Enhancing the Solubility and Transdermal Delivery of Drugs Using Ionic Liquid-In-Oil Microemulsions

The development of hydrophobic drug and protein delivery carriers remains a challenge. To synthesize L-(-)-carnitine-based ionic liquid (IL), this study applies the density functional theory to investigate the hydrogen bonds and van der Waals force that govern L-(-)-carnitine-based IL formation. An ionic liquid-in-oil microemulsion (IL/O ME) is then developed to facilitate the transdermal delivery of proteins and increase the solubility of drugs. IL/O ME is prepared using isopropyl myristate (IPM), Tween 80/Span 20, and L-(-)-carnitine-based IL. The skin permeation studies conducted using mouse skin show that the insulin permeation percentage of the developed IL/O ME is 3.55 folds higher than that of phosphate-buffered saline and 2.91 folds better than that of a hydrophilic L-(-)-carnitine-based IL. In addition, the solubility of two drug molecules, that is, rosiglitazone and bezafibrate, in IL/O ME is at least 49.28 folds higher than their solubility in water or IPM. Therefore, IL/O ME can significantly improve the solubility of drugs and increase the permeability of proteins (e.g., insulin), thus demonstrating a promising potential as a delivery carrier.     

Ionic Liquids and Deep Eutectic Solvents for Enhanced Delivery of Antibodies in the Gastrointestinal Tract

Monoclonal antibodies (mAbs) are currently used for the treatment of numerous conditions including cancer, psoriasis, arthritis, and atopic dermatitis, among others. All mAbs are currently administered by either intravenous or subcutaneous injections. Herein, the use of a novel ionic liquid and deep eutectic solvent, choline and glycolate (CGLY), as a platform for gastrointestinal administration of therapeutic antibodies is reported. CGLY maintains the stability and structure of TNFα antibody. CGLY significantly enhances paracellular transport of TNFα antibody in vitro. CGLY also reduces the viscosity of the intestinal mucus, another key barrier for antibody transport. In vivo results in rats demonstrate that CGLY effectively delivers TNFα antibody into the intestinal mucosa as well as systemic circulation. One week repeat dose study followed by histology and serum biochemistry analysis indicates that CGLY is well tolerated by rats. Overall, this work illustrates the promise of using choline-based ionic liquids and deep eutectic solvents as an oral delivery platform for local as well as systemic delivery of therapeutic antibodies.     

Microneedle-Based Local Delivery of CCL22 and IL-2 Enriches Treg Homing to the Skin Allograft and Enables Temporal Monitoring of Immunotherapy Efficacy

Skin allografts only serve as temporary dressing for patients suffering major burns due to their high immunogenicity and rejection by the immune system, requiring systemic immunosuppressive therapies that lead to deleterious side effects. Microneedle arrays composed of hyaluronic acid (HA) and placed on skin allografts can locally deliver immunomodulators and simultaneously sample immune cells in interstitial fluid to monitor the response to the therapy. The cells can be retrieved from the microneedles for downstream analysis by degrading the HA using a reducing agent. Using an allogeneic skin transplantation model, it is shown that the microneedle-mediated local delivery of the chemokine CCL22 (to attract T_regs) and the cytokine IL-2 (to promote their expansion) increases the local immune suppression in the allograft. Moreover, immune cell population in the allograft correlates with that seen in the microneedles. The delivery and sampling functions of the microneedle arrays can help regulate the immune system locally, without inducing systemic immune suppression, and facilitate the monitoring of the response to the therapy following skin transplantation.     

Evolution‐Based Design of an Injectable Hydrogel

A new class of simple, linear, amphiphilic peptides are developed that have the ability to undergo triggered self‐assembly into self‐supporting hydrogels. Under non‐gelling aqueous conditions, these peptides exist in a random coil conformation and peptide solutions have the viscosity of water. On the addition of a buffered saline solution, the peptides assemble into a β‐sheet rich network of fibrils, ultimately leading to hydrogelation. A family of nine peptides is prepared to study the influence of peptide length and amino acid composition on the rate of self‐assembly and hydrogel material properties. The amino acid composition is modulated by varying residue hydrophobicity and hydrophilicity on the two opposing faces of the amphiphile. The conformation of peptides in their soluble and gel state is studied by circular dichroism (CD), while the resultant material properties of their gels is investigated using oscillatory sheer rheology. One weight percent gels formed under physiological conditions have storage modulus (G′) values that vary from ≈20 to ≈800 Pa, with sequence length and hydrophobic character playing a dominant roll in defining hydrogel rigidity. Based on the structural and functional data provided by the nine‐peptide family members, an optimal sequence, namely LK13, is evolved. LK13 (LKLKLKLKLKLKL‐NH₂) undergoes triggered self‐assembly, affording the most rigid gel of those studied (G′=797 ± 105). It displays shear thin‐recovery behavior, allowing its delivery by syringe and is cytocompatibile as assessed with murine C3H10t1/2 mesenchymal stem cells.     

