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For decades, infants admitted to the neonatal intensive care unit have been hooked up to many wires in order to track vital signs.  These wires include at minimum a three lead EKG and pulse oximeter. Some infants may also be connected to a temperature probe, or need five lead EKG monitoring. In addition to the monitors, many of these infants are also receiving intravenous fluids, on oxygen support or need continuous blood pressure monitoring, adding many tubes and lines. All of these wires can be intimidating and frustrating for new parents trying to care for their infants.  A multidisciplinary team of researchers at Northwestern University in Chicago, IL have come together to help solve this problem creating wireless vital sign monitors, eliminating the need for many of these cords attached to these newborns.

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Binodal, wireless epidermal electronic systems with in-sensor analytics for neonatal intensive care

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Binodal, wireless epidermal electronic systems with in-sensor analytics for neonatal intensive care

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published 01 March 2019

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Sensitive sensing

Neonatal care, particularly for premature babies, is complicated by the infants' fragility and by the need for a large number of tethered sensors to be attached to their tiny bodies. Chung et al. developed a pair of sensors that only require water to adhere to the skin and allow for untethered monitoring of key vital signs (see the Perspective by Guinsburg). On-board data processing allowed for efficient wireless near-field communication using standard protocols. The absence of cables makes it easier to handle the infants and allows for skin-to-skin contact between the babies and their parents or caregivers.

Science, this issue p. eaau0780; see also p. 924

Structured Abstract

Abstract

Existing vital sign monitoring systems in the neonatal intensive care unit (NICU) require multiple wires connected to rigid sensors with strongly adherent interfaces to the skin. We introduce a pair of ultrathin, soft, skin-like electronic devices whose coordinated, wireless operation reproduces the functionality of these traditional technologies but bypasses their intrinsic limitations. The enabling advances in engineering science include designs that support wireless, battery-free operation; real-time, in-sensor data analytics; time-synchronized, continuous data streaming; soft mechanics and gentle adhesive interfaces to the skin; and compatibility with visual inspection and with medical imaging techniques used in the NICU. Preliminary studies on neonates admitted to operating NICUs demonstrate performance comparable to the most advanced clinical-standard monitoring systems.

Sensor designs, system configurations, and wireless, battery-free modes of operation

Figure 1A presents schematic representations of the two wireless EESs. The electronic layer in each EES incorporates a collection of thin, narrow serpentine metal traces (Cu, 50 to 100 μm in width, 5 μm in thickness) that interconnect multiple, chip-scale integrated circuit components. One EES mounts on the chest to record electrocardiograms (ECGs; Fig. 1A, left) through skin-interfaced electrodes that consist of filamentary metal mesh microstructures in fractal geometries; the other mounts on the base of the foot to record photoplethysmograms (PPGs; Fig. 1A, right) by reflection-mode measurements. A microfluidic chamber filled with a nontoxic ionic liquid (1-ethyl-3-methylimidazolium ethyl sulfate) between the electronics and the lower encapsulation layer provides mechanical isolation between the interconnected components and the skin (). A thin film of silicone elastomer encapsulates the top, bottom, and sides to enable operation even when completely immersed in water (fig. S1).

In addition to the electronics, each EES incorporates a magnetic loop antenna (fig. S2) tuned to compliance with near-field communication (NFC) protocols and configured to allow simultaneous wireless data transmission and wireless power delivery through a single link. The low conductivity of the ionic liquid allows stable electrical operation in this radio-frequency (RF) environment (). (See supplementary materials and fig. S3 for details of fabrication methods.) The resulting binodal system captures and continuously transmits ECG, PPG, and skin temperature data from each EES. From these data, HR, heart rate variability (HRV), RR, SpO ₂, and a surrogate of systolic blood pressure (BP) can be extracted.

The images in Fig. 1B show the overall size and ultrathin, soft form factor of these systems. Finite element analysis and experimental results indicate that these devices can bend to radii that are much smaller (6.4 mm and 5 mm, respectively; fig. S4) than required (> ~140 mm and > ~50 mm for the chest and foot, respectively, depending on gestational age) to interface with the chest and the limb of each neonate, without adverse mechanical effects on the device or skin. The electromagnetic properties of both the ECG EES and PPG EES undergo negligible changes when stretched and bent in this manner (figs. S5 and S6). Stretching the ECG EES uniaxially by up to 16% ( Fig. 1C) and the PPG EES by up to 13% results in strains in the electronics and antenna structures that remain below the limits for plastic deformation (~0.3%; figs. S7 to S9). Even with 20% stretching, the changes in the inductance, Q factor, and resonant frequency of the antennas are minimal (< 5%) (figs. S10 and S11). Figure 1D shows pictures of a PPG EES with its red LED activated, captured with and without external illumination.

