Nitric-Oxide-Modulatory Materials for Biomedical Applications.

Nitric oxide (NO) is an endogenous signaling molecule that participates in various physiological and biological pathways associated with vasodilation, immune response, and cell apoptosis. Interestingly, NO has versatile and distinct functions in vivo depending on its concentration and the duration of exposure; it aids cellular proliferation at nanomolar concentrations but causes cellular death at micromolar concentrations. Therefore, achieving the precise and on-demand modulation of microenvironmental NO concentrations has become a major research target in biomedical fields. To this end, many studies have investigated feasible means for developing functional moieties that can either exogenously donate or selectively scavenge NO. However, these advances are limited by poor stability and a lack of target specificity, which represent two significant obstacles regarding the spatiotemporal adjustment of NO in vivo. Our group has addressed this issue by contributing to the development of next-generation NO-modulatory materials over the past decade. Over this period, we utilized various polymeric, inorganic, and hybrid systems to enhance the bioavailability of traditional NO donors or scavengers in an attempt to maximize their clinical usage while also minimizing their unwanted side effects. In this Account, strategies regarding the rational design of NO-modulatory materials are first summarized and discussed, depending on their specific purposes. These strategies include chemical approaches for encapsulating traditional NO donors inside specific vehicles; this prevents spontaneous NO release and allows said donors to be exposed on-demand, under a certain stimulus. The current status of these approaches and the recent contributions of other groups are also comprehensively discussed here to ensure an objective understanding of the topic. Moreover, in this paper, we discuss strategies for the selective depletion of NO from local inflammatory sites, where the overproduction of NO is problematic. Finally, the major challenges for current NO-modulatory systems are discussed, and requirements are outlined that need to be tackled to achieve their future therapeutic development. Starting from this current, relatively early stage of development, we propose that, through continuous efforts to surmount existing challenges, it will be possible in the future to achieve clinical translations regarding NO-modulatory systems. This Account provides insightful guidelines regarding the rational design of NO-modulatory systems for various biomedical applications. Moreover, it can facilitate the achievement of previously unattainable goals while revolutionizing future therapeutics.

Soft, thin skin-mounted power management systems and their use in wireless thermography.

Power supply represents a critical challenge in the development of body-integrated electronic technologies. Although recent research establishes an impressive variety of options in energy storage (batteries and supercapacitors) and generation (triboelectric, piezoelectric, thermoelectric, and photovoltaic devices), the modest electrical performance and/or the absence of soft, biocompatible mechanical properties limit their practical use. The results presented here form the basis of soft, skin-compatible means for efficient photovoltaic generation and high-capacity storage of electrical power using dual-junction, compound semiconductor solar cells and chip-scale, rechargeable lithium-ion batteries, respectively. Miniaturized components, deformable interconnects, optimized array layouts, and dual-composition elastomer substrates, superstrates, and encapsulation layers represent key features. Systematic studies of the materials and mechanics identify optimized designs, including unusual configurations that exploit a folded, multilayer construct to improve the functional density without adversely affecting the soft, stretchable characteristics. System-level examples exploit such technologies in fully wireless sensors for precision skin thermography, with capabilities in continuous data logging and local processing, validated through demonstrations on volunteer subjects in various realistic scenarios.

Super-Absorbent Polymer Valves and Colorimetric Chemistries for Time-Sequenced Discrete Sampling and Chloride Analysis of Sweat via Skin-Mounted Soft Microfluidics.

This paper introduces super absorbent polymer valves and colorimetric sensing reagents as enabling components of soft, skin-mounted microfluidic devices designed to capture, store, and chemically analyze sweat released from eccrine glands. The valving technology enables robust means for guiding the flow of sweat from an inlet location into a collection of isolated reservoirs, in a well-defined sequence. Analysis in these reservoirs involves a color responsive indicator of chloride concentration with a formulation tailored to offer stable operation with sensitivity optimized for the relevant physiological range. Evaluations on human subjects with comparisons against ex situ analysis illustrate the practical utility of these advances.

Miniaturized Battery-Free Wireless Systems for Wearable Pulse Oximetry.

