Self-rectifying magnetoelectric metamaterials for remote neural stimulation and motor function restoration.

Magnetoelectric materials convert magnetic fields into electric fields. These materials are often used in wireless electronic and biomedical applications. For example, magnetoelectrics could enable the remote stimulation of neural tissue, but the optimal resonance frequencies are typically too high to stimulate neural activity. Here we describe a self-rectifying magnetoelectric metamaterial for a precisely timed neural stimulation. This metamaterial relies on nonlinear charge transport across semiconductor layers that allow the material to generate a steady bias voltage in the presence of an alternating magnetic field. We generate arbitrary pulse sequences with time-averaged voltage biases in excess of 2 V. As a result, we can use magnetoelectric nonlinear metamaterials to wirelessly stimulate peripheral nerves to restore a sensory reflex in an anaesthetized rat model and restore signal propagation in a severed nerve with latencies of less than 5 ms. Overall, these results showing the rational design of magnetoelectric metamaterials support applications in advanced biotechnology and electronics.

Distributed sensor and actuator networks for closed-loop bioelectronic medicine.

Designing implantable bioelectronic systems that continuously monitor physiological functions and simultaneously provide personalized therapeutic solutions for patients remains a persistent challenge across many applications ranging from neural systems to bioelectronic organs. Closed-loop systems typically consist of three functional blocks, namely, sensors, signal processors and actuators. An effective system, that can provide the necessary therapeutics, tailored to individual physiological factors requires a distributed network of sensors and actuators. While significant progress has been made, closed-loop systems still face many challenges before they can truly be considered as long-term solutions for many diseases. In this review, we consider three important criteria where materials play a critical role to enable implantable closed-loop systems: Specificity, Biocompatibility and Connectivity. We look at the progress made in each of these fields with respect to a specific application and outline the challenges in creating bioelectronic technologies for the future.

Microfluidic device for the analysis of MDR cancerous cell-derived exosomes' response to nanotherapy.

Exosomes are membrane-enclosed extracellular vesicles which have been indicated as important biomarkers of cancerous cell functionality, such as multiple drug resistance (MDR). Nanoparticles based chemotherapy is a promising strategy to overcome MDR by interfering the production and composition of exosomes. Therefore, tumor-derived exosomes post-treatment by nanotherapy are implied to play critical roles of biomarkers on cancer MDR analysis. However, the efficient isolation of such exosomes from extracellular environment for their therapeutic response analysis remains challenging. In this study, we presented a microfluidic device featured exosome specific anti-CD63 immobilized ciliated micropillars, which were capable to isolate cancer-derived exosomes from cell culture medium. The captured exosomes can be recovered intact by dissolving the cilia on the micropillars using PBS soaking. Owing to the immobilized antibody in the microfluidic device, nearly 70% of exosome from the biofluid could be isolated. So the secreted exosomes of the MDR and ordinary human breast cancer cells pre-treated by free drug or nanotherapy could be isolated with high purity. The drug contents of the isolated exosomes were measured to analysis of the exosomal pathway response of MDR cells to different chemotherapeutic formulations. Such analyses and further definition of the biomarkers of these exosomes could benefit the future investigations of accurately and reliably determine design principle, functional activity, and mechanisms of nanotherapy for MDR overcoming.

Silver-Nanoparticle-Embedded Porous Silicon Disks Enabled SERS Signal Amplification for Selective Glutathione Detection.

As the major redox couple and nonprotein thiol source in human tissues, the level of glutathione (GSH) has been a concern for its relation with many diseases. However, the similar physical and chemical properties of interference molecules such as cysteine (Cys) and homocysteine (Hcy) make discriminative detection of GSH in complex biological fluids challenging. Here we report a novel surface-enhanced Raman scattering (SERS) platform, based on silver-nanoparticle-embedded porous silicon disks (PSDs/Ag) substrates for highly sensitive and selective detection of GSH in biofluids. Silver nanoparticles (AgNPs) were reductively synthesized and aggregated directly into pores of PSDs, achieving a SERS enhancement factor (EF) up to 2.59 × 107. Ellman's reagent 5,5'-ditho-bis (2-nitrobenzoic acid) (DTNB) was selected as the Raman reactive reporting agent, and the GSH quantification was determined using enzymatic recycling method, and allowed the detection limit of GSH to be down to 74.9 nM using a portable Raman spectrometer. Moreover, the significantly overwhelmed enhancement ratio of GSH over other substances enables the discrimination of GSH detection in complex biofluids.