Images in Fig. 1, E and F, compare clinical-standard technologies to our devices, as deployed on a realistic model of a neonate. Existing systems require a collection of separate electrodes, sensors, and limb-strapped systems paired to base units with hard-wired connections. An ECG requires three adhesive-backed electrodes with adjoining wires to monitor HR, HRV, and RR. Commonly used electrodes for this purpose (e.g., Red Dot, 3M Company) may require additional adhesives that further increase the risk of skin injury. Measurements of SpO ₂ rely on limb-based devices for PPG (e.g., LNCS Neo SpO ₂ sensor, Masimo), typically wrapped around the entire foot, with an additional wired interface. Continuous measurements of skin temperature, necessary to monitor for signs of hypothermia, involve another adhesive-backed sensor (e.g., HNICU-22, DeRoyal) and adjoining wire. Collectively, then, vital signs monitoring in the conventional manner requires at least four electrodes and one limb-deployed device, with five wires for external connection to yield HR, HRV, RR, skin temperature, and SpO ₂.

The block diagram in Fig. 1G summarizes the system architecture and overall wireless operation of our systems. The ECG EES includes two epidermal electrodes, an instrumentation amplifier, analog filters, an inverting amplifier, and a NFC system-on-a-chip (SoC) (fig. S12). The PPG EES includes a pair of small-scale LEDs that emit in the red (640 nm) and infrared (IR) (940 nm), a photodiode, LED drivers, an external power circuit, analog filters, an inverting amplifier, and a NFC SoC (fig. S13). A 14-bit analog-to-digital converter (ADC) operating at a sampling frequency of 200 Hz digitizes the signals captured by each module. The RF loop antennas in both the ECG EES and PPG EES serve dual purposes in power transfer and in data communication.

The standard NFC protocol at 13.56 MHz supports only low-speed, low-fidelity applications such as contactless payments and wireless identification (); thus, substantial modification in both the transponder and host reader systems at ISO15693 was required to support data transfer rates sufficient for NICU monitoring (hundreds of Hz). The results enable continuous streaming of data at rates of up to 800 bytes/s with dual channels, which is orders of magnitude larger than those previously achieved in NFC sensors (-). A key to realizing such high rates is in minimizing the overhead associated with transfer by packaging data into six blocks (24 bytes) in a circular buffer. Reading occurs with a NFC host interfaced to a microcontroller in a Bluetooth Low Energy (BLE) system configured with the customized circular buffer decoding routine (fig. S14). The primary antenna connects to the host system for simultaneous transfer of RF power to the ECG EES and the PPG EES. Operation is possible at vertical distances of up to 25 cm, through biological tissues, bedding, blankets, padded mattresses, wires, sensors, and other materials found in NICU incubators, for full-coverage wireless operation in a typical scenario (fig. S15). BLE radio transmission then allows transfer of data to a personal computer, tablet computer, or smartphone with a range of up to 20 m. Connections to central monitoring systems in the hospital can then be established in a straightforward manner.

Low-modulus mechanics, soft interface adhesion, and implications for neonatal skin safety

The essential mechanics of these systems decrease risks for skin injury relative to existing clinical standards. The global incidence of skin breakdown in hospitalized neonates ranges between 31 and 45%, with medical devices and associated adhesives being a major iatrogenic cause (, ). Additionally, pressure-related skin injuries occur in 26% of hospitalized infants less than 3 months of age () with 80% directly related to medical devices, where PPG modules are the most common culprit (). By age 7, more than 90% of children born preterm (<30 weeks gestation) and previously cared for in the NICU exhibit residual scars secondary to monitoring probes, adhesives, and invasive medical interventions (). Premature neonates are particularly high-risk given that their epidermis and dermis are only 40 to 60% as thick as adult skin, with incomplete cornification, decreased mechanical strength, and greater propensity to scar (). Although all neonatal skin is susceptible to iatrogenic injury, premature neonates are especially vulnerable. At 24 to 30 weeks gestation, the epidermis is 60% as thick as it is at 36 to 40 weeks (), and it is considerably more fragile. As a result, removal of adhesives necessary for securing medical equipment poses a greater risk with greater prematurity, where up to 15% of a neonate's total skin surface area can be traumatized daily ().

