Symposium SB07—Bioelectrical Interfaces

SUMMARY AND MOTIVATION - This paper presents non-dissolvable silk fibroin in the form of highly-bendable and flexible films, housing ultrathin electrodes and conductive traces to enable soft bionic links. These links are wrapped around challenging nerve geometries and laminated onto planar cortical surfaces, assisting in the electrical recording of neural activity from the target tissue surfaces. Various materials tests and functional demonstrations in an anesthetized animal model illustrate the suitability of non-dissolvable silk as a candidate material for use in water-stable electrical sensing devices for in vivo applications.
ADVANCES OVER PREVIOUS WORKS - Silk, due to its excellent biocompatibility, has largely facilitated the development of resorbable devices meant to function in vivo for a limited amount of time. Even though there have been research studies on the sustainability of pristine silk in an animal model, use of non-dissolvable silk films in the design of fully functional bionic links has not been reported.
METHODS - A silk substrate housing the gold electrode sites was integrated with a patterned silk film to yield a silk link. EIS measurement was carried out in an electrochemical workstation. The functional validation of the silk link was carried out in a rat model. The silk links were deployed on the sciatic nerve and the cortex in vivo using a medical grade adhesive. In vitro material tests were carried out in a saline medium using an accelerated soak model.
RESULTS –
1. Impedance: The electrode sites of the nerve links provided an impedance of ~2.1 kΩ (1 kHz), and ~22 kΩ (at 1 kHz) in case of cortical links. The impedance values were found to be consistent across different samples (Z=1.9±0.2 kΩ at 1 kHz; n=6 sites, nerve link; 21 ± 1.21 kΩ at 1 kHz, n=12 sites, cortical link).
2. Flexibility: The silk links could be bent around a silicone tube (~600 µm Ø) without inducing any cracks or delamination. Impedance measurements prior to and post wrapping showed negligible differences.
3. In vitro recording: The silk links could record minute sinusoidal signals (0.5-7 kHz), fed into the saline medium from a signal source.
4. Young’s modulus: The Young’s modulus of hydrated non-dissolvable silk films used as substrates and insulation layers was ~6-8 MPa; n=3.
5. Affinity to wet surface: The hydrated silk films used in the bionic links showed affinity to the wet surfaces and conformed well with the slimy surfaces of the sciatic nerve and the cortex in vivo.
6. Biocompatibility Test: Silk films did not exhibit any toxicity to neuronal cells including rat primary Schwann cells, DRG neurons, and hNSC. The films showed excellent cell-material interactions and good bioactivity with cells.
7. In vivo recording: The sciatic nerve was electrically stimulated, and the corresponding evoked action potentials recorded by the distally placed silk links measured ~320 µV (E#1) and ~170 µV (E#2) in an experiment trial (60 µs pulse, 600 µA). The electrocorticogram (ECoG) recording capability of the silk link was demonstrated using a rat transient ischemia (TIA) model. ECoG recordings (evoked through forepaw stimulation) prior to induction of stroke served as the baseline and recordings post induction provided functional validation of the silk link. Suppression of the ECoG activity observed post induction of stroke was captured cleanly by the silk link.
CONCLUDING OPINION - The materials and methods described here provide the basis for excellently biocompatible sensor links on ultrathin non-dissolvable silk that offers robust conformal lamination onto tissue surfaces in vivo. Upcoming research studies will focus on building a well-tested and validated soft neurotechnology toolbox that can offer a library of materials to design tissue-compliant interfaces that are well-accepted by the biological milieu. Non-dissolvable silk, given its excellent biocompatibility, transparency, flexibility, and robustness is a value-add to such a toolbox.

Graphene has proved to be an outstanding material for the fabrication of biocompatible electrodes and microelectrode arrays (MEA). Motivated by their high sensitivity, low noise, scalability and stability in aqueous electrolyte, graphene-based MEA have been used for the detection of relevant molecules and biomolecules as well as electrical cell signals, either in vivo or in vitro. Using these new technology developments we are now able to shed new light onto several diseases and pathologies.
One particular field in which this technology can be useful is electroretinography (ERG). This technique involves placing an electrode on the cornea, flashing the eye with light and recording the electrical signal produced by the retina. Usually, a metal electrode bended in a loop or a contact lens with attached wires are used. These types of electrodes mainly present two problems: discomfort produced by the used rigid materials and the difficulty to measure signals from the whole cornea, since their opacity would block the light meant to stimulate the retina. Therefore, electrodes combining flexibility and transparency could provide a solution for ERG measurements. In this work we present the fabrication and characterization of such devices based on single layer graphene technology, as well as their use on two different applications.
On the one hand we use single layer graphene electrodes to diagnose retinitis pigmentosa on a P23H rat model. Retinitis pigmentosa is a degenerative disease that causes the loss of photoreceptor cells on the retina producing night blindness and a progressive loss of the visual field. The graphene electrode, despite its small size, performs very well, enabling the diagnosis of the disease as good as its bulkier, more uncomfortable gold counterpart. Furthermore, the graphene device shows better resolution when dealing with the high frequency components of the ERG signals.
On the other hand, we use this technology to gain insight on the spatial distribution of electrical signals across the retina. With a flexible and transparent graphene MEA we can measure individual signals on different locations of the cornea without blocking the light used to elicit the retinal response. These measurements can shed new light on how the electrical signals are produced and propagated inside the eye. Using these devices, we have detected differences on the signal recorded on the centre of the cornea compared to that coming from the edges.
Altogether, SLG electrodes provide an outstanding solution to perform ERG. Graphene transparency, flexibility and biocompatibility allow us to fabricate devices that can compete with the current state of the art ERG electrodes.

Acknowledgements :
This work has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement no. 732032 and the FIS2017-85787-R project financed by the Spanish Ministerio de Ciencia, Innovación y Universidades, the Spanish Research Agency (AEI) and the European Development Fund. The ICN2 is funded by the CERCA programme / Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706).

Stretchable thin-film electronics are expected to open up a new class of applications ranging from wearable electronics for health-monitoring and human-machine interfaces, implantable electronics, and in vitro characterization. In this talk, we will review recent progress and outlook of hypoallergenic electronic sensor that can be worn on the skin continuously for a week without discomfort. The elastic electrode constructed of breathable nanoscale meshes holds promise for the development of noninvasive on-skin devices that can monitor a person's health such as electrocardiogram and skin moisture levels continuously over a long period. Then, similar nanomesh sensors is applied to in vitro characterization. These can monitor the field potential of cardiomyocytes on gel, while enabling them to move dynamically without interference.

Human skin is excellent at detecting pressures over a wide range of values, from the light movement of air against its surface (< 1 kPa) to the load of heavy weights (> 10 kPa). An electronic analog to skin (e-skin) is highly desirable, both to provide closed-loop (tactile) feedback for robotic limbs and to enable wearable devices for human health monitoring (e.g. detecting pulse). Towards the development of e-skin, numerous thin film-based pressure sensors have been demonstrated in the literature; these devices are typically designed to undergo changes in either resistance or capacitance in response to pressure, transducing a mechanical force into an electrical signal. In such devices, different microstructures or porous structures may be leveraged to control the physical deformation of the sensing material that occurs in response to the applied force.

