Design and evaluation of an MMP-9-responsive hydrogel for vital pulp therapy.

OBJECTIVE: To design and evaluate a matrix metalloproteinase 9 (MMP-9)-responsive hydrogel for vital pulp therapy. METHODS: A peptide linker with optimized sensitivity toward MMP-9 was crosslinked with 4-arm poly (ethylene glycol)-norbornene (PEG-NB) by thiol-norbornene photo-polymerization. This resulted in the formation of a hydrogel network in which the peptide IDR-1002 was incorporated. Hydrogel characterization and gelation kinetics were examined with Fourier-transform infrared spectroscopy, scanning electron microscopy, rheological testing, and swelling evaluation. Hydrogel degradation was examined through multiple exposure to pre-activated MMP-9, to simulate flare-ups of dental pulp inflammation. The IDR-1002 released from degraded hydrogels was measured with high-performance liquid chromatography. Effect of IDR-1002 released from hydrogels on one-week-old multispecies oral biofilms was evaluated using confocal laser scanning microscopy. RESULTS: MMP-9-responsive, injectable, and photo-crosslinkable hydrogels were successfully synthesized. When hydrogel degradation and release of IDR-1002 were examined with exposure to pre-activated MMP-9, IDR-1002 release was significantly correlated with elevated levels of MMP-9 (p < 0.05). The effectiveness of IDR-1002 in killing bacteria in multispecies oral biofilms was significantly enhanced when the hydrogels were immersed in 10 nM or 20 nM pre-activated MMP-9, compared to immersion in phosphate-buffered saline (p < 0.05). CONCLUSIONS: The MMP-9-responsive hydrogel is a promising candidate for on-demand delivery of bioactive agent in vital pulp therapy. CLINICAL SIGNIFICANCE: MMP-9 is one of the most important diagnostic and prognostic biomarkers for pulpitis. An MMP-9-responsive hydrogel has potential to be used as an in-situ on-demand release system for the diagnosis and treatment of dental pulp inflammation.

A Versatile Chitosan-Based Hydrogel Accelerates Infected Wound Healing via Bacterial Elimination, Antioxidation, Immunoregulation, and Angiogenesis.

Drug-resistant bacterial infection of cutaneous wounds causes great harm to the human body. These infections are characterized by a microenvironment with recalcitrant bacterial infections, persistent oxidative stress, imbalance of immune regulation, and suboptimal angiogenesis. Treatment strategies available to date are incapable of handling the healing dynamics of infected wounds. A Schiff base and borate ester cross-linked hydrogel, based on phenylboronic acid-grafted chitosan (CS-PBA), dibenzaldehyde-grafted poly(ethylene glycol), and tannic acid (TA), is fabricated in the present study. Customized phenylboronic acid-modified zinc oxide nanoparticles (ZnO) are embedded in the hydrogel prior to gelation. The CPP@ZnO-P-TA hydrogel effectively eliminates methicillin-resistant Staphylococcus aureus (MRSA) due to the pH-responsive release of Zn2+ and TA. Killing is achieved via membrane damage, adenosine triphosphate reduction, leakage of intracellular components, and hydrolysis of bacterial o-nitrophenyl-ß-d-galactopyranoside. The CPP@ZnO-P-TA hydrogel is capable of scavenging reactive oxygen and nitrogen species, alleviating oxidative stress, and stimulating M2 polarization of macrophages. The released Zn2+ and TA also induce neovascularization via the PI3K/Akt pathway. The CPP@ZnO-P-TA hydrogel improves tissue regeneration in vivo by alleviating inflammatory responses, stimulating angiogenesis, and facilitating collagen deposition. These findings suggest that this versatile hydrogel possesses therapeutic potential for the treatment of MRSA-infected cutaneous wounds.

