Bio-Inspired Organic Synaptor with In Situ Ion-Doped Ultrathin Polyelectrolyte Containing Acetylcholine-Like Cation.

An ion-based synaptic transistor (synaptor) is designed to emulate a biological synapse using controlled ion movements. However, developing a solid-state electrolyte that can facilitate ion movement while achieving large-scale integration remains challenging. Here, a bio-inspired organic synaptor (BioSyn) with an in situ ion-doped polyelectrolyte (i-IDOPE) is demonstrated. At the molecular scale, a polyelectrolyte containing the tert-amine cation, inspired by the neurotransmitter acetylcholine is synthesized using initiated chemical vapor deposition (iCVD) with in situ doping, a one-step vapor-phase deposition used to fabricate solid-state electrolytes. This method results in an ultrathin, but highly uniform and conformal solid-state electrolyte layer compatible with large-scale integration, a form that is not previously attainable. At a synapse scale, synapse functionality is replicated, including short-term and long-term synaptic plasticity (STSP and LTSP), along with a transformation from STSP to LTSP regulated by pre-synaptic voltage spikes. On a system scale, a reflex in a peripheral nervous system is mimicked by mounting the BioSyns on various substrates such as rigid glass, flexible polyethylene naphthalate, and stretchable poly(styrene-ethylene-butylene-styrene) for a decentralized processing unit. Finally, a classification accuracy of 90.6% is achieved through semi-empirical simulations of MNIST pattern recognition, incorporating the measured LTSP characteristics from the BioSyns.

Circulating small extracellular vesicles promote proliferation and migration of vascular smooth muscle cells via AXL and MerTK activation.

The proliferation and migration of vascular smooth muscle cells (VSMCs) after vascular injury lead to neointimal hyperplasia, thus aggravating vascular diseases. However, the molecular mechanisms underlying neointima formation are not fully elucidated. Extracellular vesicles (EVs) are mediators of various intercellular communications. The potential of EVs as regulators in cardiovascular diseases has raised significant interest. In the current study we investigated the role of circulating small extracellular vesicles (csEVs), the most abundant EVs (1010 EVs/mL serum) in VSMC functions. csEVs were prepared from bovine, porcine or rat serum. We showed that incubation with csEVs (0.5 × 1010-2 × 1010) dose-dependently enhanced the proliferation and migration of VSMCs via the membrane phosphatidylserine (PS). In rats with ligation of right carotid artery, we demonstrated that application of csEVs in the ligated vessels aggravated neointima formation via interaction of membrane PS with injury. Furthermore, incubation with csEVs markedly enhanced the phosphorylation of AXL and MerTK in VSMCs. Pretreatment with BSM777607 (pan-TAM inhibitor), bemcentinib (AXL inhibitor) or UNC2250 (MerTK inhibitor) blocked csEV-induced proliferation and migration of VSMCs. We revealed that csEV-activated AXL and MerTK shared the downstream signaling pathways of Akt, extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK) that mediated the effects of csEVs. We also found that csEVs increased the expression of AXL through activation of transcription factor YAP, which might constitute an AXL-positive feedback loop to amplify the signals. Finally, we demonstrated that dual inhibition of AXL/MerTK by ONO-7475 (0.1 µM) effectively hindered csEV-mediated proliferation and migration of VSMCs in ex vivo mouse aorta injury model. Based on these results, we propose an essential role for csEVs in proliferation and migration of VSMCs and highlight the feasibility of dual AXL/MerTK inhibitors in the treatment of vascular diseases.

Novel innovative computer-based test (Inno-CBT) item types for national licensing examinations for health care professionals.

