High-speed and large-scale intrinsically stretchable integrated circuits.

Intrinsically stretchable electronics with skin-like mechanical properties have been identified as a promising platform for emerging applications ranging from continuous physiological monitoring to real-time analysis of health conditions, to closed-loop delivery of autonomous medical treatment1-7. However, current technologies could only reach electrical performance at amorphous-silicon level (that is, charge-carrier mobility of about 1 cm2 V-1 s-1), low integration scale (for example, 54 transistors per circuit) and limited functionalities8-11. Here we report high-density, intrinsically stretchable transistors and integrated circuits with high driving ability, high operation speed and large-scale integration. They were enabled by a combination of innovations in materials, fabrication process design, device engineering and circuit design. Our intrinsically stretchable transistors exhibit an average field-effect mobility of more than 20 cm2 V-1 s-1 under 100% strain, a device density of 100,000 transistors per cm2, including interconnects and a high drive current of around 2 µA µm-1 at a supply voltage of 5 V. Notably, these achieved parameters are on par with state-of-the-art flexible transistors based on metal-oxide, carbon nanotube and polycrystalline silicon materials on plastic substrates12-14. Furthermore, we realize a large-scale integrated circuit with more than 1,000 transistors and a stage-switching frequency greater than 1 MHz, for the first time, to our knowledge, in intrinsically stretchable electronics. Moreover, we demonstrate a high-throughput braille recognition system that surpasses human skin sensing ability, enabled by an active-matrix tactile sensor array with a record-high density of 2,500 units per cm2, and a light-emitting diode display with a high refreshing speed of 60 Hz and excellent mechanical robustness. The above advancements in device performance have substantially enhanced the abilities of skin-like electronics.

Spiral NeuroString: High-Density Soft Bioelectronic Fibers for Multimodal Sensing and Stimulation.

Bioelectronic fibers hold promise for both research and clinical applications due to their compactness, ease of implantation, and ability to incorporate various functionalities such as sensing and stimulation. However, existing devices suffer from bulkiness, rigidity, limited functionality, and low density of active components. These limitations stem from the difficulty to incorporate many components on one-dimensional (1D) fiber devices due to the incompatibility of conventional microfabrication methods (e.g., photolithography) with curved, thin and long fiber structures. Herein, we introduce a fabrication approach, ‶spiral transformation″, to convert two-dimensional (2D) films containing microfabricated devices into 1D soft fibers. This approach allows for the creation of high density multimodal soft bioelectronic fibers, termed Spiral NeuroString (S-NeuroString), while enabling precise control over the longitudinal, angular, and radial positioning and distribution of the functional components. We show the utility of S-NeuroString for motility mapping, serotonin sensing, and tissue stimulation within the dynamic and soft gastrointestinal (GI) system, as well as for single-unit recordings in the brain. The described bioelectronic fibers hold great promises for next-generation multifunctional implantable electronics.

Environmentally stable and stretchable polymer electronics enabled by surface-tethered nanostructured molecular-level protection.

Stretchable polymer semiconductors (PSCs) are essential for soft stretchable electronics. However, their environmental stability remains a longstanding concern. Here we report a surface-tethered stretchable molecular protecting layer to realize stretchable polymer electronics that are stable in direct contact with physiological fluids, containing water, ions and biofluids. This is achieved through the covalent functionalization of fluoroalkyl chains onto a stretchable PSC film surface to form densely packed nanostructures. The nanostructured fluorinated molecular protection layer (FMPL) improves the PSC operational stability over an extended period of 82 days and maintains its protection under mechanical deformation. We attribute the ability of FMPL to block water absorption and diffusion to its hydrophobicity and high fluorination surface density. The protection effect of the FMPL (~6 nm thickness) outperforms various micrometre-thick stretchable polymer encapsulants, leading to a stable PSC charge carrier mobility of ~1 cm2 V-1 s-1 in harsh environments such as in 85-90%-humidity air for 56 days or in water or artificial sweat for 42 days (as a benchmark, the unprotected PSC mobility degraded to 10-6 cm2 V-1 s-1 in the same period). The FMPL also improved the PSC stability against photo-oxidative degradation in air. Overall, we believe that our surface tethering of the nanostructured FMPL is a promising approach to achieve highly environmentally stable and stretchable polymer electronics.

Neuromorphic sensorimotor loop embodied by monolithically integrated, low-voltage, soft e-skin.