The effects of heating on the physicochemical properties of tricalcium silicate root canal sealers

Abstract This study evaluated the effect of heating on the physicochemical properties and surface changes of tricalcium silicate sealers. Three tricalcium silicate root canal sealers (Bio-C Sealer, BioRoot-RCS, EndoSequence BC Sealer), and one epoxy resin-based sealer (AH Plus; control) were tested. The effect of heating on setting time (ST) and flowability were assessed according to ANSI/ADA 57 and ISO 6876 standards. Solubility and dimensional change (DC) of the set sealers were evaluated at 24 hours and after 30 days; the pH of the water used in the DC testing was also measured. Tests were repeated with heated sealers in an oven at 100 °C for 1 min. SEM and EDS analysis were performed. Data were analyzed using One-Way ANOVA and Tukey post-hoc tests (α=5%). Heating decreased the ST for AH Plus and EndoSequence (p<0.05). Heating reduced flowability (p<0.05) and increased pH for AH Plus (p<0.05). The solubility of Bio-C (dried specimens) was not in accordance with the ANSI/ADA standard. The solubility of EndoSequence was significantly higher (p<0.05) when it was heated and dried after 30 days. DC of Bio-C (24 h and 30 days), BioRoot-RCS (30 days) and AH Plus (24 h and 30 days) were not in accordance with the standards. SEM and EDS analysis showed significant changes in sealer microstructure after heating. In conclusion, heating decreased the ST and increased the solubility of EndoSequence BC sealer. No significant changes in flowability, DC, and pH were identified for all three tricalcium silicate sealers after heat application. However, all sealers had significant surface changes.

Resumo Este estudo avaliou o efeito do aquecimento nas propriedades físico-químicas e nas alterações superficiais de cimentos de silicato tricálcico. Três cimentos endodônticos de silicato tricálcico (Bio-C Sealer, BioRoot-RCS, EndoSequence BC Sealer) e um cimento à base de resina epóxi (AH Plus) foram testados para avaliar o efeito do aquecimento no tempo de presa (TP) e escoamento de acordo com as normas ANSI/ADA 57 e ISO 6876. A solubilidade e alteração dimensional (AD) dos cimentos foram avaliadas após 24 horas e 30 dias. O pH da água usada no teste de AD também foi medido. Os testes foram repetidos com cimentos aquecidos em um forno a 100 °C por 1 min. Análises em MEV e EDS foram realizadas. Os dados foram analisados pelos testes de ANOVA-1 via e post hoc de Tukey (α=5%). O aquecimento diminuiu o TP para AH Plus e EndoSequence (p<0,05). O aquecimento reduziu o escoamento (p<0,05) e aumentou o pH do AH Plus (p<0,05). A solubilidade do Bio-C (amostras desidratadas) não estava de acordo com o padrão ANSI/ADA. A solubilidade da EndoSequence foi significativamente maior (p<0,05) quando aquecida e desidratada após 30 dias. As AD de Bio-C (24 h e 30 dias), BioRoot-RCS (30 dias) e AH Plus (24 h e 30 dias) não estavam de acordo com as normas ADA e ISO. A análise em MEV e EDS mostrou alterações significativas na estrutura dos cimentos após aquecimento. Em conclusão, o aquecimento diminuiu o TP e aumentou a solubilidade do cimento EndoSequence BC. Não foram identificadas mudanças significativas no escoamento, AD e pH para os cimentos de silicato tricálcico após aquecimento. Porém, todos os cimentos tiveram alterações significativas na superfície.

Effect of rapamycin on human periodontal ligament stem cells that have been exposed to sodium hypochlorite.

AIMS: The present study investigated the effect of rapamycin on the viability and osteogenic differentiation potential of human periodontal ligament stem cells (hPDLSCs) in the presence of sodium hypochlorite (NaOCl). MAIN METHODS: After determining the minimum inhibitory concentration of NaOCl and optimum concentration of rapamycin, the viability of hPDLSCs was evaluated using the MTT assay subsequent to their exposure to NaOCl, rapamycin, or a combination of both. Osteogenic differentiation was evaluated by the cell mineralization assay performed by alizarin red S staining, alkaline phosphatase activity, and monitoring the expression of osteogenic genes markers Runt-related transcription factor 2, osteocalcin, and osteoprotegerin, using real-time quantitative polymerase chain reaction (RT-qPCR). The expression of autophagy-related genes PI3K, Akt, and mTOR, was also analyzed with RT-qPCR. KEY FINDINGS: Stem cells treated with rapamycin showed the highest percentage of viable cells in the presence of NaOCl. The same trend was observed for all osteogenic differentiation assays. The hPDLSCs treated with rapamycin demonstrated the highest calcium nodule deposition, alkaline phosphatase activity, and the expression of osteogenic gene markers. These effects were not adversely affected by the presence of NaOCl. Rapamycin significantly inhibited mTOR gene expression, while there were no differences in the gene expression of PI3K and Akt. SIGNIFICANCE: Rapamycin counteracts the cytotoxic effect of NaOCl by enhancing the viability and osteogenic differentiation potential of hPDLSCs. Rapamycin appears to accomplish these processes via autophagy activation, by inhibiting mTOR gene expression. The incorporation of rapamycin in regenerative endodontic therapy may encourage a higher success rate.

