Intrathecal gastrodin alleviates allodynia in a rat spinal nerve ligation model through NLRP3 inflammasome inhibition.

BACKGROUND: Gastrodin (GAS), a main bioactive component of the herbal plant, Gastrodia elata Blume, has shown to have beneficial effects on neuroinflammatory diseases such as Alzheimer's disease in animal studies and migraine in clinical studies. Inflammasome is a multimeric protein complex having a core of pattern recognition receptor and has been implicated in the development of neuroinflammatory diseases. Gastrodin has shown to modulate the activation of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. This study investigated the effects of GAS on the intensity of mechanical allodynia and associated changes in NLRP3 inflammasome expression at the spinal level using L5/6 spinal nerve ligation model (SNL) in rats. METHODS: Intrathecal (IT) catheter implantation and SNL were used for drug administration and pain model in male Sprague-Dawley rats. The effect of gastrodin or MCC950 (NLRP3 inflammasome inhibitor) on mechanical allodynia was measured by von Frey test. Changes in NLRP3 inflammasome components and interleukin-1ß (IL-1ß) and cellular expression were examined in the spinal cord and dorsal root ganglion. RESULTS: The expression of NLRP3 inflammasome components was found mostly in the neurons in the spinal cord and dorsal root ganglion. The protein and mRNA levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and IL-1ß were upregulated in SNL animals compared to Sham animals. IT administration of GAS significantly attenuated the expression of NLRP3 inflammasome and the intensity of SNL-induced mechanical allodynia. NLRP3 inflammasome inhibitor, MCC950, also attenuated the intensity of allodynia, but the effect is less strong and shorter than that of GAS. CONCLUSIONS: Expression of NLRP3 inflammasome and IL-1ß is greatly increased and mostly found in the neurons at the spinal level in SNL model, and IT gastrodin exerts a significant anti-allodynic effect in SNL model partly through suppressing the expression of NLRP3 inflammasome.

Smart contact lens systems for ocular drug delivery and therapy.

Ocular drug delivery and therapy systems have been extensively investigated with various methods including direct injections, eye drops and contact lenses. Nowadays, smart contact lens systems are attracting a lot of attention for ocular drug delivery and therapy due to their minimally invasive or non-invasive characteristics, highly enhanced drug permeation, high bioavailability, and on-demand drug delivery. Furthermore, smart contact lens systems can be used for direct light delivery into the eyes for biophotonic therapy replacing the use of drugs. Here, we review smart contact lens systems which can be classified into two groups of drug-eluting contact lens and ocular device contact lens. More specifically, this review covers smart contact lens systems with nanocomposite-laden systems, polymeric film-incorporated systems, micro and nanostructure systems, iontophoretic systems, electrochemical systems, and phototherapy systems for ocular drug delivery and therapy. After that, we discuss the future opportunities, challenges and perspectives of smart contact lens systems for ocular drug delivery and therapy.

Bimetallic Nanocatalysts Immobilized in Nanoporous Hydrogels for Long-Term Robust Continuous Glucose Monitoring of Smart Contact Lens.

Smart contact lenses for continuous glucose monitoring (CGM) have great potential for huge clinical impact. To date, their development has been limited by challenges in accurate detection of glucose without hysteresis for tear glucose monitoring to track the blood glucose levels. Here, long-term robust CGM in diabetic rabbits is demonstrated by using bimetallic nanocatalysts immobilized in nanoporous hydrogels in smart contact lenses. After redox reaction of glucose oxidase, the nanocatalysts facilitate rapid decomposition of hydrogen peroxide and nanoparticle-mediated charge transfer with drastically improved diffusion via rapid swelling of nanoporous hydrogels. The ocular glucose sensors result in high sensitivity, fast response time, low detection limit, low hysteresis, and rapid sensor warming-up time. In diabetic rabbits, smart contact lens can detect tear glucose levels consistent with blood glucose levels measured by a glucometer and a CGM device, reflecting rapid concentration changes without hysteresis. The CGM in a human demonstrates the feasibility of smart contact lenses for further clinical applications.

Smart Wireless Near-Infrared Light Emitting Contact Lens for the Treatment of Diabetic Retinopathy.

