Soft robot-enabled controlled release of oral drug formulations.

The creation of highly effective oral drug delivery systems (ODDSs) has long been the main objective of pharmaceutical research. Multidisciplinary efforts involving materials, electronics, control, and pharmaceutical sciences encourage the development of robot-enabled ODDSs. Compared with conventional rigid robots, soft robots potentially offer better mechanical compliance and biocompatibility with biological tissues, more versatile shape control and maneuverability, and multifunctionality. In this paper, we first describe and highlight the importance of manipulating drug release kinetics, i.e. pharmaceutical kinetics. We then introduce an overview of state-of-the-art soft robot-based ODDSs comprising resident, shape-programming, locomotive, and integrated soft robots. Finally, the challenges and outlook regarding future soft robot-based ODDS development are discussed.

Fundamental Limits to the Electrochemical Impedance Stability of Dielectric Elastomers in Bioelectronics.

Incorporation of elastomers into bioelectronics that reduces the mechanical mismatch between electronics and biological systems could potentially improve the long-term electronics-tissue interface. However, the chronic stability of elastomers in physiological conditions has not been systematically studied. Here, using electrochemical impedance spectrum we find that the electrochemical impedance of dielectric elastomers degrades over time in physiological environments. Both experimental and computational results reveal that this phenomenon is due to the diffusion of ions from the physiological solution into elastomers over time. Their conductivity increases by 6 orders of magnitude up to 10-8 S/m. When the passivated conductors are also composed of intrinsically stretchable materials, higher leakage currents can be detected. Scaling analyses suggest fundamental limitations to the electrical performances of interconnects made of stretchable materials.

Three-dimensional mesostructures as high-temperature growth templates, electronic cellular scaffolds, and self-propelled microrobots.

Recent work demonstrates that processes of stress release in prestrained elastomeric substrates can guide the assembly of sophisticated 3D micro/nanostructures in advanced materials. Reported application examples include soft electronic components, tunable electromagnetic and optical devices, vibrational metrology platforms, and other unusual technologies, each enabled by uniquely engineered 3D architectures. A significant disadvantage of these systems is that the elastomeric substrates, while essential to the assembly process, can impose significant engineering constraints in terms of operating temperatures and levels of dimensional stability; they also prevent the realization of 3D structures in freestanding forms. Here, we introduce concepts in interfacial photopolymerization, nonlinear mechanics, and physical transfer that bypass these limitations. The results enable 3D mesostructures in fully or partially freestanding forms, with additional capabilities in integration onto nearly any class of substrate, from planar, hard inorganic materials to textured, soft biological tissues, all via mechanisms quantitatively described by theoretical modeling. Illustrations of these ideas include their use in 3D structures as frameworks for templated growth of organized lamellae from AgCl-KCl eutectics and of atomic layers of WSe2 from vapor-phase precursors, as open-architecture electronic scaffolds for formation of dorsal root ganglion (DRG) neural networks, and as catalyst supports for propulsive systems in 3D microswimmers with geometrically controlled dynamics. Taken together, these methodologies establish a set of enabling options in 3D micro/nanomanufacturing that lie outside of the scope of existing alternatives.

Cyborg Organoids: Implantation of Nanoelectronics via Organogenesis for Tissue-Wide Electrophysiology.

Tissue-wide electrophysiology with single-cell and millisecond spatiotemporal resolution is critical for heart and brain studies. Issues arise, however, from the invasive, localized implantation of electronics that destroys well-connected cellular networks within matured organs. Here, we report the creation of cyborg organoids: the three-dimensional (3D) assembly of soft, stretchable mesh nanoelectronics across the entire organoid by the cell-cell attraction forces from 2D-to-3D tissue reconfiguration during organogenesis. We demonstrate that stretchable mesh nanoelectronics can migrate with and grow into the initial 2D cell layers to form the 3D organoid structure with minimal impact on tissue growth and differentiation. The intimate contact between the dispersed nanoelectronics and cells enables us to chronically and systematically observe the evolution, propagation, and synchronization of the bursting dynamics in human cardiac organoids through their entire organogenesis.

Morphable 3D mesostructures and microelectronic devices by multistable buckling mechanics.

