Immunochemotherapy mediated by thermosponge nanoparticles for synergistic anti-tumor effects.

The efficacy of immunotherapy was demonstrated to be compromised by reduced immunogenicity of tumor cells and enhanced suppressive properties of the tumor microenvironment in cancer treatment. There is growing evidence that low-dose chemotherapy can modulate the immune system to improve the anti-tumor effects of immunotherapy through multiple mechanisms, including the enhancement of tumor immunogenicity and reversal of the immunosuppressive tumor microenvironment. Here, we fabricated thermosponge nanoparticles (TSNs) for the co-delivery of chemotherapeutic drug paclitaxel (PTX) and immunostimulant interleukin-2 (IL-2) to explore the synergistic anti-tumor effects of chemotherapy and immunotherapy. The distinct temperature-responsive swelling/deswelling character facilitated the effective post-entrapment of cytokine IL-2 in nanoparticles by a facile non-solvent mild incubation method with unaffected bioactivity and favorable pharmacokinetics. PTX and IL-2 co-loaded TSNs exhibited significant inhibition on tumor growth and metastasis, and prolonged overall survival for tumor-bearing mice compared with the corresponding monotherapies. The synergistic effect was evidenced from the remodeled tumor microenvironment in which low-dose chemotherapeutics disrupted the immunosuppressive tumor microenvironment and enhanced tumor immunogenicity, and immunostimulant cytokine promoted the anti-tumor immune response of immune effector cells. The immunochemotherapy mediated by this thermosponge nanoplatform may provide a promising treatment strategy against cancer.

Tumor Microenvironment Responsive Nanogel for the Combinatorial Antitumor Effect of Chemotherapy and Immunotherapy.

A biomimetic nanogel with tumor microenvironment responsive property is developed for the combinatorial antitumor effects of chemotherapy and immunotherapy. Nanogels are formulated with hydroxypropyl-ß-cyclodextrin acrylate and two opposite charged chitosan derivatives for entrapping anticancer drug paclitaxel and precisely controlling the pH responsive capability, respectively. The nanogel supported erythrocyte membrane can achieve "nanosponge" property for delivering immunotherapeutic agent interleukin-2 without reducing the bioactivity. By responsively releasing drugs in tumor microenvironment, the nanogels significantly enhanced antitumor activity with improved drug penetration, induction of calreticulin exposure, and increased antitumor immunity. The tumor microenvironment is remodeled by the combination of these drugs in low dosage, as evidenced by the promoted infiltration of immune effector cells and reduction of immunosuppressive factors.