Microalgae-Based Biohybrid Microrobot for Accelerated Diabetic Wound Healing.

A variety of wound healing platforms have been proposed to alleviate the hypoxic condition and/or to modulate the immune responses for the treatment of chronic wounds in diabetes. However, these platforms with the passive diffusion of therapeutic agents through the blood clot result in the relatively low delivery efficiency into the deep wound site. Here, a microalgae-based biohybrid microrobot for accelerated diabetic wound healing is developed. The biohybrid microrobot autonomously moves at velocity of 33.3 µm s-1 and generates oxygen for the alleviation of hypoxic condition. In addition, the microrobot efficiently bound with inflammatory chemokines of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) for modulating the immune responses. The enhanced penetration of microrobot is corroborated by measuring fibrin clots in biomimetic wound using microfluidic devices and the enhanced retention of microrobot is confirmed in the real wounded mouse skin tissue. After deposition on the chronic wound in diabetic mice without wound dressing, the wounds treated with microrobots are completely healed after 9 days with the significant decrease of inflammatory cytokines below 31% of the control level and the upregulated angiogenesis above 20 times of CD31+ cells. These results confirm the feasibility of microrobots as a next-generation platform for diabetic wound healing.

Biocompatible Potato-Starch Electrolyte-Based Coplanar Gate-Type Artificial Synaptic Transistors on Paper Substrates.

In this study, we propose the use of artificial synaptic transistors with coplanar-gate structures fabricated on paper substrates comprising biocompatible and low-cost potato-starch electrolyte and indium-gallium-zinc oxide (IGZO) channels. The electrical double layer (EDL) gating effect of potato-starch electrolytes enabled the emulation of biological synaptic plasticity. Frequency dependence measurements of capacitance using a metal-insulator-metal capacitor configuration showed a 1.27 µF/cm2 at a frequency of 10 Hz. Therefore, strong capacitive coupling was confirmed within the potato-starch electrolyte/IGZO channel interface owing to EDL formation because of internal proton migration. An electrical characteristics evaluation of the potato-starch EDL transistors through transfer and output curve resulted in counterclockwise hysteresis caused by proton migration in the electrolyte; the hysteresis window linearly increased with maximum gate voltage. A synaptic functionality evaluation with single-spike excitatory post-synaptic current (EPSC), paired-pulse facilitation (PPF), and multi-spike EPSC resulted in mimicking short-term synaptic plasticity and signal transmission in the biological neural network. Further, channel conductance modulation by repetitive presynaptic stimuli, comprising potentiation and depression pulses, enabled stable modulation of synaptic weights, thereby validating the long-term plasticity. Finally, recognition simulations on the Modified National Institute of Standards and Technology (MNIST) handwritten digit database yielded a 92% recognition rate, thereby demonstrating the applicability of the proposed synaptic device to the neuromorphic system.

Multifunctional Nanodroplets Encapsulating Naphthalocyanine and Perfluorohexane for Bimodal Image-Guided Therapy.

Although nanocarriers containing perfluorocarbon (PFC) have been widely investigated as an ultrasound (US) imaging agent and a high intensity focused ultrasound (HIFU) agent, these carriers have suffered from low stability and biocompatibility limiting their further biomedical applications. Here, we developed surface cross-linked polymer nanodroplets as a HIFU therapeutic agent guided by bimodal photoacoustic (PA) and US imaging. Pluronic F127 was reacted with 4-nitrophenyl chloroformate (NPC) and mixed with naphthalocyanine (Nc) in dichloromethane, which was added into the aqueous solution of amine-functionalized six-arm-branched poly(ethylene glycol) (PEG) to form an oil-in-water emulsion for the cross-linking reaction between the terminal NPC of Pluronic F127 and the primary amine of six-arm PEG. The resulting solution was sonicated with liquid perfluorohexane (PFH) to prepare PEG cross-linked Pluronic F127 nanoparticles encapsulating Nc and PFH (Nc/PFH@PCPN). Nc/PFH@PCPN appeared to be stable without any coalescence or vaporization in the physiological condition. Upon the application of HIFU, Nc/PFH@PCPN was vaporized and showed increased US intensity for 180 min. The Nc dye in the nanodroplets enabled the stable encapsulation of PFH and the bimodal US/PA imaging. In vivo PA/US image-guided HIFU ablation therapy confirmed that the nanodroplets increased the cavitation effect, induced necrosis and apoptosis of tumor cells, and reduced tumor growth significantly for 12 days. Taken together, the multifunctional Nc/PFH@PCPN was successfully developed as a new platform for PA/US image-guided HIFU therapy.