NIR Laser-Triggered Microneedle-Based Liquid Band-Aid for Wound Care

Microneedles (MNs) have attracted widespread scientific and industrial interest in the past decade as an efficient, painless, low-cost, and relatively safe transdermal drug delivery device. However, their drawbacks such as insufficient dose accuracy and limited penetration depth may limit the clinical applications. Here, a light-controlled liquid band-aid based on MNs is developed for antibacterial applications. Metal–organic framework-derived peroxidase-like nanozyme loaded in MNs can not only convert light energy into heat to enhance drug permeation but also decompose hydrogen peroxide into hydroxyl radicals for antibacteria. The heat generated by the nanozyme can facilitate MNs to melt and form a liquid band-aid, which is beneficial to insulate the wound from the surrounding bacterial environment. These studies in a Staphylococcus aureus-infected mice model also prove that this laser-triggered liquid band-aid can efficiently reduce skin inflammation and promote wound healing. Together, these results demonstrate that the rational design of MNs can enhance antibacterial and wound healing efficiency.     

Engineered Proteinticles for Targeted Delivery of siRNA to Cancer Cells

Considering the problems of small interfering RNA (siRNA) delivery using traditional viral and nonviral vehicles, a new siRNA delivery system to enhance efficiency and safety needs to be developed. Here human ferritin‐based proteinticles are genetically engineered to simultaneously display various functional peptides on the surface of proteinticles: cationic peptide to capture siRNA, tumor cell targeting and penetrating peptides, and enzymatically cleaved peptide to release siRNA inside tumor cell. In the in vitro treatment of poly‐siRNA‐proteinticle complex, both of the tumor cell targeting and penetrating peptides are important for efficient delivery of siRNA, and the red fluorescent protein (RFP) expression in RFP‐expressing tumor cells is notably suppressed by the delivered siRNA with the complementary sequence to RFP mRNA. It seems that the human ferritin‐based proteinticle is an efficient, stable, and safe tool for siRNA delivery, having a great potential for application to in vivo cancer treatment. The unique feature of proteinticles is that multiple and functional peptides can be simultaneously and evenly placed and also easily switched on the proteinticle surface through a simple genetic modification, which is likely to make proteinticles appropriate for targeted delivery of siRNA to a wide range of cancer cells.     

A Patch of Detachable Hybrid Microneedle Depot for Localized Delivery of Mesenchymal Stem Cells in Regeneration Therapy

Mesenchymal stem cells (MSCs) have been widely used for regenerative therapy. In most current clinical applications, MSCs are delivered by injection but face significant issues with cell viability and penetration into the target tissue due to a limited migration capacity. Some therapies have attempted to improve MSC stability by their encapsulation within biomaterials; however, these treatments still require an enormous number of cells to achieve therapeutic efficacy due to low efficiency. Additionally, while local injection allows for targeted delivery, injections with conventional syringes are highly invasive. Due to the challenges associated with stem cell delivery, a local and minimally invasive approach with high efficiency and improved cell viability is highly desired. In this study, a detachable hybrid microneedle depot (d‐HMND) for cell delivery is presented. The system consists of an array of microneedles with an outer poly(lactic‐co‐glycolic) acid shell and an internal gelatin methacryloyl (GelMA)‐MSC mixture (GMM). The GMM is characterized and optimized for cell viability and mechanical strength of the d‐HMND required to penetrate mouse skin tissue is also determined. MSC viability and function within the d‐HMND is characterized in vitro and the regenerative efficacy of the d‐HMND is demonstrated in vivo using a mouse skin wound model.     

