Fabrication of lidocaine-loaded polymer dissolving microneedles for rapid and prolonged local anesthesia.

There is an urgent need for research into effective interventions for pain management to improve patients' life quality. Traditional needle and syringe injection were used to administer the local anesthesia. However, it causes various discomforts, ranging from brief stings to trypanophobia and denial of medical operations. In this study, a dissolving microneedles (MNs) system made of composite matrix materials of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and sodium hyaluronate (HA) was successfully developed for the loading of lidocaine hydrochloride (LidH). The morphology, size and mechanical properties of the MNs were also investigated. After the insertion of MNs into the skin, the matrix at the tip of the MNs was swelled and dissolved by absorption of interstitial fluid, leading to a rapid release of loaded LidH from MNs' tips. And the LidH in the back patching was diffused into deeper skin tissue through microchannels created by MNs insertion, forming a prolonged anesthesia effect. In addition, the back patching of MNs could be acted as a drug reservoir to form a prolonged local anesthesia effect. The results showed that LidH MNs provided a superior analgesia up to 8 h, exhibiting a rapid and long-lasting analgesic effects. Additionally, tissue sectioning and in vitro cytotoxicity tests indicated that the MNs patch we developed had a favorable biosafety profile.

Proteomic analysis of the initial wake up of vibrio splendidus persister cells.

Vibrio splendidus is a ubiquitous pathogen that causes various diseases in aquaculture with a wide range of hosts. In our previous studies, we showed that L-glutamic acid was the optimal carbon source that could revive V. splendidus persister cells. In our present study, single cell observation under microscopy showed that V. splendidus could revive using L-glutamic acid as carbon source. A proteomic analysis was carried out to further illustrate the initial wake up of persister cells with L-glutamic acid. To collect the initially revived cells, SDS-PAGE was used to determine the revived time. The total proteins from the persister cells and the revived cells were analyzed using LC‒MS/MS. A total of 106 proteins, including 42 downregulated proteins and 64 upregulated proteins, were identified. GO analysis of the differentially expressed proteins (DEPs) showed that biological processes, including protein complex assembly, protein oligomerization, and arginine metabolism; cellular components, including extracellular membrane, plasma membrane and ribosome; and molecular functions, including the activities of arginine binding and structural constituent of ribosome, were enriched. KEGG analysis showed that lipopolysaccharide biosynthesis, porphyrin and chlorophyll metabolism, and peptidoglycan biosynthesis were upregulated, while the ribosome was downregulated. This is the first time to study the initial wake up of persister cells based on proteomic analysis, and the results revealed the main pathways involved in the early resuscitation of V. splendidus persister cells.

Wearable SERS Sensor Based on Omnidirectional Plasmonic Nanovoids Array with Ultra-High Sensitivity and Stability.

Surface-enhanced Raman spectroscopy (SERS) is a promising technology for wearable sensors due to its fingerprint spectrum and high detection sensitivity. However, since SERS-activity is sensitive to both the distribution of "hotspots" and excitation angle, it is profoundly challenging to develop a wearable SERS sensor with high stability under various deformations during movements. Herein, inspired by omnidirectional light-harvesting of the compound eye of Xenos Peckii, a wearable SERS sensor is developed using omnidirectional plasmonic nanovoids array (OPNA), which is prepared by assembling a monolayer of metal nanoparticles into the artificial plasmonic compound-eye (APC). Specifically, APC is an interconnected frame containing omnidirectional "pockets" and acts as an "armour", not only rendering a broadband and omnidirectional enhancement of "hotspots" in the delicate nanoparticles array, but also maintaining an integrity of the "hotspots" against external mechanical deformations. Furthermore, an asymmetry super-hydrophilic pattern is fabricated on the surface of OPNA, endowing the hydrophobic OPNA with the ability to spontaneously extract and concentrate the analytes from sweat. Such an armored SERS sensor can enable the wearable and in situ analysis with high sensitivity and stability, exhibiting great potential in point-of-care analysis.