DW1029M, a novel botanical drug candidate, inhibits advanced glycation end-product formation, rat lens aldose reductase activity, and TGF-ß1 signaling.

DW1029M is a botanical extract consisting of Morus bark and Puerariae radix, produced by Dong-Wha Pharmaceutical, for nephroprotective drug development; it has been in phase II clinical trials in Korea. In our mechanistic investigations, we found that DW1029M inhibits advanced glycation end products (AGEs), rat lens aldose reductase (RLAR), and transforming growth factor (TGF)-ß1 signaling, all of which are implicated in diabetic complications such as diabetic nephropathy and diabetic retinopathy. DW1029M inhibits AGE formation via Fe(2+) chelation. The extract contains 13 active constituents that inhibit AGE formation, 8 active constituents that inhibit RLAR activity, and 1 inhibitor of TGF-ß1 signaling. Our results suggest DW1029M protects against diabetic nephropathy via blockade of AGE formation, RLAR activity, and TGF-ß1 signaling.

Statistical analysis on static recrystallization texture evolution in cold-rolled AZ31 magnesium alloy sheet.

Cast AZ31B-H24 magnesium alloy, comprising Mg with 3.27 wt% Al and 0.96 wt% Zn, was cold rolled and subsequently annealed. Global texture evolutions in the specimens were observed by X-ray diffractometry after the thermomechanical processing. Image-based microstructure and texture for the deformed, recrystallized, and grown grains were observed by electron backscattered diffractometry. Recrystallized grains could be distinguished from deformed ones by analyzing grain orientation spread. Split basal texture of ca. ±10-15° in the rolling direction was observed in the cold-rolled sample. Recrystallized grains had widely spread basal poles at nucleation stage; strong {0001} basal texture developed with grain growth during annealing.

Supramolecular Hydrogels for Precisely Controlled Antimicrobial Peptide Delivery for Diabetic Wound Healing.

Diabetic wound patients are often exposed to bacterial infections with delayed healing process due to hyperglycemia in the damaged skin tissue. Antimicrobial peptides (AMPs) have been investigated for the treatment of infection-induced diabetic wounds, but their low stability and toxicity have limited their further applications to diabetic chronic wound healing. Here, we developed a precisely controlled AMP-releasing injectable hydrogel platform, which could respond to infection-related materials of matrix metalloproteinases (MMPs) and reactive oxygen species (ROS). The injectable supramolecular hydrogel was prepared by the simple mixing of hyaluronic acid modified with cyclodextrin (HA-CD) and adamantane (Ad-HA). Ad-HA was conjugated with AMP via the cyclic peptide linker composed of MMP and ROS cleavable sequence (Ad-HA-AMP). Remarkably, only when the AMP-tethered hydrogel was exposed to both MMP and ROS simultaneously, AMP was released from the hydrogel, enabling the controlled release of AMP without causing cytotoxicity. In addition, we confirmed the enhanced serum stability of the Ad-HA-AMP conjugate. The antimicrobial activity of Ad-HA-AMP was maintained much longer than that of the native AMP. Finally, we could demonstrate the greatly improved wound-healing effect of AMP-tethered hydrogels with enhanced safety for the treatment of infection-induced diabetic chronic wounds. Taken together, we successfully demonstrated the feasibility of sHG-AMP for diabetic chronic wound healing.

Multifunctional Intelligent Wearable Devices Using Logical Circuits of Monolithic Gold Nanowires.

