A Wireless Battery-Free Implant With Optical Telemetry for In Vivo Cortical Stimulation.

We present a 100 µm-thick, wireless, and battery-free implant for brain stimulation through a U.S. Food and Drug Administration-approved collagen dura substitute without contact with the brain's surface, while providing visible-light spectrum telemetry to track the onset of stimulation. The device is fabricated on a 16 × 6.67 mm2 biocompatible parylene/PDMS substrate and is encapsulated with a 2 µm-thick transparent parylene layer that enables the relay of the LED brightness. The in vivo rodent testing confirmed the implant's ability to trigger motor response while generating observable brightness through the skin. The results reveal the prospect of wireless stimulation with enhanced safety by eliminating contact between the implant and the brain, with optical telemetry for facilitated tracking.

Development of a novel, concentric micro-ECoG array enabling simultaneous detection of a single location by multiple electrode sizes.

Objective.Detection of the epileptogenic zone is critical, especially for patients with drug-resistant epilepsy. Accurately mapping cortical regions exhibiting high activity during spontaneous seizure events while detecting neural activity up to 500 Hz can assist clinicians' surgical decisions and improve patient outcomes.Approach.We designed, fabricated, and tested a novel hybrid, multi-scale micro-electrocorticography (micro-ECoG) array with a unique embedded configuration. This array was compared to a commercially available microelectrode array (Neuronexus) for recording neural activity in rodent sensory cortex elicited by somatosensory evoked potentials and pilocarpine-induced seizures.Main results.Evoked potentials and spatial maps recorded by the multi-scale array ('micros', 'mesos', and 'macros' refering to the relative electrode sizes, 40 micron, 1 mm, and 4 mm respectively) were comparable to the Neuronexus array. The SSEPs recorded with the micros had higher peak amplitudes and greater signal power than those recorded by the larger mesos and macro. Seizure onset events and high-frequency oscillations (∼450 Hz) were detected on the multi-scale, similar to the commercially available array. The micros had greater SNR than the mesos and macro over the 5-1000 Hz frequency range during seizure monitoring. During cortical stimulation experimentation, the mesos successfully elicited motor effects.Significance.Previous studies have compared macro- and microelectrodes for localizing seizure activity in adjacent regions. The multi-scale design validated here is the first to simultaneously measure macro- and microelectrode signals from the same overlapping cortical area. This enables direct comparison of microelectrode recordings to the macroelectrode recordings used in standard neurosurgical practice. Previous studies have also shown that cortical regions generating high-frequency oscillations are at an increased risk for becoming epileptogenic zones. More accurate mapping of these micro seizures may improve surgical outcomes for epilepsy patients.

Hydrogel Check-Valves for the Treatment of Hydrocephalic Fluid Retention with Wireless Fully-Passive Sensor for the Intracranial Pressure Measurement.

Hydrocephalus (HCP) is a neurological disease resulting from the disruption of the cerebrospinal fluid (CSF) drainage mechanism in the brain. Reliable draining of CSF is necessary to treat hydrocephalus. The current standard of care is an implantable shunt system. However, shunts have a high failure rate caused by mechanical malfunctions, obstructions, infection, blockage, breakage, and over or under drainage. Such shunt failures can be difficult to diagnose due to nonspecific systems and the lack of long-term implantable pressure sensors. Herein, we present the evaluation of a fully realized and passive implantable valve made of hydrogel to restore CSF draining operations within the cranium. The valves are designed to achieve a non-zero cracking pressure and no reverse flow leakage by using hydrogel swelling. The valves were evaluated in a realistic fluidic environment with ex vivo CSF and brain tissue. They display a successful operation across a range of conditions, with negligible reverse flow leakage. Additionally, a novel wireless pressure sensor was incorporated alongside the valve for in situ intracranial pressure measurement. The wireless pressure sensor successfully replicated standard measurements. Those evaluations show the reproducibility of the valve and sensor functions and support the system's potential as a chronic implant to replace standard shunt systems.

Passive and Flexible Wireless Electronics Fabricated on Parylene/PDMS Substrate for Stimulation of Human Stem Cell-Derived Cardiomyocytes.

