foundations for this technology: (i) schemes for wireless power transfer, low-noise sensing, and high-speed data communications via a single radio-frequency link with negligible absorption in biological tissues; (ii) efficient algorithms for real-time data analytics, signal processing, and dynamic baseline modulation implemented on the sensor platforms themselves; (iii) strategies for time-synchronized streaming of wireless data from two separate devices; and (iv) designs that enable visual inspection of the skin interface while also allowing magnetic resonance imaging and x-ray imaging of the neonate. The resulting systems can be much smaller in size, lighter in weight, and less traumatic to the skin than any existing alternative. RESULTS: We report the realization of this class of NICU monitoring technology, embodied as a pair of devices that, when used in a timesynchronized fashion, can reconstruct full vital signs information with clinical-grade precision. One device mounts on the chest to capture electrocardiograms (ECGs); the other rests on the base of the foot to simultaneously record photoplethysmograms (PPGs). This binodal system captures and continuously transmits ECG, PPG, and (from each device) skin temperature data, yielding measurements of heart rate, heart rate variability, respiration rate, blood oxygenation, and pulse arrival time as a surrogate of systolic blood pressure. Successful tests on neonates with gestational ages ranging from 28 weeks to full term demonstrate the full range of functions in two level III NICUs. The thin, lightweight, low-modulus characteristics of these wireless devices allow for interfaces to the skin mediated by forces that are nearly an order of magnitude smaller than those associated with adhesives used for conventional hardware in the NICU. This reduction greatly lowers the potential for iatrogenic injuries. CONCLUSION: The advances outlined here serve as the basis for a skin-like technology that not only reproduces capabilities currently provided by invasive, wired systems as the standard of care, but also offers multipoint sensing of temperature and continuous tracking of blood pressure, all with substantially safer device-skin interfaces and compatibility with medical imaging. By eliminating wired connections, these platforms also facilitate therapeutic skin-to-skin contact between neonates and parents, which is known to stabilize vital signs, reduce morbidity, and promote parental bonding. Beyond use in advanced hospital settings, these systems also offer costeffective capabilities with potential relevance to global health.▪ RES The list of author affiliations is available in the full article online. *These authors contributed equally to this work. †Corresponding author. Email: apaller@northwestern.edu (A.S.P.); stevexu@northwestern.edu (S.X.); jrogers@ northwestern.edu (J.A.R.) This is an open-access article distributed under the terms of the Creative Commons Attribution license (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cite this article as H. U. Chung et al., Science 363, eaau0780 (2019). DOI: 10.1126/science.aau0780 A B C D ECG PPG 1 cm 1 cm 3 cm 5 cm 5 cm Wireless, skin-like systems for vital signs monitoring in neonatal intensive care. (A) Images and finite-element modeling results for ECG and PPG devices bent around glass cylinders. (B) A neonate with an ECG device on the chest. (C and D) A mother holding her infant with a PPG device on the foot and an ECG device on the chest (C) and on the back (D). ON OUR WEBSITE ◥ Read the full article at http://dx.doi. org/10.1126/ science.aau0780 .................................................. Downloaded from https://www.science.org on July 15, 2022 RESEARCH ARTICLE ◥ BIOMEDICINE Binodal, wireless epidermal electronic systems with in-sensor analytics for neonatal intensive care Ha Uk Chung1,2*, Bong Hoon Kim1,3,4,5*, Jong Yoon Lee4,6*, Jungyup Lee4 *, Zhaoqian Xie3,7,8*, Erin M. Ibler9,10, KunHyuck Lee1,3, Anthony Banks1,4,5,11, Ji Yoon Jeong4 , Jongwon Kim3,12, Christopher Ogle1,5, Dominic Grande4,6, Yongjoon Yu4 , Hokyung Jang4 , Pourya Assem6 , Dennis Ryu1,5, Jean Won Kwak1,8, Myeong Namkoong1,13, Jun Bin Park4 , Yechan Lee4 , Do Hoon Kim4 , Arin Ryu4 , Jaeseok Jeong4 , Kevin You4 , Bowen Ji3,7,8,14, Zhuangjian Liu15, Qingze Huo3,7,8, Xue Feng16, Yujun Deng7,17, Yeshou Xu7,18, Kyung-In Jang19, Jeonghyun Kim20, Yihui Zhang16, Roozbeh Ghaffari1,5,13, Casey M. Rand10,21, Molly Schau22, Aaron Hamvas21,22,23, Debra E. Weese-Mayer10,21,23, Yonggang Huang3,5,7,8, Seung Min Lee24, Chi Hwan Lee25, Naresh R. Shanbhag6 , Amy S. Paller5,9,23†, Shuai Xu1,5,9†, John A. Rogers1,3,4,5,8,13,26,27† 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. C ontinuous recording and real-time graphical display of vital signs are essential for critical care. Each year in the United States, approximately 300,000 neonates, including a large fraction with exceptionally fragile health due to severe prematurity and very low birth weight (<1500 g), are admitted to neonatal intensive care units (NICUs) (1). Existing monitoring systems for the NICU require multiple electrode/sensor interfaces to the skin, with hardwired connections to separately located base units that