Although multifunctional wearable devices have been widely investigated for healthcare systems, augmented/virtual realities, and telemedicines, there are few reports on multiple signal monitoring and logical signal processing by using one single nanomaterial without additional algorithms or rigid application-specific integrated circuit chips. Here, multifunctional intelligent wearable devices are developed using monolithically patterned gold nanowires for both signal monitoring and processing. Gold bulk and hollow nanowires show distinctive electrical properties with high chemical stability and high stretchability. In accordance, the monolithically patterned gold nanowires can be used to fabricate the robust interfaces, programmable sensors, on-demand heating systems, and strain-gated logical circuits. The stretchable sensors show high sensitivity for strain and temperature changes on the skin. Furthermore, the micro-wrinkle structures of gold nanowires exhibit the negative gauge factor, which can be used for strain-gated logical circuits. Taken together, this multifunctional intelligent wearable device would be harnessed as a promising platform for futuristic electronic and biomedical applications.

Bioinspired urease-powered micromotor as an active oral drug delivery carrier in stomach.

Self-propelling micro- and nano-motors (MNMs) have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal (GI) tract diseases. However, the propulsion of current MNMs reported so far is mostly based on the redox reaction of metals (such as Zn and Mg) with severe propulsion gas generation, remaining non-degradable residue in the GI tract. Here, we develop a bioinspired enzyme-powered biopolymer micromotor mimicking the mucin penetrating behavior of Helicobacter pylori in the stomach. It converts urea to ammonia and the subsequent increase of pH induces local gel-sol transition of the mucin layer facilitating the penetration into the stomach tissue layer. The successful fabrication of micromotors is confirmed by high-resolution transmission electron microscopy, electron energy loss spectroscopy, dynamic light scattering analysis, zeta-potential analysis. In acidic condition, the immobilized urease can efficiently converted urea to ammonia, comparable with that of neutral condition because of the increase of surrounding pH during propulsion. After administration into the stomach, the micromotors show enhanced penetration and prolonged retention in the stomach for 24 h. Furthermore, histological analysis shows that the micromotors are cleared within 3 days without causing any toxicity in the GI tract. The enhanced penetration and retention of the micromotors as an active oral delivery carrier in the stomach would be successfully harnessed for the treatment of various GI tract diseases.

Wireless theranostic smart contact lens for monitoring and control of intraocular pressure in glaucoma.

Glaucoma is one of the irreversible ocular diseases that can cause vision loss in some serious cases. Although Triggerfish has been commercialized for monitoring intraocular pressure in glaucoma, there is no smart contact lens to monitor intraocular pressure and take appropriate drug treatment in response to the intraocular pressure levels. Here, we report a precisely integrated theranostic smart contact lens with a sensitive gold hollow nanowire based intraocular pressure sensor, a flexible drug delivery system, wireless power and communication systems and an application specific integrated circuit chip for both monitoring and control of intraocular pressure in glaucoma. The gold hollow nanowire based intraocular pressure sensor shows high ocular strain sensitivity, chemical stability and biocompatibility. Furthermore, the flexible drug delivery system can be used for on-demand delivery of timolol for intraocular pressure control. Taken together, the intraocular pressure levels can be successfully monitored and controlled by the theranostic smart contact lens in glaucoma induced rabbits. This theranostic smart contact lens would be harnessed as a futuristic personal healthcare platform for glaucoma and other ocular diseases.

Multispectral upconversion nanoparticles for near infrared encoding of wearable devices.

Individual recognition technology such as iris recognition and bar coding has been extensively investigated for non-face-to-face authorization. However, there are still strong unmet needs for facile, rapid, and robust individual recognition. Here, we developed multispectral transparent films of upconversion nanoparticles (UCNPs) for near-infrared (NIR) encoding of wearable devices including contact lenses and patch devices. A multispectral UCNP film in a contact lens showed various luminescence colors of patterns under 980 nm NIR light irradiation and each color could be assigned to a specific code by RGB value analysis. The encoded film of UCNPs in the contact lens was successfully decoded by the RGB value analysis with a charge coupled digital (CCD) camera. Furthermore, the UCNP barcode film could be applied in the form of attachable barcode patches onto various substrates like porcine skin and paper currency. Taken together, we could confirm the feasibility of multispectral UCNP transparent films as a facile individual recognition platform for non-face-to-face authorization.