Here, we demonstrate a simple, non-lithographic method for fabricating resistive pressure sensors with a broad range of working pressures (up to 40 kPa) and a low limit of detection. The device is soft, compact and comformable, with a thickness of around 300 microns. One advantage of this device design is that all electrical contact is made at the interface between the two layers; therefore very small changes in pressure can be measured, resulting in a low limit of detection (20 Pa). As the applied pressure increases, the pores themselves can deform drastically and form new contacts between the layers. This sensor has a sandwich structure comprised of metallized top and bottom sheets of porous polydimethylsiloxane (PDMS), fabricated using a simple templating method. In this method, a spin-coated layer of PDMS is pressed onto a layer of powder. The PDMS is then cured and the template is subsequently dissolved. To metallize the structures, the inner faces of each of these porous layers are coated with a layer of conductive silver nanowires, which coats the surface of the pores. The Ag nanowires layers are initially in light contact, and the device undergoes a change in resistance when pressure is applied perpendicular to the plane of the sheets.

In this work, we investigate how the properties of the porous layers affect both the mechanical properties and the response of the device by varying both pore size and elastomer stiffness. The stiffness of the elastomer was tuned by varying the ratio of base to crosslinker in the material (5:1, 10:1, and 15:1); as the fraction of crosslinker in elastomer increased, the response time of the sensor was found to decrease. To vary pore size, three different powder templates were utilized: KCl, NaCl, and sugar, with typical diameters of 60-80 µm, 150-200 µm, and 400-550 µm, respectively. The sensor fabricated with a KCl template (which had the smallest pores) and 10:1 PDMS demonstrated the best performance, with a sensitivity of 14.1 kPa^-1 (up to 3.5 kPa), 4.8 kPa^-1 (up to 10 kPa), 1.84 kPa^-1 (up to 40 kPa) and no performance degradation over 1000 loading and unloading cycles.

Wearable electronic applications of these devices, including pulse measurement, facial movements, and sound tracking, are demonstrated in this work. Overall the combination of non-lithographically-defined pores and solution-processed Ag nanowires yields a simple to fabricate device which exhibits high sensitivity and a low limit of detection. In addition to providing tactile feedback to robotic limbs, such devices may have applications in intrinsically stretchable bioelectronics.

Heart failure is a critical public health issue affecting tens of millions of people each year. One paradigm that has revolutionized treatment plans is the continuous flow Ventricular Assist Device (VAD). However, due to the thrombogenic nature of the VAD, complications associated with bleeding events and thrombosis require the patients to take blood thinners, which limit the overall quality-of-life and survival of implanted patients. When on a continuous regiment of blood thinners, VAD patients require frequent monitoring to ensure that prothrombin time (and the corresponding international normalized ratio, INR) is within a clinically acceptable range. Currently, the standard of care requires outpatient testing of prothrombin time (PT) every 1-4 weeks. This is time-consuming and burdensome to patients and healthcare systems, and furthermore recent studies indicate that patients may benefit from more frequent testing intervals. An affordable, point-of-care test (POCT) coagulometer for home monitoring of PT would fill these needs.
In this work, a fully printed point-of-care test (POCT) for the measurement of PT using electrical transduction is demonstrated. In order to create a low-cost device, an inexpensive testing platform was designed, which consists of a printed silver nanowire thin-film resistor to provide high electrode surface area and to set the baseline impedance signal. The nanowires had diameters of 30-50 nm and lengths of 2-6 µm and were synthesized using the polyol method. After all rinsing steps, the silver nanowire concentration was measured using atomic absorption spectroscopy (AAS) and then concentrated in water at 10 mg mL^-1. The resultant Ag nanowire inks were printed using an aerosol jet printer under ultrasonic atomization, forming thin films with a resistance in the range of 50–200 Ω. Interrogation of whole blood modulates the impedance of the Ag nanowire film, with the impedance maximum corresponding to the PT. Measured using electrochemical impedance spectroscopy (EIS), the operating frequency was found to be optimal at 15kHz, at which a stable and reproducible clotting time response was obtained. The functionality of the device was demonstrated in whole blood derived from both animal and human subjects. Devices were printed on both glass and polyimide, establishing the ability to measure identical clotting times even on a flexible substrate under strain / bending. These results lay the groundwork for fully printed impedimetric coagulometers that could address the unmet need for a low-cost, robust POCT to improve outcomes for VAD patients by straightforward monitoring of PT/INR.

The optical method to determine oxygen saturation in blood is limited to only tissues that can be transilluminated. The status quo provides a single-point measurement and lacks 2D oxygenation mapping capability. We have demonstrated a flexible and printed sensor array composed of organic light-emitting diodes and organic photodiodes, which senses reflected light from tissue to determine the oxygen saturation. We use the reflectance oximeter array beyond the conventional sensing locations. The sensor is implemented to measure oxygen saturation on the forehead with 1.1% mean error and to create 2D oxygenation maps of adult forearms under pressure-cuff–induced ischemia. In addition, we present mathematical models to determine oxygenation in the presence and absence of a pulsatile arterial blood signal. The mechanical flexibility, 2D oxygenation mapping capability, and the ability to place the sensor in various locations make the reflectance oximeter array promising for medical sensing applications such as monitoring of real-time chronic medical conditions as well as postsurgery recovery management of tissues, organs, and wounds.

Soft, noninvasive and multifunctional epidermal electronics (a.k.a. e-tattoos) have demonstrated many exciting applications in mobile health, human-machine interface (HMI) and so on. However, e-tattoos are only practically useful when they are low cost and wireless. Previously, our group has invented a dry and digital manufacturing approach named the “cut-and-paste” method for the rapid prototyping of e-tattoos using a paper/vinyl cutter plotter [1]. This method has been demonstrated to work for thin film metals [1, 2], various polymer sheets [1, 3], ceramics [4], as well as 2D materials such as graphene [5, 6]. The cut-and-pasted e-tattoos can be low cost, large area, and applicable for the measurement of a variety of physiological signals such as multichanel electromyogram (EMG), electrocardiogram (ECG), seismocardiogram (SCG), electrooculogram (EOG), skin hydration, and so on [1-3, 5, 6]. To make the e-tattoos go wireless, we now report the “cut-solder-paste” process to incorporate integrated circuits (ICs) for signal readout and processing, near field communication (NFC) [7], as well as Bluetooth transmission [8]. To overcome the limited patterning resolution of the cutter plotter and to recycle the ICs, we propose a modular concept in which the wireless charging layer (NFC layer), the wireless communication layer (Bluetooth layer), the readout circuit layer, and the sensor/electrode layer are fabricated individually and stacked up at the final step of fabrication. The thickness of a fully assembled multilayer e-tattoo (excluding IC chips) is less than 300 um and the overall stretchability is still beyond 20%. In addition to already mentioned capabilities, such e-tattoos can also wireless track motion, mechano-acoustic heart signals, and oxygen saturation (SpO2) (Fig. 3) [3, 7, 8]. The NFC-enabled e-tattoos can be wirelessly charged so no battery is needed but the sampling rate is limited to 25 Hz and the wireless communication distance is limited to 5 cm. The Bluetooth-enabled e-tattoos require on-tattoo batteries but the sampling rate can be up to 4 kHz and the wireless communication range can be up to 10 m. Combining the NFC layer and the Bluetooth layer in one e-tattoo, we demonstrate that such wireless e-tattoo can also be wirelessly charged on-the-go via stretchable fabric feeding coils [8], enabling long-term, ambulatory and continuous sensing. Moreover, we propose that different layers can be disassembled and reassembled multiple times. After disassembly, the electrode layer should be disposed but the other layers can be reassembled into new e-tattoos. The low-cost, rapid prototyping method together with the wireless and reconfigurable capabilities represent exciting advancement towards practically useful wireless e-tattoos.


