Microdroplet based disposable sensor patch for detection of α-amylase in human blood serum

Concentration of α-amylase in human serum is a key indicator of various pancreatic ailments and an affordable point-of-care detection of this biomarker can benefit millions suffering from these diseases. In view of this situation, we report the development of a flexible patch-sensor, which simply requires a microdroplet of aqueous starch-FeSO4 solution to detect α-amylase in serum. The detection is achieved through the generation of mixing vortices (∼12 rpm) inside the droplet with the help of an imposed thermal gradient. Such vortices due to Marangoni and natural convections are found to be strongest at an optimal temperature difference of ∼18 °C – 23 °C across the droplet which in turn facilitate mixing and promote the specific starch-amylase enzymatic reaction. Subsequently, the large (∼80%) variation in the electrical resistance across the droplet is correlated to detect the level of the α-amylase in the analyte. Importantly, the sensor can detect even in the limits of 15–110 units/liter. Further, the sensitivity of flexible sensors is ∼8.6% higher than the non-flexible one. Interestingly, the sensitivity of the proposed sensor has been nearly three-times than the previously reported optical ones. The results of patch-sensor match very closely with the standard path-lab tests while detecting unknown level of amylase in serum. The prototype has shown significant potential to translate into an affordable device for the real-time detection and easy prognosis of pancreatic disorders

Multishank Thin-Film Neural Probes and Implantation System for High-Resolution Neural Recording Applications

Abstract Silicon probes have played a key role in studying the brain. However, the stark mechanical mismatch between these probes and the brain leads to chronic damage in the surrounding neural tissue, limiting their application in research and clinical translation. Mechanically flexible probes made of thin plastic shanks offer an attractive tissue‐compatible alternative but are difficult to implant into the brain. They also struggle to achieve the electrode density and layout necessary for the high‐resolution applications their silicon counterparts excel at. Here, a multishank high‐density flexible neural probe design is presented, which emulates the functionality of stiff silicon arrays for recording from neural population across multiple sites within a given region. The flexible probe is accompanied by a detachable 3D printed implanter, which delivers the probe by means of hydrophobic‐coated shuttles. The shuttles can then be retracted with minimal movement and the implanter houses the electronics necessary for in vivo recording applications. Validation of the probes through extracellular recordings from multiple brain regions and histological evidence of minimal foreign body response opens the path to long‐term chronic monitoring of neural ensembles

Transparent neural interfaces for simultaneous electrophysiology and advanced brain imaging

Imaging and electrophysiology are the most fundamental tools in neuroscience research. On the one hand, optical imaging can target specific molecules with high spatial resolution *in vitro* and *in vivo*. Spectroscopic techniques like magnetic resonance imaging (MRI) can access deep regions of the brain over a large area and is the state-of-the-art in clinical brain imaging. On the other hand, microelectrode arrays (MEAs) and neural probes are indispensable in deciphering the electrical activity of neurons. Unfortunately, simultaneous imaging and electrophysiology is challenging with conventional metal electrodes which are non-transparent. In MRI, the issue is compounded by the heating effect in metals and loss of signal due to their significantly different magnetic susceptibility compared to biological tissue. Conducting polymer electrodes are prospective alternatives since their compositions are closer to biological tissues. Poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS), one of the most widely used conducting polymers, exhibits volumetric capacitance effect which reduces electrode impedance and significantly improves the signal-to-noise ratio of neural interfaces. This work presents PEDOT:PSS-based optically transparent and MRI compatible MEAs. To begin with, a scalable and repeatable patterning technique of PEDOT:PSS on glass was developed which manifested in *in vitro* MEAs. The PEDOT:PSS electrodes exhibited superior electrochemical properties than other alternative transparent conductors. The transparent MEAs enabled simultaneous electrical recordings and Ca2+ imaging from neurons and allowed super-resolved imaging of diffraction limited cellular structures in addition to state-of-the art fluorescence imaging. Subsequently, the MEAs were implemented for studying the spread of tau pathology in neurodegenerative diseases and its effects on overall neuronal activity. They were integrated into a microfluidic neuronal culture platform to selectively examine the activity-dependent uptake of tau protein at the pre-synapse. Next, the *in vitro* glass-based transparent MEAs were translated into ultra-thin flexible MEAs for *in vivo* applications. As micro-electrocorticography (µECoG) arrays, the flexible MEAs enabled MRI imaging with minimal artifacts and showed promise for simultaneous functional MRI and electrophysiology. The structure of the flexible MEAs were also favourable for long-term organoid cultures and a modified design enabled continuous electrophysiology for weeks. It is expected that the versatile, transparent PEDOT:PSS MEAs would add new capabilities to neuroscience research by enabling complementary electrophysiology and multi-modal imaging.Cambridge Commonwealth, European and International Trus