Correction: In situ growth of fluorescent silicon nanocrystals in a monolithic microcapsule as a photostable, versatile platform.

Correction for 'In situ growth of fluorescent silicon nanocrystals in a monolithic microcapsule as a photostable, versatile platform' by Guixian Zhu, et al., Nanoscale, 2016, 8, 15645-15657.

In situ growth of fluorescent silicon nanocrystals in a monolithic microcapsule as a photostable, versatile platform.

A facile, one-step method was developed for the in situ formation of fluorescent silicon nanocrystals (SiNC) in a microspherical encapsulating matrix. The obtained SiNC encapsulated polymeric microcapsules (SiPM) possess uniform size (0.1-2.0 µm), strong fluorescence, and nanoporous structure. A unique two stage, time dependent reaction was developed, as the growth of SiNC was slower than the formation of polymeric microcapsules. The resulting SiPM with increasing reaction time exhibited two levels of stability, and correspondingly, the release of SiNC in aqueous media showed different behavior. With reaction time <1 h, the obtained low-density SiPM (LD-SiPM) as matrix microcapsules, would release encapsulated SiNC on demand. With >1 h reaction time, resulting high-density SiPM (HD-SiPM) became stable SiNC reservoirs. SiPM exhibit stable photoluminescence. The porous structure and fluorescence quenching effects make SiPM suitable for bioimaging, drug loading and sorption of heavy metals (Hg(2+) as shown) as an intrinsic indicator. SiPM were able to reduce metal ions, forming SiPM/metal oxide and SiPM/metal hybrids, and their applications in bio-sensing and catalysis were also demonstrated.

Inkjet-Print Micromagnet Array on Glass Slides for Immunomagnetic Enrichment of Circulating Tumor Cells.

We report an inkjet-printed microscale magnetic structure that can be integrated on regular glass slides for the immunomagnetic screening of rare circulating tumor cells (CTCs). CTCs detach from the primary tumor site, circulate with the bloodstream, and initiate the cancer metastasis process. Therefore, a liquid biopsy in the form of capturing and analyzing CTCs may provide key information for cancer prognosis and diagnosis. Inkjet printing technology provides a non-contact, layer-by-layer and mask-less approach to deposit defined magnetic patterns on an arbitrary substrate. Such thin film patterns, when placed in an external magnetic field, significantly enhance the attractive force in the near-field close to the CTCs to facilitate the separation. We demonstrated the efficacy of the inkjet-print micromagnet array integrated immunomagnetic assay in separating COLO205 (human colorectal cancer cell line) from whole blood samples. The micromagnets increased the capture efficiency by 26% compared with using plain glass slide as the substrate.

Plasmonic nanograting enhanced quantum dots excitation for cellular imaging on-chip.

We present the design and integration of a two-dimensional (2D) plasmonic nanogratings structure on the electrode of colloidal quantum dot-based light-emitting diodes (QDLEDs) as a compact light source towards arrayed on-chip imaging of tumor cells. Colloidal quantum dots (QDs) were used as the emission layer due to their unique capabilities, including multicolor emission, narrow bandwidth, tunable emission wavelengths, and compatibility with silicon fabrication. The nanograting, based on a metal-dielectric-metal plasmonic waveguide, aims to enhance the light intensity through the resonant reflection of surface plasmon (SP) waves. The key parameters of plasmonic nanogratings, including periodicity, slit width, and thicknesses of the metal and dielectric layers, were designed to tailor the frequency bandgap such that it matches the wavelength of operation. We fabricated QDLEDs with the integrated nanogratings and demonstrated an increase in electroluminescence intensity, measured along the direction perpendicular to the metal electrode. We found an increase of 34.72% in QDLED electroluminescence intensity from the area of the pattern and an increase of 32.63% from the photoluminescence of QDs deposited on a metal surface. We performed ex vivo transmission-mode microscopy to evaluate the nucleus-cytoplasm ratios of MDA-MB 231 cultured breast cancer cells using QDLEDs as the light source. We showed wavelength dependent imaging of different cell components and imaging of cells at higher magnification using enhanced emission from QDLEDs with integrated plasmonic nanogratings.