1. Yang, S., et al., "Cut-and-Paste" Manufacture of Multiparametric Epidermal Sensor Systems. Advanced Materials, 2015. 27(41): p. 6423–6430.
2. Wang, Y., et al., Low-cost, μm-thick, tape-free electronic tattoo sensors with minimized motion and sweat artifacts. npj Flexible Electronics, 2018. 2(1): p. 6.
3. Ha, T., et al., A chest-laminated ultrathin and stretchable e-tattoo for the measurement of electrocardiogram, seismocardiogram, and cardiac time intervals. Advanced Science, 2019: p. 1900290.
4. Yang, S., E. Ng, and N. Lu, Indium Tin Oxide (ITO) Serpentine Ribbons on Soft Substrates Stretched beyond 100%. Extreme Mechanics Letters, 2015. 2: p. 37-45.
5. Ameri, S.K., et al., Imperceptible Electrooculography Graphene Sensor System for Human-Robot Interface npj 2D Materials and Applications, 2018. 2: p. 19.
6. Ameri, S.K., et al., Graphene Electronic Tattoo Sensors. Acs Nano, 2017. 11(8): p. 7634-7641.
7. Jeong, H., et al., Modular and Reconfigurable NFC-Enabled Wireless Electronic Tattoos for Biometric Sensing. Advanced Materials Technologies, 2019: p. 1900117.
8. Jeong, H., et al., Wireless E-Tattoos Chargeable On-The-Go. To be submitted, 2019.

As the quality of life increases, people’s interest in better healthcare grows, and their demand for customized healthcare devices for individuals increases. Accordingly, there is an increasing interest in wearable devices that can be worn on the body and detect biological signals in real time. Thus, many researchers have intensively studied to develop skin-attachable wearable electronics without any physical inconvenience in daily life. These wearable electronics vitally need not only bio-signal sensing devices but also data storage components to manage a user's health condition in real time. Therefore, nonvolatile memory is a key part of these customized healthcare wearable devices. Among various nonvolatile memories, a resistive random-access memory (RRAM) is attracting attention as a next-generation nonvolatile memory device because of its advantages of high-speed switching, low power consumption, low manufacturing cost, etc. However, in order to apply RRAMs to skin-attachable wearable devices, problems such as ultra-lightweight, unbreakable, and free-form design must be resolved. To overcome these problems, organic-based RRAMs can be an attractive candidate with advantages such as flexibility, simple process, and so on. However, these organic-based RRAMs are difficult to apply to skin-attachable devices due to their sensitivity to the external environmental factors. In particular, moisture could cause degradation of an organic thin film and fatally affect the memory operations of organic-based RRAMs. Therefore, resolving issues such as degradation of the electrical performance of organic-based RRAMs due to external moisture before implementing for skin-attachable wearable devices become an important factor.
In this study, we demonstrate a novel organic material, nitrocellulose (NC), as a switching layer of RRAM for the first time that meets the requirements of the skin-attachable wearable devices. NC is obtained by nitriding cellulose and can be formed at low temperature through a simple solution process. To fabricate NC based RRAMs, we deposited NC by solution process on the p+Si wafer, and top electrode, Al/Au, was deposited by the thermal evaporator. Fabricated NC based RRAMs shows bipolar switching behavior for current-voltage (I-V) characteristic. The 'Set' voltage, which is converted from a high resistance state (HRS) to a low resistance state (LRS), is about 2.5 V, and the 'Reset' voltage, which is converted from LRS to HRS, is -1.5 V. NC based RRAM shows a resistance switching window of 10² and maintains switching operations after 100 cycles of consecutive endurance tests. Data retention results show reliable data storage performance of up to 10⁴ seconds under constant voltage stress of 0.3 V. As one of the previous researches of organic-based RRAMs proposes, the switching operation in organic-based RRAMs using the easily oxidizable metal electrode is attributed to the formed native oxide layer between the organic layer and the metal electrode. Likewise, as Al is one of the easily oxidized metals when it is used as a top electrode of NC based RRAMs, it is easily oxidized by the oxygen functional groups present in NC. Thus, We can deduce that NC based RRAMs show the switching operation by the formed native Al oxide. We found a new layer was formed between Al and NC by high-resolution transmission electron microscopy (HR-TEM) images. In addition, an energy dispersive X-ray spectrometer (EDS) mapping and an X-ray depth photoelectron spectroscopy (XPS depth) analysis confirmed that the newly formed layer is Al oxide. Additionally, NC based RRAMs show robust memory operations even after dipping in deionized water (DI water) for 24 hours due to the high moisture stability of the nitrocellulose. Finally, this RRAM is fabricated on polyimide (PI) to demonstrate the applicability of flexible memory suitable for skin-attachable wearable devices.

Rubber’s inherently dissipative nature and its extreme elastic properties make it the material of choice for children’s toys such as bouncing balls and air-filled balloons. This talk takes inspiration from these toys to understand materials properties and design soft actuators: Bouncing balls help exploring the dissipative properties for damping structures inspired by fruit while balloon shaped actuators inspired by plants enable fast and strong actuators.
Potential applications include design guidelines for protective structures in two and three dimensions such as cushioning e-skin complete with stretchable sensors and soft actuators for exoskeletons.

Wearable electronics enable an intimate experience between users and their devices. In contrast to conventional large, rigid-body electronics, wearables conform to the human body even during routine motion. Wearable electronics can be applied to strain sensing, contributing to fields such as physiotherapy, virtual reality gaming, and robotics. Current efforts to prototype soft strain sensors often disregard the integration of the sensor onto a wearable platform, instead using temporary mounting techniques such as taping or gluing onto skin or articles of clothing. While these methods enable characterization of the strain sensors, they are not suitable for practical wearability. Here, we present an alternative method for the fabrication of wearable strain sensors by creating ready-to-wear prototypes by fabricating stretchable metal strain sensors on the surfaces of commercially available wearable nitrile butadiene rubber (NBR) gloves. In this presentation, we discuss the fabrication method, which uses a stencil mask to pattern a spray-coated latex resist, followed by electroless-nickel immersion-gold deposition selectively within the regions unprotected by the resist. We discuss the surface morphology, resolution of the patterning technique, electrical performance, and durability of these strain sensors. We also demonstrate the versatility of this ready-to-wear strain sensor as a low-cost, lightweight, fitted glove sensor in relation to gesture monitoring in an American Sign Language translator and remote control of a soft robotic hand that mirrors the gestures made by the glove user.