Artificial skin that simultaneously mimics sensory feedback and mechanical properties of natural skin holds substantial promise for next-generation robotic and medical devices. However, achieving such a biomimetic system that can seamlessly integrate with the human body remains a challenge. Through rational design and engineering of material properties, device structures, and system architectures, we realized a monolithic soft prosthetic electronic skin (e-skin). It is capable of multimodal perception, neuromorphic pulse-train signal generation, and closed-loop actuation. With a trilayer, high-permittivity elastomeric dielectric, we achieved a low subthreshold swing comparable to that of polycrystalline silicon transistors, a low operation voltage, low power consumption, and medium-scale circuit integration complexity for stretchable organic devices. Our e-skin mimics the biological sensorimotor loop, whereby a solid-state synaptic transistor elicits stronger actuation when a stimulus of increasing pressure is applied.

High-sensitivity vector bend sensor based on a fiber directional coupler inscribed by a femtosecond laser.

In this Letter, we demonstrate a high-sensitivity vector bend sensor based on a fiber directional coupler. The fiber directional coupler is composed of two parallel waveguides inscribed within a no-core fiber (NCF) by a femtosecond laser. Since the two written waveguides have closely matched refractive indices and geometries, the transmission spectrum of the fiber directional coupler possesses periodic resonant dips. Such a fiber directional coupler exhibits a good bending-dependent spectral shift response due to its asymmetric structure. Experimental results show that bending sensitivities of -97.11 nm/m-1 and 58.22 nm/m-1 are achieved for the 0° and 180° orientations in the curvature range of 0-0.62 m-1, respectively. In addition, the proposed fiber directional coupler is shown to be insensitive to external humidity changes, thus improving its suitability in high-accuracy bending measurements.

Flexible and Implantable Polyimide Aptamer-Field-Effect Transistor Biosensors.

Monitoring neurochemical signaling across time scales is critical to understanding how brains encode and store information. Flexible (vs stiff) devices have been shown to improve in vivo monitoring, particularly over longer times, by reducing tissue damage and immunological responses. Here, we report our initial steps toward developing flexible and implantable neuroprobes with aptamer-field-effect transistor (FET) biosensors for neurotransmitter monitoring. A high-throughput process was developed to fabricate thin, flexible polyimide probes using microelectromechanical-system (MEMS) technologies, where 150 flexible probes were fabricated on each 4 in. Si wafer. Probes were 150 µm wide and 7 µm thick with two FETs per tip. The bending stiffness was 1.2 × 10-11 N·m2. Semiconductor thin films (3 nm In2O3) were functionalized with DNA aptamers for target recognition, which produces aptamer conformational rearrangements detected via changes in FET conductance. Flexible aptamer-FET neuroprobes detected serotonin at femtomolar concentrations in high-ionic strength artificial cerebrospinal fluid. A straightforward implantation process was developed, where microfabricated Si carrier devices assisted with implantation such that flexible neuroprobes detected physiological relevant serotonin in a tissue-hydrogel brain mimic.

Wearable aptamer-field-effect transistor sensing system for noninvasive cortisol monitoring.

Wearable technologies for personalized monitoring require sensors that track biomarkers often present at low levels. Cortisol­a key stress biomarker­is present in sweat at low nanomolar concentrations. Previous wearable sensing systems are limited to analytes in the micromolar-millimolar ranges. To overcome this and other limitations, we developed a flexible field-effect transistor (FET) biosensor array that exploits a previously unreported cortisol aptamer coupled to nanometer-thin-film In2O3 FETs. Cortisol levels were determined via molecular recognition by aptamers where binding was transduced to electrical signals on FETs. The physiological relevance of cortisol as a stress biomarker was demonstrated by tracking salivary cortisol levels in participants in a Trier Social Stress Test and establishing correlations between cortisol in diurnal saliva and sweat samples. These correlations motivated the development and on-body validation of an aptamer-FET array­based smartwatch equipped with a custom, multichannel, self-referencing, and autonomous source measurement unit enabling seamless, real-time cortisol sweat sensing.

Implantable aptamer-field-effect transistor neuroprobes for in vivo neurotransmitter monitoring.

While tools for monitoring in vivo electrophysiology have been extensively developed, neurochemical recording technologies remain limited. Nevertheless, chemical communication via neurotransmitters plays central roles in brain information processing. We developed implantable aptamer­field-effect transistor (FET) neuroprobes for monitoring neurotransmitters. Neuroprobes were fabricated using high-throughput microelectromechanical system (MEMS) technologies, where 150 probes with shanks of either 150- or 50-µm widths and thicknesses were fabricated on 4-inch Si wafers. Nanoscale FETs with ultrathin (~3 to 4 nm) In2O3 semiconductor films were prepared using sol-gel processing. The In2O3 surfaces were coupled with synthetic oligonucleotide receptors (aptamers) to recognize and to detect the neurotransmitter serotonin. Aptamer-FET neuroprobes enabled femtomolar serotonin detection limits in brain tissue with minimal biofouling. Stimulated serotonin release was detected in vivo. This study opens opportunities for integrated neural activity recordings at high spatiotemporal resolution by combining these aptamer-FET sensors with other types of Si-based implantable probes to advance our understanding of brain function.