Liquid Manipulation Lithography to Fabricate a Multifunctional Microarray of Organosilanes on an Oxide Surface under Ambient Conditions

A novel method to produce a multifunctional microarray in which different types of self‐assembled monolayers (SAMs) are positioned on predefined surface sites on an oxide‐covered silicon substrate is described. To achieve this, a liquid‐transportation system called “liquid manipulation lithography” (LML) is developed. This system allows the delivery of different varieties of molecular inks, trialkoxysilanes, onto each predefined surface position of the given substrate even under ambient conditions. Under optimum conditions, the transferred trialkoxysilane inks first form one‐molecule‐thick microstructures at each surface position through the hydrolysis of the reactive silanes with surface water adsorbed on the substrate, followed by a condensation reaction. Three types of trialkoxysilanes with long alkyl‐chains, specifically triethoxysilylundecanal (TESUD), N‐(6‐aminohexyl)‐3‐aminopropyltrimethoxysilane (AHAPS), and octadecyltrimethoxysilane (OTS), are used as model molecular inks due to their high‐end group‐functionalities in biological and electronic applications. The precise positioning of the ink with sub‐micrometer edge resolution is performed by carefully controlling a femtoliter‐scale liquid‐injection micromanipulator under a microscope. To ensure that the prepared SAM microarray is available for parallel analysis of biomolecular interactions, the area‐selective immobilization of a protein molecule is explored. Successful observation of the area‐selective biomolecular attachment confirmed a high industrial potential for the method as a lithography‐free process for the miniaturization of a multifunctional SAM array on an oxide substrate.     

Electrodeless Reverse Electrodialysis Patches as an Ionic Power Source for Active Transdermal Drug Delivery

Reverse electrodialysis (RED) is one of the promising sustainable technologies generating electric power from the mixing energy of two different salt solutions. Most of the reports on the RED systems are focused on scale‐up development and the improvement of maximum power density. However, regarding biocompatible and eco‐friendly natures, the RED system also has a great potential use where low electrical power is necessary, in particular for skin‐wearable biomedical devices. In this work, electronics‐free RED patches are devised as an ionic power source for active transdermal drug delivery. The electrodeless RED patches generate reliable voltages, which are proportional to the number of ion‐exchange membranes and salinity ratios, and successfully facilitate in vitro delivery of ionic drugs through mouse skin without involving any electronic component for the first time; 9, 20, and 36‐fold increases with lidocaine, ketorolac, and risedronate, respectively. Indeed, by using an osteoporosis‐induced mouse model, the RED patch delivery demonstrates powerful in vivo therapeutic effects against the diffusion‐based topical administration. The new ionic power source can allow transport of various types of drugs in the transdermal route and, more importantly, can be used for the operation of other portable biomedical devices.     

Development of new no-flow underfill materials for both eutectic Sn-Pb solder and a high temperature melting lead-free solder

In recent years, no-flow underfill technology has drawn more attention due to its potential cost-savings advantages over conventional underfill technology, and as a result several no-flow underfill materials have been developed and reported. However, most of these materials are not suitable for lead-free solder, such as Sn/Ag (m.p. 225/spl deg/C), Sn/Ag/Cu (m.p. 217/spl deg/C), applications that usually have higher melting temperatures than the eutectic Sn-Pb solder (m.p. 183/spl deg/C). Due to the increasing environmental concern, the demand for friendly lead-free solders has become an apparent trend. This paper demonstrates a study on two new formulas of no-flow underfill developed for lead-free solders with a melting point around 220/spl deg/C. As compared to the G25, a no-flow underfill material developed in our research group, which uses a solid metal chelate curing catalyst to match the reflow profile of eutectic Sn-Pb solder, these novel formulas employ a liquid curing catalyst thus provides ease in preparation of the no-flow underfill materials. In this study, curing kinetics, glass transition temperature (Tg), thermal expansion coefficient (TCE), storage modulus (E') and loss modulus (E') of these materials were studied with a differential scanning calorimetry (DSC), a thermo-mechanical analysis (TMA), and a dynamic-mechanical analysis (DMA), respectively. The pot-life in terms of viscosity of these materials was characterized with a stress rheometer. The adhesive strength of the materials on the surface of silicon chips were studied with a die-shear instrument. The influences of fluxing agents on the materials curing kinetics were studied with a DSC. The materials compatibility to the solder penetration and wetting on copper clad during solder reflow was investigated with both eutectic Sn-Pb and 95.9Sn/3.4Ag/0.7Cu solders on copper laminated FR-4 organic boards.     

