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.

Vitamin A Ameliorated Irinotecan-Induced Diarrhea in a Piglet Model Involving Enteric Glia Modulation and Immune Cells Infiltration.

Vitamin A (VA) and its metabolite, retinoic acid (RA), play important roles in modulating intestinal mucosal immunity, yet little is known about their regulatory effects on enteric nervous system function. The study aims to explore the protective effects of dietary VA on diarrhea in a piglet model involving enteric glia and immune cell modulation. Twenty-eight weaned piglets were fed either the basal or VA (basal diet supplemented with 18,000 IU/kg VA) diet and with or without irinotecan (CPT-11) injection. CPT-11 induced increased diarrhea incidence, immune infiltration, and reactive enteric gliosis. A diet supplemented with 18,000 IU/kg VA ameliorated the adverse effects of CPT-11 on the gut barrier. VA reduced diarrhea incidence and attenuated enteric glial gliosis, immune cell infiltrations, and inflammatory responses of CPT-induced piglets. An in vitro experiment with 1 nmol/L RA showed direct protective effects on monocultures of enteric glial cells (EGCs) or macrophages in LPS-simulated inflammatory conditions. Furthermore, 1 ng/mL glial-derived neurotropic factors (GDNF) could inhibit M1-macrophage polarization and pro-inflammatory cytokines production. In summary, VA exerted protective effects on the intestinal barrier by modulating enteric glia and immune cells, perhaps enhancing epithelial recovery under CPT-11 challenge. Our study demonstrated that RA signaling might promote the roles of enteric glia in intestinal immunity and tissue repair, which provided a reference for the VA supplementation of patient diets.

A transient, closed-loop network of wireless, body-integrated devices for autonomous electrotherapy.

Temporary postoperative cardiac pacing requires devices with percutaneous leads and external wired power and control systems. This hardware introduces risks for infection, limitations on patient mobility, and requirements for surgical extraction procedures. Bioresorbable pacemakers mitigate some of these disadvantages, but they demand pairing with external, wired systems and secondary mechanisms for control. We present a transient closed-loop system that combines a time-synchronized, wireless network of skin-integrated devices with an advanced bioresorbable pacemaker to control cardiac rhythms, track cardiopulmonary status, provide multihaptic feedback, and enable transient operation with minimal patient burden. The result provides a range of autonomous, rate-adaptive cardiac pacing capabilities, as demonstrated in rat, canine, and human heart studies. This work establishes an engineering framework for closed-loop temporary electrotherapy using wirelessly linked, body-integrated bioelectronic devices.

Implantation and Control of Wireless, Battery-free Systems for Peripheral Nerve Interfacing.

Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.

Photocurable bioresorbable adhesives as functional interfaces between flexible bioelectronic devices and soft biological tissues.

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic-tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

Stretchable, dynamic covalent polymers for soft, long-lived bioresorbable electronic stimulators designed to facilitate neuromuscular regeneration.

Bioresorbable electronic stimulators are of rapidly growing interest as unusual therapeutic platforms, i.e., bioelectronic medicines, for treating disease states, accelerating wound healing processes and eliminating infections. Here, we present advanced materials that support operation in these systems over clinically relevant timeframes, ultimately bioresorbing harmlessly to benign products without residues, to eliminate the need for surgical extraction. Our findings overcome key challenges of bioresorbable electronic devices by realizing lifetimes that match clinical needs. The devices exploit a bioresorbable dynamic covalent polymer that facilitates tight bonding to itself and other surfaces, as a soft, elastic substrate and encapsulation coating for wireless electronic components. We describe the underlying features and chemical design considerations for this polymer, and the biocompatibility of its constituent materials. In devices with optimized, wireless designs, these polymers enable stable, long-lived operation as distal stimulators in a rat model of peripheral nerve injuries, thereby demonstrating the potential of programmable long-term electrical stimulation for maintaining muscle receptivity and enhancing functional recovery.

Effects of GABA Supplementation on Intestinal SIgA Secretion and Gut Microbiota in the Healthy and ETEC-Infected Weanling Piglets.

