Engineering intelligent chassis cells via recombinase-based MEMORY circuits.

Synthetic biologists seek to engineer intelligent living systems capable of decision-making, communication, and memory. Separate technologies exist for each tenet of intelligence; however, the unification of all three properties in a living system has not been achieved. Here, we engineer completely intelligent Escherichia coli strains that harbor six orthogonal and inducible genome-integrated recombinases, forming Molecularly Encoded Memory via an Orthogonal Recombinase arraY (MEMORY). MEMORY chassis cells facilitate intelligence via the discrete multi-input regulation of recombinase functions enabling inheritable DNA inversions, deletions, and genomic insertions. MEMORY cells can achieve programmable and permanent gain (or loss) of functions extrachromosomally or from a specific genomic locus, without the loss or modification of the MEMORY platform - enabling the sequential programming and reprogramming of DNA circuits within the cell. We demonstrate all three tenets of intelligence via a probiotic (Nissle 1917) MEMORY strain capable of information exchange with the gastrointestinal commensal Bacteroides thetaiotaomicron.

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.

Wireless multi-lateral optofluidic microsystems for real-time programmable optogenetics and photopharmacology.

In vivo optogenetics and photopharmacology are two techniques for controlling neuronal activity that have immense potential in neuroscience research. Their applications in tether-free groups of animals have been limited in part due to tools availability. Here, we present a wireless, battery-free, programable multilateral optofluidic platform with user-selected modalities for optogenetics, pharmacology and photopharmacology. This system features mechanically compliant microfluidic and electronic interconnects, capabilities for dynamic control over the rates of drug delivery and real-time programmability, simultaneously for up to 256 separate devices in a single cage environment. Our behavioral experiments demonstrate control of motor behaviors in grouped mice through in vivo optogenetics with co-located gene delivery and controlled photolysis of caged glutamate. These optofluidic systems may expand the scope of wireless techniques to study neural processing in animal models.

Three-dimensional electronic microfliers inspired by wind-dispersed seeds.

Large, distributed collections of miniaturized, wireless electronic devices1,2 may form the basis of future systems for environmental monitoring3, population surveillance4, disease management5 and other applications that demand coverage over expansive spatial scales. Aerial schemes to distribute the components for such networks are required, and-inspired by wind-dispersed seeds6-we examined passive structures designed for controlled, unpowered flight across natural environments or city settings. Techniques in mechanically guided assembly of three-dimensional (3D) mesostructures7-9 provide access to miniature, 3D fliers optimized for such purposes, in processes that align with the most sophisticated production techniques for electronic, optoelectronic, microfluidic and microelectromechanical technologies. Here we demonstrate a range of 3D macro-, meso- and microscale fliers produced in this manner, including those that incorporate active electronic and colorimetric payloads. Analytical, computational and experimental studies of the aerodynamics of high-performance structures of this type establish a set of fundamental considerations in bio-inspired design, with a focus on 3D fliers that exhibit controlled rotational kinematics and low terminal velocities. An approach that represents these complex 3D structures as discrete numbers of blades captures the essential physics in simple, analytical scaling forms, validated by computational and experimental results. Battery-free, wireless devices and colorimetric sensors for environmental measurements provide simple examples of a wide spectrum of applications of these unusual concepts.

Battery-free, wireless soft sensors for continuous multi-site measurements of pressure and temperature from patients at risk for pressure injuries.

Capabilities for continuous monitoring of pressures and temperatures at critical skin interfaces can help to guide care strategies that minimize the potential for pressure injuries in hospitalized patients or in individuals confined to the bed. This paper introduces a soft, skin-mountable class of sensor system for this purpose. The design includes a pressure-responsive element based on membrane deflection and a battery-free, wireless mode of operation capable of multi-site measurements at strategic locations across the body. Such devices yield continuous, simultaneous readings of pressure and temperature in a sequential readout scheme from a pair of primary antennas mounted under the bedding and connected to a wireless reader and a multiplexer located at the bedside. Experimental evaluation of the sensor and the complete system includes benchtop measurements and numerical simulations of the key features. Clinical trials involving two hemiplegic patients and a tetraplegic patient demonstrate the feasibility, functionality and long-term stability of this technology in operating hospital settings.