Effect of Extracellular Ribonucleic Acids on Neurovascularization in Osteoarthritis.

Osteoarthritis is a degenerative disease characterized by abnormal neurovascularization at the osteochondral junctions, the regulatory mechanisms of which remain poorly understood. In the present study, a murine osteoarthritic model with augmented neurovascularization at the osteochondral junction is used to examine this under-evaluated facet of degenerative joint dysfunction. Increased extracellular RNA (exRNA) content is identified in neurovascularized osteoarthritic joints. It is found that the amount of exRNA is positively correlated with the extent of neurovascularization and the expression of vascular endothelial growth factor (VEGF). In vitro binding assay and molecular docking demonstrate that synthetic RNAs bind to VEGF via electrostatic interactions. The RNA-VEGF complex promotes the migration and function of endothelial progenitor cells and trigeminal ganglion cells. The use of VEGF and VEGFR2 inhibitors significantly inhibits the amplification of the RNA-VEGF complex. Disruption of the RNA-VEGF complex by RNase and polyethyleneimine reduces its in vitro activities, as well as prevents excessive neurovascularization and osteochondral deterioration in vivo. The results of the present study suggest that exRNAs may be potential targets for regulating nerve and blood vessel ingrowth under physiological and pathological joint conditions.

Elimination of methicillin-resistant Staphylococcus aureus biofilms on titanium implants via photothermally-triggered nitric oxide and immunotherapy for enhanced osseointegration.

BACKGROUND: Treatment of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium (Ti) implants. There is a need to explore more effective approaches for the treatment of MRSA biofilm infections. METHODS: Herein, an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles (PDA), nitric oxide (NO) release donor sodium nitroprusside (SNP) and osteogenic growth peptide (OGP) onto Ti implants, denoted as Ti-PDA@SNP-OGP. The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy, X-ray photoelectron spectroscope, water contact angle, photothermal property and NO release behavior. The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2',7'-dichlorofluorescein diacetate probe, 1-N-phenylnaphthylamine assay, adenosine triphosphate intensity, o-nitrophenyl-ß-D-galactopyranoside hydrolysis activity, bicinchoninic acid leakage. Fluorescence staining, assays for alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization, quantitative real­time reverse transcription­polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells (MSCs), RAW264.7 cells and their co-culture system. Giemsa staining, ELISA, micro-CT, hematoxylin and eosin, Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms, inhibition of inflammatory response, and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo. RESULTS: Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light irradiation, and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species (ROS)-mediated oxidative stress, destroying bacterial membrane integrity and causing leakage of intracellular components (P < 0.01). In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs, but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype (P < 0.05 or P < 0.01). The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways (P < 0.01). In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model (P < 0.01). CONCLUSIONS: These findings suggest that Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

Enhancing Methotrexate Delivery in the Brain by Mesoporous Silica Nanoparticles Functionalized with Cell-Penetrating Peptide using in Vivo and ex Vivo Monitoring.

The blood-brain barrier (BBB) acts as a physical/biochemical barrier that protects brain parenchyma from potential hazards exerted by different xenobiotics found in the systemic circulation. This barrier is created by "a lipophilic gate" as well as a series of highly organized influx/efflux mechanisms. The BBB bottleneck adversely affects the efficacy of chemotherapeutic agents in treating different CNS malignancies such as glioblastoma, an aggressive type of cancer affecting the brain. In the present study, mesoporous silica nanoparticles (MSNs) were conjugated with the transactivator of transcription (TAT) peptide, a cell-penetrating peptide, to produce MSN-NH-TAT with the aim of improving methotrexate (MTX) penetration into the brain. The TAT-modified nanosystem was characterized by Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and N2 adsorption-desorption analysis. In vitro hemolysis and cell viability studies confirmed the biocompatibility of the MSN-based nanocarriers. In addition, in vivo studies showed that the MTX-loaded MSN-NH-TAT improved brain-to-plasma concentration ratio, brain uptake clearance, and the drug's blood terminal half-life, compared with the use of free MTX. Taken together, the results of the present study indicate that MSN functionalization with TAT is crucial for delivery of MTX into the brain. The present nanosystem represents a promising alternative drug carrier to deliver MTX into the brain via overcoming the BBB.