Recent Advances in Polymer Microneedles for Drug Transdermal Delivery: Design Strategies and Applications.

In recent years, transdermal drug delivery based on microneedles (MNs) technology has received extensive attention, which offers a safer and painless alternative to hypodermic needle injections. They can pierce the stratum corneum and deliver drugs to the epidermis and dermis-structures of skin, showing prominent properties such as minimally invasiveness, bypassing first-pass metabolism, and can be self-administered. A range of materials has been used to fabricate MNs, such as silicon, metal, glass, and polymers. Among them, polymer MNs have gained increasing attention from pharmaceutical and cosmetic companies as one of the promising drug delivery methods. MN products have recently become available on the market, and some of them are under evaluation for efficacy and safety. This paper focuses on the current state of polymer MNs in drug transdermal delivery. The materials and methods for the fabrication of polymer MNs and their drug administration are described. The recent progress of polymer MNs for treatment of cancer, vaccine delivery, blood glucose regulation, androgenetic alopecia, obesity, tissue healing, myocardial infarction, and gout are reviewed. The challenges of MNs technology are summarized and the future development trend of MNs is also prospected.

Achieving enhanced solid-state photochromism and mechanochromism by introducing a rigid steric hindrance group.

For photochromic molecules, effective isomerization usually requires conformational freedom, which is usually unavailable under solvent-free conditions. In this work, we report a new method, which can realize the reversible switching of spiropyran molecules by introducing a rigid aromatic ring group and this method can provide the required free volume to transform from a closed-ring to an open-ring form. This new molecule can quickly change color in the solid state under ultraviolet light, and can be erased after being heated at 60 °C for about 5 minutes. Furthermore, this new compound presents mechanochromicity when a mechanical force is applied. What is more, it can be used for at least 30 cycles of print-erase operations without apparent fatigue. This new molecule exhibits improved photochromic and anti-fatigue properties in the solid state, which can promote its application in both ultraviolet printing and anti-counterfeiting materials.

Fabrication of separable microneedles with phase change coating for NIR-triggered transdermal delivery of metformin on diabetic rats.

To enhance the compliance of drug delivery for patients, the novel near-infrared (NIR) light-triggered and separable microneedles (MNs) have been developed in this work. Firstly, prussian blue nanoparticles (PB NPs) as the photo-thermal conversion factor and metformin as the hypoglycemic drug were embedded into the separable arrowheads, which consisted by poly (vinyl alcohol) and sucrose (PVA/Suc). The arrowheads of MNs were located on soluble solids supporting substrates that produced by poly(vinyl pyrrolidone) (PVP). Lauric acid (LA) as the phase transition coating covered on the surface of the MNs due to its lower phase transition temperature (~44 °C). Then, the separable arrowheads could be left into the skin because of the absorbing the interstitial fluid (IF) by the solid supporting substrates. With the irradiation of NIR light, LA could be melted due to the role of PB NPs in photo-thermal conversion, thus releasing the metformin from arrowheads. Compared with the traditional subcutaneous injections, the hypoglycemic effect was evaluated by the drug-release behaviors induced by NIR in vivo. The results showed that metformin could be allowed to on-demand release under the NIR irradiation. And the as-obtained MNs exhibited a good hypoglycemic effect, hypotoxicity and low inflammation reaction compared with those of traditional subcutaneous injections. The results indicate that the fabricated MNs have the potential treatment for diabetes due to their safety, convenience and painlessness.

Studies on the activation of isocitrate dehydrogenase kinase/phosphatase (AceK) by Mn2+ and Mg2.

Isocitrate dehydrogenase kinase/phosphatase (AceK) is a bifunctional enzyme with both kinase and phosphatase activities that are activated by Mg2+. We have studied the interactions of Mn2+and Mg2+ with AceK using isothermal titration calorimetry (ITC) combined with molecular docking simulations and show for the first time that Mn2+ also activates the enzyme activities. However, Mn2+ and Mg2+ exert their effects by different mechanisms. Although they have similar binding constants (of 1.11 × 105 and 0.98 × 105 M-1, respectively) for AceK and induce conformational changes of the enzyme, they do not compete for the same binding site. Instead Mn2+ appears to bind to the regulatory domain of AceK, and its effect is transmitted to the active site of the enzyme by the conformational change that it induces. The information in this study should be very useful for understanding the molecular mechanism underlying the interaction between AceK and metal ions, especially Mn2+ and Mg2+.

