With the increasing interest and demand for epidermal electronics, a strong interface between a sensor and a biological surface is essential, yet achieving such interface is still a challenge. Here, ...a calcium (Ca)‐modified biocompatible silk fibroin as a strong adhesive for epidermal electronics is proposed and the physical principles behind its interfacial and adhesive properties are reported. A strong adhesive characteristic (>800 N m−1) is observed because of the increase in both viscoelastic property and mechanical interlocking through the incorporation of Ca ions. Furthermore, additional key characteristics of the Ca‐modified silk: reusability, stretchability, biocompatibility, and conductivity, are reported. These characteristics enable a wide range of applications as demonstrated in four epidermal electronic systems: capacitive touch sensor, resistive strain sensor, hydrogel‐based drug delivery, and electrocardiogram monitoring sensor. As a reusable, biocompatible, conductive, and strong adhesive with water‐degradability, the Ca‐modified silk adhesive is a promising candidate for the next‐generation adhesive for epidermal biomedical sensors.
The physical mechanism of a biocompatible silk adhesive is demonstrated by metal–chelate bonding and water‐capturing by Ca ions that contribute to forming a suitable viscoelasticity of a Ca‐modified silk adhesive. The silk adhesive adheres to various substrates, facilitating a strong mechanical contact of epidermal electronics on human skin while being reusable.
Investigation and modulation of neural circuits in vivo at the cellular level are very important for studying functional connectivity in a brain. Recently, neural probes with stimulation capabilities ...have been introduced, and they provided an opportunity for studying neural activities at a specific region in the brain using various stimuli. However, previous methods have a limitation in dissecting long-range neural circuits due to inherent limitations on their designs. Moreover, the large size of the previously reported probes induces more significant tissue damage. Herein, we present a multifunctional multi-shank MEMS neural probe that is monolithically integrated with an optical waveguide for optical stimulation, microfluidic channels for drug delivery, and microelectrode arrays for recording neural signals from different regions at the cellular level. In this work, we successfully demonstrated the functionality of our probe by confirming and modulating the functional connectivity between the hippocampal CA3 and CA1 regions in vivo.
Low-intensity transcranial focused ultrasound stimulation (TFUS) holds great promise as a highly focal technique for transcranial stimulation even for deep brain areas. Yet, knowledge about the ...safety of this novel technique is still limited.
To systematically review safety related aspects of TFUS. The review covers the mechanisms-of-action by which TFUS may cause adverse effects and the available data on the possible occurrence of such effects in animal and human studies.
Initial screening used key term searches in PubMed and bioRxiv, and a review of the literature lists of relevant papers. We included only studies where safety assessment was performed, and this results in 33 studies, both in humans and animals.
Adverse effects of TFUS were very rare. At high stimulation intensity and/or rate, TFUS may cause haemorrhage, cell death or damage, and unintentional blood-brain barrier (BBB) opening. TFUS may also unintentionally affect long-term neural activity and behaviour. A variety of methods was used mainly in rodents to evaluate these adverse effects, including tissue staining, magnetic resonance imaging, temperature measurements and monitoring of neural activity and behaviour. In 30 studies, adverse effects were absent, even though at least one Food and Drug Administration (FDA) safety index was frequently exceeded. Two studies reported microhaemorrhages after long or relatively intense stimulation above safety limits. Another study reported BBB opening and neuronal damage in a control condition, which intentionally and substantially exceeded the safety limits.
Most studies point towards a favourable safety profile of TFUS. Further investigations are warranted to establish a solid safety framework for the therapeutic window of TFUS to reliably avoid adverse effects while ensuring neural effectiveness. The comparability across studies should be improved by a more standardized reporting of TFUS parameters.
•TFUS is an emerging non-invasive stimulation method with excellent focality•We summarize the safety-related data from the available literature.•Adverse effects were absent in 30 studies, and were reported in 3 studies.•Many studies used parameters outside safety limits for diagnostic ultrasound.•Further studies are warranted to establish the safety margin for TFUS.
Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
Multi-functional neural probes integrated with various stimulation modalities are becoming essential tools in neuroscience to study the brain more effectively. In this paper, we present a new ...multi-functional neural probe that allows chemical stimulation through drug delivery and simultaneous recording of individual neuron signals through a microelectrode array. By embedding microchannels in silicon using a proposed glass reflow process, we successfully fabricated 40 μm thick silicon neural probes suitable for small animal experiments. The electrochemical impedance spectroscopy confirms that impedance of iridium microelectrodes is low enough (<1 MΩ at 1 kHz) to measure neural signals. Flow rate characterization in a 0.9% w/v agarose gel shows the capability to deliver a small volume of drugs (<1 μl) at a controlled flow rate. We demonstrate the viability and potential of this new probe by conducting in vivo experiments on mice. Because of the proposed compact structure, both action potentials of individual neurons and local field potentials (LFP) at the thalamus region of a mouse brain were successfully detected with a noise level of ~30 μVpp. Furthermore, we successfully induced absence seizure by injecting seizure-inducing drugs (baclofen) at a local target region and observed distinctive changes in neural signal patterns. Specifically, spike-wave discharge (SWD), which is an indicative signal pattern of absence seizure, was successfully recorded. These signals were also directly compared to SWD detected after inducing absence seizure through direct injection of baclofen through the abdomen. This work demonstrates the potential of our multi-functional neural probes for use in effective investigation of brain functions and disorders by using widely available mouse models.
MEMS devices for drug delivery Lee, Hyunjoo J.; Choi, Nakwon; Yoon, Eui-Sung ...