In the near future, wearable electronics that can serve as devices for point of care diagnostics, brain machine interfaces, and therapeutic responsive stimulation may not only facilitate health monitoring and disease diagnosis, but on-the-spot treatment and intervention. Low cost energy storage, flexibility, and capacity for internal functionality are ideal characteristics that those devices should exhibit.

In this project, we demonstrate a thin, flexible self-powered epidermal electronic device that provides an efficient interface for high quality electrophysiological signal acquisition. This medical patch-like device is built on a micrometer thick parylene substrate with microfabricated gold interconnects and consists of three main parts; i) a biological interface, ii) a microcontroller/bluetooth module, and iii) a flexible battery. Because of its conformability, it can be attached as a patch on different human body areas. To determine the configuration and material composition for optimal signal acquisition, we microfabricated various designs with gold interconnects that lead to several biological interfaces. Gold electrode contacts coated with conductive poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) enriched with D-sorbitol or PEDOT:PSS based anisotropic layers enable low impedance, adhesive interfaces with high spatial resolution. Additionally, internal ion gated organic electrochemical transistor (IGT)-based interfaces were tested to acquire locally amplified physiological signals. The signals are sent to a microcontroller with high speed data acquisition for processing and storage. The heart of the device is a battery based on an electrolyte sandwiched between a composite film of highly conductive PEDOT:PSS and an aluminum electrode, serving as cathode and anode respectively. The battery shows an average cell discharge voltage of 0.5V and can provide specific energy of at least ~15 Whkg^-1 , which can operate our system continuously for at least 40 hours.

The resulting optimal patch was attached on human subjects to obtain high quality electrocardiogram (ECG). Detection algorithms run by our devices can locate ST segment abnormalities that indicate coronary ischemia. Our findings communicate concrete steps towards subtle wearable bioelectronics systems and medical care devices that can record and potentially intervene with the electrophysiological signal of human body.

Organic electrochemical transistors (OECTs) have been shown to be promising devices for amplification of electrical signals and selective sensing of ions and biologically important molecules in an aqueous environment, and thus have potential to be utilised in bioelectronic applications. The sensitivity, selectivity and intensity of the response of this device is determined by the organic semiconducting polymer employed as the active layer. Until now, most OECTs have been fabricated with commercially available conducting poly(3,4-ethylenedioxythiophene) (PEDOT:PSS) as the active layer, and therefore operated in depletion mode with limited modulation. This work presents the design of new organic semiconducting materials which demonstrate significant improvements in OECT performance, through operation in accumulation mode, with high transconductance and low operating voltage, combined with good operational stability.
We discuss here the design, synthesis and performance of novel intrinsic semiconducting polymers for efficient accumulation mode OECT devices. Key aspects such as ion and charge transport in the bulk semiconductor and operational voltage and stability of the devices are addressed in order to elucidate important structure-property relationships. A range of new semiconducting polymers, designed to exhibit facile electrochemical doping of either holes or electrons, facilitate ion penetration and migration, as well as have aqueous compatibility are reported. Electrochemical stability will also be discussed. Optimisation of a series of polymer parameters including electrochemical doping, charge carrier mobility and capacitance are discussed. This approach leads to the design of polymers that can outperform state-of-the-art PEDOT:PSS based depletion mode devices with peak transconductances above 20 mS, peak currents in the mA regime, on/off ratios above 105 and excellent switching times below 1 ms. In addition, we demonstrate that polymers with sufficiently high electron affinities and low ionisation potentials can achieve charge carrier ambipolarity, with both p and n-type device operation.

While human organs and tissues are mostly soft; conventional electronics are hard. Seamlessly merging electronics with human is of imminent importance in addressing grand societal challenges in health and joy of living. However, the main challenge lies in the huge mechanical mismatch between the current form of rigid electronics and the soft curvy nature of biology. Here, I will present a new form of electronics, namely “rubbery electronics and bioelectronics”, with skin-like softness and stretchability, which is constructed all based upon elastic rubbery electronic materials. These rubbery electronic materials are structured in the format of composites, which can be scalably manufactured from common and commercial available materials without dedicated and complicated synthesis. Specifically, we build nanofibril organic semiconductor and metallic nanowires percolated in the elastomeric polymer matrix in a composite format for the rubbery semiconductors and conductors, respectively. Employing these rubbery electronic materials, we have achieved fully rubber format devices, including transistors and sensors, logic gates, active matrices, elastic sensory skin systems, and biointegrated devices, etc. I will showcase a few examples including artificial skins, biomedical implants, and wearable applications.

Conjugated polymer films can transform electrical energy into volume changes when included in electrochemical devices via the exchange of ions and solvent. So far, this volumetric change has been limited to 40% and 100% for reversible and irreversible systems, respectively, thus restricting potential applications of this technology. We report a thiophene based conjugated polymer that reversibly expands by about 300% upon addressing, relative to its previous contracted state, while the first irreversible actuation can achieve values ranging from 1000-10000%, depending on the voltage applied. From experimental and theoretical studies, we find that this large and reversible volumetric switching is due to reorganization of the polymer during swelling as it transforms between a solid-state phase and a gel, still maintaining percolation for conductivity. The polymer was utilized as an electroactive cladding to reduce the void sizes of a porous carbon filter electrode by 85% and for controlled delivery of large biomolecules.

Bioelectrical interfaces between biological systems and electronic devices are crucial in understanding physiological pathways, monitoring onset of diseases at early stages, and transferring information across brain-machine interfaces. Simultaneous transduction of ionic-electronic signals would be of particular interest in this context since ionic transmitters are the means of information transfer in biological media while traditional electronics utilize electrons or holes. In this presentation, we propose strongly correlated oxides (mainly focused on perovskite nickelate) as a potential candidate for this purpose.^1,2 We show that perovskite nickelates can be doped with small ions such as H⁺ and Na⁺ and show large amplified response in their electrical resistance through the Mott metal-insulator transition. The capability of reversibly accepting small ions and converting ionic signal to electrical signals renders perovskite nickelate a strong candidate for bioelectrical and haptic interface applications. We will present case studies of mouse brain interfacing with nickelate devices to record neurotransmitter release. We will also discuss the structural as well as electronic mechanisms leading to experimental observations based on X-day absorption techniques and first-principle calculation studies. Collaborative contributions will be pointed out in the presentation.


References
1. Zhang, H.-T. et al. Perovskite nickelates as bio-electronic interfaces. Nat. Commun. 10, 1651 (2019).
2. Sun, Y. et al. Strongly correlated perovskite lithium ion shuttles. Proc. Natl. Acad. Sci. 115, 9672–9677 (2018).