Surfactant-Mediated Crystallization-Driven Self-Assembly of Crystalline/Ionic Complexed Block Copolymers in Aqueous Solution.

A series of crystalline/ionic complexed block copolymers (BCPs) with various compositions have been prepared by sequential reactions. The BCPs with different hydrophilic fractions can self-assemble into various morphologies, such as spindlelike, rodlike, and spherical micelles with different crystallinity of the core. Bis(2-ethylhexyl) sulfosuccinate sodium salt (AOT) is added as a surfactant to induce the morphological transition of BCPs in aqueous media. The introduced AOT can be tightly bound to the cationic units, and a water-insoluble unit in the corona forms, leading to a reduced tethering density. Consequently, morphological variety changing from rods to platelets to fibril to dendrite-like micelles can be observed.

Structural control of side-chain chromophores to achieve highly efficient electro-optic activity.

A series of chromophores J1-J4 have been synthesized based on julolidine donors modified with different rigid steric hindrance groups. Compared with the chromophore (J1) without the isolation group, chromophores J2, J3 and J4 show better stability. Structural analysis and photophysical property measurements were carried out to compare the molecular mobility and steric hindrance effect of the different donor-modified chromophores. All of these chromophores with isolation groups showed superb thermal stabilities with high thermal decomposition temperatures above 250 °C. Furthermore, with rigid steric hindrance, chromophores J3 and J4 showed more enhanced thermal stabilities with thermal decomposition temperatures of 269 °C and 275 °C, respectively. Density functional theory was used to calculate the hyperpolarizability (ß), and the high molecular hyperpolarizability of these chromophores can be effectively translated into large electro-optic coefficients. The electro-optic coefficients of poled films containing 20 wt% of these new chromophores doped in amorphous polycarbonate were 127, 266 and 209 pm V-1 at 1310 nm for chromophores J1-J3, respectively, while the film containing chromophore J4 showed the largest r33 value of only 97 pm V-1 at 25 wt%. These results indicated that the introduced isolation group can reduce intermolecular electrostatic interactions, thus enhancing the macroscopic electro-optic activity, while the size of the isolation group should be suitable.

Primary splenic pregnancy with hemorrhagic shock.

Primary splenic pregnancy, a type of abdominal pregnancy, is very rare and potentially life-threatening, particularly without an accurate preoperative diagnosis. Herein we describe the case of a 27-year-old woman who had primary splenic pregnancy with hemorrhagic shock due to spleen rupture, who was successfully treated by laparotomy.

Development of an immersive virtual reality head-mounted display with high performance.

To resolve the contradiction between large field of view and high resolution in immersive virtual reality (VR) head-mounted displays (HMDs), an HMD monocular optical system with a large field of view and high resolution was designed. The system was fabricated by adopting aspheric technology with CNC grinding and a high-resolution LCD as the image source. With this monocular optical system, an HMD binocular optical system with a wide-range continuously adjustable interpupillary distance was achieved in the form of partially overlapping fields of view (FOV) combined with a screw adjustment mechanism. A fast image processor-centered LCD driver circuit and an image preprocessing system were also built to address binocular vision inconsistency in the partially overlapping FOV binocular optical system. The distortions of the HMD optical system with a large field of view were measured. Meanwhile, the optical distortions in the display and the trapezoidal distortions introduced during image processing were corrected by a calibration model for reverse rotations and translations. A high-performance not-fully-transparent VR HMD device with high resolution (1920×1080) and large FOV [141.6°(H)×73.08°(V)] was developed. The full field-of-view average value of angular resolution is 18.6 pixels/degree. With the device, high-quality VR simulations can be completed under various scenarios, and the device can be utilized for simulated trainings in aeronautics, astronautics, and other fields with corresponding platforms. The developed device has positive practical significance.