Wireless multilateral devices for optogenetic studies of individual and social behaviors.

Advanced technologies for controlled delivery of light to targeted locations in biological tissues are essential to neuroscience research that applies optogenetics in animal models. Fully implantable, miniaturized devices with wireless control and power-harvesting strategies offer an appealing set of attributes in this context, particularly for studies that are incompatible with conventional fiber-optic approaches or battery-powered head stages. Limited programmable control and narrow options in illumination profiles constrain the use of existing devices. The results reported here overcome these drawbacks via two platforms, both with real-time user programmability over multiple independent light sources, in head-mounted and back-mounted designs. Engineering studies of the optoelectronic and thermal properties of these systems define their capabilities and key design considerations. Neuroscience applications demonstrate that induction of interbrain neuronal synchrony in the medial prefrontal cortex shapes social interaction within groups of mice, highlighting the power of real-time subject-specific programmability of the wireless optogenetic platforms introduced here.

Surgical implantation of wireless, battery-free optoelectronic epidural implants for optogenetic manipulation of spinal cord circuits in mice.

The use of optogenetics to regulate neuronal activity has revolutionized the study of the neural circuitry underlying a number of complex behaviors in rodents. Advances have been particularly evident in the study of brain circuitry and related behaviors, while advances in the study of spinal circuitry have been less striking because of technical hurdles. We have developed and characterized a wireless and fully implantable optoelectronic device that enables optical manipulation of spinal cord circuitry in mice via a microscale light-emitting diode (µLED) placed in the epidural space (NeuroLux spinal optogenetic device). This protocol describes how to surgically implant the device into the epidural space and then analyze light-induced behavior upon µLED activation. We detail optimized optical parameters for in vivo stimulation and demonstrate typical behavioral effects of optogenetic activation of nociceptive spinal afferents using this device. This fully wireless spinal µLED system provides considerable versatility for behavioral assays compared with optogenetic approaches that require tethering of animals, and superior temporal and spatial resolution when compared with other methods used for circuit manipulation such as chemogenetics. The detailed surgical approach and improved functionality of these spinal optoelectronic devices substantially expand the utility of this approach for the study of spinal circuitry and behaviors related to mechanical and thermal sensation, pruriception and nociception. The surgical implantation procedure takes ~1 h. The time required for the study of behaviors that are modulated by the light-activated circuit is variable and will depend upon the nature of the study.

Skin-integrated wireless haptic interfaces for virtual and augmented reality.

Traditional technologies for virtual reality (VR) and augmented reality (AR) create human experiences through visual and auditory stimuli that replicate sensations associated with the physical world. The most widespread VR and AR systems use head-mounted displays, accelerometers and loudspeakers as the basis for three-dimensional, computer-generated environments that can exist in isolation or as overlays on actual scenery. In comparison to the eyes and the ears, the skin is a relatively underexplored sensory interface for VR and AR technology that could, nevertheless, greatly enhance experiences at a qualitative level, with direct relevance in areas such as communications, entertainment and medicine1,2. Here we present a wireless, battery-free platform of electronic systems and haptic (that is, touch-based) interfaces capable of softly laminating onto the curved surfaces of the skin to communicate information via spatio-temporally programmable patterns of localized mechanical vibrations. We describe the materials, device structures, power delivery strategies and communication schemes that serve as the foundations for such platforms. The resulting technology creates many opportunities for use where the skin provides an electronically programmable communication and sensory input channel to the body, as demonstrated through applications in social media and personal engagement, prosthetic control and feedback, and gaming and entertainment.

Battery-free, lightweight, injectable microsystem for in vivo wireless pharmacology and optogenetics.

Pharmacology and optogenetics are widely used in neuroscience research to study the central and peripheral nervous systems. While both approaches allow for sophisticated studies of neural circuitry, continued advances are, in part, hampered by technology limitations associated with requirements for physical tethers that connect external equipment to rigid probes inserted into delicate regions of the brain. The results can lead to tissue damage and alterations in behavioral tasks and natural movements, with additional difficulties in use for studies that involve social interactions and/or motions in complex 3-dimensional environments. These disadvantages are particularly pronounced in research that demands combined optogenetic and pharmacological functions in a single experiment. Here, we present a lightweight, wireless, battery-free injectable microsystem that combines soft microfluidic and microscale inorganic light-emitting diode probes for programmable pharmacology and optogenetics, designed to offer the features of drug refillability and adjustable flow rates, together with programmable control over the temporal profiles. The technology has potential for large-scale manufacturing and broad distribution to the neuroscience community, with capabilities in targeting specific neuronal populations in freely moving animals. In addition, the same platform can easily be adapted for a wide range of other types of passive or active electronic functions, including electrical stimulation.