Clinical and pathologic factors associated with the relapse of fibrous gingival hyperplasia.

BACKGROUND: The association between clinicopathologic characteristics and the relapse of fibrous gingival hyperplasia is unknown. METHODS: The records of 211 consecutive patients with a clinicopathologic diagnosis of fibrous gingival hyperplasia were retrieved. Patients who experienced relapse after surgical excision of the lesion were considered case patients (n = 30). All control patients were informed that there was no recurrence (n = 181). Logistic regression was used to evaluate the associations among different characteristics and the recurrence. Stratified analyses on sex was applied to identify the different associations. RESULTS: Binary logistic regression showed that patients with ulcer (odds ratio [OR], 3.23; 95% CI, 1.18 to 8.83) or mechanical stimulation (OR, 2.42; 95% CI, 1.03 to 5.68) had a higher risk of experiencing recurrence. Stratified analysis of sex identified significant association in females (ulcer: OR, 4.04; 95% CI, 1.14 to 14.34; mechanical stimulation: OR, 3.30; 95% CI, 1.15 to 9.42). No significant difference was observed in males (ulcer: OR, 2.44; 95% CI, 0.40 to 15.06; mechanical stimulation: OR, 1.62; 95% CI, 0.28 to 9.40). Male patients with larger epulides had fewer recurrence (OR, 0.13; 95% CI, 0.02 to 0.74). There was no significant difference in pathologic calcification between case and control patients (P > .05). CONCLUSIONS: Patients with ulcer and mechanical stimulation may have a high risk of experiencing recurrent epulis. PRACTICAL IMPLICATIONS: More attention should be paid to patients with ulcer and mechanical stimulation. Apart from complete surgical removal, it is important to remove local stimulation to prevent recurrence of these lesions.

Stem cell membrane-coated abiotic nanomaterials for biomedical applications.

Nanoscale materials have been extensively employed for diagnostic and therapeutic purposes. However, the developed nanosystems still suffer from some limitations, namely the rapid elimination by the immune system, lack of targeting to specific cells, and insufficient biocompatibility. Therefore, novel strategies based upon a biomimetic approach have received attention to improving the pharmacokinetics and safety profile of nanosystems. One promising strategy is the application of a biomimetic coating consisting of cell membranes derived from different cell types onto nanoparticle cores. Stem cells have been investigated to develop targeted nanodevices owing to their excellent intrinsic tissue-specific homing features, protecting them from the immune system to reach the sites of inflammation. This targeting ability is conferred by a surface repertoire of stem cell-associated biomolecules. Such nanoscopical materials offer sustained circulation and boosted drug accumulation at target sites, augmenting therapeutic efficacy and safety. Additionally, the coating of nanoparticles with cell membranes acts as a camouflage mechanism to increase their circulation time. The current review explores the particular features of stem cell membrane coating as multifunctional biomimetic surface functionalization agents to camouflage nanoparticle cores. Biomedical applications of engineered stem cell membrane-coated nanoparticles, challenges in clinical translation, and their future prospects are addressed.

Macrophage Cell Membrane-Cloaked Nanoplatforms for Biomedical Applications.

Biomimetic approaches utilize natural cell membrane-derived nanovesicles to camouflage nanoparticles to circumvent some limitations of nanoscale materials. This emergent cell membrane-coating technology is inspired by naturally occurring intercellular interactions, to efficiently guide nanostructures to the desired locations, thereby increasing both therapeutic efficacy and safety. In addition, the intrinsic biocompatibility of cell membranes allows the crossing of biological barriers and avoids elimination by the immune system. This results in enhanced blood circulation time and lower toxicity in vivo. Macrophages are the major phagocytic cells of the innate immune system. They are equipped with a complex repertoire of surface receptors, enabling them to respond to biological signals, and to exhibit a natural tropism to inflammatory sites and tumorous tissues. Macrophage cell membrane-functionalized nanosystems are designed to combine the advantages of both macrophages and nanomaterials, improving the ability of those nanosystems to reach target sites. Recent studies have demonstrated the potential of these biomimetic nanosystems for targeted delivery of drugs and imaging agents to tumors, inflammatory, and infected sites. The present review covers the preparation and biomedical applications of macrophage cell membrane-coated nanosystems. Challenges and future perspectives in the development of these membrane-coated nanosystems are addressed.