In this paper, we report the development of a wireless, passive, biocompatible, and flexible system for stimulation of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMS). Fabricated on a transparent parylene/PDMS substrate, the proposed stimulator enables real-time excitation and characterization of hiPSC-CMs cultured on-board. The device comprises a rectenna operating at 2.35 GHz which receives radio frequency (RF) energy from an external transmitter and converts it into DC voltage to deliver monophasic stimulation. The operation of the stimulator was primarily verified by delivering monophasic voltage pulses through gold electrodes to hiPSC-CMs cultured on the Matrigel-coated substrates. Stimulated hiPSC-CMs beat in accordance with the monophasic pulses when delivered at 0.5, 1, and 2 Hz pulsing frequency, while no significant cell death was observed. The wireless stimulator could generate monophasic pulses with an amplitude of 8 V at a distance of 15 mm. These results demonstrated the proposed wireless stimulator's efficacy for providing electrical stimulation to engineered cardiac tissues. The proposed stimulator will have a wide application in tissue engineering where a fully wireless stimulation of electroconductive cells is needed. The device also has potential to be employed as a cardiac stimulator by delivering external stimulation and regulating the contractions of cardiac tissue.

Modeling optical design parameters for fine stimulation in sciatic nerve of optogenetic mice.

Optogenetics presents an alternative method for interfacing with the nervous system over the gold-standard of electrical stimulation. While electrical stimulation requires electrodes to be surgically embedded in tissue for in vivo studies, optical stimulation offers a less-invasive approach that may yield more specific, localized stimulation. The advent of optogenetic laboratory animals-whose motor neurons can be activated when illuminated with blue light-enables research into refining optical stimulation of the mammalian nervous system where subsets of nerve fibers within a nerve may be stimulated without embedding any device directly into the nerve itself. However, optical stimulation has a major drawback in that light is readily scattered and absorbed in tissue thereby limiting the depth with which a single emission source can penetrate. We hypothesize that the use of multiple, focused light emissions deployed around the circumference of a nerve can overcome these light-scattering limitations. To understand the physical parameters necessary to produce pinpointed light stimulation within a single nerve, we employed a simplified Monte Carlo simulation to estimate the size of nerves where this technique may be successful, as well as the necessary optical lens design for emitters to be used during future in vivo studies. By modeling multiple focused beams, we find that only fascicles within a nerve diameter less than 1 mm are fully accessible to focused optical stimulation; a minimum of 4 light sources is required to generate a photon intensity at a point in a nerve over the initial contact along its surface. To elicit the same effect in larger nerves, focusing lenses would require a numerical aperture [Formula: see text]. These simulations inform on the design of instrumentation capable of stimulating disparate motor neurons in mouse sciatic nerve to control hindlimb movement.

Optogenetic modulation of cortical neurons using organic light emitting diodes (OLEDs).

OBJECTIVE: There is a need for low power, scalable photoelectronic devices and systems for emerging optogenetic needs in neuromodulation. Conventional light emitting diodes (LEDs) are constrained by power and lead-counts necessary for scalability. Organic LEDs (OLEDs) offer an exciting approach to decrease power and lead-counts while achieving high channel counts on thin, flexible substrates that conform to brain surfaces or peripheral neuronal fibers. In this study, we investigate the potential for using OLEDs to modulate neuronal networks cultured in vitro on a transparent microelectrode array (MEA) and subsequently validate neurostimulation in vivo in a transgenic mouse model. APPROACH: Cultured mouse cortical neurons were transfected with light-sensitive opsins such as blue-light sensitive channel-rhodopsin (ChR2) and green-light sensitive chimeric channel-rhodopsin (C1V1tt) and stimulated using blue and green OLEDs (with 455 and 520 nm peak emission spectra respectively) at a power of ~1 mW mm-2 under pulsed conditions. MAIN RESULTS: We demonstrate neuromodulation and optostimulus-locked, single unit-neuronal activity in neurons expressing stimulating opsins (34 units on n = 4 MEAs, each with 16 recordable channels). We also validated the optostimulus-locked response in preliminary experiments in a channel-rhodopsin expressing transgenic mouse model, where at least three isolatable single neuronal cortical units respond to OLED stimulation. SIGNIFICANCE: The above results indicate the feasibility of generating sufficient luminance from OLEDs to perform neuromodulation both in vitro and in vivo. This opens up the possibility of developing thin, flexible OLED films with multiple stimulation sites that can conform to the shape of the neuronal targets in the brain or the peripheral nervous system. However, stability of these OLEDs under chronic conditions still needs to be carefully assessed with appropriate packaging approaches.

Eccrine Sweat as a Biofluid for Profiling Immune Biomarkers.