Ambiently and Mechanically Stable Ionogels for Soft Ionotronics

Stretchable ionic conductors such as hydrogels and ionic-liquid-based gels (aka ionogels) have garnered great attention as they enable the development of soft ionotronics. Notably, soft ionotronic devices inevitably operate in humid environments or under mechanical loads. However, many previously reported hydrogels and ionogels, however, are unstable in environments with varying humidity levels owing to hydrophilicity, and their liquid components (i.e., ionic liquid, water) may leak easily from polymer matrices under mechanical loads, causing deterioration of device performance. This work presents novel hydrophobic ionogels with strong ionic liquid retention capability. The ionogels are ambiently and mechanically stable, capable of not absorbing moisture in environments with high relative humidity and almost not losing liquid components during long periods of mechanical loading. Moreover, the ionogels exhibit desirable conductivity (10⁻⁴–10⁻⁵ S cm⁻¹), large rupturing strain (>2000%), moderate fractocohesive length (0.51–1.03 mm), and wide working temperature range (−60 to 200 °C). An ionic skin is further designed by integrating the concept of sensory artificial skins and triboelectric nanogenerators, which can convert multiple stimuli into various types of signals, including resistance, capacitance, short-circuit current, and open-circuit voltage. This work may open new avenues for the development of soft ionotronics with stable performance.     

Neuron-Inspired Self-Powered Hydrogels with Excellent Adhesion,Recyclability and Dual-Mode Output for Multifunctional Ionic Skin

Hydrogels are promising materials for electronic skin due to their flexibility and modifiability. Reported hydrogel electronic skins can recognize stimulations and output signals, but the single output signal and the requirement of external power source limit their further applications. In this study, inspired by the neuron system, the self-powered neuron system-like hydrogels based on gelatin, water/glycerin and ionic liquid modified metal organic frameworks (MOFs) are prepared. The optimized hydrogel exhibits excellent adhesion (40 kPa), stretchability (0%–100%), water retention (>92% at 0% relative humidity (RH) atmosphere), ionic conductivity (>10⁻³ S m⁻¹) and stability (>30 days). Besides, the neuron system-like hydrogels are highly sensitive to pressure (0—10 N) and humidity (0%–75% RH) with dual-modal output, without external power source. Finally, the optimized hydrogel ionic skin is applied in human motion detection, energy harvesting, and low humidity sensing. This study provides a preliminary exploration of self-powered ionic skin for multi-application scenarios.     

Solvent‐Free Ionic Liquid Electrolytes for Mesoscopic Dye‐Sensitized Solar Cells

Ionic liquids have been identified as a new class of solvent that offers opportunities to move away from the traditional solvents. The physical‐chemical properties of ionic liquids can be tuned and controlled by tailoring their structures. The typical properties of ionic liquids, such as non‐volatility, electrochemical stability and high conductivity, render them attractive as electrolytes for dye‐sensitized solar cells. However, the high viscosity of ionic liquids leads to mass transport limitations on the photocurrents in the solar cells at full sunlight intensity, but the contribution of a Grotthous‐type exchange mechanism in these viscous electrolytes helps to alleviate these diffusion problems. This article discusses recent developments in the field of high‐performance dye‐sensitized solar cells with ionic liquid‐based electrolytes and their characterization by electrochemical impedance analysis.     

Ionic liquid ion sources for silicon reactive machining

In this article the authors report on ionic liquid ion sources (ILISs) for silicon reactive machining and direct microfabrication of silicon structures. The authors have developed a specific source geometry using the ionic liquid EMI-BF4 to obtain stable emission currents up to the 10 μA regime. ILIS EMI-BF4 engraving properties were then investigated in low and high current regime showing very different etching characteristics. The results and the chemical analysis of the patterned substrates suggest that reactive ion species can be generated from ILIS. This possibility is of major interest to allow decisive advances in the field of focused ion beam applications.     

Electricity over glass [fiber optic to transfer electric power]

Photonic Power Systems Inc. has developed a system that uses a laser to inject power in the form of light into a fiber-optic cable and photovoltaic (PV) array to convert the light back into electricity for powering devices. This paper discusses the use of optical fiber instead of copper wire in power delivery. This method of power transfer is highly advantageous in situations where sparks or shorts can be a fatal problem, where electromagnetic interference is more than just an inconvenience. At the heart of the system is an array of PV cells whose efficiency is achieved by converting light at whatever frequencies the sun provides.     

Enhanced Skin Permeation of Anti-Aging Peptides Using Bioactive Ionic Liquids at Low Concentrations