The inherently thin, soft mechanical properties of the sensors ( Fig. 1A) reported here allow for adhesion via van der Waals forces alone. Effective moduli in the range of 200 to 300 kPa ( Fig. 2A) lead to minimal normal and shear stresses at the skin interface associated with natural motions of the neonate. The mechanical decoupling afforded by the microfluidic channel decreases these stresses by up to a factor of 2.5 ( Fig. 2B) relative to otherwise similar designs without the microfluidics. Experimental and theoretical studies reveal additional fundamental aspects of the soft mechanics and adhesion in these systems. Simulations that use the cohesive zone model (fig. S16) allow quantitative examination of the physics associated with removal of conventional adhesives (e.g., Argyle Hydrogel Adhesive Baby Tape Strips, Covidien) and EES devices (modeled as an effective medium; Fig. 2, C and D) from surfaces with mechanical properties reflective of neonatal skin. The differences between the magnitudes of deformations induced in the skin, at identical peel forces, are notable ( Fig. 2C). The forces at steady-state peeling rates are different by approximately a factor of ~10 ( Fig. 2D), with reduction in the maximum von Mises stress on the skin by a factor of 4.3. Experimental testing on adult skin ( Fig. 2, E and F) shows similar behavior, including a substantial reduction in peel force (~1000%; fig. S17) of an EES relative to that of a traditional adhesive. Analysis of these experimental results defines the adhesion energy at the interface between the EES and skin: G = 16 N/m.

The presence of the microfluidic channel (fig. S18) serves an important role in determining the adhesion properties of the EES, as shown in Fig. 2G. At steady state (>2 s), the peel forces ( F) with and without the microfluidics are approximately the same, consistent with a scaling relationship that depends only on G and the width of the device, W, as F = G × W (). In other words, the adhesion energy defines the steady-state peeling force. At the initiation of peeling, however, in the non-steady-state regime when the forces on the skin are most important, the cohesive strength determines the force. Specifically, the interface starts to delaminate when the normal stress reaches ~20 kPa ( Fig. 2G, inset). The microfluidic channel reduces the effective modulus of the EES and, as a consequence, increases the ability of the device to deform under applied force. The consequent reduction in the size of the cohesive zone at the delamination front (fig. S19) decreases the peel force for the same peak stress (cohesive strength).

Further reductions can be achieved by the addition of perforations through the open regions of the EES platform, as shown in fig. S20 for different patterns of holes. Figure 2H highlights the peel force, the primary driver of epidermal stripping in fragile neonatal skin (), as a function of time during peeling for a regular triangular pattern of holes (diameter D = 200 μm). The force scales with 1 - α (fig. S21)-that is, the area of contact between the EES and the skin. This scaling also applies to other patterns of holes (e.g., figs. S22 and S23 for square patterns without and with 45° rotation, respectively). For sufficiently small holes (e.g., 200 μm; see figs. S24 to S28), the relation between the peel force and time depends only on 1 - α and is approximately independent of pattern. Oscillations in the force only appear for holes larger than the characteristic size of the cohesive zone (~500 μm, as in Fig. 2I). An optimized approach to reducing interface stresses and peel forces, therefore, combines microfluidic channel structures with small perforation holes, the latter of which can be naturally accommodated within the open network designs characteristic of epidermal electronics ( Fig. 1A).

Compatibility with medical imaging techniques used in the NICU

Magnetic resonance imaging (MRI) is essential in the NICU because of its ability to deliver precise assessment of white matter, gray matter, and posterior fossa abnormalities with functional capabilities that exceed those of ultrasound (, ). The EES platforms exploit designs that minimize disturbances in the time-dependent magnetic fields associated with MRI scanning, thereby reducing distortions and shadowing artifacts in the final images and eliminating any parasitic heating from magnetically induced eddy currents. Calculations of the gradients of the magnetic field density near electrodes with different structures (mesh, solid, and commercial electrodes, see fig. S29) on biological tissues in a 3-T MRI scanner reveal the underlying effects. The results show that mesh electrodes induce the weakest disturbance to the magnetic field among mesh (layout of Fig. 1A), solid (i.e., no mesh), and commercial electrodes with similar overall sizes and geometries ( Fig. 3, A and C) for both the in-plane |∇ p B| and out-of-plane |∇ z B| gradient of the magnetic field density. The maximum value of |∇ p B| for the mesh electrode is smaller than that of the commercial electrode by a factor of ~3 ( Fig. 3E), whereas |∇ z B| is smaller by a factor of 4 ( Fig. 3F). The mesh design also has advantages in its soft, flexible mechanics and associated benefits in interfacial stresses and adhesion, as described previously. Additional simulations guide selection of designs that ensure that the resonant frequencies of the EES have no overlap with the working frequencies of typical MRI scanners (64 MHz, 128 MHz, 298 MHz, and 400 MHz for 1.5-T, 3-T, 7-T, and 9.4-T MRI scanners, respectively; Fig. 3G), thereby avoiding large gradients of the magnetic field density ( Fig. 3, B and D, and figs. S30 and S31). Similar simulations for the PPG EES indicate gradients of the magnetic field density that are smaller than those for the ECG EES (fig. S32). These features allow the devices to remain in place on neonates undergoing MRI imaging to mitigate the risks of injury and complications with removal and re-adhesion.