Diabetic retinopathy is currently treated by highly invasive repeated therapeutic injections and surgical interventions without complete vision recovery. Here, a noninvasive smart wireless far red/near-infrared (NIR) light emitting contact lens developed successfully for the repeated treatment of diabetic retinopathy with significantly improved compliance. A far red/NIR light emitting diode (LED) is connected with an application-specific integrated circuit chip, wireless power, and communication systems on a PET film, which is embedded in a silicone elastomer contact lens by thermal crosslinking. After in vitro characterization, it is confirmed that the retinal vascular hyper-permeability induced by diabetic retinopathy in rabbits is reduced to a statistically significant level by simply repeated wearing of smart far red/NIR LED contact lens for 8 weeks with 120 µW light irradiation for 15 min thrice a week. Histological analysis exhibits the safety and feasibility of LED contact lenses for treating diabetic retinopathy. This platform technology for smart LED contact lens would be harnessed for various biomedical photonic applications.

Supramolecular host-guest hyaluronic acid hydrogels enhance corneal wound healing through dynamic spatiotemporal effects.

Severe corneal wounds can lead to ulceration and scarring if not promptly and adequately treated. Hyaluronic acid (HA) has been investigated for the treatment of corneal wounds due to its remarkable biocompatibility, transparency and mucoadhesive properties. However, linear HA has low retention time on the cornea while many chemical moieties used to crosslink HA can cause toxicity, which limits their clinical ocular applications. Here, we used supramolecular non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane to form shear-thinning HA hydrogels and evaluated their impact on corneal wound healing. Supramolecular HA hydrogels facilitated adhesion and spreading of encapsulated human corneal epithelial cells ex vivo and improved corneal wound healing in vivo as an in situ-formed, acellular therapeutic membrane. The HA hydrogels were absorbed within the corneal stroma over time, modulated mesenchymal cornea stromal cell secretome production, reduced cellularity and inflammation of the anterior stroma, and significantly mitigated corneal edema compared to treatment with linear HA and untreated control eyes. Taken together, our results demonstrate supramolecular HA hydrogels as a promising and versatile biomaterial platform for corneal wound healing.

Multifunctional materials for implantable and wearable photonic healthcare devices.

Numerous light-based diagnostic and therapeutic devices are routinely used in the clinic. These devices have a familiar look as items plugged in the wall or placed at patients' bedsides, but recently, many new ideas have been proposed for the realization of implantable or wearable functional devices. Many advances are being fuelled by the development of multifunctional materials for photonic healthcare devices. However, the finite depth of light penetration in the body is still a serious constraint for their clinical applications. In this Review, we discuss the basic concepts and some examples of state-of-the-art implantable and wearable photonic healthcare devices for diagnostic and therapeutic applications. First, we describe emerging multifunctional materials critical to the advent of next-generation implantable and wearable photonic healthcare devices and discuss the path for their clinical translation. Then, we examine implantable photonic healthcare devices in terms of their properties and diagnostic and therapeutic functions. We next describe exemplary cases of noninvasive, wearable photonic healthcare devices across different anatomical applications. Finally, we discuss the future research directions for the field, in particular regarding mobile healthcare and personalized medicine.

Wireless smart contact lens for diabetic diagnosis and therapy.

A smart contact lens can be used as an excellent interface between the human body and an electronic device for wearable healthcare applications. Despite wide investigations of smart contact lenses for diagnostic applications, there has been no report on electrically controlled drug delivery in combination with real-time biometric analysis. Here, we developed smart contact lenses for both continuous glucose monitoring and treatment of diabetic retinopathy. The smart contact lens device, built on a biocompatible polymer, contains ultrathin, flexible electrical circuits and a microcontroller chip for real-time electrochemical biosensing, on-demand controlled drug delivery, wireless power management, and data communication. In diabetic rabbit models, we could measure tear glucose levels to be validated by the conventional invasive blood glucose tests and trigger drugs to be released from reservoirs for treating diabetic retinopathy. Together, we successfully demonstrated the feasibility of smart contact lenses for noninvasive and continuous diabetic diagnosis and diabetic retinopathy therapy.

Hyaluronate-Gold Nanoparticle/Glucose Oxidase Complex for Highly Sensitive Wireless Noninvasive Glucose Sensors.