Single-Step Dual-Layer Photolithography for Tunable and Scalable Nanopatterning.

Conventional photolithography, due to its scalability, robustness, and straightforward processes, has been widely applied to micro- and nanostructure manufacturing in electronics, optics, and biology. However, optical diffraction limits the ultimate resolution of conventional photolithography, which hinders its potential in nanoscale patterning for broader applications. Here, we introduce a derivative of conventional photolithography for nanoscale patterning called dual-layer photolithography (DLPL), which is based on the controlled exposure and development of overlapping positive and negative photoresists. In a typical experiment, substrates are sequentially coated by two layers of photoresists (both positive and negative). Then, we purposefully control the exposure time to generate slightly larger features in the positive photoresist than those in the negative photoresist. After development, their overlapping areas become the final features, which outline the original features. We demonstrate line widths down to 300 nm here, which can be readily improved with more precise control. By adjusting the lithography parameters and material deposition, the feature sizes, shapes (e.g., rings, numbers, letters), line widths (300-900 nm), and materials (e.g., SiO2, Cr, and Ag) of these features can be independently controlled. Combined with anisotropic etching, more complex three-dimensional nanostructures can be fabricated as well, as we demonstrate here with Si. We further fabricate photodetectors as an example application to show that these nanostructures fabricated by DLPL can be used to promote light-trapping MAPbI3 perovskite films to achieve good photoelectric properties. This strategy is not limited to ultraviolet photolithography and may also be incorporated into other energetic beam-based lithographic approaches, including deep and extreme ultraviolet photolithographies and electron beam lithography, to enhance their resolution.

Narrower Nanoribbon Biosensors Fabricated by Chemical Lift-off Lithography Show Higher Sensitivity.

Wafer-scale nanoribbon field-effect transistor (FET) biosensors fabricated by straightforward top-down processes are demonstrated as sensing platforms with high sensitivity to a broad range of biological targets. Nanoribbons with 350 nm widths (700 nm pitch) were patterned by chemical lift-off lithography using high-throughput, low-cost commercial digital versatile disks (DVDs) as masters. Lift-off lithography was also used to pattern ribbons with 2 µm or 20 µm widths (4 or 40 µm pitches, respectively) using masters fabricated by photolithography. For all widths, highly aligned, quasi-one-dimensional (1D) ribbon arrays were produced over centimeter length scales by sputtering to deposit 20 nm thin-film In2O3 as the semiconductor. Compared to 20 µm wide microribbons, FET sensors with 350 nm wide nanoribbons showed higher sensitivity to pH over a broad range (pH 5 to 10). Nanoribbon FETs functionalized with a serotonin-specific aptamer demonstrated larger responses to equimolar serotonin in high ionic strength buffer than those of microribbon FETs. Field-effect transistors with 350 nm wide nanoribbons functionalized with single-stranded DNA showed greater sensitivity to detecting complementary DNA hybridization vs 20 µm microribbon FETs. In all, we illustrate facile fabrication and use of large-area, uniform In2O3 nanoribbon FETs for ion, small-molecule, and oligonucleotide detection where higher surface-to-volume ratios translate to better detection sensitivities.

Flexible Multiplexed In2O3 Nanoribbon Aptamer-Field-Effect Transistors for Biosensing.

Flexible sensors are essential for advancing implantable and wearable bioelectronics toward monitoring chemical signals within and on the body. Developing biosensors for monitoring multiple neurotransmitters in real time represents a key in vivo application that will increase understanding of information encoded in brain neurochemical fluxes. Here, arrays of devices having multiple In2O3 nanoribbon field-effect transistors (FETs) were fabricated on 1.4-µm-thick polyethylene terephthalate (PET) substrates using shadow mask patterning techniques. Thin PET-FET devices withstood crumpling and bending such that stable transistor performance with high mobility was maintained over >100 bending cycles. Real-time detection of the small-molecule neurotransmitters serotonin and dopamine was achieved by immobilizing recently identified high-affinity nucleic-acid aptamers on individual In2O3 nanoribbon devices. Limits of detection were 10 fM for serotonin and dopamine with detection ranges spanning eight orders of magnitude. Simultaneous sensing of temperature, pH, serotonin, and dopamine enabled integration of physiological and neurochemical data from individual bioelectronic devices.