Experiment and simulation results also yield information on parasitic heating during an MRI scan. Full three-dimensional multi-physics modeling shows that, at the end of a single scan for 0.5 ms, the copper layer of an ECG EES undergoes heating by only 1°C ( Fig. 3H). The resultant maximum temperature change at the skin interface is 0.04°C, far below the threshold for sensation, due to the insulating effects of the polydimethylsiloxane (PDMS) and the microfluidic channel. The maximum change in temperature occurs ~0.24 s after initiating the scan ( Fig. 3H and fig. S33). This time scale is on the same order as that for heat conduction (0.1 s) in the microfluidic channel (fig. S33). Experimental measurements support these findings. Figure 3I shows the change of temperature during an MRI scan (3-T MAGNETOM Prisma, Siemens Healthineers), measured on a sample of phantom skin (designed to match the conductivity and dielectric constant of tissue at 33 MHz) at a location underneath the ECG EES near the loop antenna and adjacent to the device. The results show a temperature difference of ~0.1°C. Figure 3J presents measurements in the middle region of the ECG EES where the values of |∇ z B| and |∇ p B| are comparable to those for bare phantom skin. Simulation results for the PPG EES suggest even smaller changes in temperature than those for the ECG EES (fig. S34). Additional testing with another MRI system (9.4-T Bruker Biospec MRI system, Bruker BioSpin Corporation) and an ECG EES placed over cadaveric rat tissue ( Fig. 4A) shows no observable magnetically induced displacement forces or torques and no measurable changes in temperature. The results meet FDA requirements for an "MRI-safe" label for medical devices (). Imaging results indicate that the ECG EES causes less shadowing and image distortion compared to a conventional NICU ECG electrode ( Fig. 4B).

The EES eliminates radio-opaque wires, thereby improving evaluation by x-ray imaging, a modality required for 90% of low-birth weight neonates (). Experimental results show that an ECG EES placed over the same tissue in a rodent model imaged using a computed tomography/x-ray system (nanoScan PET/CT, Mediso) exhibits improved radiolucency in comparison to standard ECG electrodes and wires ( Fig. 4, C and D). The optical transparency of the silicone and the open mesh designs of the electronics and antenna structures also provide direct visual access to the skin and tissue beneath the sensor (fig. S35), thereby obviating the need to remove the sensor to monitor the underlying skin for signs of infection or irritation.

Real-time measurements, in-sensor analytics, and data transmission

Exploiting this collection of attractive electronic, mechanical, and radiolucent properties for practical use in a NICU environment requires in-sensor processing and data analytics to reduce bandwidth requirements on wireless transmission and to ensure operational robustness. For example, computational facilities on the NFC SoC of the ECG EES can support a streamlined version of the Pan-Tompkins algorithm () for accurate, on-board analysis of the QRS complex of ECG signals in real-time to yield HR and HRV on a beat-to-beat basis. Figure 5A summarizes an approach that starts with digital bandpass filtering ( f c1 = 5 Hz, f c2 = 15 Hz) to attenuate the noise. Differentiating and squaring the resulting data yields the slope of QRS peaks and prevents false peak detection associated with the T wave. Applying a moving average and a dynamic threshold identifies a running estimate of the R peak and the magnitude of the noise. Automatic adjustments of the threshold rely on these estimates for the preceding beat cycle (fig. S36). The R-to-R intervals determined in this way yield the instantaneous HR. Simultaneous recordings obtained using a clinical-standard system, henceforth referred to as "gold standard" data, validate the ECG EES module hardware and in-sensor analytics via measurements on a healthy adult volunteer ( Fig. 5, B and C). The ECG signals and computed HR values from these two platforms show no measurable differences. Periodic modulations of the amplitude of the R peak define the RR ( Fig. 5D), which also agrees with the gold standard (visual counting by a physician in this case; Fig. 5E).

Measurements of skin temperature rely on sensors internal to the NFC SoC in each EES, where transmission at a sampling frequency of 1 Hz is sufficient for monitoring purposes. The low thermal mass of the EES and the small thickness of the substrate layer (PDMS; 50 μm in thickness) that separates the SoC from the skin ensure fast thermal response times and excellent thermal coupling, respectively. Comparisons against readings from a thermometer (Fisherbrand 13202376, Fisher Scientific) serve as means to calibrate the sensor ( Fig. 5F) via testing in a water bath (fig. S37). Thermal images captured with an IR camera (FLIR A325SC, FLIR Systems) during operation indicate negligible heating associated with the electronics or the antenna structures ( Fig. 5G). Figure 5H shows temperature readings from the ECG EES for 60 s. Comparison tests of this system against FDA-cleared monitoring equipment (Dash 3000, GE Healthcare) on healthy adult volunteers ( n = 3) show excellent agreement for HR (mean difference = 0.1 bpm, SD = 2.55 bpm) and RR (mean difference = 0.3 bpm, SD = 0.95 bpm) as shown in Fig. 5, I and J, respectively.

