Marvin J. Slepian

A Physically Transient Form of Silicon Electronics

Reversible Implants Silicon electronics are generally designed to be stable and robust—it would be counterproductive if the key parts of your computer or cell phone slowly dissolved away while you were using it. In order to develop transient electronics for use as medical implants, Hwang et al. (p. 1640, see the cover) produced a complete set of tools and materials that would be needed to make standard devices. Devices were designed to have a specific lifetime, after which the component materials, such as porous silicon and silk, would be resorbed by the body. A platform of materials and fabrication methods furnishes resorbable electronic devices for in vivo use. A remarkable feature of modern silicon electronics is its ability to remain physically invariant, almost indefinitely for practical purposes. Although this characteristic is a hallmark of applications of integrated circuits that exist today, there might be opportunities for systems that offer the opposite behavior, such as implantable devices that function for medically useful time frames but then completely disappear via resorption by the body. We report a set of materials, manufacturing schemes, device components, and theoretical design tools for a silicon-based complementary metal oxide semiconductor (CMOS) technology that has this type of transient behavior, together with integrated sensors, actuators, power supply systems, and wireless control strategies. An implantable transient device that acts as a programmable nonantibiotic bacteriocide provides a system-level example.

Conformal piezoelectric energy harvesting and storage from motions of the heart, lung, and diaphragm

Significance Heart rate monitors, pacemakers, cardioverter-defibrillators, and neural stimulators constitute broad classes of electronic implants that rely on battery power for operation. Means for harvesting power directly from natural processes of the body represent attractive alternatives for these and future types of biomedical devices. Here we demonstrate a complete, flexible, and integrated system that is capable of harvesting and storing energy from the natural contractile and relaxation motions of the heart, lung, and diaphragm at levels that meet requirements for practical applications. Systematic experimental evaluations in large animal models and quantitatively accurate computational models reveal the fundamental modes of operation and establish routes for further improvements. Here, we report advanced materials and devices that enable high-efficiency mechanical-to-electrical energy conversion from the natural contractile and relaxation motions of the heart, lung, and diaphragm, demonstrated in several different animal models, each of which has organs with sizes that approach human scales. A cointegrated collection of such energy-harvesting elements with rectifiers and microbatteries provides an entire flexible system, capable of viable integration with the beating heart via medical sutures and operation with efficiencies of ∼2%. Additional experiments, computational models, and results in multilayer configurations capture the key behaviors, illuminate essential design aspects, and offer sufficient power outputs for operation of pacemakers, with or without battery assist.

Paradoxical effects of exercise on the QT interval in patients with polymorphic ventricular tachycardia receiving type Ia antiarrhythmic agents.

We analyzed the results of exercise testing performed in the absence of all antiarrhythmic drugs in 11 case patients with newly documented polymorphic ventricular tachycardia in response to type Ia antiarrhythmic agents. These results were compared with those found in 11 control patients matched for age, sex, and heart disease to determine whether the response of the QT interval to exercise testing was abnormal in patients who developed worsening of arrhythmia while taking antiarrhythmic drugs. QT, RR, and QTc intervals (by Bazetts method) were evaluated at rest and at 3 minutes of exercise in both groups. At rest, there was no significant difference in the QT interval (410 +/- 13 vs. 386 +/- 11 msec), RR interval (890 +/- 56 vs. 781 +/- 43 msec), or corrected QT interval (438 +/- 10 vs. 438 +/- 4 msec) in the case patients and the control patients. Both groups demonstrated a similar chronotropic response to exercise. The QT interval shortened in both groups with exercise (p less than 0.001), but the degree of shortening tended to be greater in the control patients (to 310 +/- 9 msec) than in the case patients (to 357 +/- 11 msec) (p = 0.06). Thus, there was a paradoxical increase in the QTc interval in the patients who experienced a proarrhythmic effect of type Ia drugs but not in the control patients (to 482 +/- 8 vs. 431 +/- 5 msec; p less than 0.001). Ten of 11 case patients but only one of 11 control patients had an increase in QTc interval of more than 10 msec with exercise (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Conformal piezoelectric systems for clinical and experimental characterization of soft tissue biomechanics

Mechanical assessment of soft biological tissues and organs has broad relevance in clinical diagnosis and treatment of disease. Existing characterization methods are invasive, lack microscale spatial resolution, and are tailored only for specific regions of the body under quasi-static conditions. Here, we develop conformal and piezoelectric devices that enable in vivo measurements of soft tissue viscoelasticity in the near-surface regions of the epidermis. These systems achieve conformal contact with the underlying complex topography and texture of the targeted skin, as well as other organ surfaces, under both quasi-static and dynamic conditions. Experimental and theoretical characterization of the responses of piezoelectric actuator-sensor pairs laminated on a variety of soft biological tissues and organ systems in animal models provide information on the operation of the devices. Studies on human subjects establish the clinical significance of these devices for rapid and non-invasive characterization of skin mechanical properties.