The emerging research field of organic bioelectronics has developed rapidly over the last few years and elegant examples of biomedically important applications including for example in-vivo drug delivery and neural interfacing have been demonstrated.

The organic electrochemical transistor (OECT), capable of transducing small ionic fluxes into electronic signals in an aqueous environment, is an ideal device to utilise in bioelectronic applications. To date, nearly all OECTs have been fabricated with commercially available PEDOT:PSS, heavily limiting the variability in performance. We have previously shown that tailor-made semiconducting polymers are fully capable of matching the performance of PEDOT:PSS. To capitalise on this discovery and the versatility of the organic chemistry toolbox, further materials development is needed. In my talk I will discuss our recent work in this area covering examples of both molecular and polymeric semiconducting materials and their performance in bioelectronic devices.

Direct measurement and stimulation of ionic, biomolecular, cellular, and tissue-scale activity is a staple of bioelectronic diagnosis and/or therapy. Such bi-directional interfacing can be enhanced by a unique set of properties imparted by organic electronic materials. These materials, based on conjugated polymers, can be adapted for use in biological settings and show significant molecular-level interaction with their local environment, readily swell, and provide soft, seamless mechanical matching with tissue. At the same time, their swelling and mixed conduction allows for enhanced ionic-electronic coupling for transduction of biosignals. These properties serve to enable new capabilities in bioelectronics. In the first part of my talk I will focus on the design of polymer bioelectronic materials for enhanced electrophysiological sensors based on electrochemical transistors. Synthetic design and processing can yield stable and high performance mixed conductors with high volumetric capacity, high transconductance, and steep subthreshold switching characteristics for low power sensing. Rising areas in stability and circuit integration are highlighted. I will then discuss the unique form factors enabled by polymer electronics, and their applications in regenerative engineering, including the development of thermo-responsive conductive hydrogel composites with osteoinductive characteristics. New materials design will continue to fill critical need gaps for challenging problems in bio-electronic interfacing.

Mixed ionic/electronic conductors have demonstrated importance for a number of applications including bioelectronics, neuromorphic computing, and energy storage. Of particular interest are organic electrochemical transistors (OECTs), which have multiple uses for biosensing, but also provide a valuable platform for studying the fundamental properties of mixed conducting materials. The current understanding of the doping mechanism for p-type, accumulation mode OECTs is that the application of a negative gate bias causes the injection of anions into the polymer film along with a corresponding accumulation of holes. However, the highest performing materials demonstrate extensive swelling in the presence of electrolyte, suggesting that there is some intrinsic cation uptake prior to electrochemical biasing. Here we carefully examine the role of the cation on the doping mechanism of poly(3-{[2-(2-methoxyethoxy)ethoxy]methyl}thiophene-2,5-diyl) (P3MEEMT), a high performing OECT active layer material with glycolated side chains. We study the mass of the polymer film at different doping levels using Electrochemical Quartz Crystal Microbalance (EQCM) and find significant mass loss during the initial stages of doping for smaller cations. We confirm the initial presence and the subsequent expulsion of cations from the polymer film by Glow Discharge Optical Emission Spectroscopy (GDOES). From these measurements we propose the following doping mechanism for this polymer: 1) initial diffusion of electrolyte (cation and anions) into the film, 2) cation expulsion and hole accumulation upon applying a gate bias, 3) anion insertion and further hole accumulation. Lastly, we show that the cation expulsion step does not exist when very large cations are used, presumably because large cations cannot diffusively enter the film initially. These findings help clarify the doping mechanism in the highest performing mixed ionic/electronic conductors and demonstrate that OECT operation depends not only on the anion, but also the cation, paving the way to further improvements.

In this study, we draw attention to electrochemical side–reactions of redox–active polymers for organic electrochemical transistors (OECTs)¹. We find that electron–rich polymers such as PEDOT:PSS¹ or pg2T-TT² can undergo oxygen reduction reactions (ORRs) and form hydrogen peroxide (H₂O₂) as a side product. H₂O₂ is an oxidant that can cause harm to biological systems and devices. Hydrogen peroxide production occurs through an electron transfer from the electron–rich conjugated polymer to molecular oxygen dissolved in the electrolyte, with the ionization potential (IP) of the redox-active polymer determining whether or not the reaction occurs spontaneously under ambient conditions.
To prevent this side–reaction from taking place during device operation, we designed a redox–active polymer with an IP > 4.9 eV. The polymer is a donor–acceptor type copolymer with polar side chains, specially designed to achieve a high redox-stability in aqueous electrolytes. OECTs were fabricated and tested where we observe a turn on voltage at –0.4 V (vs Ag/AgCl), a peak transconductance of 200 S/cm (at V_G = –0.7 V), and good device stability with no sign of H₂O₂ formation during device operation. This study elucidates the interaction of redox-active conjugated polymers and molecular oxygen which has previously been overlooked with potentially critical issues for operating electrochemical devices in oxygen containing aqueous electrolytes (biological environments).

1. Khodagholy, D. et al. High transconductance organic electrochemical transistors. Nat Commun 4, (2013).
2. Giovannitti, A. et al. Controlling the mode of operation of organic transistors through side-chain engineering. Proc. Natl. Acad. Sci. 113, 12017–12022 (2016).

The modern healthcare and biomedical systems show a clear trend towards personalized, predictive, and preventive medicine. Development of the concept, commonly known as mobile health (mHealth), means that a huge shift in the paradigms of medical device architectures is to be expected in the near future thanks to the increased portability of medical devices as well as increase in number of specific mobile-based apps. An ideal wearable device should possess a set of important requirements, such as (i) low cost of fabrication, (ii) being conformable and compatible with human skin, and (iii) multifunctionality. The latter is of special importance if the goal is to build not just a single specific device, but to rather develop a technology and basis for scalable fabrication of devices that are capable to detect a plurality of vital signals (HR, EEG, ECG, hydration, galvanic response, etc.).
In order to develop the universal technology that meets all three requirements mentioned above, we propose to utilize graphene in combination with epidermal technology. The conventional epidermal biosensors are based on metal and silicon based thin films that are patterned into special structures for softness and stretchability and embedded into soft biocompatible polymers. The choice of two-dimensional materials is the most natural due to their ultra-thinness, allowing extreme flexibility, transparency, and conformability to almost any rough surface, including skin [1]. Graphene based passive electrodes have been successfully used to epidermal sensing of electrocardiograms (ECG), electromyogram (EOG), electroencephalogram (EEG), skin temperature, and skin hydration [1], [2]. It is important to emphasize that the research work is based on large-area CVD-grown graphene, allowing us to develop low-cost, wearable, and fully conformable to skin devices. Furthermore, large area fabrication gives an ultimate promise for future devices fully based on 2D materials to be available on market. In terms of possible applications, the proposed technology can be easily expanded towards other fields of healthcare biosensing, such as in vivo electrophysiology, UV exposure sensing, pressure sensing, or even towards building electronic skin, and prosthetics.