Advanced drug delivery reviews,
03/2018, Volume:
128
Journal Article
Peer reviewed
Novel drug delivery systems based on microtechnology have advanced tremendously, but yet face some technological and societal hurdles to fully achieve their potential. The novel drug delivery systems ...aim to deliver drugs in a spatiotemporal- and dosage-controlled manner with a goal to address the unmet medical needs from oral delivery and hypodermic injection. The unmet needs include effective delivery of new types of drug candidates that are otherwise insoluble and unstable, targeted delivery to areas protected by barriers (e.g. brain and posterior eye segment), localized delivery of potent drugs, and improved patient compliance. After scrutinizing the design considerations and challenges associated with delivery to areas that cannot be efficiently targeted through standard drug delivery (e.g. brain, posterior eye segment, and gastrointestinal tract), this review provides a summary of recent advances that addressed these challenges and summarizes yet unresolved problems in each target area. The opportunities for innovation in devising the novel drug delivery systems are still high; with integration of advanced microtechnology, advanced fabrication of biomaterials, and biotechnology, the novel drug delivery is poised to be a promising alternative to the oral administration and hypodermic injection for a large spectrum of drug candidates.
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The aim of this study was to compare outcomes between cases of Acanthamoeba keratitis (AK) diagnosed and treated with or without the use of in vivo confocal microscopy (IVCM).
We performed a ...retrospective comparative case series of 26 eyes of 23 patients diagnosed with AK at the Massachusetts Eye and Ear Infirmary over a 5-year period. The characteristics of all identified cases were summarized. We compared the time from presentation to diagnosis of AK (primary outcome), visual acuity, and rates of therapeutic penetrating keratoplasty between eyes diagnosed by culture-only group (n = 8) and by IVCM to diagnose AK (n = 9) and later confirmed by culture (IVCM/C group).
The diagnostic delay was significantly longer in the culture only group (25 ± 29 days) compared with the IVCM/C group (3 ± 3 days, P < 0.01). At 6 months, there was a significant difference in best-corrected visual acuity between the culture-only group (1.46 ± 1.07, n = 7) and the IVCM/C group (0.22 ± 0.22, n = 8), after adjusting for initial baseline visual acuity (P = 0.02). Therapeutic penetrating keratoplasty was performed in 50% of culture-only (n = 7) and 11% of IVCM/C group eyes (n = 9), but this was not statistically significant (P = 0.13).
IVCM can expedite the diagnosis of AK, and its use as an adjunct tool in the diagnosis of AK may result in better patient outcomes compared with basing treatment decisions on corneal cultures alone.
•An MR-compatible system for mice MRI was fabricated via optimization of ultrasound transducer components.•EPI was conducted concurrently with ultrasound sonication using a 9.4 T high resolution MRI ...scanner.•Visualization of ultrasound-induced heat effects was shown as local EPI signal changes at the beam focus.
Visualization of focused ultrasound in high spatial and temporal resolution is crucial for accurately and precisely targeting brain regions noninvasively. Magnetic resonance imaging (MRI) is the most widely used noninvasive tool for whole-brain imaging. However, focused ultrasound studies employing high-resolution (> 9.4 T) MRI in small animals are limited by the small size of the radiofrequency (RF) volume coil and the noise sensitivity of the image to external systems such as bulky ultrasound transducers. This technical note reports a miniaturized ultrasound transducer system packaged directly above a mouse brain for monitoring ultrasound-induced effects using high-resolution 9.4 T MRI. Our miniaturized system integrates MR-compatible materials with electromagnetic (EM) noise reduction techniques to demonstrate echo-planar imaging (EPI) signal changes in the mouse brain at various ultrasound acoustic intensities. The proposed ultrasound-MRI system will enable extensive research in the expanding field of ultrasound therapeutics.
The development of portable volatile organic compound (VOC) sensors is essential for home healthcare and workplace safety because VOCs are environmental pollutants that may critically affect human ...health. Here, we report a compact and portable sensor platform based on a capacitive micromachined ultrasonic transducer (CMUT) array offering multiplex detection of various VOCs (toluene, acetone, ethanol, and methanol) using a single read-out system. Three CMUT resonant devices were functionalized with three different layers: (1) phenyl-selective peptide, (2) colloids of single-walled nanotubes and peptide, and (3) poly(styrene-co-allyl alcohol). As each device exhibited different sensitivities to the four VOCs, we performed principal component analysis to achieve selective detection of all four gases. For the simultaneous detection of VOCs using CMUT sensors, the changes in the resonant frequencies of three devices were monitored in real time, but using only a single oscillator through an electrically controlled relay to achieve compactness. In addition, by devising a wireless system, measurement results were transmitted to a smartphone to monitor the concentration of VOCs. We used multiple sensors to obtain a larger number of fingerprints for pattern recognition to enhance selectivity but interfaced these sensors with a single read-out circuit to minimize the footprint of the overall system. The compact CMUT-based sensor array based on a multiplex detection scheme is a promising sensor platform for portable VOC monitoring.
Current transcranial ultrasound stimulation for small animal in vivo experiment is limited to acute stimulation under anesthesia in stereotaxic fixation due to bulky and heavy curved transducers.
We ...developed a miniaturized ultrasound ring array transducer which is capable of invoking motor responses through neuromodulation of freely-moving awake mice.
The developed transducer is a 32-element, 183-kHz ring array with a weight of 0.035 g (with PCB: 0.73 g), a diameter of 8.1 mm, a focal length of 2.3 mm, and lateral resolution of 2.75 mm. By developing an affixation scheme suitable for freely-moving animals, the transducer was successfully coupled to the mouse brain and induced motor responses in both affixed and awake states.
Ultrasound neuromodulation of a freely-moving animal is now possible using the developed lightweight and compact system to conduct a versatile set of in vivo experiments.
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