Selection and characterization of novel DNA aptamers specifically recognized by Singapore grouper iridovirus-infected fish cells.

Singapore grouper iridovirus (SGIV) is a major viral pathogen of grouper aquaculture, and has caused heavy economic losses in China and South-east Asia. In this study, we generated four ssDNA aptamers against SGIV-infected grouper spleen (GS) cells using SELEX (systematic evolution of ligands by exponential enrichment) technology. Four aptamers exhibited high affinity to SGIV-infected GS cells, in particular the Q2 aptamer. Q2 had a binding affinity of 12.09 nM, the highest of the four aptamers. These aptamers also recognized SGIV-infected tissues with high levels of specificity. Protease treatment and flow cytometry analysis of SGIV-infected cells revealed that the target molecules of the Q3, Q4 and Q5 aptamers were trypsin-sensitive proteins, whilst the target molecules of Q2 might be membrane lipids or surface proteins that were not trypsin-sensitive. The generated aptamers appeared to inhibit SGIV infection in vitro. Aptamer Q2 conferred the highest levels of protection against SGIV and was able to inhibit SGIV infection in a dose-dependent manner. In addition, Q2 was efficiently internalized by SGIV-infected GS cells and localized at the viral assembly sites. Our results demonstrated that the four novel aptamers we generated were specific for SGIV-infected cells and could potentially be applied as rapid molecular diagnostic test reagents or therapeutic drugs targeting SGIV.

Design and Calibration of a New 6 DOF Haptic Device.

For many applications such as tele-operational robots and interactions with virtual environments, it is better to have performance with force feedback than without. Haptic devices are force reflecting interfaces. They can also track human hand positions simultaneously. A new 6 DOF (degree-of-freedom) haptic device was designed and calibrated in this study. It mainly contains a double parallel linkage, a rhombus linkage, a rotating mechanical structure and a grasping interface. Benefited from the unique design, it is a hybrid structure device with a large workspace and high output capability. Therefore, it is capable of multi-finger interactions. Moreover, with an adjustable base, operators can change different postures without interrupting haptic tasks. To investigate the performance regarding position tracking accuracy and static output forces, we conducted experiments on a three-dimensional electric sliding platform and a digital force gauge, respectively. Displacement errors and force errors are calculated and analyzed. To identify the capability and potential of the device, four application examples were programmed.

Efficacy and safety of remifemin on peri-menopausal symptoms induced by post-operative GnRH-a therapy for endometriosis: a randomized study versus tibolone.

BACKGROUND: The aim of this study was to investigate clinical efficacy and safety of Remifemin on peri-menopausal symptoms in endometriosis patients with a post-operative GnRH-a therapy. MATERIAL AND METHODS: We treated 116 women who had endometriosis with either Remifemin (n=56) 20 mg bid po or Tibolone (n=60) 2.5 mg qd po for 12 weeks after GnRH-a injection. The efficacy was evaluated by Kupperman menopausal index (KMI), and hot flash/sweating scores. The safety parameters such as liver and renal functions, lipid profile, endometrial thickness, and serum sex hormone level, as well as the incidence of adverse events were recorded. RESULTS: (1) After GnRH-a therapy, KMI and hot flash/sweating scores in both groups increased significantly (P<0.05) but we found no significant difference for KMI (2.87±1.40 for Remifemin and 2.70±1.26 for Tibolone) and hot flash/sweating scores (0.94±1.72 for Remifemin and 1.06±1.78 for Tibolone) between the 2 groups (P>0.05). (2) No statistical change was observed in liver or renal functions and lipid profile in both groups before and after the treatment (P>0.05). The post-therapeutic serum FSH, LH, and E2 level and endometrial thickness decreased remarkably in both groups (P<0.05). E2 level in the Remifemin group was obviously lower than that in the Tibolone group (P<0.05), and FSH and LH levels were strongly higher (P<0.05). No significant difference in thickness were found in either group (P>0.05). The Remifemin group had far fewer adverse events than the Tibolone group (P<0. 05). CONCLUSIONS: Compared with Tibolone, Remifemin had a similar clinical efficacy and was safer for the peri-menopausal symptoms induced by GnRH-a in endometriosis patients.