[1] S. Kabiri Ameri et al., “Graphene Electronic Tattoo Sensors,” ACS Nano, vol. 11, no. 8, pp. 7634–7641, Aug. 2017.
[2] S. K. Ameri et al., “Imperceptible electrooculography graphene sensor system for human–robot interface,” npj 2D Mater. Appl., vol. 2, no. 1, pp. 1–7, 2018.

One of the major challenges in deciphering the fundamental principles of cognition is the lack of appropriate tools for seamless interfacing with neurons across all their signaling modalities. Gaining holistic understanding of neural circuits and their control of behavior requires invention of neural probes that can simultaneously record and modulate electro-chemical activity of neurons while evoking minimal inflammatory response for periods ranging from minutes to years. Multifunctional fibers have recently emerged as a promising platform for integrating multiple functional elements to probe and control neural activity that also minimizes the foreign body response.

In my presentation, I will describe our efforts in further expanding the multifunctionality of polymer-based fiber probes by incorporating an electrochemical sensor that enables real-time tracking of neurotransmitter dynamics in behaving animals. This is achieved by introducing a carbon nanotube (CNT) based electrocatalytic electrode within the multifunctional fiber-based probes during their fabrication via thermal drawing process. The resulting devices can be implanted chronically and perform electrical recording and stimulation of neurons, light delivery through waveguides for optogenetics, drug and gene delivery via microfluidic channels, and voltammetry via the CNT electrodes for dynamic detection of dopamine. We envision that these multimodal, miniature, and mechanically compliant probes will facilitate understanding of the neurophysiological underpinnings of dopamine-dependent behaviors including reward, addiction, and motor control.

Nanoscale materials enable unique opportunities at the interface between the physical and life sciences, for example, by integrating nanoelectronic devices with cells and/or tissue to make possible bidirectional communication at the length scales relevant to biological function. In this presentation, I will overview a new paradigm for seamlessly merging electronic arrays with the brain and other key components of the nervous system in three-dimensions. First, I will discuss the design considerations of matching structural, mechanical and topological characteristics of neural probes and brain tissue, thus leading to mesh electronics systems that are immune-privileged and enable uniquely stable electrophysiology such that it is possible to track and stably record from the same single neurons and neural circuits on the time scale of at least year. Second, I will describe a selection of new opportunities using the mesh electronics paradigm, including (i) nonlinear lesion-free implantation in the retina and brain, (ii) development of new nanoelectronic devices for subcellular resolution recording, and (iii) and advances in interfacing that can enable scalable recording and stimulation of large numbers of neurons. I will conclude with discussion of opportunities and challenges pushing towards tools that can significantly advance fundamental neuroscience and electronic medicine in humans.
Selected References
(1) http://meshelectronics.org/
(2) T.-M. Fu, et al., Nat. Methods 13, 875-882 (2016).
(3) G. Hong, et al., Science 360, 1447-1451 (2018).
(4) X. Yang, et al., Nat. Mater. 18, 510–517 (2019).
(5) G. Hong & C.M. Lieber, Nat. Rev. Neurosci. 20, 330–345 (2019).

Mammalian brains consist of billions of neurons operating at millisecond time scales, which current recording techniques only capture a tiny fraction. Recent advances in CMOS device design have led to high-recording quality planar probes, with diminishing sizes to ameliorate the extent of tissue damage. Matching these powerful silicon electronics to the inherently three dimensional architecture of the brain has remained challenging however, as devices are constrained to the planar two dimensional surfaces required for silicon processing. Here we describe a chronic interface using arrays of microwires read out by CMOS-based devices with a low-tissue damage, and controllable, three dimensional distribution of recording sites. The core concept is using a bundle of insulated microwires mated to a large-scale CMOS microelectrode array, such as found in modern camera chips or displays. We show recent results on the mechanics and tissue damage from microwire insertion scales strongly with wire diameter. Microwires with <25µm diameters are shown to have minimal to no vascular disruption or bleeding, as opposed to more conventional 75 to 100 µm devices. These microwires are then arranged into bundles to control the spatial arrangement and three dimensional structure of the distal (neuronal) end, while providing a robust parallel contact plane on the proximal side which is interfaced to a planar pixel array. The modular nature of the design enables a wide array of microwire types and size to be mated to a variety of different CMOS chips, making the same fundamental platform scalable from a few hundred electrodes to tens of thousands. We thus link the rapid progress and power of commercial multiplexing, digitisation and data acquisition hardware together with a bio-compatible, flexible and sensitive neural interface array. We present recent massively parallel recording using mouse and rat models, showing both spiking activity from single neurons and local field potentials within both chronic and acute settings.

The interaction between the cell membrane and the measuring electrode is crucial for crucial for sensitive measurement of cell electric activities. We are interested in exploring nanotechnology and novel materials to improve the membrane-electrode coupling efficiency. Recently, we and other groups show that vertical nanopillars protruding from a flat surface support cell survival and can be used as subcellular sensors to probe biological processes in live cells. The nanopillar electrodes deform plasma membrane inwards and induce membrane curvature when the cell engulfs them, leading to a reduction of the membrane-electrode gap distance and a higher sealing resistance. As an electrode sensor, nanoelectrodes offer several advantages such as high sensitivity, subcellular spatial resolution, and precise control of the sensor geometry. Furthermore, we found that the high membrane curvature induced by nanoscale electrodes significantly affects the distribution of curvature-sensitive proteins and stimulates several cellular processes in live cells. Our studies show a strong interplay between biological cells and nanoscale topography, which is an essential consideration for future development of interfacing devices.

In this talk, I will discuss several projects related to engineering conductive materials and developing fabrication methods to allow electronics with effective electrical interfaces with biological systems, through tuning their electrical as well as mechanical properties. The end result is a soft electrical interface that has both low interfacial impedance as well as match mechanical properties with biological tissue. Several applications of such electronics will be presented.

Bioelectronic medicines targeted at the peripheral nervous system have the potential to address a wide variety of diseases, from diabetes to bladder dysfunction. The foundational concepts have existed for decades but implementation has been limited and fraught with persistent challenges, including lack in target specificity, nerve interface biofouling, and inability to acquire real time physiologic signals for conditional delivery of corrective stimuli, leading to excess and unnecessary stimulation. Here we present a set of materials, a treatment strategy and supporting technology platform that address many of these challenges, using bladder control as model system. Specifically, we report capabilities for continuous monitoring of bladder function using an ultralow modulus, stretchable strain gauge to measure dimensional changes, real-time data analytics to identify pathological behavior based on the resulting data, and automated, closed-loop optogenetic neuromodulation of bladder sensory afferents to normalize bladder function in the context of acute cystitis, with generic applicability to many other organ systems and conditions.