BACKGROUND: An effective test mechanism to evaluate clinical knowledge and skills of the entry-level healthcare professionals is important for providing clinical competency and improving patient care. This study aimed to develop novel, innovative computer-based test (Inno-CBT) item types for application in the national examination of Korean healthcare professionals. METHODS: This exploratory study was conducted from May 2021 to March 2022 by a team of faculty members from pharmacy schools in South Korea. A literature search using PubMed, Google Scholar, RISS, Web of Science, and KoreaMed was performed. Forum presentations, media articles, and previous reports by the Korea Health Personnel Licensing Examination Institute (KHPLEI) were included. Workshops were held, information and ideas were collected and conceptualized, and item types were designed, drafted, and refined. By repeating this process, the Inno-CBT item types were finalized. RESULTS: Forty-one Inno-CBT item types with 28 subtypes were developed. New digital technologies, such as a reactive responsive media interface, an animation insertion, multimedia embedding, and network surfing, were utilized in these novel types. It was anticipated that these Inno-CBT item types would effectively measure abilities in healthcare knowledge, problem-solving skills, and professional behaviors. Some potential barriers to implementing the Inno-CBT item types include item difficulty, operational unfamiliarity, complexity in scoring protocols, and network security. CONCLUSIONS: A variety of styles of novel Inno-CBT item types were developed to evaluate the multifaceted and in-depth professional abilities required for healthcare professionals. Prior to implementing these item types in the national examination, item validation and technical support should be conducted.

Gene Prioritization and Network Topology Analysis of Targeted Genes for Acquired Taxane Resistance by Meta-Analysis.

Network topology-based approaches prove to be highly efficient in addressing multifactorial phenomena such as acquired drug resistance in cancer. The aim of this study was to identify differentially expressed genes across multiple microarray datasets (meta-DEGs), to prioritize meta-DEGs to find the most promising genes linked to acquired taxane resistance (ATR), and to analyze the relevant biological networks using topology analysis. A total of 771 meta-DEGs were identified by performing a cross-platform meta-analysis of ATR-related microarray datasets. A gene prioritization method was used to simultaneously identify activated or deactivated genes on a co-expression map and protein-protein interaction (PPI) network. The top 10 prioritized genes in the gene co-expression and the top 1% highly ranked genes in the PPI network were identified. The selected meta-DEGs were used to construct biological networks, and topological analysis was performed using network centrality measures. Using integrative analyses, we identified ATR candidate genes, including several previously unidentified genes that were found to be associated with ATR. From the gene co-expression network, PRSS23 was the highest-ranking gene at local average connectivity measure and ADAM9 was ranked highest in other centralities. In protein interaction network, HSPA1A, ANXA1, and PA2G4 showed highest ranks in network centrality analyses. This study provides a comprehensive overview of the gene expression patterns associated with ATR. Furthermore, it presents a new approach to identification of unveiled candidate genes to ATR, using a gene prioritization method and network analysis.

Enhanced dissolution of valsartan-vanillin binary co-amorphous system loaded in mesoporous silica particles.

The study was aimed to prepare a co-amorphous system of valsartan (VAL) with vanillin (VAN) for improving its solubility and dissolution followed by its confinement in mesoporous silica particles (MSPs) to stabilise the co-amorphous system and prevent its recrystallization. Amorphous VAL and VAN were obtained through quench-cooling and VAL/VAN binary co-amorphous system (VAL/VAN-CAS) was prepared through solvent evaporation technique. The particle size and morphology of VAL/VAN-CAS-MSPs were studied using scanning electron microscopy (SEM) and solid-state characterisation was performed by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The in vitro dissolution was investigated by dialysis bag diffusion method. SEM analysis revealed irregular shaped VAL/VAN-CAS-MSPs with a size range of 5-25 µm, while outcomes of DSC and XRPD confirmed the formation of VAL/VAN-CAS. The in vitro dissolution profiles demonstrated a significantly increased dissolution in first 60 minutes from VAL/VAN-CAS (∼68%) and VAL/VAN-CAS-MSPs (∼76%) compared to powder VAL (∼25%).

Effect of poly-L-arginine in inhibiting scrapie prion protein of cultured cells.

Biological effect of poly-L-arginine (PLR), the linear homopolymer comprised of L-arginine, was investigated to determine the activity of suppressing prions. PLR decreased the level of scrapie prion protein (PrPSc) in cultured cells permanently infected with prions in a concentration-dependent manner. The PrPSc inhibition efficacy of PLR was greater than that of another prion-suppressant poly-L-lysine (PLK) in a molecular mass-dependent fashion. The effective concentration of PLR to inhibit prions was achieved safely below the cytotoxic concentrations, and overall cytotoxicity of PLR was similar to that of PLK. PLR did not alter the cellular prion protein (PrPC) level and was unable to change the states of preformed recombinant PrP aggregates and PrPSc from prion-infected cells. These data eliminate the possibility that the action mechanism of PLR is through removal of PrPC and pre-existing PrPSc. However, PLR formed complexes with plasminogen that stimulates prion propagation via conversion of PrPC to the misfolded isoform, PrPSc. The plasminogen-PLR complex demonstrated the greater positive surface charge values than the similar complex with PLK, raising the possibility that PLR interferes with the role of cofactor for PrPSc generation better than PLK.