Multifunctional micro/nanomotors as an emerging platform for smart healthcare applications.

Self-propelling micro- and nano-motors (MNMs) are emerging as a multifunctional platform for smart healthcare applications such as biosensing, bioimaging, and targeted drug delivery with high tissue penetration, stirring effect, and rapid drug transport. MNMs can be propelled and/or guided by chemical substances or external stimuli including ultrasound, magnetic field, and light. In addition, enzymatically powered MNMs and biohybrid micromotors have been developed using the biological components in the body. In this review, we describe emerging MNMs focusing on their smart propulsion systems, and diagnostic and therapeutic applications. Finally, we highlight several MNMs for in vivo applications and discuss the future perspectives of MNMs on their current limitations and possibilities toward further clinical applications.

Smart Contact Lenses with a Transparent Silver Nanowire Strain Sensor for Continuous Intraocular Pressure Monitoring.

Continuous intraocular pressure (IOP) monitoring can provide a paradigm shift in the management of patients with glaucoma as a facile alternative to conventional diagnostic methods. However, the low sensitivity and functional instability of current IOP sensors have limited their clinical utility in the management of glaucoma. Here, we have developed a smart contact lens integrated with a transparent silver nanowire IOP strain sensor and wireless circuits for noninvasive, continuous IOP monitoring. After confirming the robust stability of the IOP sensor within the smart contact lens in the presence of tears and repeated eyelid blink model cycles, we were able to monitor IOP changes on polydimethylsiloxane model eyes in vitro. In vivo tests demonstrated that our fully integrated wireless smart contact lens could successfully monitor the change in IOP in living rabbit eyes, which was clearly validated by the conventional invasive tonometer IOP test. Taken together, we could confirm the feasibility of our smart contact lens as a noninvasive platform for continuous IOP monitoring of glaucoma patients.

Biomimetic Supramolecular Drug Delivery Hydrogels for Accelerated Skin Tissue Regeneration.

Skin tissue is regenerated by the combinational function of skin cells, extracellular matrix (ECM), and bioactive molecules. As an artificial ECM, supramolecular hydrogels exhibited outstanding capability to mimic the physical properties of ECM. However, the lack of biochemical function in supramolecular hydrogels has limited further tissue engineering applications. Here, we developed self-assembling supramolecular drug delivery hydrogels to mimic the skin tissue regeneration process. The supramolecular hydrogels were prepared to encapsulate fibroblasts by the host-guest interaction of cyclodextrin-modified gelatin (GE-CD) and adamantane-modified hyaluronate (Ad-HA) in conjugation with human growth hormone (hGH) for accelerated skin tissue regeneration. In vitro, GE-CD/Ad-HA-hGH hydrogels showed highly facilitated cell growth by the controlled hGH delivery. After a subcutaneous injection into the back of mice, IVIS imaging of bioengineered fibroblasts to express red fluorescence protein (RFP) revealed prolonged cell survival and proliferation in the supramolecular hydrogels for more than 21 days. We could also observe the improved skin tissue regeneration by the facilitated fibroblast proliferation with angiogenesis. Taken together, we could confirm the feasibility of biomimetic supramolecular drug delivery GE-CD/Ad-HA-hGH hydrogels for various tissue engineering applications.

Non-Invasive Topical Drug-Delivery System Using Hyaluronate Nanogels Crosslinked via Click Chemistry.

Hyaluronate (HA) has been widely investigated for noninvasive topical drug delivery of chemical drugs and biopharmaceuticals. However, previous noninvasive delivery systems have been facilitated mostly by chemical conjugation of drugs with HA, which can cause reduced therapeutic efficacy and safety issues in chemically modified drugs. Here, HA nanogels were synthesized by crosslinking via "click" chemistry for noninvasive topical delivery of a model drug without chemical modification. The model-drug-encapsulating HA nanogels could be uptaken to the skin melanoma cells in vitro by HA-mediated endocytosis. In addition, histological analysis showed that HA nanogels could be topically delivered to the deep skin and tongue tissues through the noninvasive delivery routes. Taken together, HA nanogels could be effectively used for the noninvasive topical delivery of various therapeutic drugs.