Pathogenic enterotoxigenic Escherichia coli (ETEC) has been considered a major cause of diarrhea which is a serious public health problem in humans and animals. This study was aimed at examining the effect of γ-aminobutyric acid (GABA) supplementation on intestinal secretory immunoglobulin A (SIgA) secretion and gut microbiota profile in healthy and ETEC-infected weaning piglets. A total of thirty-seven weaning piglets were randomly distributed into two groups fed with the basal diet or supplemented with 40 mg·kg-1 of GABA for three weeks, and some piglets were infected with ETEC at the last week. According to whether ETEC was inoculated or not, the experiment was divided into two stages (referred as CON1 and CON2 and GABA1 and GABA2). The growth performance, organ indices, amino acid levels, and biochemical parameters of serum, intestinal SIgA concentration, gut microbiota composition, and intestinal metabolites were analyzed at the end of each stage. We found that, in both the normal and ETEC-infected piglets, jejunal SIgA secretion and expression of some cytokines, such as IL-4, IL-13, and IL-17, were increased by GABA supplementation. Meanwhile, we observed that some low-abundance microbes, like Enterococcus and Bacteroidetes, were markedly increased in GABA-supplemented groups. KEGG enrichment analysis revealed that the nitrogen metabolism, sphingolipid signaling pathway, sphingolipid metabolism, and microbial metabolism in diverse environments were enriched in the GABA1 group. Further analysis revealed that alterations in microbial metabolism were closely correlated to changes in the abundances of Enterococcus and Bacteroidetes. In conclusion, GABA supplementation can enhance intestinal mucosal immunity by promoting jejunal SIgA secretion, which might be related with the T-cell-dependent pathway and altered gut microbiota structure and metabolism.

Wireless, battery-free, fully implantable multimodal and multisite pacemakers for applications in small animal models.

Small animals support a wide range of pathological phenotypes and genotypes as versatile, affordable models for pathogenesis of cardiovascular diseases and for exploration of strategies in electrotherapy, gene therapy, and optogenetics. Pacing tools in such contexts are currently limited to tethered embodiments that constrain animal behaviors and experimental designs. Here, we introduce a highly miniaturized wireless energy-harvesting and digital communication electronics for thin, miniaturized pacing platforms weighing 110 mg with capabilities for subdermal implantation and tolerance to over 200,000 multiaxial cycles of strain without degradation in electrical or optical performance. Multimodal and multisite pacing in ex vivo and in vivo studies over many days demonstrate chronic stability and excellent biocompatibility. Optogenetic stimulation of cardiac cycles with in-animal control and induction of heart failure through chronic pacing serve as examples of modes of operation relevant to fundamental and applied cardiovascular research and biomedical technology.

Fabrication and Deformation of 3D Multilayered Kirigami Microstructures.

Mechanically guided 3D microassembly with controlled compressive buckling represents a promising emerging route to 3D mesostructures in a broad range of advanced materials, including single-crystalline silicon (Si), of direct relevance to microelectronic devices. During practical applications, the assembled 3D mesostructures and microdevices usually undergo external mechanical loading such as out-of-plane compression, which can induce damage in or failure of the structures/devices. Here, the mechanical responses of a few mechanically assembled 3D kirigami mesostructures under flat-punch compression are studied through combined experiment and finite element analyses. These 3D kirigami mesostructures consisting of a bilayer of Si and SU-8 epoxy are formed through integration of patterned 2D precursors with a prestretched elastomeric substrate at predefined bonding sites to allow controlled buckling that transforms them into desired 3D configurations. In situ scanning electron microscopy measurement enables detailed studies of the mechanical behavior of these structures. Analysis of the load-displacement curves allows the measurement of the effective stiffness and elastic recovery of various 3D structures. The compression experiments indicate distinct regimes in the compressive force/displacement curves and reveals different geometry-dependent deformation for the structures. Complementary computational modeling supports the experimental findings and further explains the geometry-dependent deformation.

Battery-free, stretchable optoelectronic systems for wireless optical characterization of the skin.

Recent advances in materials, mechanics, and electronic device design are rapidly establishing the foundations for health monitoring technologies that have "skin-like" properties, with options in chronic (weeks) integration with the epidermis. The resulting capabilities in physiological sensing greatly exceed those possible with conventional hard electronic systems, such as those found in wrist-mounted wearables, because of the intimate skin interface. However, most examples of such emerging classes of devices require batteries and/or hard-wired connections to enable operation. The work reported here introduces active optoelectronic systems that function without batteries and in an entirely wireless mode, with examples in thin, stretchable platforms designed for multiwavelength optical characterization of the skin. Magnetic inductive coupling and near-field communication (NFC) schemes deliver power to multicolored light-emitting diodes and extract digital data from integrated photodetectors in ways that are compatible with standard NFC-enabled platforms, such as smartphones and tablet computers. Examples in the monitoring of heart rate and temporal dynamics of arterial blood flow, in quantifying tissue oxygenation and ultraviolet dosimetry, and in performing four-color spectroscopic evaluation of the skin demonstrate the versatility of these concepts. The results have potential relevance in both hospital care and at-home diagnostics.

