Protocol for a randomized controlled trial to evaluate a year-long (NICU-to-home) evidence-based, high dose physical therapy intervention in infants at risk of neuromotor delay.

INTRODUCTION: Developmental disabilities and neuromotor delay adversely affect long-term neuromuscular function and quality of life. Current evidence suggests that early therapeutic intervention reduces the severity of motor delay by harnessing neuroplastic potential during infancy. To date, most early therapeutic intervention trials are of limited duration and do not begin soon after birth and thus do not take full advantage of early neuroplasticity. The Corbett Ryan-Northwestern-Shirley Ryan AbilityLab-Lurie Children's Infant Early Detection, Intervention and Prevention Project (Project Corbett Ryan) is a multi-site longitudinal randomized controlled trial to evaluate the efficacy of an evidence-based physical therapy intervention initiated in the neonatal intensive care unit (NICU) and continuing to 12 months of age (corrected when applicable). The study integrates five key principles: active learning, environmental enrichment, caregiver engagement, a strengths-based approach, and high dosage (ClinicalTrials.gov identifier NCT05568264). METHODS: We will recruit 192 infants at risk for neuromotor delay who were admitted to the NICU. Infants will be randomized to either a standard-of-care group or an intervention group; infants in both groups will have access to standard-of-care services. The intervention is initiated in the NICU and continues in the infant's home until 12 months of age. Participants will receive twice-weekly physical therapy sessions and caregiver-guided daily activities, assigned by the therapist, targeting collaboratively identified goals. We will use various standardized clinical assessments (General Movement Assessment; Bayley Scales of Infant and Toddler Development, 4th Edition (Bayley-4); Test of Infant Motor Performance; Pediatric Quality of Life Inventory Family Impact Module; Alberta Infant Motor Scale; Neurological, Sensory, Motor, Developmental Assessment; Hammersmith Infant Neurological Examination) as well as novel technology-based tools (wearable sensors, video-based pose estimation) to evaluate neuromotor status and development throughout the course of the study. The primary outcome is the Bayley-4 motor score at 12 months; we will compare scores in infants receiving the intervention vs. standard-of-care therapy.

Advances in Bioresorbable Materials and Electronics.

Transient electronic systems represent an emerging class of technology that is defined by an ability to fully or partially dissolve, disintegrate, or otherwise disappear at controlled rates or triggered times through engineered chemical or physical processes after a required period of operation. This review highlights recent advances in materials chemistry that serve as the foundations for a subclass of transient electronics, bioresorbable electronics, that is characterized by an ability to resorb (or, equivalently, to absorb) in a biological environment. The primary use cases are in systems designed to insert into the human body, to provide sensing and/or therapeutic functions for timeframes aligned with natural biological processes. Mechanisms of bioresorption then harmlessly eliminate the devices, and their associated load on and risk to the patient, without the need of secondary removal surgeries. The core content focuses on the chemistry of the enabling electronic materials, spanning organic and inorganic compounds to hybrids and composites, along with their mechanisms of chemical reaction in biological environments. Following discussions highlight the use of these materials in bioresorbable electronic components, sensors, power supplies, and in integrated diagnostic and therapeutic systems formed using specialized methods for fabrication and assembly. A concluding section summarizes opportunities for future research.

Implantable bioelectronic systems for early detection of kidney transplant rejection.

Early-stage organ transplant rejection can be difficult to detect. Percutaneous biopsies occur infrequently and are risky, and measuring biomarker levels in blood can lead to false-negative and -positive outcomes. We developed an implantable bioelectronic system capable of continuous, real-time, long-term monitoring of the local temperature and thermal conductivity of a kidney for detecting inflammatory processes associated with graft rejection, as demonstrated in rat models. The system detects ultradian rhythms, disruption of the circadian cycle, and/or a rise in kidney temperature. These provide warning signs of acute kidney transplant rejection that precede changes in blood serum creatinine/urea nitrogen by 2 to 3 weeks and approximately 3 days for cases of discontinued and absent administration of immunosuppressive therapy, respectively.

3D-printed epidermal sweat microfluidic systems with integrated microcuvettes for precise spectroscopic and fluorometric biochemical assays.