Piezo-Actuated One-Axis Vibrational Patterning for Mold-Free Continuous Fabrication of High-Precision Period-Programmable Micro- and Nanopatterns.

We present a mold-free high-resolution nanopatterning technology named piezo-actuated one-axis vibrational patterning (POP) that enables continuous and scalable fabrication of micro- and nanopatterns with precisely programmable periods and dimensions. POP utilizes the piezoelectric stack-actuated high-precision uniaxial vibration of a flat, pattern-free rigid tool edge to conduct sub-50 nm-periodic indentations on various compliant substrates laterally fed underneath. By controlling the tool vibration frequency, tool temperature, and substrate feed rate and by combining sequential tool strokes along multiple directions, diverse functional micro- and nanopatterns with variable periods and depths and multidimensional profiles can be continuously created without resorting to mold prefabrication. With its simple but universal principle, excellent scalability, and versatile processability, POP can be practically applied to many functional devices particularly requiring large-area micro- and nanopatterns with specifically designed periods and dimensions.

Urease-Powered Polydopamine Nanomotors for Intravesical Therapy of Bladder Diseases.

Intravesical therapeutic delivery has been extensively investigated for various bladder diseases such as bladder cancer, overactive bladder, urinary incontinence, and interstitial cystitis. However, conventional drug carriers have a low therapeutic delivery efficiency because of the passive diffusion of drug molecules in a bladder and the rapid clearance by periodic urination. Here, we report biocompatible and bioavailable enzyme-powered polymer nanomotors which can deeply penetrate into a mucosa layer of the bladder wall and remain for a long-term period in the bladder. The successful fabrication of nanomotors was confirmed by high-resolution transmission electron microscopy, energy-dispersive X-ray mapping, zeta-potential analysis, Fourier transform infrared spectroscopy, and urease activity and nanomotor trajectory analyses. After injection into the bladder, urease-immobilized nanomotors became active, moving around in the bladder by converting urea into carbon dioxide and ammonia. The nanomotors resulted in the facilitated penetration to the mucosa layer of the bladder wall and the prolonged retention in the bladder even after repeated urination. The enhanced penetration and retention of the nanomotors as a drug delivery carrier in the bladder would be successfully harnessed for treating a variety of bladder diseases.

Low-temperature large-area fabrication of ZnO nanowires on flexible plastic substrates by solution-processible metal-seeded hydrothermal growth.

We have developed the low-temperature conformal ZnO nanowire fabrication on flexible plastic substrates by utilizing the solution-processible metal seed-assisted hydrothermal ZnO crystallization. Structural evolution of ZnO nanowires controlled by major parameters involving growth temperature, growth time, and seed coating condition, has been systematically investigated towards uniform and large-area growth of conformal ZnO nanowires. Direct ZnO nanowire growth on flexible plastics without undergoing the high-temperature seed sintering has been realized by developing the low-temperature Ag-seeded hydrothermal ZnO nanowire growth. The nanoporous Ag layer favorable for ZnO crystal nucleation and continued nanowire growth can be reduced from the Ag ion solution coating at the temperature as low as 130 °C. This tactfully enables the selective hydrothermal growth of ZnO nanowires on the Ag patterns on flexible plastics. Such an all-solution-processible low-temperature fabrication protocol may provide an essential and practical solution to develop many diverse applications including wearable and transparent electronics, sensors, and photocatalytic devices. As one example, we demonstrate that a transparent UV sensor can be devised based on the ZNW growth on the Ag micromesh electrode.

Light-Guided Nanomotor Systems for Autonomous Photothermal Cancer Therapy.