The PPG EES relies on similar NFC protocols, but with in-sensor analytic methods that not only reduce requirements on transmission bandwidth but also provide, when used in conjunction with adaptive circuits, crucial functionality for stable operation. Specifically, the processing in this case enables (i) dynamic baseline control to ensure that the input to the ADC on the NFC SoC lies within the linear response range and (ii) real-time calculation of SpO ₂ from the PPG traces ( Fig. 6A). Here, the processing begins with application of a moving-average filter to the photodetector response from the red and IR LEDs. When the larger of these two averaged PPG amplitudes (typically that associated with the IR response) lies outside of a range that is optimal for the ADC (0.25 to 0.7 V), a programmable difference amplifier with voltage dividers at V₊ dynamically adjusts the baseline level. The circuit shown in Fig. 6B demonstrates the operation where the governing equation is where V tr is the voltage output of the amplifier, V pre is the voltage of the input signal, R s is the input resistance, and R f is the feedback resistance. The voltage divider at V₊ with resistors R d1 and R d2 is governed by the following equation with V ref = 1.8 V:Sixteen different baseline states can be accessed via activation of binary values from four general-purpose input-output pins (GPIOs; a ₀, a ₁, a ₂, a ₃) on the SoC (fig. S38), applied through an R-2R resistor ladder. Figure 6C shows dynamic control of the output voltage V tr of a sinusoidal input signal (frequency = 50 mHz, amplitude = 40 mV, V offset = -30 mV). Starting with the default setting of the GPIO ports ( a ₀, a ₁, a ₂, a ₃; all high, or 1111), the baseline level automatically adjusts to lower levels associated as the value of V tr drifts above the upper boundary of the specified voltage range, and vice versa as V tr falls below the lower boundary. The result maintains V tr in the allowed range. Figure 6D summarizes the operation in an actual PPG recording. Without this type of real-time, in-sensor processing (IR_Non in Fig. 6D), robust operation would be impossible: PPG signals would quickly drift outside of the narrow operating range of the ADC as a result of patient-to-patient variations in skin pigmentation and unavoidable, time-dependent fluctuations in optical scattering that result from micromotions relative to underlying blood vessels and subdermal structures ().

Calculating SpO ₂ involves determining the ratio ( R oa) between the alternating and direct components of the PPG signals according to

for data from the red and IR LEDs ( Fig. 6E). An empirical calibration formula determined by comparison to an FDA-cleared fingertip oximeter measurement (MightySat Fingertip Oximeter, Masimo) converts the R oa to SpO ₂ ( Fig. 6F). Time-dependent variations of SpO ₂ determined in this manner appear in Fig. 6G with demonstration in a decrease with a breath hold in an adult volunteer.

The time-synchronized outputs from the ECG EES and the PPG EES allow for determination of advanced physiological parameters that are of high clinical value but not regularly collected in routine practice in NICUs. A key example is the measurement of pulse arrival time (PAT), defined by the time lapse between the maximum fiducial point in the ECG signal (R peak) and the corresponding minimal fiducial point in the PPG signal at valley as in Fig. 6H, as a direct correlate to systolic blood pressure (, ). Blood pressure is an essential physiological marker of perfusion, autonomic function, and vascular tone for critically ill newborns (). Cuff-based blood pressure measurements with sphygmomanometers fail to provide continuous measurement, overestimate blood pressure in premature neonates (), and pose a direct risk for pressure-related injuries (). Although arterial lines offer a continuous measurement of blood pressure in neonates, these invasive interventions can cause thrombosis, hematomas, infection, and even death (). Thus, the ability to capture PAT noninvasively and continuously would be of high clinical value in the NICU, with prior reports providing evidence that PAT correlates with blood pressure in infants (-).

The Moens-Korteweg equation provides a linear relationship between PAT and BP (, ). Measurements of 1/PAT performed in processing of ECG and PPG data in the host (fig. S39), together with corresponding values of systolic BP captured using a sphygmomanometer on a healthy adult during a period of rest after exercising (running at 6 miles per hour for 15 min), exhibit the expected linear relationship ( Fig. 6I). A calibration plot with a linear fit is shown in Fig. 6J. The binodal configuration of the system naturally yields not only a surrogate marker of BP but also temperatures at two different locations (trunk and limb), to improve monitoring for hypothermia and provide a noninvasive method to track peripheral perfusion. In current clinical practice, measurements of skin temperature are typically limited to a single body location because of the need to minimize wired connections and adhesive interfaces to the skin. Comparison tests of this system against FDA-cleared monitoring equipment (Dash 3000, GE Healthcare) on healthy adult volunteers ( n = 3) show excellent agreement for SpO ₂ (mean difference = 0.3%, SD = 1.37%) as shown in Fig. 6K. Figure 6L illustrates the ability of an ECG EES and a PPG EES to capture differential skin temperature between the torso and peripheral limbs.