Sustained release docetaxel-incorporated lipid nanoparticles with improved pharmacokinetics for oral and parenteral administration.

The aim of this study was to develop docetaxel-incorporated lipid nanoparticles (DTX-NPs) to improve the pharmacokinetic behaviour of docetaxel (DTX) after oral and parenteral administration via sustained release. DTX-NPs were prepared by nanotemplate engineering technique with palmityl alcohol as a solid lipid and Tween-40/Span-40/Myrj S40 as a surfactants mixture. Spherical DTX-NPs below 100 nm were successfully prepared with a narrow particle size distribution, 96% of incorporation efficiency and 686 times increase in DTX solubility. DTX-NPs showed a sustained release over 24 h in phosphate-buffered saline and simulated gastric and intestinal fluids, while DTX-micelles released DTX completely within 12 h. The half-maximal inhibitory concentration (IC50) of DTX-NPs against human breast cancer MCF-7 cells was 1.9 times lower than that of DTX-micelles and DTX solution. DTX-NPs demonstrated 3.7- and 2.8-fold increase in the area under the plasma concentration-time curve compared with DTX-micelles after oral and parenteral administration, respectively.

Identification of novel therapeutic target genes in acquired lapatinib-resistant breast cancer by integrative meta-analysis.

Acquired resistance to lapatinib is a highly problematic clinical barrier that has to be overcome for a successful cancer treatment. Despite efforts to determine the mechanisms underlying acquired lapatinib resistance (ALR), no definitive genetic factors have been reported to be solely responsible for the acquired resistance in breast cancer. Therefore, we performed a cross-platform meta-analysis of three publically available microarray datasets related to breast cancer with ALR, using the R-based RankProd package. From the meta-analysis, we were able to identify a total of 990 differentially expressed genes (DEGs, 406 upregulated, 584 downregulated) that are potentially associated with ALR. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs showed that "response to organic substance" and "p53 signaling pathway" may be largely involved in ALR process. Of these, many of the top 50 upregulated and downregulated DEGs were found in oncogenesis of various tumors and cancers. For the top 50 DEGs, we constructed the gene coexpression and protein-protein interaction networks from a huge database of well-known molecular interactions. By integrative analysis of two systemic networks, we condensed the total number of DEGs to six common genes (LGALS1, PRSS23, PTRF, FHL2, TOB1, and SOCS2). Furthermore, these genes were confirmed in functional module eigens obtained from the weighted gene correlation network analysis of total DEGs in the microarray datasets ("GSE16179" and "GSE52707"). Our integrative meta-analysis could provide a comprehensive perspective into complex mechanisms underlying ALR in breast cancer and a theoretical support for further chemotherapeutic studies.

Docetaxel-loaded thermosensitive and bioadhesive nanomicelles as a rectal drug delivery system for enhanced chemotherapeutic effect.