Noninvasive real-time biosensors to measure glucose levels in the body fluids have been widely investigated for continuous glucose monitoring of diabetic patients. However, they suffered from low sensitivity and reproducibility due to the instability of nanomaterials used for glucose biosensors. Here, we developed a hyaluronate-gold nanoparticle/glucose oxidase (HA-AuNP/GOx) complex and an ultralow-power application-specific integrated circuit chip for noninvasive and robust wireless patch-type glucose sensors. The HA-AuNP/GOx complex was prepared by the facile conjugation of thiolated HA to AuNPs and the following physical binding of GOx. The wireless glucose sensor exhibited slow water evaporation (0.11 µL/min), fast response (5 s), high sensitivity (12.37 µA·dL/mg·cm2) and selectivity, a low detection limit (0.5 mg/dL), and highly stable enzymatic activity (∼14 days). We successfully demonstrated the strong correlation between glucose concentrations measured by a commercially available blood glucometer and the wireless patch-type glucose sensor. Taken together, we could confirm the feasibility of the wireless patch-type robust glucose sensor for noninvasive and continuous diabetic diagnosis.

Multimodal Cancer Theranosis Using Hyaluronate-Conjugated Molybdenum Disulfide.

Among various 2D nanomaterials, molybdenum disulfide (MoS2 ) exhibits unique visible photoluminescence with high absorption at the near-infrared (NIR) range. Despite these optical properties, the efforts to use MoS2 nanomaterials for optical imaging and photothermal therapy are hampered by their instability and low intracellular delivery efficiency. Multifunctional MoS2 conjugated with hyaluronate (HA) for cancer theranosis is reported herein. HA facilitates the delivery of MoS2 to tumor cells by the HA-receptor mediated endocytosis. In BALB/c nude mice inoculated with a colorectal cancer cell line of HCT116, HA-MoS2 conjugates appear to be accumulated in the primary tumor at a content more than that in the liver and kidney. The disulfide bonding between MoS2 and thiolated HA seems to degrade in the cytoplasm, releasing MoS2 sheets in stacks and enhancing luminescence efficiency. The HA-MoS2 conjugates are readily detected via photoacoustic imaging as well as upconversion and downconversion fluorescence imaging. With NIR light illumination, HA-MoS2 conjugates enable highly effective photothermal tumor ablation. All these results confirm the promising potential of HA-MoS2 conjugates for cancer theranosis.

Flexible deep brain neural probe for localized stimulation and detection with metal guide.

In this paper, we present the design, fabrication, and performance evaluation of a polyimide-based flexible neural probe for the precise site stimulation and recording in the deep brain. The probe consists of five electrodes: one for stimulation, another for ground and the other three for recording electrodes. This probe is designed to be foldable, enabling easy insertion into the deep brain via temporary tungsten guide sticks. Because of its small cross-sectional area and the flexibility of the polyimide, the probe causes minimum damage to the neural tissue and does not show any evidence of serious immune reactions such as high density of macrophage or microglia. Around the simulation electrodes, an additional ground electrode prevents the stimulation of the undesired sites in the brain. To ensure we stimulate the target point specifically, for instance STh in this study, we confirm through both finite element analyses and in vitro tests. With the additional ground electrodes, we observe the leakage power decreased by about 80%. To check the performance of the probe, we demonstrate animal experiments using rats, and neural spike signals from STh in the 7-mm deep brain are successfully recorded after implantation.

The Prevalence of Obesity and Metabolic Syndrome in the Korean Military Compared with the General Population.

BACKGROUND: Obesity and related metabolic disorders are growing health challenges worldwide and individuals at military service are not exceptions. The purpose of this study was to examine the prevalence of obesity and metabolic syndrome (MS) in the Korean military and to compare with the general population. METHODS: This was a cross-sectional study of 4,803 young military participants who underwent a corporal health-screening program between October 2013 and October 2014. The National Cholesterol Education Program Adult Treatment Panel III criteria was used to identify MS. We also sampled 1,108 men aged 19-29 years from the Korea National Health and Nutritional Examination Survey from 2010 to 2013 to compare with their military counterparts. RESULTS: The mean age of military participants was 20.8 ± 1.1 years, and 20.6% (n = 988) were obese. The prevalence of MS was 0.8% in military participants, while 7.9% in general population. The risk factors of MS were less prominent among military participants relative to civilians, with the exception of high blood pressure, of which prevalence was higher among military participants (21.5% vs. 18.2%, respectively). In multiple logistic analysis, high physical activity conferred lower odds of MS and obesity in military participants (odds ratios, 0.19 and 0.81, respectively). Age older than 25 years increased risk of most components of MS among civilians. CONCLUSION: The prevalence of obesity and MS is lower in military participants compared with civilians of similar age. Monitoring of high blood pressure and proper stress management are warranted in those at military service.

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.

Networked concave microwell arrays for constructing 3D cell spheroids.