PURPOSE: Sweat is a relatively unexplored biofluid for diagnosis and monitoring of disease states. In this study, the proteomic profiling of immune-related biomarkers from healthy individuals are presented. EXPERIMENTAL DESIGN: Eccrine sweat samples are collected from 50 healthy individuals. LC-MS/MS is performed on two pools of sweat samples from five male and female participants. Individual sweat samples are analyzed by antibody isotyping microarrays (n = 49), human cytokine arrays (n = 30), and quantitative ELISAs for interleukin-1α (n = 16), epidermal growth factor (n = 6), and angiogenin (n = 7). RESULTS: In sweat, 220 unique proteins are identified by shotgun analysis. Detectable antibody isotypes include IgA (100% positive; median 1230 ± 28 700 pg mL-1 ), IgD (18%; 22.0 ± 119 pg mL-1 ), IgG1 (96%; 1640 ± 6750 pg mL-1 ), IgG2 (37%; 292 ± 6810 pg mL-1 ), IgG3 (71%; 74.0 ± 119 pg mL-1 ), IgG4 (69%; 43.0 ± 42.0 pg mL-1 ), and IgM (41%; 69.0 ± 1630 pg mL-1 ). Of 42 cytokines, three are readily detected in all sweat samples (p < 0.01). The median concentration for interleukin-1α is 352 ± 521 pg mL-1 , epidermal growth factor is 86.5 ± 147 pg mL-1 , and angiogenin is 38.3 ± 96.3 pg mL-1 . Multiple other cytokines are detected at lower levels. CONCLUSIONS AND CLINICAL RELEVANCE: Sweat can be used for profiling antibodies and innate immune biomarkers.

A compact, low-cost, quantitative and multiplexed fluorescence detection platform for point-of-care applications.

An effective method of combating infectious diseases is the deployment of hand-held devices at the point-of-care (POC) for screening or self-monitoring applications. There is a need for very sensitive, low-cost and quantitative diagnostic devices. In this study, we present a low-cost, multiplexed fluorescence detection platform that has a high sensitivity and wide dynamic range. Our system features inexpensive 3 × 3 mm interference filters with a high stopband rejection, sharp transition edges, and greater than 90% transmission in the passband. In addition to the filters, we improve signal-to-noise ratio by leveraging time for accuracy using a charge-integration-based readout. The fluorescence sensing platform provides a sensitivity to photon flux of ∼1×104photons/mm2sec and has the potential for 2-3 orders of magnitude improvement in sensitivity over standard colorimetric detection that uses colored latex microspheres. We also detail the design, development, and characterization of our low-cost fluorescence detection platform and demonstrate 100% and 97.96% reduction in crosstalk probability and filter cost, respectively. This is achieved by reducing filter dimensions and ensuring appropriate channel isolation in a 2 × 2 array configuration. Practical considerations with low-cost interference filter system design, analysis, and system performance are also discussed. The performance of our platform is compared to that of a standard laboratory array scanner. We also demonstrate the detection of antibodies to human papillomavirus (HPV16) E7 protein, as a potential biomarker for early cervical cancer detection in human plasma.

Application of flat panel OLED display technology for the point-of-care detection of circulating cancer biomarkers.

Point-of-care molecular diagnostics can provide efficient and cost-effective medical care, and they have the potential to fundamentally change our approach to global health. However, most existing approaches are not scalable to include multiple biomarkers. As a solution, we have combined commercial flat panel OLED display technology with protein microarray technology to enable high-density fluorescent, programmable, multiplexed biorecognition in a compact and disposable configuration with clinical-level sensitivity. Our approach leverages advances in commercial display technology to reduce pre-functionalized biosensor substrate costs to pennies per cm(2). Here, we demonstrate quantitative detection of IgG antibodies to multiple viral antigens in patient serum samples with detection limits for human IgG in the 10 pg/mL range. We also demonstrate multiplexed detection of antibodies to the HPV16 proteins E2, E6, and E7, which are circulating biomarkers for cervical as well as head and neck cancers.

An on-chip system to monitor the pH of cell culture media.

We presents an ion sensitive field effect transistor to measure the pH of the cell culture media of human mammary adenocarcinoma (SKBR3). We use a drift mitigation technique that cycles the transistor to reset the drift in the system. We use to technique in the system to demonstrate an integrated system to monitor the pH continuously. As a part of the system a pulse width modulation circuit is designed in a 0.5 µm CMOS process which cycles the vertical electric field of the ion sensitive field effect transistor to reset the threshold voltage drift. We demonstrate the viability of a complete integrated system implementing our drift mitigation technique to monitor cultured cells. The integration is important in this application to allow for autonomous operation inside an incubator during cell culture.

A self-powered 2-dimensional motion detection chip.

We demonstrate a self-powered chip to detect motion which enables constant, non-invasive monitoring. The chip was implemented in a standard 0.18 µm CMOS process. A P-N junction photodiode array was fabricated in the chip to detect when light is blocked by the movement of a hand or finger. The interface circuit detects the change between the shadowing and the exposure to determine the specific movement. This entire chip operates without any off-chip power supply and provides digitized outputs including 1 bit direction output and an 8 bits output indicative of the velocity in two dimensions.