Three-dimensional (3D) structures capable of reversible transformations in their geometrical layouts have important applications across a broad range of areas. Most morphable 3D systems rely on concepts inspired by origami/kirigami or techniques of 3D printing with responsive materials. The development of schemes that can simultaneously apply across a wide range of size scales and with classes of advanced materials found in state-of-the-art microsystem technologies remains challenging. Here, we introduce a set of concepts for morphable 3D mesostructures in diverse materials and fully formed planar devices spanning length scales from micrometres to millimetres. The approaches rely on elastomer platforms deformed in different time sequences to elastically alter the 3D geometries of supported mesostructures via nonlinear mechanical buckling. Over 20 examples have been experimentally and theoretically investigated, including mesostructures that can be reshaped between different geometries as well as those that can morph into three or more distinct states. An adaptive radiofrequency circuit and a concealable electromagnetic device provide examples of functionally reconfigurable microelectronic devices.

A mechanically driven form of Kirigami as a route to 3D mesostructures in micro/nanomembranes.

Assembly of 3D micro/nanostructures in advanced functional materials has important implications across broad areas of technology. Existing approaches are compatible, however, only with narrow classes of materials and/or 3D geometries. This paper introduces ideas for a form of Kirigami that allows precise, mechanically driven assembly of 3D mesostructures of diverse materials from 2D micro/nanomembranes with strategically designed geometries and patterns of cuts. Theoretical and experimental studies demonstrate applicability of the methods across length scales from macro to nano, in materials ranging from monocrystalline silicon to plastic, with levels of topographical complexity that significantly exceed those that can be achieved using other approaches. A broad set of examples includes 3D silicon mesostructures and hybrid nanomembrane-nanoribbon systems, including heterogeneous combinations with polymers and metals, with critical dimensions that range from 100 nm to 30 mm. A 3D mechanically tunable optical transmission window provides an application example of this Kirigami process, enabled by theoretically guided design.

Engineered elastomer substrates for guided assembly of complex 3D mesostructures by spatially nonuniform compressive buckling.

Approaches capable of creating three-dimensional (3D) mesostructures in advanced materials (device-grade semiconductors, electroactive polymers etc.) are of increasing interest in modern materials research. A versatile set of approaches exploits transformation of planar precursors into 3D architectures through the action of compressive forces associated with release of prestrain in a supporting elastomer substrate. Although a diverse set of 3D structures can be realized in nearly any class of material in this way, all previously reported demonstrations lack the ability to vary the degree of compression imparted to different regions of the 2D precursor, thus constraining the diversity of 3D geometries. This paper presents a set of ideas in materials and mechanics in which elastomeric substrates with engineered distributions of thickness yield desired strain distributions for targeted control over resultant 3D mesostructures geometries. This approach is compatible with a broad range of advanced functional materials from device-grade semiconductors to commercially available thin films, over length scales from tens of microns to several millimeters. A wide range of 3D structures can be produced in this way, some of which have direct relevance to applications in tunable optics and stretchable electronics.

Three-Dimensional Multiscale, Multistable, and Geometrically Diverse Microstructures with Tunable Vibrational Dynamics Assembled by Compressive Buckling.

Microelectromechanical systems remain an area of significant interest in fundamental and applied research due to their wide ranging applications. Most device designs, however, are largely two-dimensional and constrained to only a few simple geometries. Achieving tunable resonant frequencies or broad operational bandwidths requires complex components and/or fabrication processes. The work presented here reports unusual classes of three-dimensional (3D) micromechanical systems in the form of vibratory platforms assembled by controlled compressive buckling. Such 3D structures can be fabricated across a broad range of length scales and from various materials, including soft polymers, monocrystalline silicon, and their composites, resulting in a wide scope of achievable resonant frequencies and mechanical behaviors. Platforms designed with multistable mechanical responses and vibrationally de-coupled constituent elements offer improved bandwidth and frequency tunability. Furthermore, the resonant frequencies can be controlled through deformations of an underlying elastomeric substrate. Systematic experimental and computational studies include structures with diverse geometries, ranging from tables, cages, rings, ring-crosses, ring-disks, two-floor ribbons, flowers, umbrellas, triple-cantilever platforms, and asymmetric circular helices, to multilayer constructions. These ideas form the foundations for engineering designs that complement those supported by conventional, microelectromechanical systems, with capabilities that could be useful in systems for biosensing, energy harvesting and others.