Development of unconventional technologies for wireless collection, storage and analysis of quantitative, clinically relevant information on physiological status is of growing interest. Soft, biocompatible systems are widely regarded as important because they facilitate mounting on external (e.g. skin) and internal (e.g. heart, brain) surfaces of the body. Ultra-miniaturized, lightweight and battery-free devices have the potential to establish complementary options in bio-integration, where chronic interfaces (i.e. months) are possible on hard surfaces such as the fingernails and the teeth, with negligible risk for irritation or discomfort. Here we report materials and device concepts for flexible platforms that incorporate advanced optoelectronic functionality for applications in wireless capture and transmission of photoplethysmograms, including quantitative information on blood oxygenation, heart rate and heart rate variability. Specifically, reflectance pulse oximetry in conjunction with near-field communication (NFC) capabilities enables operation in thin, miniaturized flexible devices. Studies of the material aspects associated with the body interface, together with investigations of the radio frequency characteristics, the optoelectronic data acquisition approaches and the analysis methods capture all of the relevant engineering considerations. Demonstrations of operation on various locations of the body and quantitative comparisons to clinical gold standards establish the versatility and the measurement accuracy of these systems, respectively.

Soft Elastomers with Ionic Liquid-Filled Cavities as Strain Isolating Substrates for Wearable Electronics.

Managing the mechanical mismatch between hard semiconductor components and soft biological tissues represents a key challenge in the development of advanced forms of wearable electronic devices. An ultralow modulus material or a liquid that surrounds the electronics and resides in a thin elastomeric shell provides a strain-isolation effect that enhances not only the wearability but also the range of stretchability in suitably designed devices. The results presented here build on these concepts by (1) replacing traditional liquids explored in the past, which have some nonnegligible vapor pressure and finite permeability through the encapsulating elastomers, with ionic liquids to eliminate any possibility for leakage or evaporation, and (2) positioning the liquid between the electronics and the skin, within an enclosed, elastomeric microfluidic space, but not in direct contact with the active elements of the system, to avoid any negative consequences on electronic performance. Combined experimental and theoretical results establish the strain-isolating effects of this system, and the considerations that dictate mechanical collapse of the fluid-filled cavity. Examples in skin-mounted wearable include wireless sensors for measuring temperature and wired systems for recording mechano-acoustic responses.

Epidermal electronics with advanced capabilities in near-field communication.

Epidermal electronics with advanced capabilities in near field communications (NFC) are presented. The systems include stretchable coils and thinned NFC chips on thin, low modulus stretchable adhesives, to allow seamless, conformal contact with the skin and simultaneous capabilities for wireless interfaces to any standard, NFC-enabled smartphone, even under extreme deformation and after/during normal daily activities.

The effect of Er:YAG laser irradiation on hydroxyapatite-coated implants and fluoride-modified TiO2-blasted implant surfaces: a microstructural analysis.

The purpose of this study was to evaluate the microscopic changes and surface roughness on hydroxyapatite (HA)-coated implants following exposure to different powers and durations of Er:YAG laser irradiation in order to determine the proper pulse energy level and irradiation time. Ten HA-coated implants and ten fluoride-modified TiO2 implants were used. The implants were divided into a control (one implant) and test group (nine implants) for each implant type. Implants in the test groups were sub-divided into three groups (three implants per group) based on the applied laser pulse energy and irradiation time. The measurement of surface roughness was performed on all implants in the test groups using a white light interferometer before and after laser irradiation. R a values were recorded and compared in order to evaluate changes in surface roughness. For HA-coated implants, the R a values increased in all test groups after laser irradiation. However, mean R a values in the fluoride-modified TiO2-blasted implant test group were decreased after irradiation. There was no statistical difference. Scanning electron microscope analysis revealed surface alterations in both the HA-coated and fluoridated TiO2-blasted implants irradiated for 1.5 min at 100 mJ/pulse, 10 Hz. When the pulse energy and irradiation time increased, greater surface alterations, including surface flattening and microfractures, were observed. In conclusion, the results of the current study suggest that no changes could be observed in both HA-coated implants and fluoride-modified TiO2-blasted implants after irradiation at an intensity of 100 mJ/pulse, 10 Hz for 1 min performed to achieve surface detoxification.