Delaying aging is an eternal goal for humanity. Acetyl hexapeptide-8 (AHP-8) is an effective skin anti-aging drug that locally interrupts the signal transmission of muscle contractions and promotes collagen production, thus smoothening wrinkles. However, its high molecular weight and strong hydrophilicity limit its skin permeation capacity. To solve this problem, an ionic liquid with excellent bioactivity, MAC, is synthesized from l -malic acid and l -carnitine and used as a permeation enhancer to improve the anti-aging effects of AHP-8. The ratio of MAC's components is optimized based on density functional theory calculations and cytotoxicity experiments. Low concentrations of MAC significantly increase AHP-8 transdermal delivery, reaching a maximum at 5-10 wt% MAC. The pro-permeation mechanism of MAC is investigated using molecular dynamics simulations, and the penetration enhancement and anti-aging performance of AHP-8 are demonstrated by conducting cellular, animal, and clinical experiments. The results show that MAC/AHP-8 outperforms AHP-8 in terms of collagen and hyaluronic acid synthesis, anti-inflammation, anti-oxidation, and inhibition of muscle contraction, thus significantly reducing the number and area of wrinkles and increasing skin moisture and elasticity. This study presents MAC as a simple and efficient transdermal vehicle for the clinical application of AHP-8.     

Model of the formation of a polycrystalline n-ZnO/p-CuO heterojunction

A model of the formation of a heterojunction based on polycrystalline films of zinc and copper oxides is considered. Faces of the unit cells, between which epitaxial relations are fulfilled, are revealed on the basis of an analysis of the crystalline structure of the zinc and copper oxides. It is also shown that, in addition to fulfillment of the rule of epitaxial relations, the closeness of the values of the ionic radii for double-charged Cu⁺⁺ and Zn⁺⁺ ions makes it possible to form a polycrystalline heterojunction in a ZnO/CuO system.     

Liquid‐Crystalline Electrolytes for Lithium‐Ion Batteries: Ordered Assemblies of a Mesogen‐Containing Carbonate and a Lithium Salt

Thermotropic liquid‐crystalline (LC) electrolytes for lithium‐ion batteries are developed for the first time. A rod‐like LC molecule having a cyclic carbonate moiety is used to form self‐assembled two‐dimensional ion‐conductive pathways with lithium salts. Electrochemical and thermal stability, and efficient ionic conduction is achieved for the liquid crystal. The mixture of the carbonate derivative and lithium bis(trifluoromethylsulfonyl)imide is successfully applied as an electrolyte in lithium‐ion batteries. Reversible charge–discharge for both positive and negative electrodes is observed for the lithium‐ion batteries composed of the LC electrolyte.     

Self‐Assembly Behavior of an Oligothiophene‐Based Conjugated Liquid Crystal and Its Implication for Ionic Conductivity Characteristics

In this work, a joint experimental and computational study on the synthesis, self‐assembly, and ionic conduction characteristics of a new conjugated liquid crystal quaterthiophene/poly(ethylene oxide) (PEO4) consisting of terminal tetraethyleneglycol monomethyl ether groups on both ends of a quaterthiophene core is performed. In agreement with molecular dynamic simulations, temperature‐dependent grazing‐incidence wide angle X‐ray scattering and X‐ray diffraction indicate that the molecule spontaneously forms a smectic phase at ambient temperature as characterized both in bulk and thin film configurations. Significantly, this smectic phase is maintained upon blending with bis(trifluoro‐methanesulfonyl)imide as ion source at a concentration ratio up to r = [Li⁺]/[EO] = 0.05. Nanosegregation between oligothiophene and PEO moieties and π–π stacking of thiophene rings lead to the formation of efficient 2D pathways for ion transport, resulting in thin‐film in‐plane ionic conductivity as high as 5.2 × 10^?4 S cm^?1 at 70 °C and r = 0.05 as measured by electrochemical impedance spectroscopy. Upon heating the samples above a transition temperature around 95 °C, an isotropic phase forms associated with a pronounced drop in ionic conductivity. Upon cooling, partial and local reordering of the conducting smectic domains leads to an ionic conductivity decrease compared to the as‐cast state.     

Painless drug delivery through microneedle-based transdermal patches featuring active infusion

This paper presents the first microneedle-based transdermal patch with integrated active dispensing functionality. The electrically controlled system consists of a low-cost dosing and actuation unit capable of controlled release of liquid in the microliter range at low flow-rates and minimally invasive, side-opened, microneedles. The system was successfully tested in vivo by insulin administration to diabetic rats. Active infusion of insulin at 2 mul/h was compared to passive, diffusion-driven, delivery. Continuous active infusion caused significantly higher insulin concentrations in blood plasma. After a 3-h delivery period, the insulin concentration was five times larger compared to passive delivery. Consistent with insulin concentrations, actively administered insulin resulted in a significant decrease of blood glucose levels. Additionally, insertion and liquid injection was verified on human skin. This study shows the feasibility of a patch-like system with on-board liquid storage and dispensing capability. The proposed device represents a first step towards painless and convenient administration of macromolecular drugs such as insulin or vaccines.