may be stand-alone or wall-mounted, for heart rate (HR), respiratory rate (RR), temperature, blood oxygenation (SpO2), and blood pressure (BP). Although such technologies are essential to clinical care, the associated web of wires complicates even the most basic bedside tasks, such as turning a neonate from prone to supine. This hardware also interferes with emergency clinical interventions and radiological studies, and impedes therapeutic skin-to-skin contact (colloquially known as kangaroo mother care) between parents and their infant. Moreover, the adhesives that couple these wired electrodes to the fragile skin of the neonates are a frequent cause of iatrogenic injuries and subsequent scarring (2–4). A fully wireless alternative that eliminates mechanical stresses and potentially reduces injury risk, and that deploys effectively on the full range of gestational ages encountered in the NICU, would represent a substantial advance over the existing standard of care. Although textile-based sensors are of interest, these technologies retain wired connections across the body, and their inability to support an intimate connection to the skin precludes reliable operation at clinical-grade levels of accuracy, particularly with motion (5–7). Recent advances in materials science and biomedical engineering serve as the basis for devices that have a skin-like form factor. Although such systems can support various types of biophysical measurements of physiological health (8–13), additional advances are needed to meet the challenging requirements of the NICU, where comprehensive, continuous sensing with wireless functionality, clinical-grade measurement fidelity, and mechanical form factors that eliminate risk of harm to exceptionally fragile neonatal skin are essential. We have developed a wireless, battery-free vital signs monitoring system that exploits a binodal pair of ultrathin, low-modulus measurement modules, each referred to as an epidermal electronic system (EES), capable of softly and noninvasively interfacing onto neonatal skin. Successful pilot-phase demonstrations on neonates with gestational ages ranging from 28 weeks to full term in two tertiary-level NICUs have established quantitative equivalency to clinical standards. 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 mm in width, 5 mm 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 RESEARCH Chung et al., Science 363, eaau0780 (2019) 1 March 2019 1 of 12 1 Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA. 2 Department of Electrical Engineering and Computer Science, Northwestern University, Evanston, IL 60208, USA. 3 Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA. 4 Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. 5 Center for Bio-integrated Electronics, Northwestern University, Evanston, IL 60208, USA. 6 Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. 7 Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, USA. 8 Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, USA. 9 Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. 10Center for Autonomic Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA. 11Loomis Laboratory of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. 12Department of Mechanical Engineering, Kyung Hee University, Yongin 17104, Republic of Korea. 13Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA. 14Department of Micro/Nano Electronics, Shanghai Jiao Tong University, Shanghai 200240, China. 15Institute of High Performance Computing, A*Star, 138632 Singapore. 16Applied Mechanics Laboratory, Department of Engineering Mechanics, Center for Mechanics and Materials, Center for Flexible Electronics Technology, Tsinghua University, Beijing 100084, China. 17State Key Laboratory of Mechanical System and Vibration, Shanghai Jiao Tong University, Shanghai 200240, China. 18Key Laboratory of C&PC Structures of the Ministry of Education, Southeast University, Nanjing 2100096, China. 19Department of Robotics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea. 20Department of Electronics Convergence Engineering, Kwangwoon University, Seoul 01897, Republic of Korea. 21Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA. 22Division of Neonatology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA. 23Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA. 24Department of Energy Electronics Convergence, Kookmin University, Seoul 02707, Republic of Korea. 25Weldon School of Biomedical Engineering, School of Mechanical Engineering, Center for Implantable Devices, and Birck Nanotechnology Center, Purdue University, West Lafayette, IN 47907, USA. 26Department of Chemistry, Northwestern University, Evanston, IL 60208, USA. 27Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. *These authors contributed equally to this work. †Corresponding author. Email: apaller@northwestern.edu (A.S.P.); stevexu@northwestern.edu (S.X.); jrogers@northwestern.edu (J.A.R.) Downloaded from https://www.science.org on July 15, 2022 between the interconnected components and the skin (14). 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 (14). (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, SpO2, 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