Systems for capture, storage and analysis of eccrine sweat can provide insights into physiological health status, quantify losses of water, electrolytes, amino acids and/or other essential species, and identify exposures to adverse environmental species or illicit drugs. Recent advances in materials and device designs serve as the basis for skin-compatible classes of microfluidic platforms and in situ colorimetric assays for precise assessments of sweat rate, sweat loss and concentrations of wide-ranging types of biomarkers in sweat. This paper presents a set of findings that enhances the performance of these systems through the use of microfluidic networks, integrated valves and microscale optical cuvettes formed by three dimensional printing in hard/soft hybrid materials systems, for accurate spectroscopic and fluorometric assays. Field studies demonstrate the capability of these microcuvette systems to evaluate the concentrations of copper, chloride, and glucose in sweat, along with the pH of sweat, with laboratory-grade accuracy and sensitivity.

A Sewing Approach to the Fabrication of Eco/bioresorbable Electronics.

Eco/bioresorbable electronics represent an emerging class of technology defined by an ability to dissolve or otherwise harmlessly disappear in environmental or biological surroundings after a period of stable operation. The resulting devices provide unique capabilities as temporary biomedical implants, environmental sensors, and related systems. Recent publications report schemes to overcome challenges in fabrication that follow from the low thermostability and/or high chemical reactivity of the eco/bioresorbable constituent materials. Here, this work reports the use of high-speed sewing machines, as the basis for a high-throughput manufacturing technique that addresses many requirements for these applications, without the need for high temperatures or reactive solvents. Results demonstrate that a range of eco/bioresorbable metal wires and polymer threads can be embroidered into complex, user-defined conductive patterns on eco/bioresorbable substrates. Functional electronic components, such as stretchable interconnects and antennas are possible, along with fully integrated systems. Examples of the latter include wirelessly powered light-emitting diodes, radiofrequency identification tags, and temporary cardiac pacemakers. These advances add to a growing range of options in high-throughput, automated fabrication of eco/bioresorbable electronics.

Materials and Design Approaches for a Fully Bioresorbable, Electrically Conductive and Mechanically Compliant Cardiac Patch Technology.

Myocardial infarction (MI) is one of the leading causes of death and disability. Recently developed cardiac patches provide mechanical support and additional conductive paths to promote electrical signal propagation in the MI area to synchronize cardiac excitation and contraction. Cardiac patches based on conductive polymers offer attractive features; however, the modest levels of elasticity and high impedance interfaces limit their mechanical and electrical performance. These structures also operate as permanent implants, even in cases where their utility is limited to the healing period of tissue damaged by the MI. The work presented here introduces a highly conductive cardiac patch that combines bioresorbable metals and polymers together in a hybrid material structure configured in a thin serpentine geometry that yields elastic mechanical properties. Finite element analysis guides optimized choices of layouts in these systems. Regular and synchronous contraction of human induced pluripotent stem cell-derived cardiomyocytes on the cardiac patch and ex vivo studies offer insights into the essential properties and the bio-interface. These results provide additional options in the design of cardiac patches to treat MI and other cardiac disorders.

A Miniaturized, Battery-Free, Wireless Wound Monitor That Predicts Wound Closure Rate Early.

Diabetic foot ulcers are chronic wounds that affect millions and increase the risk of amputation and mortality, highlighting the critical need for their early detection. Recent demonstrations of wearable sensors enable real-time wound assessment, but they rely on bulky electronics, making them difficult to interface with wounds. Herein, a miniaturized, wireless, battery-free wound monitor that measures lactate in real-time and seamlessly integrates with bandages for conformal attachment to the wound bed is introduced. Lactate is selected due to its multifaceted role in initiating healing. Studies in healthy and diabetic mice reveal distinct lactate profiles for normal and impaired healing wounds. A mathematical model based on the sensor data predicts wound closure rate within the first 3 days post-injury with ≈76% accuracy, which increases to ≈83% when pH is included. These studies underscore the significance of monitoring biomarkers during the inflammation phase, which can offer several benefits, including short-term use of wound monitors and their easy removal, resulting in lower risks of injury and infection at the wound site. Improvements in prediction accuracy can be achieved by designing mathematical models that build on multiple wound parameters such as pro-inflammatory and metabolic markers. Achieving this goal will require designing multi-analyte wound monitors.

Simple, miniaturized biosensors for wireless mapping of thermoregulatory responses.