Flexible Electronics: An Epidermal Stimulation and Sensing Platform for Sensorimotor Prosthetic Control, Management of Lower Back Exertion, and Electrical Muscle Activation (Adv. Mater. 22/2016).

The design of an ultrathin, conformal electronic device that integrates electrotactile stimulation with electromyography, temperature, and strain sensing in a single, simple platform is reported by J. A. Rogers and co-workers on page 4462. Demonstrated application possibilities include prosthetic control with sensory feedback, monitors, and stimulation signals related to lower back exertion, and electrical muscle stimulation with feedback control.

[Suppression effect of Mai Shu on formation of atherosclerotic plaque of apolipoprotein E knock-out mice].

The research aimed to investigate the suppression effect of Mai Shu which contains hawthorn, hippophae, medlar, phytosterols（ß-sitosterol, stigmasterol and campesterol）, ß-glucan and lycopeneon formation of atherosclerotic plaque in apolipoprotein E knock-out (ApoE-/-) mice. Liquid chromatography-ultravioletmass spectrometry（LC-UV-MC） methods were used to analyze the main chemical composition of Mai Shu. Atherosclerotic mice models were established by high-fat diet. The mice were administrated with Mai Shu (1, 2, 4 g·kg-1·d-1) or other contrast materials by intragastric route for 10 weeks continuously. At the end of administration, the blood of mice was collected for tests of the serum total cholesterol（TC）, total triglyceride（TG） and high density lipoprotein cholesterol（HDL-C） level. Atherosclerotic lesions in aorta and aortic root were assessed by calculating the relative area of lesions（oil red O stained）. Intravital fluorescence microscopic system was used to evaluate the leukocyte-endothelial adhesion in mesenteric artery of mice by detecting the rolling velocity of white blood cells（WBC）. Collagenous fibers and macrophages in lesions were detected by sirius red staining and immunological histological chemistry to evaluate the atherosclerotic plaque stability. Results showed that Mai Shu contains various flavonoids（9.5%）, phytosterols（23.8%） and polysaccharides（8.9%）. The serum lipid level of model animals was significantly higher than the control animals. Serum TC level was decreased by Mai Shu (4 g·kg-1, P < 0.001) compared to the untreated model. Serum TG level was reduced by Mai Shu (1, 2, 4 g·kg-1) compared to model（P < 0.01）. Area of atherosclerotic lesions in aorta and aortic root was decreased in Mai Shu group (aorta: 1 g·kg-1, P < 0.05; 2 g·kg-1, P < 0.01; 4 g·kg-1, P < 0.001; aortic root: 2, 4 g·kg-1, P < 0.01). Rolling velocity of white blood cells of Mai Shu (4 g·kg-1, P < 0.001) group was increased over the untreated model. Collagenous fibers in lesions were observationally increased by Mai Shu (1, 2 g·kg-1) and macrophages were decreased (2, 4 g·kg-1) compared to model. These results demonstrate that Mai Shu can obviously decrease the serum lipid levels and the risk of leukocyte-endothelial adhesion in ApoE-/- mice. The effect of Mai Shu may be associated with the decrease of macrophages in plaque.

An Epidermal Stimulation and Sensing Platform for Sensorimotor Prosthetic Control, Management of Lower Back Exertion, and Electrical Muscle Activation.

The design of an ultrathin, conformal electronic device that integrates electrotactile stimulation with electromyography, temperature, and strain sensing in a single, simple platform is reported. Experiments demonstrate simultaneous use of multiple modes of operation of this type of device in the sensorimotor control of robotic systems, in the monitoring of lower back exertion and in muscle stimulation.

Materials and fractal designs for 3D multifunctional integumentary membranes with capabilities in cardiac electrotherapy.