Chemical Lift-Off Lithography of Metal and Semiconductor Surfaces.

Chemical lift-off lithography (CLL) is a subtractive soft-lithographic technique that uses polydimethylsiloxane (PDMS) stamps to pattern self-assembled monolayers of functional molecules for applications ranging from biomolecule patterning to transistor fabrication. A hallmark of CLL is preferential cleavage of Au-Au bonds, as opposed to bonds connecting the molecular layer to the substrate, i.e., Au-S bonds. Herein, we show that CLL can be used more broadly as a technique to pattern a variety of substrates composed of coinage metals (Pt, Pd, Ag, Cu), transition and reactive metals (Ni, Ti, Al), and a semiconductor (Ge) using straightforward alkanethiolate self-assembly chemistry. We demonstrate high-fidelity patterning in terms of precise features over large areas on all surfaces investigated. We use patterned monolayers as chemical resists for wet etching to generate metal microstructures. Substrate atoms, along with alkanethiolates, were removed as a result of lift-off, as previously observed for Au. We demonstrate the formation of PDMS-stamp-supported bimetallic monolayers by performing CLL on two different metal surfaces using the same PDMS stamp. By expanding the scope of the surfaces compatible with CLL, we advance and generalize CLL as a method to pattern a wide range of substrates, as well as to produce supported metal monolayers, both with broad applications in surface and materials science.

Scalable Fabrication of Quasi-One-Dimensional Gold Nanoribbons for Plasmonic Sensing.

Plasmonic nanostructures have a wide range of applications, including chemical and biological sensing. However, the development of techniques to fabricate submicrometer-sized plasmonic structures over large scales remains challenging. We demonstrate a high-throughput, cost-effective approach to fabricate Au nanoribbons via chemical lift-off lithography (CLL). Commercial HD-DVDs were used as large-area templates for CLL. Transparent glass slides were coated with Au/Ti films and functionalized with self-assembled alkanethiolate monolayers. Monolayers were patterned with lines via CLL. The lifted-off, exposed regions of underlying Au were selectively etched into large-area grating-like patterns (200 nm line width; 400 nm pitch; 60 nm height). After removal of the remaining monolayers, a thin In2O3 layer was deposited and the resulting gratings were used as plasmonic sensors. Distinct features in the extinction spectra varied in their responses to refractive index changes in the solution environment with a maximum bulk sensitivity of ∼510 nm/refractive index unit. Sensitivity to local refractive index changes in the near-field was also achieved, as evidenced by real-time tracking of lipid vesicle or protein adsorption. These findings show how CLL provides a simple and economical means to pattern large-area plasmonic nanostructures for applications in optoelectronics and sensing.

Photothermal Intracellular Delivery Using Gold Nanodisk Arrays.

Local heating using pulsed laser-induced photothermal effects on plasmonic nanostructured substrates can be used for intracellular delivery applications. However, the fabrication of plasmonic nanostructured interfaces is hampered by complex nanomanufacturing schemes. Here, we demonstrate the fabrication of large-area plasmonic gold (Au) nanodisk arrays that enable photothermal intracellular delivery of biomolecular cargo at high efficiency. The Au nanodisks (350 nm in diameter) were fabricated using chemical lift-off lithography (CLL). Nanosecond laser pulses were used to excite the plasmonic nanostructures, thereby generating transient pores at the outer membranes of targeted cells that enable the delivery of biomolecules via diffusion. Delivery efficiencies of >98% were achieved using the cell impermeable dye calcein (0.6 kDa) as a model payload, while maintaining cell viabilities at >98%. The highly efficient intracellular delivery approach demonstrated in this work will facilitate translational studies targeting molecular screening and drug testing that bridge laboratory and clinical investigations.

Phenylalanine Monitoring via Aptamer-Field-Effect Transistor Sensors.