Temperature is the most commonly collected vital sign in all of clinical medicine; it plays a critical role in care decisions related to topics ranging from infection to inflammation, sleep, and fertility. Most assessments of body temperature occur at isolated anatomical locations (e.g. axilla, rectum, temporal artery, or oral cavity). Even this relatively primitive mode for monitoring can be challenging with vulnerable patient populations due to physical encumbrances and artifacts associated with the sizes, weights, shapes and mechanical properties of the sensors and, for continuous monitoring, their hard-wired interfaces to data collection units. Here, we introduce a simple, miniaturized, lightweight sensor as a wireless alternative, designed to address demanding applications such as those related to the care of neonates in high ambient humidity environments with radiant heating found in incubators in intensive care units. Such devices can be deployed onto specific anatomical locations of premature infants for homeostatic assessments. The estimated core body temperature aligns, to within 0.05 °C, with clinical grade, wired sensors, consistent with regulatory medical device requirements. Time-synchronized, multi-device operation across multiple body locations supports continuous, full-body measurements of spatio-temporal variations in temperature and additional modes of determining tissue health status in the context of sepsis detection and various environmental exposures. In addition to thermal sensing, these same devices support measurements of a range of other essential vital signs derived from thermo-mechanical coupling to the skin, for applications ranging from neonatal and infant care to sleep medicine and even pulmonary medicine.

Implantable, Bioresorbable Radio Frequency Resonant Circuits for Magnetic Resonance Imaging.

Magnetic resonance imaging (MRI) is widely used in clinical care and medical research. The signal-to-noise ratio (SNR) in the measurement affects parameters that determine the diagnostic value of the image, such as the spatial resolution, contrast, and scan time. Surgically implanted radiofrequency coils can increase SNR of subsequent MRI studies of adjacent tissues. The resulting benefits in SNR are, however, balanced by significant risks associated with surgically removing these coils or with leaving them in place permanently. As an alternative, here the authors report classes of implantable inductor-capacitor circuits made entirely of bioresorbable organic and inorganic materials. Engineering choices for the designs of an inductor and a capacitor provide the ability to select the resonant frequency of the devices to meet MRI specifications (e.g., 200 MHz at 4.7 T MRI). Such devices enhance the SNR and improve the associated imaging capabilities. These simple, small bioelectronic systems function over clinically relevant time frames (up to 1 month) at physiological conditions and then disappear completely by natural mechanisms of bioresorption, thereby eliminating the need for surgical extraction. Imaging demonstrations in a nerve phantom and a human cadaver suggest that this technology has broad potential for post-surgical monitoring/evaluation of recovery processes.

Ultrathin Crystalline Silicon Nano and Micro Membranes with High Areal Density for Low-Cost Flexible Electronics.

Ultrathin crystalline silicon is widely used as an active material for high-performance, flexible, and stretchable electronics, from simple passive and active components to complex integrated circuits, due to its excellent electrical and mechanical properties. However, in contrast to conventional silicon wafer-based devices, ultrathin crystalline silicon-based electronics require an expensive and rather complicated fabrication process. Although silicon-on-insulator (SOI) wafers are commonly used to obtain a single layer of crystalline silicon, they are costly and difficult to process. Therefore, as an alternative to SOI wafers-based thin layers, here, a simple transfer method is proposed for printing ultrathin multiple crystalline silicon sheets with thicknesses between 300 nm to 13 µm and high areal density (>90%) from a single mother wafer. Theoretically, the silicon nano/micro membrane can be generated until the mother wafer is completely consumed. In addition, the electronic applications of silicon membranes are successfully demonstrated through the fabrication of a flexible solar cell and flexible NMOS transistor arrays.

A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals.

Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals.

A battery-less wireless implant for the continuous monitoring of vascular pressure, flow rate and temperature.