Use of colloidal quantum dots as a digitally switched swept light source for gold nanoparticle based hyperspectral microscopy.

We propose a method to utilize colloidal quantum dots (QDs) as a swept light source for hyperspectral microscopy. The use of QD allows for uniform multicolor emission which covers visible-NIR wavelengths. We used 8 colors of CdSe/ZnS and CdTe/ZnS colloidal quantum dots with the peak emission wavelengths from 520 nm to 800 nm. The QDs are packed in a compact enclosure, composing a low-cost, solid-state swept light source that can be easily used in most microscopes. Multicolor emission from the QDs is simply controlled by digitally switching excitation UVLEDs, eliminating the use of mechanically-driven gratings or filters. We used gold nanoparticles as optical markers for hyperspectral microscopy. Due to the effect of localized surface plasmon resonance, gold nanoparticles demonstrate size and shape-dependent absorption spectra. Employed in a standard microscope, the QD light source enabled multispectral absorption imaging of macrophage cells labeled with gold nanorods and nanospheres.

Discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone as a potent and selective I(Kur) inhibitor.

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.

An investigation of simultaneous variations in cerebral blood flow velocity and arterial blood pressure during sleep apnea.

Obstructive Sleep Apnea (OSA) is a major sleep disorder with a prevalence of about 15 % among US adult population and can lead to cardiovascular diseases and stroke. In this study, we have investigated the OSA-induced concurrent rise in cerebral blood flow velocity and blood pressure in 5 positively diagnosed sleep apnea subjects. The subject population had a mean AHI of 57.94±25.73 and BMI of 33.66±7.27 kg/m(2). The results of this preliminary study yielded a relatively high correlation between rise in blood pressure and rise in cerebral blood flow velocity during apnea episodes (r=0.61±0.16) compared to normal breathing (r=0.28±0.26). These findings suggest that cerebral autoregulation may be less effective during apnea episodes.

Relation between arterial blood pressure and cerebral blood flow velocity in simulated sleep apnea.

Obstructive Sleep Apnea (OSA) is one of the most common breathing disorder, affecting approximately 27% of U.S. adults. Limited data have suggested that OSA causes cerebral autoregulation impairment, thus being an important risk factor to stroke. The objective of this paper is to investigate and measure the relation between arterial blood pressure (BP) and cerebral blood flow velocity (CBFV) in simulated apnea. Sixteen healthy subjects (9 male, 7 female) of 29±4.89 yrs age and body mass index of 24.07±4.84 kg/m(2) participated in the study. Four protocols were used; sitting 30 seconds, 90 s, and supine 30 s and 90 s. Our results showed that systolic BP and peak CBFV were correlated with average r=0.672 +0.265. Also, CBFV exhibited a significantly higher percent rise than BP. Thus, our findings suggest that cerebral autoregulation may be impaired during apnea episodes.

Concurrent variations of cerebral blood flow and arterial blood pressure in simulated sleep apnea.

Obstructive Sleep Apnea (OSA) is one of the most common sleep disordered breathing which affects about 15 % of US adult population. OSA is considered to be an important risk factor for the development of cardiac dysfunction and stroke. In this paper, we present the initial results of our investigation of the relationship between arterial blood pressure and cerebral blood flow velocity in simulated apnea. Sixteen healthy subjects (9 male, 7 female) of 29 ± 4.89 yrs age and body mass index of 24.07 ± 4.84 kg/m(2) participated in the study. Our findings indicate that cerebral blood flow velocity variations has a relatively high correlation to changes in blood pressure during simulated apnea (r = 0.74 ± 0.06), suggesting that cerebral autoregulation may not compensate for the pressure changes during apnea.