Core-shell structured microneedles with programmed drug release functions for prolonged hyperuricemia management.

An appropriate non-oral platform via transdermal delivery of drugs is highly recommended for the treatment of hyperuricemia. Herein, a core-shell structured microneedle patch with programmed drug release functions was designed to regulate serum uric acid (SUA) levels for prolonged hyperuricemia management. The patch was fabricated using a three-step casting method. Allopurinol (AP), an anti-hyperuricemic drug, was encapsulated within the carboxymethyl cellulose (CMC) layer, forming the "shell" of the MNs. The MN's inner core was composed of polyvinylpyrrolidone (PVP) loaded with urate oxidase-calcium peroxide nanoparticles (UOx-CaO2 NPs). When the as-fabricated core-shell structured microneedles were inserted into the skin, the loaded AP was first released immediately to effectively inhibit the production of SUA due to the water solubility of CMC. Subsequently, the internal SUA was further metabolized by UOx, leading to exposure of CaO2 NPs. The sustained release of UOx accompanied by the decomposition of CaO2 NPs contributed to maintaining a state of normal uric acid levels over an extended period. More attractively, uric acid could be oxidized due to the strong oxidant of CaO2, which was beneficial to the continuous consumption of uric acid. In vivo results showed that the as-fabricated MNs exhibited an excellent anti-hyperuricemia effect to reduce SUA levels to the normal state within 3 h and maintain the normouricemia state for 12 h. In addition, the levels of creatinine (Cr) and blood urea nitrogen (BUN) in the serum remained within the normal range, and the activities of adenosine deaminase (ADA) and xanthine oxidase (XOD) in the liver were effectively inhabited, mitigating the risk of liver and kidney damage for clinical anti-hyperuricemia management.

Silk fibroin and hydroxypropyl cellulose composite injectable hydrogel-containing extracellular vesicles for myocardial infarction repair.

Extracellular vesicles (EVs) have been recognized as one of the promising specific drugs for myocardial infarction (MI) prognosis. Nevertheless, low intramyocardial retention of EVs remains a major impediment to their clinical application. In this study, we developed a silk fibroin/hydroxypropyl cellulose (SF/HPC) composite hydrogel combined with AC16 cell-derived EVs targeted modification by folic acid for the treatment of acute myocardial infarction repair. EVs were functionalized by distearoylphosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG-FA) via noncovalent interaction for targeting and accelerating myocardial infarction repair.In vitro, cytocompatibility analyses revealed that the as-prepared hydrogels had excellent cell viability by MTT assay and the functionalized EVs had higher cell migration by scratch assay.In vivo, the composite hydrogels can promote myocardial tissue repair effects by delaying the process of myocardial fibrosis and promoting angiogenesis of infarct area in MI rat model.

Integration of metformin-loaded MIL-100(Fe) into hydrogel microneedles for prolonged regulation of blood glucose levels.

The transdermal drug delivery based on microneedles (MNs) provides a suitable and painless self-administration for diabetic patients. In this work, the hydrogel-forming MNs were firstly fabricated using poly(vinyl alcohol) (PVA) and chitosan (CS) as matrix. A hypoglycemic drug, metformin (Met), had been loaded into MIL-100(Fe). Then, both of free Met and Met-loaded MIL-100(Fe) were integrated into hydrogel-forming MNs for regulation of blood glucose levels (BGLs) on diabetic rats. After penetrated into the skin, the free Met could be firstly released from MNs. Due to the absorption of interstitial fluid and subsequent release of loaded Met from MIL-100(Fe), leading to a sustainable and long-term drug release behaviors. A notable hypoglycemic effect and low risk of hypoglycemia could be obtained on diabetic rat modelsin vivo. The as-fabricated hydrogel-forming MNs expected to become a new type of transdermal drug delivery platform for transdermal delivery of high-dose drugs to form a long-term hypoglycemic effect.