Devices for monitoring blood haemodynamics can guide the perioperative management of patients with cardiovascular disease. Current technologies for this purpose are constrained by wired connections to external electronics, and wireless alternatives are restricted to monitoring of either blood pressure or blood flow. Here we report the design aspects and performance parameters of an integrated wireless sensor capable of implantation in the heart or in a blood vessel for simultaneous measurements of pressure, flow rate and temperature in real time. The sensor is controlled via long-range communication through a subcutaneously implanted and wirelessly powered Bluetooth Low Energy system-on-a-chip. The device can be delivered via a minimally invasive transcatheter procedure or it can be mounted on a passive medical device such as a stent, as we show for the case of the pulmonary artery in a pig model and the aorta and left ventricle in a sheep model, where the device performs comparably to clinical tools for monitoring of blood flow and pressure. Battery-less and wireless devices such as these that integrate capabilities for flow, pressure and temperature sensing offer the potential for continuous monitoring of blood haemodynamics in patients.

Self-powered, light-controlled, bioresorbable platforms for programmed drug delivery.

Degradable polymer matrices and porous scaffolds provide powerful mechanisms for passive, sustained release of drugs relevant to the treatment of a broad range of diseases and conditions. Growing interest is in active control of pharmacokinetics tailored to the needs of the patient via programmable engineering platforms that include power sources, delivery mechanisms, communication hardware, and associated electronics, most typically in forms that require surgical extraction after a period of use. Here we report a light-controlled, self-powered technology that bypasses key disadvantages of these systems, in an overall design that is bioresorbable. Programmability relies on the use of an external light source to illuminate an implanted, wavelength-sensitive phototransistor to trigger a short circuit in an electrochemical cell structure that includes a metal gate valve as its anode. Consequent electrochemical corrosion eliminates the gate, thereby opening an underlying reservoir to release a dose of drugs by passive diffusion into surrounding tissue. A wavelength-division multiplexing strategy allows release to be programmed from any one or any arbitrary combination of a collection of reservoirs built into an integrated device. Studies of various bioresorbable electrode materials define the key considerations and guide optimized choices in designs. In vivo demonstrations of programmed release of lidocaine adjacent the sciatic nerves in rat models illustrate the functionality in the context of pain management, an essential aspect of patient care that could benefit from the results presented here.

Closed-loop network of skin-interfaced wireless devices for quantifying vocal fatigue and providing user feedback.

Vocal fatigue is a measurable form of performance fatigue resulting from overuse of the voice and is characterized by negative vocal adaptation. Vocal dose refers to cumulative exposure of the vocal fold tissue to vibration. Professionals with high vocal demands, such as singers and teachers, are especially prone to vocal fatigue. Failure to adjust habits can lead to compensatory lapses in vocal technique and an increased risk of vocal fold injury. Quantifying and recording vocal dose to inform individuals about potential overuse is an important step toward mitigating vocal fatigue. Previous work establishes vocal dosimetry methods, that is, processes to quantify vocal fold vibration dose but with bulky, wired devices that are not amenable to continuous use during natural daily activities; these previously reported systems also provide limited mechanisms for real-time user feedback. This study introduces a soft, wireless, skin-conformal technology that gently mounts on the upper chest to capture vibratory responses associated with vocalization in a manner that is immune to ambient noises. Pairing with a separate, wirelessly linked device supports haptic feedback to the user based on quantitative thresholds in vocal usage. A machine learning-based approach enables precise vocal dosimetry from the recorded data, to support personalized, real-time quantitation and feedback. These systems have strong potential to guide healthy behaviors in vocal use.

Responsive materials and mechanisms as thermal safety systems for skin-interfaced electronic devices.

Soft, wireless physiological sensors that gently adhere to the skin are capable of continuous clinical-grade health monitoring in hospital and/or home settings, of particular value to critically ill infants and other vulnerable patients, but they present risks for injury upon thermal failure. This paper introduces an active materials approach that automatically minimizes such risks, to complement traditional schemes that rely on integrated sensors and electronic control circuits. The strategy exploits thin, flexible bladders that contain small volumes of liquid with boiling points a few degrees above body temperature. When the heat exceeds the safe range, vaporization rapidly forms highly effective, thermally insulating structures and delaminates the device from the skin, thereby eliminating any danger to the skin. Experimental and computational thermomechanical studies and demonstrations in a skin-interfaced mechano-acoustic sensor illustrate the effectiveness of this simple thermal safety system and suggest its applicability to nearly any class of skin-integrated device technology.

Bioresorbable, wireless, and battery-free system for electrotherapy and impedance sensing at wound sites.