Pilot studies in neonatal intensive care units and validation against clinical standards

Preliminary testing of the EES system in both healthy neonates and premature infants in two tertiary-level NICUs demonstrates feasibility and measurement validity. Shown in Fig. 7, A to C, is a healthy term neonate with an ECG EES and a PPG EES mounted on the chest and the foot, respectively, where van der Waals forces govern the mechanical interface to the skin, with minimal mechanical, mass, or thermal load ( Fig. 7A; gestational age, 38 weeks 3 days; birth weight 2.75 kg). The silicone encapsulation also enables reliable operation of the systems when completely immersed in water (fig. S1), thereby supporting compatibility with NICU incubators commonly set at humidity above 80% to maintain temperature homeostasis and prevent dehydration in premature neonates ().

Figure 7B illustrates the use in a mode that facilitates physical contact between parent and neonate, which is difficult to replicate with hard-wired conventional systems. Figure 7C shows an alternative mounting location, where the ECG EES resides on the back of the neonate to facilitate chest-to-chest skin interaction, while highlighting the intimate contact with the skin, even while naturally deformed and wrinkled. In Fig. 7, D and E, the sensor system is on a neonate admitted in the NICU, highlighting intimate contact of the ECG EES to the skin, even with motion and position adjustment. An additional example of skin-to-skin contact in a chest-to-chest position is shown in Fig. 7E, with the PPG EES on the upper limb to illustrate another option for placement. Representative results of continuous recordings are shown in Fig. 7F for the neonate in Fig. 7A. Calculated HR, SpO ₂, and RR from the experimental system are consistent with measurements obtained from gold-standard equipment operating concomitantly (Intellivue MX800, Philips). The temperature and PAT data appear alone because of the absence of a comparator system ( Fig. 7G).

Further validation studies involve deployment on neonates ( n = 3) ranging in gestational age from 28 to 40 weeks admitted to the NICU with synchronous, concomitant measurements from standard-of-care monitors (Intellivue MX800, Philips; table S1). The resultant data show strong agreement in HR, RR, and SpO ₂ ( Fig. 8, A to C). The mean difference is -0.17 beats per minute for HR, 0.76 breaths per minute for respiratory rate, and 1.02% for SpO ₂. Advanced physiological parameters such as PAT and continuous differential skin temperature are also shown ( Fig. 8, D to G). Additional studies in n = 18 neonates admitted to the NICU with gestational ages as low as 28 weeks and weights as low as 1470 g, using related device platforms with onboard power supplies to facilitate testing, further validate the operation and applicability across a larger cohort of subjects (fig. S40 and table S1) with similar performance relative to gold-standard monitoring equipment (Intellivue MX800, Philips).

Beyond efficacy and safety, the eventual diffusion of medical technologies depends on economic considerations. Table S2 outlines the cost structures associated with all aspects of device construction, including components, fabrication processing fees, and encapsulation materials. The results suggest costs (ECG EES or PPG EES) of less than $20 USD per unit at scaled production. Full compatibility with autoclave sterilization (2540E, Heidolph) enables safe reuse (fig. S41) and further improved economics, with potential to facilitate deployment in low- and middle-income countries in the context of global health.

Conclusion

The results presented here represent preliminary feasibility testing and validation of this system for use in NICUs. Comprehensive clinical studies, which are ongoing, will yield additional supporting data to verify the measurements across an increased range of age groups and ethnic backgrounds. These findings will also accelerate efforts to address any remaining challenges, including those potentially related to nursing acceptance, compatibility with legacy monitoring systems, and device sterilization for reuse. For clinical work, additional testing will assess the utility of these platforms in other clinical indications, including those associated with subjects who have altered skin barrier function (e.g., burn victims or patients with epidermolysis bullosa).

The results reported here follow from a collection of advances in engineering science to establish the basis for a wireless, skin-like technology that not only reproduces comprehensive vital signs monitoring capabilities currently provided by invasive, wired systems but also adds multipoint sensing of temperature and continuous tracking of blood pressure. These sensors explicitly address the needs of the NICU because of their high mechanical compliance and noninvasive skin adhesive interface, their water resistance, and their compatibility with essential medical imaging and inspection. In addition to advanced capabilities in monitoring, the skin-like profiles and fully wireless operational modes offer direct therapeutic value by reducing the barriers for skin-to-skin contact between parent and child. Further clinical validation and testing may lead to broad adoption in both high-resource and low-resource settings.