Red Blood Cell Membrane-Camouflaged Polydopamine and Bioactive Glass Composite Nanoformulation for Combined Chemo/Chemodynamic/Photothermal Therapy.

Combinations of different therapeutic strategies, including chemotherapy (CT), chemodynamic therapy (CDT), and photothermal therapy (PTT), are needed to effectively address evolving drug resistance and the adverse effects of traditional cancer treatment. Herein, a camouflage composite nanoformulation (TCBG@PR), an antitumor agent (tubercidin, Tub) loaded into Cu-doped bioactive glasses (CBGs) and subsequently camouflaged by polydopamine (PDA), and red blood cell membranes (RBCm), was successfully constructed for targeted and synergetic antitumor therapies by combining CT of Tub, CDT of doped copper ions, and PTT of PDA. In addition, the TCBG@PRs composite nanoformulation was camouflaged with a red blood cell membrane (RBCm) to improve biocompatibility, longer blood retention times, and excellent cellular uptake properties. It integrated with long circulation and multimodal synergistic treatment (CT, CDT, and PTT) with the benefit of RBCms to avoid immune clearance for efficient targeted delivery to tumor locations, producing an "all-in-one" nanoplatform. In vivo results showed that the TCBG@PRs composite nanoformulation prolonged blood circulation and improved tumor accumulation. The combination of CT, CDT, and PTT therapies enhanced the antitumor therapeutic activity, and light-triggered drug release reduced systematic toxicity and increased synergistic antitumor effects.

Facile preparation of self-healing hydrogels based on chitosan and PVA with the incorporation of curcumin-loaded micelles for wound dressings.

The increased demand for improved strategies for wound healing has, in recent years, motivated the development of multifunctional hydrogels with favorable bio-compatibility and antibacterial properties. To this regard, the current study presented the design of a novel self-healing composite hydrogel that could perform as wound dressing for the promotion of wound healing. The composite hydrogels were composed of polyvinyl alcohol (PVA), borax and chitosan functionalized with sialic acid (SA-CS) and curcumin loaded pluronic F127 micelles. The hydrogels were formed through the boronic ester bond formation between PVA, SA-CS and borax under physiological conditions and demonstrated adjustable mechanical properties, gelation kinetics and antibacterial properties. When incubating with NIH3T3 cells, the hydrogels also demonstrated good biocompatibility. These aspects offer a promising foundation for their prospective applications in developing clinical materials for wound healing.

Release of exosomes from injectable silk fibroin and alginate composite hydrogel for treatment of myocardial infarction.

Myocardial infarction (MI) is considered as a significant cause of death globally. Exosomes (EXOs) are essential for intercellular communication and pathophysiology of several cardiovascular diseases. Nevertheless, the short half-life and rapid clearance of EXOs leads to a lack of therapeutic doses delivered to the lesioned area. Therefore, an injectable silk fibroin and alginate (SF/Alg) composite hydrogel was developed to bind folate receptor-targeted EXOs (FA-EXOs) derived from H9C2 cells for the therapy of myocardial injury following myocardial infarction-ischemia/reperfusion (MI-I/R). The resulting composite exhibits a variety of properties, including adjustable gelation kinetics, shear-thinning injectability, soft and dynamic stability that adapts to the heartbeat, and outstanding cytocompatibility. After injected into the damaged rat heart, administration of SF/Alg + FA-EXOs significantly enhanced cardiac function as demonstrated by improved ejection fraction, fractional shortening and decreased fibrosis area. The results of real-time PCR and immunofluorescence staining show a remarkable up-regulation in the expression of proteins (CD31) and genes (VWF and Serca2a) related to the heart. Conversely, expression of fibrosis-related genes (TGF-ß1) decreased significantly. Therefore, the obtained SF/Alg + FA-EXOs system remarkably enhanced the intercellular interactions, promoted cell proliferation and angiogenesis, and achieved an outstanding therapeutic effect on MI.