Chronic wounds, particularly those associated with diabetes mellitus, represent a growing threat to public health, with additional notable economic impacts. Inflammation associated with these wounds leads to abnormalities in endogenous electrical signals that impede the migration of keratinocytes needed to support the healing process. This observation motivates the treatment of chronic wounds with electrical stimulation therapy, but practical engineering challenges, difficulties in removing stimulation hardware from the wound site, and absence of means to monitor the healing process create barriers to widespread clinical use. Here, we demonstrate a miniaturized wireless, battery-free bioresorbable electrotherapy system that overcomes these challenges. Studies based on a splinted diabetic mouse wound model confirm the efficacy for accelerated wound closure by guiding epithelial migration, modulating inflammation, and promoting vasculogenesis. Changes in the impedance provide means for tracking the healing process. The results demonstrate a simple and effective platform for wound site electrotherapy.

Sweat as a diagnostic biofluid.

Skin-interfaced microfluidic systems help assess health status and chemical exposure.

Skin-integrated systems for power efficient, programmable thermal sensations across large body areas.

Thermal sensations contribute to our ability to perceive and explore the physical world. Reproducing these sensations in a spatiotemporally programmable manner through wireless computer control could enhance virtual experiences beyond those supported by video, audio and, increasingly, haptic inputs. Flexible, lightweight and thin devices that deliver patterns of thermal stimulation across large areas of the skin at any location of the body are of great interest in this context. Applications range from those in gaming and remote socioemotional communications, to medical therapies and physical rehabilitation. Here, we present a set of ideas that form the foundations of a skin-integrated technology for power-efficient generation of thermal sensations across the skin, with real-time, closed-loop control. The systems exploit passive cooling mechanisms, actively switchable thermal barrier interfaces, thin resistive heaters and flexible electronics configured in a pixelated layout with wireless interfaces to portable devices, the internet and cloud data infrastructure. Systematic experimental studies and simulation results explore the essential mechanisms and guide the selection of optimized choices in design. Demonstration examples with human subjects feature active thermoregulation, virtual social interactions, and sensory expansion.

Remote control of muscle-driven miniature robots with battery-free wireless optoelectronics.

Bioengineering approaches that combine living cellular components with three-dimensional scaffolds to generate motion can be used to develop a new generation of miniature robots. Integrating on-board electronics and remote control in these biological machines will enable various applications across engineering, biology, and medicine. Here, we present hybrid bioelectronic robots equipped with battery-free and microinorganic light-emitting diodes for wireless control and real-time communication. Centimeter-scale walking robots were computationally designed and optimized to host on-board optoelectronics with independent stimulation of multiple optogenetic skeletal muscles, achieving remote command of walking, turning, plowing, and transport functions both at individual and collective levels. This work paves the way toward a class of biohybrid machines able to combine biological actuation and sensing with on-board computing.

Wireless, Battery-Free Implants for Electrochemical Catecholamine Sensing and Optogenetic Stimulation.

Neurotransmitters and neuromodulators mediate communication between neurons and other cell types; knowledge of release dynamics is critical to understanding their physiological role in normal and pathological brain function. Investigation into transient neurotransmitter dynamics has largely been hindered due to electrical and material requirements for electrochemical stimulation and recording. Current systems require complex electronics for biasing and amplification and rely on materials that offer limited sensor selectivity and sensitivity. These restrictions result in bulky, tethered, or battery-powered systems impacting behavior and that require constant care of subjects. To overcome these challenges, we demonstrate a fully implantable, wireless, and battery-free platform that enables optogenetic stimulation and electrochemical recording of catecholamine dynamics in real time. The device is nearly 1/10th the size of previously reported examples and includes a probe that relies on a multilayer electrode architecture featuring a microscale light emitting diode (µ-LED) and a carbon nanotube (CNT)-based sensor with sensitivities among the highest recorded in the literature (1264.1 nA µM-1 cm-2). High sensitivity of the probe combined with a center tapped antenna design enables the realization of miniaturized, low power circuits suitable for subdermal implantation even in small animal models such as mice. A series of in vitro and in vivo experiments highlight the sensitivity and selectivity of the platform and demonstrate its capabilities in freely moving, untethered subjects. Specifically, a demonstration of changes in dopamine concentration after optogenetic stimulation of the nucleus accumbens and real-time readout of dopamine levels after opioid and naloxone exposure in freely behaving subjects highlight the experimental paradigms enabled by the platform.