Miniature, wireless bioelectronic devices enable less invasive surgical implantation and the ability to target tiny nerves or brain areas. However, as these neural stimulators become smaller, we must engineer new ways to deliver power. Conventional power deliver relies on long wires to deliver power from an implanted battery or subcutaneous antenna. These leads can limit device placement and cause device failure due to lead breakage or infection. Conventional wireless power delivery through biological tissue is difficult when devices are miniaturized and placed deep in the body. Here we show that magnetic materials can effectively harvest energy from magnetic fields and power millimeter-sized bioelectronics. These materials show excellent power densities even as the devices are made small allowing them to be fully implanted and wirelessly powered. We demonstrate that these mm-sized wireless devices can be used to power different types of conventional stimulation electrodes when implanted in rabbits, pigs, and freely moving rats. Furthermore, these miniature electrical stimulators can be adapted to power many individually addressable stimulation channels while still maintaining a small overall device footprint.

Optically-controlled non-genetic biological modulation represents a promising approach for the fundamental study of biological circuits and the clinical treatment of disorders. Among existing material candidates that can transduce light energy into biologically-relevant cues, silicon and silicon carbide are particularly advantageous due to its highly tunable electrical and optical properties, ease of fabrication into multiple forms, and biocompatibility. In this talk, I will present some of the latest research in our lab, including the use of intracellular silicon for biophysical studies in cardiac system, and doped silicon carbide for several types of biological modulation. I will also present a few new directions where many other soft materials can be incorporated for bioelectronics studies.

We report on development of ultrathin optoelectronic devices for stimulating biophysical processes. All of these devices rely on near infrared irradiation in the tissue transparency window to actuate nanoscale organic semiconductor components. Our flagship technology is the photocapacitor – a device that mimics biphasic current-pulse neurostimulation and thus transduces an optical signal into directly-evoked action potentials in neurons. The devices operate in the tissue transparency window of the near-infrared, where light can penetrate deeply through skin and bone. The motivation is to provide a wireless and minimalistic implant which can perform the duty of standard implantable electrodes, but without the wiring. The devices we fabricate are not only wireless, but also 100-1000 times thinner than most existing technologies. Making implants have as small as possible mechanical footprint improves the efficacy of bioelectronic medical treatments by minimizing the risk for inflammation and making surgical implantation less invasive. On the other hand, the other block of our research efforts is directed at devices which, when stimulated with light, deliver controlled amounts of reactive oxygen species (mostly peroxide). We aim to study the effects of photoelectrochemically-generated peroxides on physiological processes, with the hope of developing novel therapeutic approaches to neurodegenerative diseases.

Measurements of pressure in organ systems such as the brain, eyes, bladder and blood vessels form an essential diagnostic basis for the assessment of patient health and progression of diseases such as traumatic brain injury, hydrocephalus (intracranial pressure), glaucoma (intraocular pressure) and hypertension (blood pressure). Therefore, the capacity for precise, continuous monitoring of pressure can be critically important in defining treatment protocols that decrease the rate of morbidity and increase the pace of recovery. Conventional sensor technologies designed for this purpose are available in the form of accurate, implantable devices that must be surgically extracted following clinical use. These procedures are costly and they expose the patient to additional risks of complications. The devices can also serve as a nidus for infection and immune-mediated inflammatory responses. Emerging classes of bioresorbable electronic sensor systems have the potential to address these disadvantages. Here, all of the constituent materials dissolve in biofluids over well-defined periods of time, with biologically benign endproducts.

Although recently reported bioresorbable pressure sensors have comparable sensitivity and accuracy to those of conventional, nonresorbable analogues, they offer stable operation over a period of only several days, which is insufficient for many applications. Extending this operational lifetime to several weeks demands solutions to daunting challenges in materials science and device design that follow directly from the requirement that the systems must ultimately dissolve completely, at a molecular level, without adverse effect. This difficulty is inherent to all classes of implantable, bioresorbable systems because immersion in biofluids immediately initiates processes of bioresorption. The most effective method to prolong their lifetimes relies on passive encapsulating layers that delay the time at which biofluids come into contact with the active materials. Bioresorbable polymers such as silk fibroin, poly(L-lactide) and poly(lactic-co-glycolic acid) (PLGA) are attractive for such purposes, but their hydrophilic nature leads to swelling and water permeation, thereby causing premature fracture, buckling and/or dissolution of the underlying materials. Inorganic alternatives such as silicon dioxide, silicon nitride and various metal oxides formed by chemical or physical vapour deposition offer exceptionally slow rates of dissolution, but the extreme difficulties in forming coatings without micro- or nanocracks, pinholes or other defects limit their practical utility.

Here, we demonstrate materials, device structures and fabrication methods for bioresorbable pressure sensors that rely on thermally grown layers of silicon dioxide on device-grade silicon wafers as biofluid barriers with defect-free, materials-level perfection over large areas. Overall fabrication involves bonding of a pair of silicon-on-insulator wafers using adhesion layers of amorphous silica formed by calcination of poly(dimethylsiloxane) (PDMS), followed by elimination of the handle wafers. Data on the biodistribution of dissolved silicon in mice at five weeks following implantation of intracranial sensors formed in this manner, together with assessments of the haematology (complete blood count), blood chemistry and MRI compatibility, confirm their biodegradability and clinical utility. Measurements of intracranial pressures in rats over 25 days illustrate high accuracy and low drift, with an overall performance that compares favourably to that of non-resorbable clinical standards. The results not only establish routes to bioresorbable pressure monitoring technologies that meet requirements for clinical use, but they also serve as a generalizable platform for broad classes of bioresorbable electronic devices that can offer stable operating characteristics over long periods of time.

Reference: Nature Biomedical Engineering 3, 37–46 (2019)

Recently, ultraconformable TTEs have been adopted in the recording of many electrophysiological signals (1,2). Medical standard wet electrodes are routinely used in electrophysiology thanks to their high signal quality. On the other hand, these electrodes exhibited many disadvantages which impose severe restrictions especially in electroencephalography applications. The major issues are related to their limited time stability, due to gel drying, and to their cumbersome nature. In order to provide an alternative technology in the broad field of brain recordings, we investigated the TTEs capabilities in electroencephalography (EEG) applications and their compatibility with the magnetoencephalography (MEG). While EEG records the variations of the electrical field generated by cortical pyramidal neurons, the MEG senses modification in the magnetic field, induced by changes of the electric field generated by the same population of neurons. These two techniques are frequently used in combination, thanks to their high temporal resolution. The simultaneous EEG/MEG assessment is essential in the understanding of dynamic cognitive processes and in focal epilepsy diagnostics. The MEG instrumentation is very sensitive to electromagnetic variations. Besides the use of a proper shielded room, also dedicated electrodes are usually adopted to perform EEG/MEG recordings. As an example, ferromagnetic materials are forbidden in order to avoid the generation of magnetic artefacts. Furthermore the vertical profiles of the electrodes has to be minimized to allow an efficient coupling with the MEG sensor. In order to met these requirements, we exploited TTEs as metal-free and ultra-thin sensors to efficiently combine EEG/MEG recordings. Indeed the fabrication method developed allows the production of sensors that are all made of polymers and with an overall thickness < 1-2 µm. We firstly validated TTEs in EEG application with the recording of alpha waves, the most known and studied brain rhythm. TTEs were also compared with Ag/AgCl electrodes, through Power Spectral Density (PSD) assessment, showing a good match over the whole signal spectrum. Then, the participant, with TTEs laminated on his head, was placed under the MEG apparatus. We were able to record neural activity at different frequencies without any high-density magnetic flux appearance in the electrode’s proximity. The EEG and MEG recordings were performed simultaneously showing well visible alpha waves. To the best of our knowledge, this is the first demonstration of dry organic electrodes performance in joint EEG/MEG assessment.
1. Zucca, A., et al. "Tattoo Conductive Polymer Nanosheets for Skin–Contact Applications." Advanced healthcare materials 4.7 (2015): 983-990.
2. Ferrari, L.M., et al. "Ultraconformable Temporary Tattoo Electrodes for Electrophysiology." Advanced Science 5.3 (2018).

