A printed flexible hybrid electronics (FHE) technology platform is described, which combines a thin-film audio speaker, printed interconnects, and printed passive components in a highly flexible system. Bimorph piezoelectric polymer speaker structures were developed and shown to give increased loudness compared with a single layer speaker, with good fidelity and easily recognizable sound. Speakers were fabricated on flexible thin polyimide substrates, which enables integration with printed electronics and other thin-film devices. Two demonstrator circuits were designed to operate the speakers and were fabricated using printed FHE techniques. One circuit was an amplifier for a portable music player, and the second provides a record and playback function using an audio integrated circuit. The fabrication of these devices included ink-jet printed interconnects and ink-jet printed resistors, which showed a good long-term stability and flexibility.

Background: Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response.Objectives: To investigate whether interindividual variability in the response to ACE inhibitors is explained by the ACE phenotypefor example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual.Methods: The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation.Results: Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration.Conclusion: Due to the fact that 20% of patients do not respond to ACEI by blood pressure drop, the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.

This paper presents two versions of a silicon mechanical heat switch designed for electrocaloric cooling. The first design, which consists of two 10-mm-by-12.8-mm micromachined silicon parts, allows investigation of the performance of a reciprocating solid thermal shunt device. This heat switch has a measured thermal contrast ratio in the range of 34-59. The second design adds self-alignment features that constrain the motion of the switch to facilitate fabrication and integration. The self-aligned heat switch has a thermal contrast ratio > 28. It has been successfully operated for > 18 000 cycles and employed in an electrocaloric cooler. Design, fabrication, and characterization of both heat switches are reported. [2016-0218]

In this paper, we combine high functionality c-Si CMOS and digitally printed components and interconnects to create an mostly printed integrated electronic system on a flexible substrate that can read and process multiple discrete sensors. Our approach is to create an integrated platform for the fabrication of mechanically flexible sensor tags that can be powered and interrogated wirelessly, precluding the need of a separate on-board power source. The high level system design is aimed at minimizing the number of non-printed components and reducing power consumption to enable energy harvesting from the RF field. Digital fabrication of these systems requires a range of materials, feature sizes, and electrical characteristics. In order to integrate the various printed components on a single substrate, we developed an integrated printer to accommodate a range of inks for printing the antenna, different types of sensors, chip interconnects, and wiring. For chip attachment to the flexible substrate, a method of integrating the die within the thickness of the substrate was developed. With proper system design and fabrication, a complete integrated tag for wireless sensing of temperature, strain, and touch was demonstrated. Our approach facilitates customization to a wide variety of sensors and user interfaces suitable for a broad range of applications including remote monitoring of health, structures, and the environment.

A patient’s recovery from lung inflammatory injury or development of multi-system organ failure is determined by the host’s ability to resolve inflammation and repair tissue damage, both of which require the clearance of apoptotic neutrophils by macrophages (efferocytosis). Here, we investigated the effects of isoflurane on macrophage efferocytosis and resolution of lung inflammatory injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic neutrophils. Isoflurane significantly increased the surface expression of the receptor tyrosine kinase Mer in macrophages, but markedly decreased the levels of a soluble form of Mer protein in the medium. Isoflurane treatment also caused a decrease in a disintegrin and metalloproteinase 17 (ADAM17) on the cell surface and a concomitant increase in its cytoplasmic fraction. These responses induced by isoflurane were completely reversed by a pharmacological inhibitor or genetic deletion of AMP-activated protein kinase (AMPK). In a mouse model of lipopolysaccharide-induced lung injury, isoflurane accelerated the recovery of lung inflammation and injury that was coupled with an increase in the number of alveolar macrophages containing apoptotic bodies. In alveolar macrophage-depleted mice, administration of isoflurane-pretreated BMDMs facilitated resolution of lung inflammation following lipopolysaccharide challenge. Thus, isoflurane promoted resolution of lipopolysaccharide-induced lung inflammatory injury via enhancement of macrophage efferocytosis. Increased macrophage efferocytosis following isoflurane treatment correlates with upregulation of Mer surface expression through AMPK-mediated blockade of ADAM17 trafficking to the cell membrane.

Printed and flexible hybrid electronics is an emerging technology with potential applications in smart labels, wearable electronics, soft robotics, and prosthetics. Printed solution-based materials are compatible with plastic film substrates that are flexible, soft, and stretchable, thus enabling conformal integration with non-planar objects. In addition, manufacturing by printing is scalable to large areas and is amenable to low-cost sheet-fed and roll-to-roll processes. FHE includes display and sensory components to interface with users and environments. On the system level, devices also require electronic circuits for power, memory, signal conditioning, and communications. Those electronic components can be integrated onto a flexible substrate by either assembly or printing. PARC has developed systems and processes for realizing both approaches. This talk presents fabrication methods with an emphasis on techniques recently developed for the assembly of off-the-shelf chips. A few examples of systems fabricated with this approach are also described.