PURPOSE: To investigate the potential of thermosensitive and biadhesive nanomicelles in improving the bioavailability of docetaxel (DCT) and its chemotherapeutic effect. METHOD: DCT-loaded nanomicelles were prepared by emulsufication and characterized in terms of physico-chemical and visco-elastic parameters. The optimzed formulation was evaluated for in vivo localization, pharmacokinetic and anti-tumor efficacy. RESULTS: The hydrodynamic size of DCT-loaded nanomicelles was approximately 13 nm and the nanomicelles exhibited a sufficient gelation strength (9250 mPa·s) and bioadhesive force (2100 dyn/cm²) to be retained in the upper part of rectum. We observed a high rectal bioavailability of 29% DCT compared to that following oral administration in rats, as it successfully evaded the multidrug efflux transporters and hepatic first-pass metabolism. Plasma concentration around ∼50 ng/mL was maintained throughout the study period (12 h) while Taxotere® attained subtherapeutic range within 4 h of drug administration. Results also revealed that the rectally administered DCT-loaded nanomicelles exhibited a significant anti-tumor effect (200 mm³) with a reduced toxicity profile when compared to orally administered DCT (950 mm³). Furthermore, histological study showed that the rectal mucosa was completely intact with no signs of irritation upon treatment with DCT-loaded nanomicelles. CONCLUSIONS: Taken together, our novel thermosensitive and biadhesive nanomicelles demonstrated the ability to improve the bioavailability and chemotherapeutic potential of DCT in vivo. To the best of our knowledge, this is the first report describing the rectal delivery of DCT-loaded nanomicelles.

Physicochemical characterization and in vivo evaluation of solid self-nanoemulsifying drug delivery system for oral administration of docetaxel.

To formulate a self-nanoemulsifying drug delivery system (SNEDDS) for the oral administration of docetaxel as an alternative to commercial docetaxel-loaded injectable products, it was prepared by spray-drying an aqueous solution containing liquid SNEDDS and colloidal silica. Its physicochemical properties and oral bioavailability were investigated compared to a clear docetaxel solution administered intravenously or orally to rats. In the docetaxel-loaded solid SNEDDS prepared with colloidal silica, the liquid SNEDDS composed of Capryol 90, Cremophore EL and Transcutol HP (45/35/20, volume ratio) was absorbed inside the pores of carriers, and docetaxel was present in a changed amorphous state. The solid SNEDDS with 3.3% (w/v) docetaxel produced nanoemulsions, and showed about 12.5% absolute bioavailability in rats. Thus, this solid SNEDDS may be a potential candidate for oral pharmaceutical product with improved oral bioavailability of docetaxel.

Formulation and Evaluation of a Self-Microemulsifying Drug Delivery System of Raloxifene with Improved Solubility and Oral Bioavailability.

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX.

Preparation of neutron-activatable holmium nanoparticles for the treatment of ovarian cancer metastases.

Nanoparticles containing stable holmium ((165) Ho) are prepared by nanotemplate engineering and subsequently irradiated in a neutron flux to yield (166) Ho, a beta-emitting radiotherapeutic isotope. After intraperitoneal injection to mice bearing SKOV-3 ovarian tumors, significant tumor accumulation of the (166) Ho-nanoparticles is observed by SPECT imaging indicating the potential of these neutron activatable nanoparticles for internal radiation therapy of ovarian cancer metastases.

High payload dual therapeutic-imaging nanocarriers for triggered tumor delivery.

The in vitro and in vivo characterization of an optimized formulation of nanoparticles (NPs) loaded with a high content of dexamethasone palmitate (DEX-P), a chemotherapeutic adjuvant that decreases interstitial fluid pressure in tumors, and (111) In, a signaling agent, is described. These NPs are uniform in size and composition. Single photon emission computed tomography imaging demonstrates significant tumor uptake of (111) In-labeled DEX-P NPs in tumor-bearing mice. As with many nanoparticle-based drug delivery systems, significant liver accumulation is observed. Assessment of liver histology and blood tests show no apparent hepatic or renal toxicity of the DEX-P NPs. Conversion of DEX-P to DEX occurs when DEX-P NPs are incubated with mouse plasma, human tumor homogenate and ascites from tumor bearing mice, but not with human plasma. This conversion is slower in plasma from Es1(e) ((-/-)) /SCID mice, a potential alternative animal model that better mimics humans; however, plasma from these mice are not completely devoid of esterase activity. The difference between blood and tumor esterase activity in humans facilitates the delivery of DEX-P NPs to tumors and the release of dexamethasone by an esterase trigger.

Augmented Oral Bioavailability and Prokinetic Activity of Levosulpiride Delivered in Nanostructured Lipid Carriers.