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

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.

Three-Dimensional Silicon Electronic Systems Fabricated by Compressive Buckling Process.

Recently developed approaches in deterministic assembly allow for controlled, geometric transformation of two-dimensional structures into complex, engineered three-dimensional layouts. Attractive features include applicability to wide ranging layout designs and dimensions along with the capacity to integrate planar thin film materials and device layouts. The work reported here establishes further capabilities for directly embedding high-performance electronic devices into the resultant 3D constructs based on silicon nanomembranes (Si NMs) as the active materials in custom devices or microscale components released from commercial wafer sources. Systematic experimental studies and theoretical analysis illustrate the key ideas through varied 3D architectures, from interconnected bridges and coils to extended chiral structures, each of which embed n-channel Si NM MOSFETs (nMOS), Si NM diodes, and p-channel silicon MOSFETs (pMOS). Examples in stretchable/deformable systems highlight additional features of these platforms. These strategies are immediately applicable to other wide-ranging classes of materials and device technologies that can be rendered in two-dimensional layouts, from systems for energy storage, to photovoltaics, optoelectronics, and others.

Self-assembled three dimensional network designs for soft electronics.

Low modulus, compliant systems of sensors, circuits and radios designed to intimately interface with the soft tissues of the human body are of growing interest, due to their emerging applications in continuous, clinical-quality health monitors and advanced, bioelectronic therapeutics. Although recent research establishes various materials and mechanics concepts for such technologies, all existing approaches involve simple, two-dimensional (2D) layouts in the constituent micro-components and interconnects. Here we introduce concepts in three-dimensional (3D) architectures that bypass important engineering constraints and performance limitations set by traditional, 2D designs. Specifically, open-mesh, 3D interconnect networks of helical microcoils formed by deterministic compressive buckling establish the basis for systems that can offer exceptional low modulus, elastic mechanics, in compact geometries, with active components and sophisticated levels of functionality. Coupled mechanical and electrical design approaches enable layout optimization, assembly processes and encapsulation schemes to yield 3D configurations that satisfy requirements in demanding, complex systems, such as wireless, skin-compatible electronic sensors.

Double-heterojunction nanorod light-responsive LEDs for display applications.

Dual-functioning displays, which can simultaneously transmit and receive information and energy through visible light, would enable enhanced user interfaces and device-to-device interactivity. We demonstrate that double heterojunctions designed into colloidal semiconductor nanorods allow both efficient photocurrent generation through a photovoltaic response and electroluminescence within a single device. These dual-functioning, all-solution-processed double-heterojunction nanorod light-responsive light-emitting diodes open feasible routes to a variety of advanced applications, from touchless interactive screens to energy harvesting and scavenging displays and massively parallel display-to-display data communication.

Multilayer Transfer Printing for Pixelated, Multicolor Quantum Dot Light-Emitting Diodes.

Here, we report multilayer stacking of films of quantum dots (QDs) for the purpose of tailoring the energy band alignment between charge transport layers and light emitting layers of different color in quantum dot light-emitting diodes (QD LED) for maximum efficiency in full color operation. The performance of QD LEDs formed by transfer printing compares favorably to that of conventional devices fabricated by spin-casting. Results indicate that zinc oxide (ZnO) and titanium dioxide (TiO2) can serve effectively as electron transport layers (ETLs) for red and green/blue QD LEDs, respectively. Optimized selections for each QD layer can be assembled at high yields by transfer printing with sacrificial fluoropolymer thin films to provide low energy surfaces for release, thereby allowing shared common layers for hole injection (HIL) and hole transport (HTL), along with customized ETLs. This strategy allows cointegration of devices with heterogeneous energy band diagrams, in a parallelized scheme that offers potential for high throughput and practical use.