The calcium binding protein S100B has attracted great attention as a biomarker for a variety of diseases. S100B is mainly expressed in glial cells and functions through intracellular and extracellular signaling pathways. The biological roles of S100B have been closely associated with its concentrations and its physiological states. The released S100B can bind to the receptor of advanced glycation end products and induce the initiation of multiple cell signaling transductions. The regulation of S100B bioactivities has been suggested through phosphoinositide 3 kinase/Akt, p53, mitogen-activated protein kinases, transcriptional factors including nuclear factor-kappaB, and cyclic adenosine monophosphate. The levels of S100B in the blood may function to predict the progress or the prognosis of many kinds of diseases, such as cerebrovascular diseases, neurodegenerative diseases, motor neuron diseases, traumatic brain injury, schizophrenia, depression, diabetes mellitus, myocardial infarction, cancer, and infectious diseases. Given that the activity of S100B has been implicated in the pathological process of these diseases, S100B should not be simply regarded as a biomarker, it may also function as therapeutic target for these diseases. Further elucidation of the roles of S100B may formulate innovative therapeutic strategies for multiple diseases.

To enable the integration of components with different supply voltage requirements, and to optimize power consumption in printed flexible electronics, we demonstrate an inkjet-printed pulsed voltage multiplier that boosts the voltage at specific circuit nodes above the supply voltage. A five-stage pulsed voltage multiplier is shown to provide an output voltage up to 18 V from a supply voltage of 10 V, with minimum 10 ms pulse rise time for a 70 pF load. This circuit allows a single power source to deliver multiple voltage levels and enables integration of low-voltage logic with components that require higher operating voltage. A key requirement for the pulsed voltage multiplier circuit is low device leakage to boost the output voltage level. To this end, the composition of the transistor semiconducting layer is modified by blending an insulating polymer with the small molecule semiconductor. This modification allows control over the transistor turn-on voltage, which enables low leakage current required for operation of the circuit.

Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients.

Wireless sensing has broad applications in a wide variety of fields such as infrastructure monitoring, chemistry, environmental engineering and cold supply chain management. Further development of sensing systems will focus on achieving light weight, flexibility, low power consumption and low cost. Fully printed electronics provide excellent flexibility and customizability, as well as the potential for low cost and large area applications, but lack solutions for high-density, high-performance circuitry. Conventional electronics mounted on flexible printed circuit boards provide high performance but are not digitally fabricated or readily customizable. Incorporation of small silicon dies or packaged chips into a printed platform enables high performance without compromising flexibility or cost. At PARC, we combine high functionality c-Si CMOS and digitally printed components and interconnects to create an integrated platform that can read and process multiple discrete sensors. Our approach facilitates customization to a wide variety of sensors and user interfaces suitable for a broad range of applications including remote monitoring of health, structures and environment. This talk will describe several examples of printed wireless sensing systems. The technologies required for these sensor systems are a mix of novel sensors, printing processes, conventional microchips, flexible substrates and energy harvesting power solutions.

We demonstrate an inkjet-printed organic thin-film transistor (OTFT) circuit for reading ferroelectric (FE) nonvolatile rewritable memories. With the large difference in polarization charge between FE memory states, we implement a single-OTFT gain stage with latch and show that a gain of -2.8 is sufficient to distinguish memory states. This paper evaluates the effect of device variations on the yield of this readout circuit.

s Mechanisms of Vasodilatation 12th International Symposium Rochester, Minn., USA, November 6–9, 2016 Guest Editors: M.V. Miller (Rochester, Minn.); R.C. Webb (Augusta, Ga.); M.P. Vanhoutte (Hong Kong)

In electronic systems, components often require different supply voltage for operation. In order to meet this requirement and to optimize power consumption for flexible electronics, we demonstrate a pulsed voltage multiplier that boosts the voltage at specific circuit nodes above the supply voltage. A five-stage pulsed voltage multiplier is shown to provide an output voltage up to 18 V from a supply voltage of 10 V, with minimum 10 ms pulse rise time for a 70 pF load. A key requirement for the pulsed voltage multiplier circuit is low device leakage to boost the output voltage level. To minimize leakage, the composition of the organic semiconducting layer is modified by blending an insulating polymer with the small molecule semiconductor. This modification allows control over the transistor turn-on voltage, which enables low leakage current required for operation of the circuits. The printed multiplier allows a single power source to deliver multiple voltage levels and enables integration of lower voltage logic with components that require higher operating voltage, for example, in the case of recording data into memory cells in sensor tags.

High-mobility group box 1 protein (HMGB1) has been implicated in inflammatory responses, and is also associated with cerebral vasospasm after subarachnoid hemorrhage (SAH). However, there are no direct evident links between HMGB1 and cerebral vasospasm. We therefore investigated the effects of HMGB1 on pial arteriole reactivity following SAH in rats. We initially found that SAH induced a significant decrease in pial arteriole dilating responses to sciatic nerve stimulation (SNS), hypercapnia (CO2), and the topical suffusion of acetylcholine (ACh), adenosine (ADO), and s-nitroso-N-acetylpenicillamine (SNAP) over a 7-day period after SAH. The percent change of arteriolar diameter was decreased to the lowest point at 48 h after SAH, in response to dilating stimuli (i.e., it decreased from 41.0 ± 19.0% in the sham group to 11.00 ± 0.70% after SNS) (n = 5, p < 0.01). HMGB1 infusion in the lateral ventricle in normal rats for 48 h did not change the pial arteriole dilating response. In addition, inhibitors of HMGB1-receptor for advanced glycation end-product or HMGB1-toll-like receptor 2/4 interaction, or the HMBG1 antagonist did not improve pial arteriole reactivity 48 h after SAH. These findings suggest that HMGB1 may not be a major player in cerebral vascular dilating dysfunction after SAH.