Polyphosphate-crosslinked collagen scaffolds for hemostasis and alveolar bone regeneration after tooth extraction.

Post-extraction bleeding and alveolar bone resorption are the two frequently encountered complications after tooth extraction that result in poor healing and rehabilitation difficulties. The present study covalently bonded polyphosphate onto a collagen scaffold (P-CS) by crosslinking. The P-CS demonstrated improved hemostatic property in a healthy rat model and an anticoagulant-treated rat model. This improvement is attributed to the increase in hydrophilicity, increased thrombin generation, platelet activation and stimulation of the intrinsic coagulation pathway. In addition, the P-CS promoted the in-situ bone regeneration and alveolar ridge preservation in a rat alveolar bone defect model. The promotion is attributed to enhanced osteogenic differentiation of bone marrow stromal cells. Osteogenesis was improved by both polyphosphate and blood clots. Taken together, P-CS possesses favorable hemostasis and alveolar ridge preservation capability. It may be used as an effective treatment option for post-extraction bleeding and alveolar bone loss. Statement of significance: Collagen scaffold is commonly used for the treatment of post-extraction bleeding and alveolar bone loss after tooth extraction. However, its application is hampered by insufficient hemostatic and osteoinductive property. Crosslinking polyphosphate with collagen produces a modified collagen scaffold that possesses improved hemostatic performance and augmented bone regeneration potential.

Doxorubicin-loaded graphene oxide nanocomposites in cancer medicine: stimuli-responsive carriers, co-delivery and suppressing resistance.

INTRODUCTION: The application of doxorubicin (DOX) in cancer therapy has been limited due to its drug resistance and poor internalization. Graphene oxide (GO) nanostructures have the capacity for DOX delivery while promoting its cytotoxicity in cancer. AREAS COVERED: The favorable characteristics of GO nanocomposites, preparation method, and application in cancer therapy are described. Then, DOX resistance in cancer, GO-mediated photothermal therapy, and DOX delivery for cancer suppression are described. Preparation of stimuli-responsive GO nanocomposites, surface functionalization, hybrid nanoparticles, and theranostic applications are emphasized in DOX chemotherapy. EXPERT OPINION: GO nanoparticle-based photothermal therapy maximizes the anti-cancer activity of DOX against cancer cells. Besides DOX delivery, GO nanomaterials are capable of loading anti-cancer agents and genetic tools to minimize drug resistance and enhance the cytolytic impact of DOX in cancer eradication. To enhance DOX accumulation, stimuli-responsive (redox-, light-, enzyme- and pH-sensitive) GO nanoparticles have been developed for DOX delivery. Development of targeted delivery of DOX-loaded GO nanomaterials against cancer cells may be achieved by surface modification of polymers such as polyethylene glycol, hyaluronic acid, and chitosan. DOX-loaded GO nanoparticles have demonstrated theranostic potential. Hybridization of GO with other nanocarriers such as silica and gold nanoparticles further broadens their potential anti-cancer therapy applications.

Characterisation of deformed or separated nickel-titanium retreatment instruments after clinical use - A multicentre experience: Defect profiles of clinically-used retreatment instruments.

OBJECTIVES: The present study examined the defect characteristics of clinically-used, discarded nickel titanium rotary retreatment instruments and analysed the impact of clinical use on their metallurgical properties. METHODS: 92 XP-endo Shaper (XPS; FKG Dentaire) and 20 XP-endo Finisher (XPFR; FKG Dentaire) instruments with structural deformation or separation were collected after retreatment from four endodontic clinics over a 20-month period. The types of defects and their relative locations were recorded. The lateral and fractured surfaces of the separated instruments were examined with scanning electron microscopy. Differential scanning calorimetry was used to investigate the thermal behaviour of new, deformed and fractured instruments. RESULTS: 77 (84%) XPS and 4 (20%) XPFR had an area with structural change while 15 (16%) XPS and 16 (80%) XPFR were fractured. All unfractured, deformed XPFR showed unwinding close to the coronal end of the flute. Fractures in XPS and XPFR were often close to the coronal end of the flutes or the expanding segments of the insruments. Most of the XPS fractures were torsional failure (67%) while XPFR failed predominantly by cyclic fatigue (81%). The austenite-finishing temperature of XPFR (40 °C) was higher than that of XPS (35 °C). Both XPS and XPFR exhibited 2-stage phase transformations. CONCLUSIONS: Torsional failure was more prevalent in XPS instruments and fatigue failure was more prevalent in XPFR instruments. amongst the investigated instruments, XPFR were more likely to separate without warning whereas XPS frequently exhibited plastic deformation. The latter may be used as a pre-separation forewarning sign during clinical retreatment. CLINICAL SIGNIFICANCE: The failure mode of XP-endo Shaper and XP-endo Finisher used clinically for retreatment appeared to be different. Plastic deformation, the forewarning sign of instrument seaparation, occurs when XP-endo instruments are used for retreatment.