Advanced materials and fractal design concepts form the basis of a 3D conformal electronic platform with unique capabilities in cardiac electrotherapies. Fractal geometries, advanced electrode materials, and thin, elastomeric membranes yield a class of device capable of integration with the entire 3D surface of the heart, with unique operational capabilities in low power defibrillation. Co-integrated collections of sensors allow simultaneous monitoring of physiological responses. Animal experiments on Langendorff-perfused rabbit hearts demonstrate the key features of these systems.

Biodegradable elastomers and silicon nanomembranes/nanoribbons for stretchable, transient electronics, and biosensors.

Transient electronics represents an emerging class of technology that exploits materials and/or device constructs that are capable of physically disappearing or disintegrating in a controlled manner at programmed rates or times. Inorganic semiconductor nanomaterials such as silicon nanomembranes/nanoribbons provide attractive choices for active elements in transistors, diodes and other essential components of overall systems that dissolve completely by hydrolysis in biofluids or groundwater. We describe here materials, mechanics, and design layouts to achieve this type of technology in stretchable configurations with biodegradable elastomers for substrate/encapsulation layers. Experimental and theoretical results illuminate the mechanical properties under large strain deformation. Circuit characterization of complementary metal-oxide-semiconductor inverters and individual transistors under various levels of applied loads validates the design strategies. Examples of biosensors demonstrate possibilities for stretchable, transient devices in biomedical applications.

3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium.

Means for high-density multiparametric physiological mapping and stimulation are critically important in both basic and clinical cardiology. Current conformal electronic systems are essentially 2D sheets, which cannot cover the full epicardial surface or maintain reliable contact for chronic use without sutures or adhesives. Here we create 3D elastic membranes shaped precisely to match the epicardium of the heart via the use of 3D printing, as a platform for deformable arrays of multifunctional sensors, electronic and optoelectronic components. Such integumentary devices completely envelop the heart, in a form-fitting manner, and possess inherent elasticity, providing a mechanically stable biotic/abiotic interface during normal cardiac cycles. Component examples range from actuators for electrical, thermal and optical stimulation, to sensors for pH, temperature and mechanical strain. The semiconductor materials include silicon, gallium arsenide and gallium nitride, co-integrated with metals, metal oxides and polymers, to provide these and other operational capabilities. Ex vivo physiological experiments demonstrate various functions and methodological possibilities for cardiac research and therapy.

Stretchable batteries with self-similar serpentine interconnects and integrated wireless recharging systems.

An important trend in electronics involves the development of materials, mechanical designs and manufacturing strategies that enable the use of unconventional substrates, such as polymer films, metal foils, paper sheets or rubber slabs. The last possibility is particularly challenging because the systems must accommodate not only bending but also stretching. Although several approaches are available for the electronics, a persistent difficulty is in power supplies that have similar mechanical properties, to allow their co-integration with the electronics. Here we introduce a set of materials and design concepts for a rechargeable lithium ion battery technology that exploits thin, low modulus silicone elastomers as substrates, with a segmented design in the active materials, and unusual 'self-similar' interconnect structures between them. The result enables reversible levels of stretchability up to 300%, while maintaining capacity densities of ~1.1 mAh cm(-2). Stretchable wireless power transmission systems provide the means to charge these types of batteries, without direct physical contact.

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.

A physically transient form of silicon electronics.

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.

Unusual strategies for using indium gallium nitride grown on silicon (111) for solid-state lighting.

Properties that can now be achieved with advanced, blue indium gallium nitride light emitting diodes (LEDs) lead to their potential as replacements for existing infrastructure in general illumination, with important implications for efficient use of energy. Further advances in this technology will benefit from reexamination of the modes for incorporating this materials technology into lighting modules that manage light conversion, extraction, and distribution, in ways that minimize adverse thermal effects associated with operation, with packages that exploit the unique aspects of these light sources. We present here ideas in anisotropic etching, microscale device assembly/integration, and module configuration that address these challenges in unconventional ways. Various device demonstrations provide examples of the capabilities, including thin, flexible lighting "tapes" based on patterned phosphors and large collections of small light emitters on plastic substrates. Quantitative modeling and experimental evaluation of heat flow in such structures illustrates one particular, important aspect of their operation: small, distributed LEDs can be passively cooled simply by direct thermal transport through thin-film metallization used for electrical interconnect, providing an enhanced and scalable means to integrate these devices in modules for white light generation.