Mechanically-Guided Deterministic Assembly of 3D Mesostructures Assisted by Residual Stresses.

Formation of 3D mesostructures in advanced functional materials is of growing interest due to the widespread envisioned applications of devices that exploit 3D architectures. Mechanically guided assembly based on compressive buckling of 2D precursors represents a promising method, with applicability to a diverse set of geometries and materials, including inorganic semiconductors, metals, polymers, and their heterogeneous combinations. This paper introduces ideas that extend the levels of control and the range of 3D layouts that are achievable in this manner. Here, thin, patterned layers with well-defined residual stresses influence the process of 2D to 3D geometric transformation. Systematic studies through combined analytical modeling, numerical simulations, and experimental observations demonstrate the effectiveness of the proposed strategy through ≈20 example cases with a broad range of complex 3D topologies. The results elucidate the ability of these stressed layers to alter the energy landscape associated with the transformation process and, specifically, the energy barriers that separate different stable modes in the final 3D configurations. A demonstration in a mechanically tunable microbalance illustrates the utility of these ideas in a simple structure designed for mass measurement.

Guided Formation of 3D Helical Mesostructures by Mechanical Buckling: Analytical Modeling and Experimental Validation.

Three-dimensional (3D) helical mesostructures are attractive for applications in a broad range of microsystem technologies, due to their mechanical and electromagnetic properties as stretchable interconnects, radio frequency antennas and others. Controlled compressive buckling of 2D serpentine-shaped ribbons provides a strategy to formation of such structures in wide ranging classes of materials (from soft polymers to brittle inorganic semiconductors) and length scales (from nanometer to centimeter), with an ability for automated, parallel assembly over large areas. The underlying relations between the helical configurations and fabrication parameters require a relevant theory as the basis of design for practical applications. Here, we present an analytic model of compressive buckling in serpentine microstructures, based on the minimization of total strain energy that results from various forms of spatially dependent deformations. Experiments at micro- and millimeter-scales, together with finite element analyses (FEA), were exploited to examine the validity of developed model. The theoretical analyses shed light on general scaling laws in terms of three groups of fabrication parameters (related to loading, material and 2D geometry), including a negligible effect of material parameters and a square root dependence of primary displacements on the compressive strain. Furthermore, analytic solutions were obtained for the key physical quantities (e.g., displacement, curvature and maximum strain). A demonstrative example illustrates how to leverage the analytic solutions in choosing the various design parameters, such that brittle fracture or plastic yield can be avoided in the assembly process.

Controlled mechanical buckling for origami-inspired construction of 3D microstructures in advanced materials.

Origami is a topic of rapidly growing interest in both the scientific and engineering research communities due to its promising potential in a broad range of applications. Previous assembly approaches of origami structures at the micro/nanoscale are constrained by the applicable classes of materials, topologies and/or capability of control over the transformation. Here, we introduce an approach that exploits controlled mechanical buckling for autonomic origami assembly of 3D structures across material classes from soft polymers to brittle inorganic semiconductors, and length scales from nanometers to centimeters. This approach relies on a spatial variation of thickness in the initial 2D structures as an effective strategy to produce engineered folding creases during the compressive buckling process. The elastic nature of the assembly scheme enables active, deterministic control over intermediate states in the 2D to 3D transformation in a continuous and reversible manner. Demonstrations include a broad set of 3D structures formed through unidirectional, bidirectional, and even hierarchical folding, with examples ranging from half cylindrical columns and fish scales, to cubic boxes, pyramids, starfish, paper fans, skew tooth structures, and to amusing system-level examples of soccer balls, model houses, cars, and multi-floor textured buildings.

An enzyme-free sensing platform for miRNA detection and in situ imaging in clinical samples based on DNAzyme cleavage-triggered catalytic hairpin assembly.

MicroRNA (miRNA) is demonstrated to be associated with the occurrence and development of various diseases including cancer. Currently, most miRNA detection methods are confined to in vitro detection and cannot obtain information on the temporal and spatial expression of miRNA in relevant tissues and cells. In this work, we established a novel enzyme-free method that can be applied to both in vitro detection and in situ imaging of miRNA by integrating DNAzyme and catalytic hairpin assembly (CHA) circuits. This developed CHA-Amplified DNAzyme miRNA (CHAzymi) detection system can realize the quantitively in vitro detection of miR-146b (the biomarker of papillary thyroid carcinoma, PTC) ranging from 25 fmol to 625 fmol. This strategy has also been successfully applied to in situ imaging of miR-146b both in human PTC cell TPC-1 and clinical samples, showing its capacity as an alternative diagnostic method for PTC. Furthermore, this CHAzymi system can be employed as a versatile sensing platform for various miRNAs by revising the relevant sequences. The results imply that this system may expand the modality of miRNA detection and show promise as a novel diagnostic tool in clinical settings, providing valuable insights for effective treatment and management of the disease.