Hyaluronic acid-based nanoplatforms for Doxorubicin: A review of stimuli-responsive carriers, co-delivery and resistance suppression.

An important motivation for the use of nanomaterials and nanoarchitectures in cancer therapy emanates from the widespread emergence of drug resistance. Although doxorubicin (DOX) induces cell cycle arrest and DNA damage by suppressing topoisomerase activity, resistance to DOX has severely restricted its anti-cancer potential. Hyaluronic acid (HA) has been extensively utilized for synthesizing nanoparticles as it interacts with CD44 expressed on the surface of cancer cells. Cancer cells can take up HA-modified nanoparticles through receptor-mediated endocytosis. Various types of nanostructures such as carbon nanomaterials, lipid nanoparticles and polymeric nanocarriers have been modified with HA to enhance the delivery of DOX to cancer cells. Hyaluronic acid-based advanced materials provide a platform for the co-delivery of genes and drugs along with DOX to enhance the efficacy of anti-cancer therapy and overcome chemoresistance. In the present review, the potential methods and application of HA-modified nanostructures for DOX delivery in anti-cancer therapy are discussed.

Recent Advances in Stimulus-Responsive Nanocarriers for Gene Therapy.

Gene therapy provides a promising strategy for curing monogenetic disorders and complex diseases. However, there are challenges associated with the use of viral delivery vectors. The advent of nanomedicine represents a quantum leap in the application of gene therapy. Recent advances in stimulus-responsive nonviral nanocarriers indicate that they are efficient delivery systems for loading and unloading of therapeutic nucleic acids. Some nanocarriers are responsive to cues derived from the internal environment, such as changes in pH, redox potential, enzyme activity, reactive oxygen species, adenosine triphosphate, and hypoxia. Others are responsive to external stimulations, including temperature gradients, light irradiation, ultrasonic energy, and magnetic field. Multiple stimuli-responsive strategies have also been investigated recently for experimental gene therapy.

Self-assembled peptide and protein nanostructures for anti-cancer therapy: Targeted delivery, stimuli-responsive devices and immunotherapy.

Self-assembled peptides and proteins possess tremendous potential as targeted drug delivery systems and key applications of these well-defined nanostructures reside in anti-cancer therapy. Peptides and proteins can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions such as pH, temperature, ionic strength, as well as host and guest molecular interactions; their countless benefits include good biocompatibility and high loading capacity for hydrophobic and hydrophilic drugs. These self-assembled nanomaterials can be adorned with functional moieties to specifically target tumor cells. Stimuli-responsive features can also be incorporated with respect to the tumor microenvironment. This review sheds light on the growing interest in self-assembled peptides and proteins and their burgeoning applications in cancer treatment and immunotherapy.

Crosstalk between Bone and Nerves within Bone.

For the past two decades, the function of intrabony nerves on bone has been a subject of intense research, while the function of bone on intrabony nerves is still hidden in the corner. In the present review, the possible crosstalk between bone and intrabony peripheral nerves will be comprehensively analyzed. Peripheral nerves participate in bone development and repair via a host of signals generated through the secretion of neurotransmitters, neuropeptides, axon guidance factors and neurotrophins, with additional contribution from nerve-resident cells. In return, bone contributes to this microenvironmental rendezvous by housing the nerves within its internal milieu to provide mechanical support and a protective shelf. A large ensemble of chemical, mechanical, and electrical cues works in harmony with bone marrow stromal cells in the regulation of intrabony nerves. The crosstalk between bone and nerves is not limited to the physiological state, but also involved in various bone diseases including osteoporosis, osteoarthritis, heterotopic ossification, psychological stress-related bone abnormalities, and bone related tumors. This crosstalk may be harnessed in the design of tissue engineering scaffolds for repair of bone defects or be targeted for treatment of diseases related to bone and peripheral nerves.