Acknowledgments: We thank C. Shen for helpful comments, and B. S. Hopkins and E. Dunne for subject recruitment. Funding: Supported by Bill & Melinda Gates Foundation grants PP1182909 and OPP1193311 (D.E.W.-M., A.H., C.M.R., R.G., S.X., and J.A.R.); the Gerber Foundation (D.E.W.-M., A.H., C.M.R., R.G., and J.A.R.); the Friends of Prentice Foundation (A.S.P., S.X., and J.A.R.); RIE2020 AME Programmatic Grant A18A1b0045 funded by A*STAR-SERC, Singapore (Z.L.); National Natural Science Foundation of China grants 11402134 and 11320101001; National Basic Research Program of China grant 2015CB351900; NSF grants 1534120 and 1635443; and Future Growth Engine Program grant 10079974 funded by the Ministry of Trade, Industry & Energy (MOTIE, South Korea). The materials and engineering efforts were supported by the Center for Bio-Integrated Electronics of the Simpson Querrey Institute at Northwestern University. The in-sensor algorithm development part of this work was supported in part by Systems on Nanoscale Information Fabrics (SONIC), one of the six Semiconductor Research Corporation (SRC) STARnet Centers sponsored by Microelectronics Advanced Research Corporation (MARCO) and Defense Advanced Research Projects Agency (DARPA). This work utilized Northwestern University Micro/Nano Fabrication Facility (NUFAB), which is partially supported by Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205), the Materials Research Science and Engineering Center (DMR-1720139), the State of Illinois, and Northwestern University. We also acknowledge the Beckman Institute, CAMI, MRL, and NUANCE facilities. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material. Author contributions: A.S.P., S.X., D.E.W.-M., A.H., Y.H., and J.A.R. conceived of the overall research goals and aims; H.U.C., B.H.K., J.L., Z.X., K.H.L., A.B., J.Y.J., J.K., Y.Y., H.J., D.R., J.W.K., M.N., Y.L., D.H.K., A.R., J.J., K.Y., K.-I.J., J.K., R.G., S.M.L., and C.H.L. were responsible for formal analysis, engineering investigation and methodology, and manufacturing for the sensors; H.U.C., J.Y.L., C.O., D.G., P.A., D.R., J.B.P., S.M.L., and N.R.S. performed software design, software validation, signal processing, and data analysis; Z.X., B.J., Z.L., Q.H., X.F., Y.D., Y.X., Y.Z., and Y.H. performed the structural designs and the mechanical, electromagnetic, and thermal analysis; E.M.I., C.M.R., M.S., A.H., D.E.W.-M., A.S.P., and S.X. were responsible for human data collection and analysis; H.U.C., J.Y.L., and S.X. conducted the statistical analyses; A.S.P., D.E.W.-M., R.G., and J.A.R. were responsible for funding acquisition; H.U.C., B.H.K., J.Y.L., J.L., Z.X., A.S.P., S.X., Y.H., and J.A.R. were responsible for original drafting of the manuscript; and all authors assisted in critical editing and review of the final manuscript. Competing interests: H.U.C., B.H.K., J.Y.L., J.L., K.L., S.X., and J.A.R. are inventors on a patent application (U.S. 62/753,303) submitted by Northwestern University and the University of Illinois. H.U.C., S.X., and J.A.R. declare equity ownership in a company that is pursuing commercialization of the technology described here. J.A.R. also declares an advisory role with this company. Data and materials availability: All data are available in the manuscript or the supplementary materials.

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Binodal, wireless epidermal electronic systems with in-sensor analytics for neonatal intensive care

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Neonatal care, particularly for premature babies, is complicated by the infants' fragility and by the need for a large number of tethered sensors to be attached to their tiny bodies. Chung et al. developed a pair of sensors that only require water to adhere to the skin and allow for untethered monitoring of key vital signs (see the Perspective by Guinsburg).

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- more accessibility to hold infants
- gentler on fragile premature skin
- more data is able to be captured which can have great implications for further research and subsequent care of these fragile infants.  (limited stimulation is also a high priority for preterm infants, so having a way to capture vital signs without having to go into their isolette or touch them is very exciting)
- can reduce parental stress (leading to positive implications for postpartum depression and attachment)

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- changing systems (since the current way of capturing vital signs hasn't changed in decades, this will be a huge undertaking)
- educating nurses and physicians on a new technology
- cost (not only the cost of the new technology, but also the cost of education as well as implementing the correct monitoring systems to display the data captured by this device)
-bugs of new technology (all new technology will have growing pains while in its rolling out phase)

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Mother exhibiting struggles around having cords attached to her baby

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Mother exhibiting struggles around having cords attached to her baby

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photograph by Alyssa Schukar

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Sensors are first to monitor babies in the NICU

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Benefits of Skin to Skin (Kangaroo care)

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Benefits of Skin to Skin (Kangaroo care)