Significant production of humic fluorescent dissolved organic matter in the continental shelf waters of the northwestern Pacific Ocean.

Fluorescent dissolved organic matter (FDOM) is important for marine organisms and the global carbon cycle contributing to the optical properties of surface seawater and organic carbon budgets. Rivers are known to be the main source of FDOM in coastal oceans and marginal seas. In this study, however, we show that the contribution of FDOM produced from organic sediments of the northwestern Pacific continental shelf is similar to that from the Changjiang River. FDOM showed relatively higher concentrations at stations off the Changjiang River mouth and in the central Yellow Sea. Based on temperature-salinity diagrams, the major source of surface FDOM in summer surface waters was found to be from the Changjiang River while that observed in the winter water column was produced mainly in the continental shelf. A good correlation between 228Ra and the humic-like FDOM (FDOMH) during the winter suggests that the FDOMH is produced mainly from marine sediments and enriched in water over the water residence times. A simple mass balance calculation shows that the excess FDOMH fluxes produced from marine sediments account for 30-40% of the riverine source. This result suggests that the continental shelf is an important hidden source of FDOM in the upper ocean.

Soft network composite materials with deterministic and bio-inspired designs.

Hard and soft structural composites found in biology provide inspiration for the design of advanced synthetic materials. Many examples of bio-inspired hard materials can be found in the literature; far less attention has been devoted to soft systems. Here we introduce deterministic routes to low-modulus thin film materials with stress/strain responses that can be tailored precisely to match the non-linear properties of biological tissues, with application opportunities that range from soft biomedical devices to constructs for tissue engineering. The approach combines a low-modulus matrix with an open, stretchable network as a structural reinforcement that can yield classes of composites with a wide range of desired mechanical responses, including anisotropic, spatially heterogeneous, hierarchical and self-similar designs. Demonstrative application examples in thin, skin-mounted electrophysiological sensors with mechanics precisely matched to the human epidermis and in soft, hydrogel-based vehicles for triggered drug release suggest their broad potential uses in biomedical devices.

Soft microfluidic assemblies of sensors, circuits, and radios for the skin.

When mounted on the skin, modern sensors, circuits, radios, and power supply systems have the potential to provide clinical-quality health monitoring capabilities for continuous use, beyond the confines of traditional hospital or laboratory facilities. The most well-developed component technologies are, however, broadly available only in hard, planar formats. As a result, existing options in system design are unable to effectively accommodate integration with the soft, textured, curvilinear, and time-dynamic surfaces of the skin. Here, we describe experimental and theoretical approaches for using ideas in soft microfluidics, structured adhesive surfaces, and controlled mechanical buckling to achieve ultralow modulus, highly stretchable systems that incorporate assemblies of high-modulus, rigid, state-of-the-art functional elements. The outcome is a thin, conformable device technology that can softly laminate onto the surface of the skin to enable advanced, multifunctional operation for physiological monitoring in a wireless mode.

Frequent sequence variation at the ETM2 locus and its association with sporadic essential tremor in Korea.

Essential tremor (ET) is the most common but a complex neurological movement disorder. ET usually affects hands, but it may also affect head, neck, face, jaw, tongue, voice, trunk and, rarely, legs and feet. Although two susceptibility loci were identified on chromosome 2p24 (ETM2) and 3q13 (ETM1 or FET1), the exact transcript(s) has not been cloned. We analyzed unrelated Korean individuals with ET for a genetic association with three reported polymorphic loci (STS-etm1240, STS-etm1231, and STS-etm1234) in a candidate region on chromosome 2p24.1. We investigated sequence polymorphisms at these three loci in 30 ET patients and 30 controls using polymerase chain reaction (PCR) amplification followed by sequence analysis. Eight different sequence variants (5 at etm1234, 2 at etm1240, and 1 at etm1231) were detected from 7 patients. Of interest, sequence variants were found only in classic ET patients but not in nonclassic ET patients and healthy individuals. Additionally, we also observed that a decrease in the number of short tandem repeats within etm1234 locus is more frequent in ET patients compared to controls. Our data thus support that ET development would be linked with the ETM2 locus and will facilitate the search for the ETM2 gene transcript.