Determination of the amino acid phenylalanine is important for lifelong disease management in patients with phenylketonuria, a genetic disorder in which phenylalanine accumulates and persists at levels that alter brain development and cause permanent neurological damage and cognitive dysfunction. Recent approaches for treating phenylketonuria focus on injectable medications that efficiently break down phenylalanine but sometimes result in detrimentally low phenylalanine levels. We have identified new DNA aptamers for phenylalanine in two formats, initially as fluorescent sensors and then, incorporated with field-effect transistors (FETs). Aptamer-FET sensors detected phenylalanine over a wide range of concentrations (fM to mM). para-Chlorophenylalanine, which inhibits the enzyme that converts phenylalanine to tyrosine, was used to induce hyperphenylalaninemia during brain development in mice. Aptamer-FET sensors were specific for phenylalanine versus para-chlorophenylalanine and differentiated changes in mouse serum phenylalanine at levels expected in patients. Aptamer-FETs can be used to investigate models of hyperphenylalanemia in the presence of structurally related enzyme inhibitors, as well as naturally occurring amino acids. Nucleic acid-based receptors that discriminate phenylalanine analogs, some that differ by a single substituent, indicate a refined ability to identify aptamers with binding pockets tailored for high affinity and specificity. Aptamers of this type integrated into FETs enable rapid, electronic, label-free phenylalanine sensing.

Intracellular Photothermal Delivery for Suspension Cells Using Sharp Nanoscale Tips in Microwells.

Efficient intracellular delivery of biomolecules into cells that grow in suspension is of great interest for biomedical research, such as for applications in cancer immunotherapy. Although tremendous effort has been expended, it remains challenging for existing transfer platforms to deliver materials efficiently into suspension cells. Here, we demonstrate a high-efficiency photothermal delivery approach for suspension cells using sharp nanoscale metal-coated tips positioned at the edge of microwells, which provide controllable membrane disruption for each cell in an array. Self-aligned microfabrication generates a uniform microwell array with three-dimensional nanoscale metallic sharp tip structures. Suspension cells self-position by gravity within each microwell in direct contact with eight sharp tips, where laser-induced cavitation bubbles generate transient pores in the cell membrane to facilitate intracellular delivery of extracellular cargo. A range of cargo sizes were tested on this platform using Ramos suspension B cells with an efficiency of >84% for Calcein green (0.6 kDa) and >45% for FITC-dextran (2000 kDa), with retained viability of >96% and a throughput of >100 000 cells delivered per minute. The bacterial enzyme ß-lactamase (29 kDa) was delivered into Ramos B cells and retained its biological activity, whereas a green fluorescence protein expression plasmid was delivered into Ramos B cells with a transfection efficiency of >58%, and a viability of >89% achieved.

A Microfabricated Sandwiching Assay for Nanoliter and High-Throughput Biomarker Screening.

Cells secrete substances that are essential to the understanding of numerous immunological phenomena and are extensively used in clinical diagnoses. Countless techniques for screening of biomarker secretion in living cells have generated valuable information on cell function and physiology, but low volume and real-time analysis is a bottleneck for a range of approaches. Here, a simple, highly sensitive assay using a high-throughput micropillar and microwell array chip (MIMIC) platform is presented for monitoring of biomarkers secreted by cancer cells. The sensing element is a micropillar array that uses the enzyme-linked immunosorbent assay (ELISA) mechanism to detect captured biomolecules. When integrated with a microwell array where few cells are localized, interleukin 8 (IL-8) secretion can be monitored with nanoliter volume using multiple micropillar arrays. The trend of cell secretions measured using MIMICs matches the results from conventional ELISA well while it requires orders of magnitude less cells and volumes. Moreover, the proposed MIMIC is examined to be used as a drug screening platform by delivering drugs using micropillar arrays in combination with a microfluidic system and then detecting biomolecules from cells as exposed to drugs.

Spin-Dependent Ionization of Chiral Molecular Films.

Spin selectivity in photo-emission from ferromagnetic substrates functionalized with chiral organic films was analyzed by ultraviolet photoelectron spectroscopy at room temperature. Using radiation with photon energy greater than the ionization potential of the adsorbed molecules, photoelectrons were collected that originated from both underlying ferromagnetic substrates and the organic films, with kinetic energies in the range of ca. 0-18 eV. We investigated chiral organic films composed of self-assembled monolayers of α-helical peptides and electrostatically adsorbed films of the protein, bovine serum albumin, with different α-helix and ß-sheet contents. Ultraviolet photoelectron spectral widths were found to depend on substrate magnetization orientation and polarization, which we attribute to helicity-dependent molecular ionization cross sections arising from photoelectron impact, possibly resulting in spin-polarized holes. These interactions between spin-polarized photoelectrons and chiral molecules are physically manifested as differences in the measured photoionization energies of the chiral molecular films. Substrate magnetization-dependent ionization energies and work function values were deconvoluted using surface charge neutralization techniques, permitting the measurement of relative spin-dependent energy barriers to transmission through chiral organic films.