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- helps baby regulate temperature (which can also stabilize blood sugars)
- babies have been shown to have more stable heart rates and breathing, and higher blood oxygenation
- helps create a bond between mother and infant (long term attachment implications)
- helps the infants immune system
-Can have a positive impact on infant weight gain (and improve nutrient absorption)

- helps moms milk supply
- improves moms breastfeeding experience
- linked to lower rates of postpartum depression and postpartum bleeding
- fathers and other parents can also have benefits related to bonding

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John Rogers, PhD (Center for Bio- Integrated Electronics)

Amy Paller, MD (Pediatric Dermatology)

Shaui (Steve) Xu, MD, MSc (Dermatology)

Aaron Hamvas, MD (Neonatology)

Debra Weese- Mayer, MD (Pediatrics)

Yonggang Huang, PhD (Department of Materials Science and Engineering)

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Having seen first hand the frustration amid new NICU parents, and also being the one to help new parents do kangaroo care, the use of these monitors would be very helpful and beneficial.  Parents would feel more comfortable with the care of their infant which can have long term implications for parenting and attachment.  Even as an experienced NICU nurse, all the cords and wires make helping parents do skin to skin difficult at times, and even eliminating just a few of those wires would be very helpful.  Given the benefit of more vital signs being captured, this would allow more information that could guide the care given to the infants.  Finally, I think that this is the technology of the future and it would be important to overcome the cost of changing systems sooner rather than later given the benefits.  All new technology implementation will have an initial cost, but in the end this will have great benefits and implications for improved care. In addition, although staff pushback may be present, it is important to work to overcome this for the benefit of the infants.

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Chung, H. U., Kim, B. H., Lee, J. Y., Lee, J., Xie, Z., Ibler, E. M., Lee, K., Banks, A., Jeong, J. Y., Kim, J., Ogle, C., Grande, D., Yu, Y., Jang, H., Assem, P., Ryu, D., Kwak, J. W., Namkoong, M., Park, J. B., … Rogers, J. A. (2019). Binodal, wireless epidermal electronic systems with in-sensor analytics for neonatal intensive care. Science, 363(6430). https://doi.org/10.1126/science.aau0780

Medgadget Editors. (2020, March 11). Advanced Wireless Neonatal Body Monitors to Improve Outcomes. In MedGadget. Retrieved from https://www.medgadget.com/2020/03/advanced-wireless-neonatal-body-monitors-to-improve-outcomes.html

Morris, A. (2019, February 28). Groundbreaking Sensors Wirelessly Monitor Babies in the NICU. In Northwestern Medicine. Retrieved from https://news.feinberg.northwestern.edu/2019/02/groundbreaking-sensors-monitor-babies-in-the-nicu-wirelessly/

Morris, A. (2019, February 28). No wires, more cuddles. In Northwestern University. Retrieved from https://news.northwestern.edu/stories/2019/02/wireless-body-sensors-premature-babies-nicu/

Seitz, J. (2017, July 18). The importance of skin-to-skin with baby after delivery. In Sanford Health. Retrieved from https://news.sanfordhealth.org/childrens/the-importance-of-skin-to-skin-after-delivery-you-should-know/

Slattery, C. (2017, January 18). Skin-to-skin contact safe for vulnerable premature babies, research shows. In ABC News. Retrieved from https://www.abc.net.au/news/2017-01-19/skin-to-skin-contact-safe-for-premature-babies,-research-shows/8193226

Zuckerman, C. (2019, February 28). Parents can better cuddle premature babies thanks to tiny new sensors. In National Geographic. Retrieved from https://www.nationalgeographic.com/science/2019/02/parents-can-better-cuddle-premature-babies-with-new-wireless-sensors/

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photograph by Royal Women's Hositpal

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My top five strengths are harmony, analytical, responsibility, deliberative, and consistency.

In addition to my strengths, I would add the following people to my team to help implement this new technology.

Amelia’s top strength is adaptability, which would be very beneficial to help us figure out how to transition the unit to wireless monitoring.  Amelia could lead by example by easily implementing this new technology.

Abraham’s top strength is arranger, which would be helpful when trying to guide the implantation process, figuring out who needs to be contacted and figuring out the process in which to do this.  He would be able to create a plan and structure with the appropriate point people throughout the process.

Fernando’s top strength is focus, which would help us stay on track and get our goals done.  He would make sure that any changes to the plan would be made and we would use Amelia to help us adapt as complications may arise.

Pablo’s top strength is positivity, which is going to be helpful when it comes to getting staff on board with this change.  Like I stated, the current technology has been used for decades, so we have to find a way to engage and get the staff excited about this major change to their workflow.

Finally, Sheila’s top strength is strategic, which would work well with Abraham to help create the plan and then work with Amelia when trying to solve any problems that may arise during the implementation process.