Microdroplet based disposable sensor patch for detection of α-amylase in human blood serum

Concentration of α-amylase in human serum is a key indicator of various pancreatic ailments and an affordable point-of-care detection of this biomarker can benefit millions suffering from these diseases. In view of this situation, we report the development of a flexible patch-sensor, which simply requires a microdroplet of aqueous starch-FeSO4 solution to detect α-amylase in serum. The detection is achieved through the generation of mixing vortices (~12 rpm) inside the droplet with the help of an imposed thermal gradient. Such vortices due to Marangoni and natural convections are found to be strongest at an optimal temperature difference of ~18 °C – 23 °C across the droplet which in turn facilitate mixing and promote the specific starch-amylase enzymatic reaction. Subsequently, the large (~80%) variation in the electrical resistance across the droplet is correlated to detect the level of the α-amylase in the analyte. Importantly, the sensor can detect even in the limits of 15–110 units/liter. Further, the sensitivity of flexible sensors is ~8.6% higher than the non-flexible one. Interestingly, the sensitivity of the proposed sensor has been nearly three-times than the previously reported optical ones. The results of patch-sensor match very closely with the standard path-lab tests while detecting unknown level of amylase in serum. The prototype has shown significant potential to translate into an affordable device for the real-time detection and easy prognosis of pancreatic disorders

Microelectrode Arrays for Simultaneous Electrophysiology and Advanced Optical Microscopy

Advanced optical imaging techniques address important biological questions in neuroscience, where structures such as synapses are below the resolution limit of a conventional microscope. At the same time, microelectrode arrays (MEAs) are indispensable in understanding the language of neurons. Here, the authors show transparent MEAs capable of recording action potentials from neurons and compatible with advanced microscopy. The electrodes are made of the conducting polymer poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS) and are patterned by optical lithography, ensuring scalable fabrication with good control over device parameters. A thickness of 380 nm ensures low enough impedance and >75% transparency throughout the visible part of the spectrum making them suitable for artefact-free recording in the presence of laser illumination. Using primary neuronal cells, the arrays record single units from multiple nearby sources with a signal-to-noise ratio of 7.7 (17.7 dB). Additionally, it is possible to perform calcium (Ca2+) imaging, a measure of neuronal activity, using the novel transparent electrodes. Different biomarkers are imaged through the electrodes using conventional and super-resolution microscopy (SRM), showing no qualitative differences compared to glass substrates. These transparent MEAs pave the way for harnessing the synergy between the superior temporal resolution of electrophysiology and the selectivity and high spatial resolution of optical imaging

Microelectrode Arrays for Simultaneous Electrophysiology and Advanced Optical Microscopy.

Funder: Cambridge TrustAdvanced optical imaging techniques address important biological questions in neuroscience, where structures such as synapses are below the resolution limit of a conventional microscope. At the same time, microelectrode arrays (MEAs) are indispensable in understanding the language of neurons. Here, the authors show transparent MEAs capable of recording action potentials from neurons and compatible with advanced microscopy. The electrodes are made of the conducting polymer poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS) and are patterned by optical lithography, ensuring scalable fabrication with good control over device parameters. A thickness of 380 nm ensures low enough impedance and >75% transparency throughout the visible part of the spectrum making them suitable for artefact-free recording in the presence of laser illumination. Using primary neuronal cells, the arrays record single units from multiple nearby sources with a signal-to-noise ratio of 7.7 (17.7 dB). Additionally, it is possible to perform calcium (Ca2+) imaging, a measure of neuronal activity, using the novel transparent electrodes. Different biomarkers are imaged through the electrodes using conventional and super-resolution microscopy (SRM), showing no qualitative differences compared to glass substrates. These transparent MEAs pave the way for harnessing the synergy between the superior temporal resolution of electrophysiology and the selectivity and high spatial resolution of optical imaging.Cambridge Trust, University of Cambridge. Wellcome Trust (065807/Z/01/Z) (203249/Z/16/Z) UK Medical Research Council (MRC) (MR/K02292X/1) Alzheimer Research UK (ARUK) (ARUK-PG013-14) Michael J Fox Foundation (16238) Infinitus China Ltd. European Union's Horizon 2020 research and innovation programme under grant agreement no. 732032 (BrainCom)

Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces.

Electrode arrays that interface with peripheral nerves are used in the diagnosis and treatment of neurological disorders; however, they require complex placement surgeries that carry a high risk of nerve injury. Here we leverage recent advances in soft robotic actuators and flexible electronics to develop highly conformable nerve cuffs that combine electrochemically driven conducting-polymer-based soft actuators with low-impedance microelectrodes. Driven with applied voltages as small as a few hundreds of millivolts, these cuffs allow active grasping or wrapping around delicate nerves. We validate this technology using in vivo rat models, showing that the cuffs form and maintain a self-closing and reliable bioelectronic interface with the sciatic nerve of rats without the use of surgical sutures or glues. This seamless integration of soft electrochemical actuators with neurotechnology offers a path towards minimally invasive intraoperative monitoring of nerve activity and high-quality bioelectronic interfaces

Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces.

Electrode arrays that interface with peripheral nerves are used in the diagnosis and treatment of neurological disorders; however, they require complex placement surgeries that carry a high risk of nerve injury. Here we leverage recent advances in soft robotic actuators and flexible electronics to develop highly conformable nerve cuffs that combine electrochemically driven conducting-polymer-based soft actuators with low-impedance microelectrodes. Driven with applied voltages as small as a few hundreds of millivolts, these cuffs allow active grasping or wrapping around delicate nerves. We validate this technology using in vivo rat models, showing that the cuffs form and maintain a self-closing and reliable bioelectronic interface with the sciatic nerve of rats without the use of surgical sutures or glues. This seamless integration of soft electrochemical actuators with neurotechnology offers a path towards minimally invasive intraoperative monitoring of nerve activity and high-quality bioelectronic interfaces

Electrophysiological In Vitro Study of Long‐Range Signal Transmission by Astrocytic Networks

Astrocytes are diverse brain cells that form large networks communicating via gap junctions and chemical transmitters. Despite recent advances, functions of astrocytic networks in the information processing in the brain are not fully understood. In culture, brain slices, and in vivo, astrocytes and neurons grow in tight association, making it challenging to establish whether signals that spread within astrocytic networks communicate with neuronal groups at distant sites, or whether astrocytes solely respond to their local environments. A multi-electrode array (MEA)-based device called AstroMEA was designed to separate neuronal and astrocytic networks, thus allowing to study the transfer of chemical and/or electrical signals transmitted via astrocytic networks capable of changing neuronal electrical behavior. AstroMEA demonstrated that cortical astrocytic networks can induce a significant upregulation in the firing frequency of neurons in response to a theta-burst charge-balanced biphasic current stimulation (5 pulses of 100 Hz x10 with 200 ms intervals, 2 s total duration) of a separate neuronal-astrocytic group in the absence of a direct neuronal contact. This result corroborates the view of astrocytic networks as a parallel mechanism of signal transmission in the brain which is separate from the neuronal connectome. Translationally, it highlights the importance of astrocytic network protection as a treatment target.Royall Scholarship; Wellcome Trust Junior Interdisciplinary Fellowship; University of Cambridge Borysiewicz Interdisciplinary Fellowship program; Yoshida Scholarship Foundation; KDDI Foundation; Shigeta Educational Foundation; NIHR BRC Centre; NIHR Clinician Scientist Award; Wellcome Trust DCF "PK/PD and ADME characterization of a novel formulation for the treatment of Parkinson’s Disease