The engineered three-dimensional (3D) cell cultivation system for the production of multicellular spheroids has attracted considerable attention due to its improved in vivo relevance to cellular communications compared with the traditional two-dimensional (2D) cell culture platform. The formation and maintenance of cell spheroids in a healthy condition is the critical factor for tissue engineering applications such as the repair of damaged tissues, the development of organ replacement parts and preclinical drug tests. However, culturing spheroids in conventional isolated single wells shows limited yield and reduced maintenance periods due to the lack of proper supplies of nutrition as well as intercellular chemical signaling. Here, we develop novel networked concave microwell arrays for the effective construction of 3D multi-cellular spheroids. The proposed method provides a suitable structure for the diffusion of oxygen, water-soluble nutrients and cytokines for cell-cell interactions between the spheroids in neighboring microwells. We have further demonstrated that hepatocyte spheroid cultured networked concave microwells show enhanced cell viability and albumin secretion compared to the un-networked control group over two weeks. Our results reveal that multi-cellular functionality can be tuned up by networking individual 3D spheroids without supplying additional chemicals or biological supplements. We anticipate our result to be useful in high-throughput cellular screening platforms to study cell-cell interactions, in response to diverse chemical stimuli as well as the development of the in vivo mimicking of the customized 3D tissue culture system.

Upconversion Nanoparticles/Hyaluronate-Rose Bengal Conjugate Complex for Noninvasive Photochemical Tissue Bonding.

The recent progress in photonic nanomaterials has contributed greatly to the development of photomedicines. However, the finite depth of light penetration is still a serious limitation, constraining their clinical applications. Here, we developed a poly(allylamine) (PAAm)-modified upconversion nanoparticle/hyaluronate-rose bengal (UCNP/PAAm/HA-RB) conjugate complex for photochemical bonding of deep tissue with near-infrared (NIR) light illumination. Compared to the conventional invasive treatment via suturing and stapling, the UCNP/PAAm/HA-RB conjugate complex could be noninvasively delivered into the deep tissue and accelerate the tissue bonding upon NIR light illumination. HA in the outer layer of the complex facilitated the penetration of RB into the collagen layer of the dermis. The NIR light triggered UCNP of NaYF4: Yb/Er (Y:Yb:Er = 78:20:2) in the complex to illuminate visible green light under the skin tissue. The activated RB in the HA-RB conjugate by the green light induced radical formation for the cross-linking of incised collagen matrix. An in vitro light propagation test and collagen fibrillogenesis analysis, an in vivo animal tissue bonding test, and an ex vivo tensile strength test of dissected skin tissues confirmed the successful photochemical tissue bonding effect of the UCNP/PAAm/HA-RB conjugate complex.

Targeted Hyaluronate-Hollow Gold Nanosphere Conjugate for Anti-Obesity Photothermal Lipolysis.

Obesity is associated with the risk of developing several severe diseases, such as metabolic disorder, diabetes, and heart diseases. Despite wide investigation and trials, a noninvasive obesity therapy is still an important medical unmet need, targeting the abnormal adipose tissue. Here, we developed hyaluronate-hollow gold nanosphere-adipocyte-targeting peptide (HA-HAuNS-ATP) conjugates for the photothermal ablation of adipose tissues. The HA-HAuNS-ATP conjugate could be noninvasively delivered into the skin and effectively target to adipocytes in the subcutaneous. With near-infrared laser illumination, HA-HAuNS-ATP conjugate enabled highly effective photothermal ablation of adipose tissues in C57BL/6 obesity mice. The photoacoustic imaging confirmed the successful transdermal delivery and the photothermal lipolysis of HA-HAuNS-ATP conjugate. Taken together, the transdermal HA-HAuNS-ATP conjugate might have a great potential for noninvasive photothermal lipolysis.

Bottom-Up Engineering of Well-Defined 3D Microtissues Using Microplatforms and Biomedical Applications.

During the last decades, the engineering of well-defined 3D tissues has attracted great attention because it provides in vivo mimicking environment and can be a building block for the engineering of bioartificial organs. In this Review, diverse engineering methods of 3D tissues using microscale devices are introduced. Recent progress of microtechnologies has enabled the development of microplatforms for bottom-up assembly of diverse shaped 3D tissues consisting of various cells. Micro hanging-drop plates, microfluidic chips, and arrayed microwells are the typical examples. The encapsulation of cells in hydrogel microspheres and microfibers allows the engineering of 3D microtissues with diverse shapes. Applications of 3D microtissues in biomedical fields are described, and the future direction of microplatform-based engineering of 3D micro-tissues is discussed.