The present study is aimed to develop and optimize levosulpiride-loaded nanostructured lipid carriers (LSP-NLCs) for improving oral bioavailability and prokinetic activity of LSP. LSP-NLCs were optimized with D-optimal mixture design using solid lipid, liquid lipid and surfactant concentrations as independent variables. The prepared LSP-NLCs were evaluated for physicochemical properties and solid-state characterization. The in vivo oral pharmacokinetics and prokinetic activity of LSP-NLCs were evaluated in rats. LSP-NLCs formulation was optimized at Precirol® ATO 5/Labrasol (80.55/19.45%, w/w) and Tween 80/Span 80 concentration of 5% (w/w) as a surfactant mixture. LSP-NLCs showed a spherical shape with a particle size of 152 nm, a polydispersity index of 0.230 and an entrapment efficiency of 88%. The DSC and PXRD analysis revealed conversion of crystalline LSP to amorphous state after loading into the lipid matrix. LSP-NLCs displayed a 3.42- and 4.38-flods increase in AUC and Cmax after oral administration compared to LSP dispersion. In addition, LSP-NLCs showed enhanced gastric emptying (61.4%), intestinal transit (63.0%), and fecal count (68.8) compared to LSP dispersion (39.7%, 38.0% and 51.0, respectively). Taken together, these results show improved oral bioavailability and prokinetic activity of LSP-NLCs and presents a promising strategy to improve therapeutic activity of LSP for efficient treatment of gastric diseases.

Formulation optimization, in vitro and in vivo evaluation of agomelatine-loaded nanostructured lipid carriers for augmented antidepressant effects.

The present study was intended to prepare and optimize agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) for augmented in vivo antidepressant potential. AGM-NLCs were optimized on several parameters including cumulative hydrophilic-lipophilic balance of surfactants, proportions of solid and liquid lipids, total amounts of drug and surfactants. AGM-NLCs were assessed for their physicochemical properties, in vitro AGM release and in vivo antidepressant effects in mice model. The optimized AGM-NLCs demonstrated spherical morphology with average particle size of 99.8 ± 2.6 nm, PDI of 0.142 ± 0.017, zeta potential of - 23.2 ± 1.2 mV and entrapment efficiency of 97.1 ± 2.1%. Thermal and crystallinity studies depict amorphous nature of AGM after its incorporation into NLCs. AGM-NLCs exhibit a sustained drug release profile after initial 2 h. Mice treated with AGM-NLCs exhibited reduced immobility time in behavioral analysis. Furthermore, cresyl violet staining demonstrated an improved neuronal morphology and survival in AGM-NLCs group. The concentrations and the expression of inflammatory markers (TNF-α and COX-2) in mice brain were significantly reduced by AGM-NLCs. Taken together, therapeutic effectiveness of AGM was markedly augmented in AGM-NLCs and thereby they could be promising nanocarriers for the effective delivery of antidepressants to brain.

Synaptic Segmented Transistor with Improved Linearity by Schottky Junctions and Accelerated Speed by Double-Layered Nitride.

Neuromorphic devices have been extensively studied to overcome the limitations of a von Neumann system for artificial intelligence. A synaptic device is one of the most important components in the hardware integration for a neuromorphic system because a number of synaptic devices can be connected to a neuron with compactness as high as possible. Therefore, synaptic devices using silicon-based memory, which are advantageous for a high packing density and mass production due to matured fabrication technologies, have attracted considerable attention. In this study, a segmented transistor devoted to an artificial synapse is proposed for the first time to improve the linearity of the potentiation and depression (P/D). It is a complementary metal oxide semiconductor (CMOS)-compatible device that harnesses both non-ohmic Schottky junctions of the source and drain for improved weight linearity and double-layered nitride for enhanced speed. It shows three distinct and unique segments in drain current-gate voltage transfer characteristics induced by Schottky junctions. In addition, the different stoichiometries of SixNy for a double-layered nitride is utilized as a charge trap layer for boosting the operation speed. This work can bring the industry potentially one step closer to realizing the mass production of hardware-based synaptic devices in the future.

Controlled therapeutic delivery of CO from carbon monoxide-releasing molecules (CORMs).