Scalable Electrophysiology of Millimeter-Scale Animals with Electrode Devices.

Millimeter-scale animals such as Caenorhabditis elegans, Drosophila larvae, zebrafish, and bees serve as powerful model organisms in the fields of neurobiology and neuroethology. Various methods exist for recording large-scale electrophysiological signals from these animals. Existing approaches often lack, however, real-time, uninterrupted investigations due to their rigid constructs, geometric constraints, and mechanical mismatch in integration with soft organisms. The recent research establishes the foundations for 3-dimensional flexible bioelectronic interfaces that incorporate microfabricated components and nanoelectronic function with adjustable mechanical properties and multidimensional variability, offering unique capabilities for chronic, stable interrogation and stimulation of millimeter-scale animals and miniature tissue constructs. This review summarizes the most advanced technologies for electrophysiological studies, based on methods of 3-dimensional flexible bioelectronics. A concluding section addresses the challenges of these devices in achieving freestanding, robust, and multifunctional biointerfaces.

Engineered bacteria for augmented in situ tumor vaccination.

In situ tumor vaccination has aroused tremendous interest with its capability for eliciting strong and systemic antitumor immune responses. Unlike traditional cancer vaccines, in situ tumor vaccination avoids the laborious process of tumor antigen identification and can modulate tumor immunosuppressive microenvironment at the same time. In recent years, bacteria have been used as both efficient tumor-targeted delivery vehicles and potent adjuvants. Regarding the rapid development in this area, in this review, we summarize recent advances in the application of bacteria for in situ cancer vaccination. We illustrate the mechanisms of bacteria as both efficient tumor immunogenic cell death inducers and tumor-targeted delivery platforms. Then we comprehensively review the engineering strategies for designing bacteria-based in situ vaccination, including chemical modification, nanotechnology, and genetic engineering. The current dilemma and future directions are discussed at the end of this review.

Energy-Efficient Ingestible Drug Delivery System in the Dynamic Gastrointestinal Environment.

Ingestible electronics are promising platforms for on-demand health monitoring and drug delivery. However, these devices and their actuators must operate in the gastrointestinal (GI) environment, which has a pH range of 1 to 8. Drug delivery systems using electrochemical dissolution of metal films are particularly susceptible to pH changes. Optimal operation in this dynamic environment stands to transform our capacity to help patients across a range of conditions. Here we present an energy-efficient ingestible electronic electrochemical drug delivery system to support subjects through operation in this dynamic environment. The proposed system consists of a drug reservoir sealed with an electrochemically dissolvable gold membrane and an electronic subsystem. An electronic subsystem controls the rate of gold dissolution by sensing and adapting to the pH of the GI environment and provides an option for energy-efficient drug delivery, reducing energy consumption by up to 42.8 %. Integrating the electronics with electrochemical drug delivery enables the proposed system to adapt to the dynamic physiological environments which makes it suitable for drug and/or therapeutic delivery at different locations in the GI tract.

Actively Triggerable Metals via Liquid Metal Embrittlement for Biomedical Applications.

Actively triggerable materials, which break down upon introduction of an exogenous stimulus, enable precise control over the lifetime of biomedical technologies, as well as adaptation to unforeseen circumstances, such as changes to an established treatment plan. Yet, most actively triggerable materials are low-strength polymers and hydrogels with limited long-term durability. By contrast, metals possess advantageous functional properties, including high mechanical strength and conductivity, that are desirable across several applications within biomedicine. To realize actively triggerable metals, a mechanism called liquid metal embrittlement is leveraged, in which certain liquid metals penetrate the grain boundaries of certain solid metals and cause them to dramatically weaken or disintegrate. In this work, it is demonstrated that eutectic gallium indium (EGaIn), a biocompatible alloy of gallium, can be formulated to reproducibly trigger the breakdown of aluminum within different physiologically relevant environments. The breakdown behavior of aluminum after triggering can further be readily controlled by manipulating its grain structure. Finally, three possible use cases of biomedical devices constructed from actively triggerable metals are demonstrated.