A soft, wearable microfluidic device for the capture, storage, and colorimetric sensing of sweat

A soft, skin-mounted microfluidic device captures microliter volumes of sweat and quantitatively measures biochemical markers by colorimetric analysis. Better health? Prepare to sweat Wearable technology is a popular way many people monitor their general health and fitness, tracking heart rate, calories, and steps. Koh et al. now take wearable technology one step further. They have developed and tested a flexible microfluidic device that adheres to human skin. This device collects and analyzes sweat during exercise. Using colorimetric biochemical assays and integrating smartphone image capture analysis, the device detected lactate, glucose, and chloride ion concentrations in sweat as well as sweat pH while stuck to the skin of individuals during a controlled cycling test. Colorimetric readouts showed comparable results to conventional analyses, and the sweat patches remained intact and functional even when used during an outdoor endurance bicycle race. The authors suggest that microfluidic devices could be used during athletic or military training and could be adapted to test other bodily fluids such as tears or saliva. Capabilities in health monitoring enabled by capture and quantitative chemical analysis of sweat could complement, or potentially obviate the need for, approaches based on sporadic assessment of blood samples. Established sweat monitoring technologies use simple fabric swatches and are limited to basic analysis in controlled laboratory or hospital settings. We present a collection of materials and device designs for soft, flexible, and stretchable microfluidic systems, including embodiments that integrate wireless communication electronics, which can intimately and robustly bond to the surface of the skin without chemical and mechanical irritation. This integration defines access points for a small set of sweat glands such that perspiration spontaneously initiates routing of sweat through a microfluidic network and set of reservoirs. Embedded chemical analyses respond in colorimetric fashion to markers such as chloride and hydronium ions, glucose, and lactate. Wireless interfaces to digital image capture hardware serve as a means for quantitation. Human studies demonstrated the functionality of this microfluidic device during fitness cycling in a controlled environment and during long-distance bicycle racing in arid, outdoor conditions. The results include quantitative values for sweat rate, total sweat loss, pH, and concentration of chloride and lactate.

Electronic sensor and actuator webs for large-area complex geometry cardiac mapping and therapy

Curved surfaces, complex geometries, and time-dynamic deformations of the heart create challenges in establishing intimate, nonconstraining interfaces between cardiac structures and medical devices or surgical tools, particularly over large areas. We constructed large area designs for diagnostic and therapeutic stretchable sensor and actuator webs that conformally wrap the epicardium, establishing robust contact without sutures, mechanical fixtures, tapes, or surgical adhesives. These multifunctional web devices exploit open, mesh layouts and mount on thin, bio-resorbable sheets of silk to facilitate handling in a way that yields, after dissolution, exceptionally low mechanical moduli and thicknesses. In vivo studies in rabbit and pig animal models demonstrate the effectiveness of these device webs for measuring and spatially mapping temperature, electrophysiological signals, strain, and physical contact in sheet and balloon-based systems that also have the potential to deliver energy to perform localized tissue ablation.

β3-Integrins Rather Than β1-Integrins Dominate Integrin-Matrix Interactions Involved in Postinjury Smooth Muscle Cell Migration

Background—Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin–extracellular matrix interactions are essential for cell migration. SMCs express both β1- and β3-integrins. In this study, we examined the relative functional roles of β1- and β3-integrin–matrix interactions in postinjury SMC migration. Methods and Results—Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-β1 and anti-αvβ3/5 antibodies (Abs) revealed expression of both β1- and β3-integrins, with β1 observed as linear streaks and β3 found in focal contacts. In a scrape-wound migration assay, anti-β1 Abs (92.0±10.7% of control, P=.1) and 0.5 mmol/L linear RGD (105±5% of control, P=.2) did not alter SMC migration at 48 hours after injury. β3-Blockade, however, via Abs (anti-β3/5 35.7±4.5% of control, anti-β3 61±12% of control, both P<.001) and cyclic RGD (0.5 mmol/L) (12±10% of control, P<.001) decreased migration. Neither...

Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow

Advances in ultrathin, skin-like electronics lead to wearable devices for continuous, noninvasive blood flow monitoring. Continuous monitoring of variations in blood flow is vital in assessing the status of microvascular and macrovascular beds for a wide range of clinical and research scenarios. Although a variety of techniques exist, most require complete immobilization of the subject, thereby limiting their utility to hospital or clinical settings. Those that can be rendered in wearable formats suffer from limited accuracy, motion artifacts, and other shortcomings that follow from an inability to achieve intimate, noninvasive mechanical linkage of sensors with the surface of the skin. We introduce an ultrathin, soft, skin-conforming sensor technology that offers advanced capabilities in continuous and precise blood flow mapping. Systematic work establishes a set of experimental procedures and theoretical models for quantitative measurements and guidelines in design and operation. Experimental studies on human subjects, including validation with measurements performed using state-of-the-art clinical techniques, demonstrate sensitive and accurate assessment of both macrovascular and microvascular flow under a range of physiological conditions. Refined operational modes eliminate long-term drifts and reduce power consumption, thereby providing steps toward the use of this technology for continuous monitoring during daily activities.

Epidermal mechano-acoustic sensing electronics for cardiovascular diagnostics and human-machine interfaces

Researchers report advances in materials and designs for skin-integrated devices capable of measuring acoustic signatures. Physiological mechano-acoustic signals, often with frequencies and intensities that are beyond those associated with the audible range, provide information of great clinical utility. Stethoscopes and digital accelerometers in conventional packages can capture some relevant data, but neither is suitable for use in a continuous, wearable mode, and both have shortcomings associated with mechanical transduction of signals through the skin. We report a soft, conformal class of device configured specifically for mechano-acoustic recording from the skin, capable of being used on nearly any part of the body, in forms that maximize detectable signals and allow for multimodal operation, such as electrophysiological recording. Experimental and computational studies highlight the key roles of low effective modulus and low areal mass density for effective operation in this type of measurement mode on the skin. Demonstrations involving seismocardiography and heart murmur detection in a series of cardiac patients illustrate utility in advanced clinical diagnostics. Monitoring of pump thrombosis in ventricular assist devices provides an example in characterization of mechanical implants. Speech recognition and human-machine interfaces represent additional demonstrated applications. These and other possibilities suggest broad-ranging uses for soft, skin-integrated digital technologies that can capture human body acoustics.

Device Thrombogenicity Emulation: A Novel Method for Optimizing Mechanical Circulatory Support Device Thromboresistance

Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation – mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device – ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers – before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device ‘thrombogenic footprint’, indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops – before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology – demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization – indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.