Blackrock Microsystems (United States)

Rho kinase (ROCK) dysfunction in pulmonary artery hypertension (PAH) and Interstitial lung disease-pulmonary hypertension (ILD-PH) contributes to the pathogenesis of these highly morbid and ultimately fatal diseases. ROC-101 is the first orally administered ROCK1&2 inhibitor to be considered for treatment of PAH and ILD-PH. In this 2-part, first-in-human study, ROC-101 (up to 40 mg QD) was administered to healthy volunteers in single (Part A, N=62) and multiple (Part B, N=30) ascending doses to assess safety, tolerability, PK, PD, and biomarkers. PK was characterized by dose-proportional increases in C_max and AUC. Target exposures were achieved due to rapid absorption (T_max, 1-3 h) and a t_1/2 of 12-14 hours. PD data demonstrated clinically meaningful ROCK1&2 inhibition and suppression of inflammatory cytokines (IL-17α, IFN-γ). ROC-101 was safe and well tolerated, as evidenced by absence of hypotension at any dose and the absence of SAEs or discontinuations. The most common TEAEs were headache and constipation (4%-5%). Clinically significant QTcF increases were not observed for single doses. The ROCK1&2 inhibitor fasudil has been approved for >30 years in Japan and China for the treatment of cerebral vasospasm and has been evaluated in several studies for the treatment of PH. The top dose of ROC-101 yielded exposures up to 25-fold higher than fasudil exposures in a historically successful investigator-initiated PH trial. Together, these data support initiation of a phase 2, proof-of-concept study in patients who have PAH or ILD-PH.

We combine experiments and simulations to investigatethe degradationdynamics and dielectric breakdown (BD) of SiOx/HfO2 gate stacks irradiated with varying dosesof 40 MeV carbon ions. The analysis of postirradiation electricalcharacteristics (current–voltage, I–V, capacitance–voltage, C–V, and conductance-voltage, G–V) reveals that the HfO2 layer is the most affectedby irradiation-induced damage, leading to the formation of defectsconsistent with oxygen vacancies. Postirradiation constant voltagestress (CVS) experiments reveal an inverse dependence of time to breakdown(tBD) and Weibull slopes (β) onthe irradiation dose. These trends are accurately reproduced by statisticalphysics-based breakdown simulations only when accounting for partialpercolation paths induced by ion strikes during irradiation, as wellas a spatially correlated defect generation process during subsequentelectrical stress. Our findings are crucial for designing radiation-hardenedmaterials and improving the resilience of electronics operating inharsh environments.

BackgroundElectrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity.MethodsWe implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations.ResultsParticipants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p < 0.0001) and seven different proprioceptive location-intensity combinations (21/40 successes, p < 0.0001). Variations in the site of stimulation within the nerve, via electrode selection, enabled discrimination among up to five locations and qualities (35/35 successes, p < 0.0001). Variations in the stimulation frequency enabled discrimination among four different intensities at the same location (13/20 successes, p < 0.0005). One participant also discriminated among individual stimulation of two different USEA electrodes, simultaneous stimulation on both electrodes, and interleaved stimulation on both electrodes (20/24 successes, p < 0.0001).ConclusionElectrode location, stimulation frequency, and stimulation pattern can be modulated to evoke functionally discriminable sensations with a range of locations, qualities, and intensities. This rich source of artificial sensory feedback may enhance functional performance and embodiment of bionic arms endowed with a sense of touch.

We assess the performance of a parylene C - aluminum oxide bilayer encapsulation strategy as it applies to implantable devices with non-planar topography. Electrochemical measurements of devices subject to in vitro accelerated lifetime testing are analyzed to evaluate benefits of bilayer encapsulation versus parylene C alone. Failure modes associated with device features and topographies are identified and solutions are presented that promote stability of device impedances.

Neural interfaces connect signal processing electronics to the nervous system via implanted microelectrode arrays such as the Utah electrode array (UEA). The UEA is coated with a biocompatible Parylene-C layer. However, in order to form active sites, Parylene-C is removed from the electrode tips of the UEA. Currently, this is achieved by manually punching aluminum foil through the electrodes to the desired length and subsequent etching of Parylene-C in oxygen plasma. This method is not only operator dependent, but also results in non-uniform tip exposure in the array. This paper examines a novel maskless approach of selectively desinsulating the tips of the UEA by using the unique architecture of the UEA (aspect ratio 15∶1) in its favor. This is achieved by biasing the back-plane of the UEA to the DC bias voltage resulting from the reactive ion etching (RIE) process. During the RIE the electric field is stronger at the tip of the electrode, leading to higher concentration of the oxygen plasma at the tip. As a result, the Parylene-C is selectively etched from the tip. The etching rate is controlled by the inductively coupled plasma (ICP) power, which controls the oxygen plasma density around the tip. The process yields high controllability and reproducibility in selectively etching the tips of the UEA. Furthermore, this method can be applied to other high aspect ratio structures, which have sharp tips.

With the advent of silicon micromachining, biomaterials and advanced technology, it is becoming possible to fabricate more sophisticated implantable neural arrays that can record from and stimulate neurons and nerve axons in the central and peripheral nervous system. To access large portion of human brain, neural arrays with hundreds of channels are needed. The Utah Electrode Array (UEA) is one example of such a neural interface that can selectively communicate with large numbers of individual neurons. The UEA is a 10×10 matrix with 100 channels/active sites. Though the UEA provides high selectivity in recording and stimulation, it has only one active site per shaft and the active site is at the tip of the shaft. In this work, we present a novel method of fabricating multiple active sites along and around the shaft of the UEA that will lead to a high channel density neural array, but with the same footprint as of the standard UEA. This new array, the Utah Multisite Electrode Array (UMEA), is capable to have 9 channels per shaft with channel density of 56.25 sites/mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> , which is 9 times more than that of the conventional UEA. It is envision that the UMEA will offer several advantages such as large volume of human brain can be mapped and different layers of human cortex can be accessed.