Mucosa-interfacing electronics.

The surface mucosa that lines many of our organs houses myriad biometric signals and, therefore, has great potential as a sensor-tissue interface for high-fidelity and long-term biosensing. However, progress is still nascent for mucosa-interfacing electronics owing to challenges with establishing robust sensor-tissue interfaces; device localization, retention and removal; and power and data transfer. This is in sharp contrast to the rapidly advancing field of skin-interfacing electronics, which are replacing traditional hospital visits with minimally invasive, real-time, continuous and untethered biosensing. This Review aims to bridge the gap between skin-interfacing electronics and mucosa-interfacing electronics systems through a comparison of the properties and functions of the skin and internal mucosal surfaces. The major physiological signals accessible through mucosa-lined organs are surveyed and design considerations for the next generation of mucosa-interfacing electronics are outlined based on state-of-the-art developments in bio-integrated electronics. With this Review, we aim to inspire hardware solutions that can serve as a foundation for developing personalized biosensing from the mucosa, a relatively uncharted field with great scientific and clinical potential.

Low-cost gastrointestinal manometry via silicone-liquid-metal pressure transducers resembling a quipu.

The evaluation of the tone and contractile patterns of the gastrointestinal (GI) tract via manometry is essential for the diagnosis of GI motility disorders. However, manometry is expensive and relies on complex and bulky instrumentation. Here we report the development and performance of an inexpensive and easy-to-manufacture catheter-like device for capturing manometric data across the dynamic range observed in the human GI tract. The device, which we designed to resemble the quipu-knotted strings used by Andean civilizations for the capture and transmission of information-consists of knotted piezoresistive pressure sensors made by infusing a liquid metal (eutectic gallium-indium) through thin silicone tubing. By exploring a range of knotting configurations, we identified optimal design schemes that led to sensing performances comparable to those of commercial devices for GI manometry, as we show for the sensing of GI motility in multiple anatomic sites of the GI tract of anaesthetized pigs. Disposable and customizable piezoresistive catheters may broaden the use of GI manometry in low-resource settings.

An automated all-in-one system for carbohydrate tracking, glucose monitoring, and insulin delivery.

Glycemic control through titration of insulin dosing remains the mainstay of diabetes mellitus treatment. Insulin therapy is generally divided into dosing with long- and short-acting insulin, where long-acting insulin provides basal coverage and short-acting insulin supports glycemic excursions associated with eating. The dosing of short-acting insulin often involves several steps for the user including blood glucose measurement and integration of potential carbohydrate loads to inform safe and appropriate dosing. The significant burden placed on the user for blood glucose measurement and effective carbohydrate counting can manifest in substantial effects on adherence. Through the application of computer vision, we have developed a smartphone-based system that is able to detect the carbohydrate load of food by simply taking a single image of the food and converting that information into a required insulin dose by incorporating a blood glucose measurement. Moreover, we report the development of comprehensive all-in-one insulin delivery systems that streamline all operations that peripheral devices require for safe insulin administration, which in turn significantly reduces the complexity and time required for titration of insulin. The development of an autonomous system that supports maximum ease and accuracy of insulin dosing will transform our ability to more effectively support patients with diabetes.

Remotely Triggered Assembly of 3D Mesostructures Through Shape-Memory Effects.

3D structures that incorporate high-performance electronic materials and allow for remote, on-demand 3D shape reconfiguration are of interest for applications that range from ingestible medical devices and microrobotics to tunable optoelectronics. Here, materials and design approaches are introduced for assembly of such systems via controlled mechanical buckling of 2D precursors built on shape-memory polymer (SMP) substrates. The temporary shape fixing and recovery of SMPs, governed by thermomechanical loading, provide deterministic control over the assembly and reconfiguration processes, including a range of mechanical manipulations facilitated by the elastic and highly stretchable properties of the materials. Experimental demonstrations include 3D mesostructures of various geometries and length scales, as well as 3D aquatic platforms that can change trajectories and release small objects on demand. The results create many opportunities for advanced, programmable 3D microsystem technologies.