Machines have greatly contributed to the human civilization, enabling tasks beyond our capacities for improved quality of life. Recently, the progress in nanotechnology has triggered to build a miniaturized machine of nanoscale. In this context, synthetic nanomotors have gained considerable interest because of their great promise for diverse applications. Currently, the movement control of these nanomotors has been widely investigated using various stimuli. Here, we demonstrate near-infrared (NIR) light controlled on/off motion of stomatocyte nanomotors powered by the conversion of hydrogen peroxide. The nanomotors encapsulating naphthalocyanine (NC) are aggregated or separated (collective motion) with or without near-IR light illumination, resulting in the well-controlled movement. Remarkably, the nanomotors can move directionally toward hydrogen peroxide released from cancer cells and photothermally ablate the cancer cells. Taken together, our stomatocyte nanomotor systems can be effectively harnessed for autonomous photothermal cancer therapy.

The Mixture of Anemarrhena asphodeloides and Coptis chinensis Attenuates High-Fat Diet-Induced Colitis in Mice.

Anemarrhena asphodeloides (AA, family Liliaceae) inhibits macrophage activation by inhibiting IRAK1 phosphorylation and helper T (Th)17 differentiation. Coptis chinensis (CC, family Ranunculaceae), which inhibits macrophage activation by inhibiting the binding of lipopolysaccharide (LPS) on toll-like receptor 4 and inducing regulatory T (Treg) cell differentiation. The mixture of AA and CC (AC-mix) synergistically attenuates 2,4,6-trinitrobenzenesulfonic acid or dextran sulfate sodium-induced colitis in mice by inhibiting NF-[Formula: see text]B activation and regulating Th17/Treg balance. In the present study, we examined the effect of AC-mix on high-fat diet (HFD)-induced colitis in mice, which induced NF-[Formula: see text]B activation and disturbed Th17/Treg balance. Long-term feeding of HFD in mice caused colitis, including increased macroscopic score and myeloperoxidase activity. Oral administration of AC-mix (20[Formula: see text]mg/kg) suppressed HFD-induced myeloperoxidase activity by 68% ([Formula: see text]). Furthermore, treatment with the AC-mix (20[Formula: see text]mg/kg) inhibited HFD-induced activation of NF-[Formula: see text]B and expression of cyclooxygenase-2, inducible NO synthase, interleukin (IL)-17, and tumor necrosis factor-alpha but increased HFD- suppressed expression of IL-10. AC-mix suppressed HFD-induced differentiation into Th17 cells by 46% ([Formula: see text]) and increased HFD-induced differentiation into regulatory T cells 2.2-fold ([Formula: see text]). AC-mix also suppressed the HFD-induced Proteobacteria/Bacteroidetes ratio on the gut microbiota by 48% ([Formula: see text]). These findings suggest that AC-mix can ameliorate HFD-induced colitis by regulating innate and adaptive immunities and correcting the disturbance of gut microbiota.

Accuracy of tablet counts estimated by members of the public and healthcare professionals.

OBJECTIVE: Intentional and accidental drug intoxication is commonly seen in the emergency department. When treating intoxicated patients, accessing the amount of the ingested drug is crucial albeit often difficult. We investigated the accuracy of estimating tablet counts when participants were asked to hold tablets in their fists and hands (semi-quantitative terms). METHODS: The widths and lengths of the participants' hands were measured. Then, the subjects were asked to hold 5-mm round, 10-mm round, 10-mm oval, and 15-mm elliptical tablets using their hands and fists and to estimate the number of tablets they were holding. Differences between the estimated and actual numbers of tablets were examined. RESULTS: A total of 47 members of the public and 32 healthcare professionals were included in our study. In our analyses of the differences between the actual and estimated amounts of tablets held in the participants' hands and fists, we found that the actual amount was higher than the estimated amount for all tablet types and in both groups. When participants held the tablets in the same manner (handful or fistful), the differences between the actual and estimated amounts were greater for 5- than 15-mm-sized tablets (P<0.05). CONCLUSION: The treatment of patients presenting with drug overdoses to the emergency department should be based on the assumption that the actual amount of drugs the patients ingested is likely greater than the amount the patients state.