Drug Delivery (Nano)Platforms for Oral and Dental Applications: Tissue Regeneration, Infection Control, and Cancer Management.

The oral cavity and oropharynx are complex environments that are susceptible to physical, chemical, and microbiological insults. They are also common sites for pathological and cancerous changes. The effectiveness of conventional locally-administered medications against diseases affecting these oral milieus may be compromised by constant salivary flow. For systemically-administered medications, drug resistance and adverse side-effects are issues that need to be resolved. New strategies for drug delivery have been investigated over the last decade to overcome these obstacles. Synthesis of nanoparticle-containing agents that promote healing represents a quantum leap in ensuring safe, efficient drug delivery to the affected tissues. Micro/nanoencapsulants with unique structures and properties function as more favorable drug-release platforms than conventional treatment approaches. The present review provides an overview of newly-developed nanocarriers and discusses their potential applications and limitations in various fields of dentistry and oral medicine.

Nonspherical Metal-Based Nanoarchitectures: Synthesis and Impact of Size, Shape, and Composition on Their Biological Activity.

Metal-based nanoentities, apart from being indispensable research tools, have found extensive use in the industrial and biomedical arena. Because their biological impacts are governed by factors such as size, shape, and composition, such issues must be taken into account when these materials are incorporated into multi-component ensembles for clinical applications. The size and shape (rods, wires, sheets, tubes, and cages) of metallic nanostructures influence cell viability by virtue of their varied geometry and physicochemical interactions with mammalian cell membranes. The anisotropic properties of nonspherical metal-based nanoarchitectures render them exciting candidates for biomedical applications. Here, the size-, shape-, and composition-dependent properties of nonspherical metal-based nanoarchitectures are reviewed in the context of their potential applications in cancer diagnostics and therapeutics, as well as, in regenerative medicine. Strategies for the synthesis of nonspherical metal-based nanoarchitectures and their cytotoxicity and immunological profiles are also comprehensively appraised.

Matrix stiffening by self-mineralizable guided bone regeneration.

Collagen membranes produced in vitro with different degrees of intrafibrillar mineralization are potentially useful for guided bone regeneration (GBR). However, highly-mineralized collagen membranes are brittle and difficult for clinical manipulation. The present study aimed at developing an intrafibrillar self-mineralization strategy for GBR membrane by covalently conjugating high-molecular weight polyacrylic acid (HPAA) on Bio-Gide® membranes (BG). The properties of the self-mineralizable membranes (HBG) and their potential to induce bone regeneration were investigated. The HBG underwent the progressive intrafibrillar mineralization as well as the increase in stiffness after immersed in supersaturated calcium phosphate solution, osteogenic medium, or after being implanted into a murine calvarial bone defect. The HBG promoted in-situ bone regeneration via stimulating osteogenic differentiation of mesenchymal stromal cells (MSCs). Hippo signaling was inhibited when MSCs were cultured on the self-mineralized HBG, and in HBG-promoted MSC osteogenesis during in-situ bone regeneration. This resulted in translocation of the transcription co-activators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) into the nucleus to induce transcription of genes promoting osteogenic differentiation of MSCs. Taken together, these findings indicated that HBG possessed the ability to self-mineralize in situ via intrafibrillar mineralization. The increase in stiffness of the extracellular matrix expedited in-situ bone regeneration by inactivating the Hippo-YAP/TAZ signaling cascade. STATEMENT OF SIGNIFICANCE: Guided bone regeneration (GBR) membranes made of naturally derived collagen have been widely used in the bone defect restoration. However, application of collagen GBR membranes run into the bottleneck with the challenges like insufficient stress strength, relatively poor dimensional stability and unsatisfactory osteoinductivity. This study develops a modified GBR membrane that can undergo progressive self-mineralization and matrix stiffening in situ. Increase in extracellular matrix stiffness provides the mechanical cues required for MSCs differentiation and expedites in-situ bone regeneration by inactivating the Hippo-YAP/TAZ signaling cascade.