Carbon monoxide (CO) has been regarded as a "silent killer" for its toxicity toward biological systems. However, a low concentration of endogenously produced CO has shown a number of therapeutic benefits such as anti-inflammatory, anti-proliferative, anti-apoptosis, and cytoprotective activities. Carbon monoxide-releasing molecules (CORMs) have been developed as alternatives to direct CO inhalation, which requires a specialized setting for strict dose control. CORMs are efficient CO donors, with central transition metals (such as ruthenium, iron, cobalt, and manganese) surrounded by CO as a ligand. CORMs can stably store and subsequently release their CO payload in the presence of certain triggers including solvent, light, temperature, and ligand substitution. However, CORMs require appropriate delivery strategies to improve short CO release half-life and target specificity. Herein, we highlighted the therapeutic potential of inhalation and CORMs-delivered CO. The applications of conjugate and nanocarrier systems for controlling CO release and improving therapeutic efficacy of CORMs are also described in detail. The review concludes with some of the hurdles that limit clinical translation of CORMs. Keeping in mind the tremendous potential and growing interest in CORMs, this review would be helpful for designing controlled CO release systems for clinical applications.

Preparation and in vitro evaluation of anti-VCAM-1-Fab'-conjugated liposomes for the targeted delivery of the poorly water-soluble drug celecoxib.

When an inflammatory stimulus is given, vascular endothelial cells express various cell adhesion molecules including the vascular cell adhesion molecule (VCAM)-1. In this study, the possibility of specifically delivering anti-inflammatory drugs to activated endothelial cells by utilizing VCAM-1 as a target receptor was explored by loading celecoxib, a selective cyclooxygenase-2 inhibitor, into liposomes coupled to the Fab' fragment against VCAM-1. Anti-VCAM-1-Fab'-conjugated liposomes were prepared by forming an amide linkage between amino groups of Fab' and the carboxylic group of glutaryl-N-phosphatidylethanolamine in liposomes using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as a cross-linker in the presence of sulpho-N-hydroxysuccinimide. The coupling of Fab' to phospholipids constituting liposomes was confirmed by SDS-PAGE analysis. Under our optimized conjugation conditions, 130.0 µg Fab' was coupled to 1 µmol liposomes. Immunoblotting analysis showed that VCAM-1 protein expression could be induced by incubating human umbilical vein endothelial cells (HUVEC) with TNF-α. Confocal laser microsopy analysis revealed that Fab' conjugation to liposomes selectively increased liposomal uptake in TNF-α-pre-stimulated (VCAM-1-expressed) HUVECs, but not in cells without VCAM-1 expression. The concentration of celecoxib loaded in Fab'-conjugated liposomes was 281.1 ± 29 µg/mL, suggesting that liposomal loading also helped to overcome the limitations in celecoxib administration caused by its poor water solubility. Celecoxib loaded in Fab'-conjugated liposomes inhibited prostaglandin E2 (PGE2) production induced by TNF-α-pre-stimulation more efficiently than when loaded in conventional liposomes. Therefore, Fab'-conjugated liposomes served as a drug delivery system with dual functions: targeted delivery and solubilizing capacity.

Triboelectric Nanogenerator: Structure, Mechanism, and Applications.

With the rapid development of the Internet of Things (IoT), the number of sensors utilized for the IoT is expected to exceed 200 billion by 2025. Thus, sustainable energy supplies without the recharging and replacement of the charge storage device have become increasingly important. Among various energy harvesters, the triboelectric nanogenerator (TENG) has attracted considerable attention due to its high instantaneous output power, broad selection of available materials, eco-friendly and inexpensive fabrication process, and various working modes customized for target applications. The TENG harvests electrical energy from wasted mechanical energy in the ambient environment. Three types of operational modes based on contact-separation, sliding, and freestanding are reviewed for two different configurations with a double-electrode and a single-electrode structure in the TENGs. Various charge transfer mechanisms to explain the operational principles of TENGs during triboelectrification are also reviewed for electron, ion, and material transfers. Thereafter, diverse methodologies to enhance the output power considering the energy harvesting efficiency and energy transferring efficiency are surveyed. Moreover, approaches involving not only energy harvesting by a TENG but also energy storage by a charge storage device are also reviewed. Finally, a variety of applications with TENGs are introduced. This review can help to advance TENGs for use in self-powered sensors, energy harvesters, and other systems. It can also contribute to assisting with more comprehensive and rational designs of TENGs for various applications.

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability.

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.