Wearable biosensing technologies have emerged as an alternative tool for the personalized healthcare management. Compared to the conventional wearable biosensors, organic electrochemical transistor (OECT) -based biosensors can be more sensitive due to the merits of in-situ amplification and ion-to-electron conversion. OECTs have been successfully used in the following applications. (1) The glucose level in sweat can be real-time and wirelessly monitored and analyzed by OECT sensors remotely controlled by a mobile phone (2) Label-free RNA detection has been realized using flexible OECTs based on the interaction between RNA molecules and the organic semiconductor channels. The devices can selectively detect RNA cancer biomarkers down to the concentration of 1 pM. (3) Fabric OECTs are successfully prepared on Nylon fibers and integrated into wearable systems for monitoring glucose and uric acid levels with high sensitivity. All the results clearly indicate that OECT biosensors can be an excellent platform for wearable healthcare monitoring. The wearable biosensing technology has many advantages, such as simple apparatus, quick detection, short waiting time, and versatility for different wearable scenarios, which could revolutionize the current wearable technologies in individual disease diagnosis and health monitoring applications.

Real-time, non-invasive pH monitoring of biofluids such as human sweat is currently attracting a great deal of interest for accessing information from our body. However, such emerging bioelectronic application poses several constraints to existing sensing technologies, as configurational versatility and ultra-sensitivity stand out as essential requirements. In this scenario, organic electrochemical transistors (OECTs) are promising electronic platforms that can interface the biological domain providing intrinsic signal amplification and they can be exploited as sensing devices without the need of a freestanding reference electrode.
In this contribution, we show the optimisation of pH responsive materials, able to successfully convert a pH chemical signal into an electrical one, which are exploited to modify the gate electrode of the OECT. The semiconducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) was electrochemically doped with pH dyes (Bromothymol Blue or Methyl Orange) and the PEDOT:dye composites were thoroughly investigated by electrochemical and spectroscopic analyses. It was demonstrated that the transduction mechanism of the proposed materials originates from the pH-dependent change of the dyes’ electronic charge. Due to its electrostatic interaction with the polymer backbone, this phenomenon affects the doping level of the semiconducting polymer. The PEDOT:dye composites were employed as sensing element in an OECT configuration to obtain a device that can reliably detect pH variations in the range 1-9 with super-Nernstian sensitivity, taking advantage on the amplification offered by the transistor. Finally, thanks to the OECT major advantages with respect to conventional electrochemical sensors, we assessed the sensor adaptability to a plastic substrate. With our flexible sensor, we were able to estimate the pH of an artificial sweat sample with a standard deviation equal to 0.06 pH units within a medically relevant range.[1] Moreover, the pH sensor was realized on sterile bandage and integrated into a smart patch. With the help of a simple, textile microfluidic system, we made our device compatible with wearable applications and continuum, small-volume sampling of biofluids.

[1] F. Mariani, I. Gualandi, M. Tessarolo, B. Fraboni and E. Scavetta, ACS Appl. Mater. Interfaces, 2018, 10 (26), 22474

Skin electronics are rapidly advancing due to the increased interest in wearable electronics, which allows monitoring of various biosignals. Ti₃C₂ MXene is a promising 2D conducting material for applications in skin electronics. It is biocompatible, easily processable in many solvents, including water, and is highly conductive. Ti₃C₂ MXene also makes an excellent candidate ink for inkjet printing. However, Ti₃C₂ MXene has only been shown so far to be printed in organic solvents and alcohols. While these inks are easily processable, they are toxic and introduce difficulties when scaling up, which is the main advantage of printed electronics. Here we report the first inkjet printable aqueous Ti₃C₂ MXene ink. The films printed thereof that were conductive at even one layer and deposited on various substrates. Ti₃C₂ MXene films were printed on a conductive flexible substrate to develop a multifunctional sensor that can record ECG signals while detecting Na⁺ ions and cytokine biomarkers.

This work presents approaches to pattern gallium (Ga)-based liquid metal alloys to form ‘softer than skin’ electrodes for biological interfaces.¹ These soft and fluidic conductors exhibit low toxicity, maintain electrical performance under tension and torsion, and are self-healing. Thus, combining Ga alloys with soft materials can form robust bio-compatible electrical interfaces. These metals can also integrate with microfluidic platforms for fundamental biological studies (i.e., organ-on-chip). This work reports methods to rapidly (~secs) form liquid metal electrodes onto or within a wide range of materials, including soft polymers, at ambient conditions (i.e., room temperature, atmospheric pressures), and outside clean-room settings. One approach utilizes the adhesion of the native surface oxide of Ga to simply ‘paint-on’ liquid metal electrodes.² This oxide ‘skin’ (~3 nm) can serve as a stretchable and self-healing dielectric for capacitive sensing (~0.1 μF/cm²) and ultra low-voltage electrowetting (0 to 2 V). Alternatively, injecting liquid metal into molds placed against rough surfaces enables patterning of liquid metals into arbitrary designs.³ Because the interface with the rough surface is non-wetting, the mold can peel off to form open-to-air electrical contacts. As a result, this technique forms open surface patterns of conductive traces of liquid metal that can interface directly with biological tissues, be transferred onto other substrates, or encapsulated by other materials.
1. Joshipura, I. D., Finn, M., Tan, S. T. M., Dickey, M. D. & Lipomi, D. J. Stretchable bioelectronics—Current and future. MRS Bulletin 42, 960–967 (2017).
2. Eaker, C. B., Joshipura, I. D., Maxwell, L. R., Heikenfeld, J. & Dickey, M. D. Electrowetting without external voltage using paint-on electrodes Lab Chip 17, 1069–1075 (2017).
3. Joshipura I.D., Ayers H.R., Castillo G, Ladd C, Tabor C., Adams J.J., Dickey, M.D. Patterning and Reversible Actuation of Liquid Gallium Alloys by Preventing Adhesion on Rough Surfaces ACS Applied Materials & Interfaces 10, 51 44686-44695 (2018)
4. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. IM Release Number: LLNL-ABS-762385

Flexible and transparent strain gauges are of interest for applications such as: e-skins, wearable sensors, voice recognition, and haptic sensing. Development of sensors with high displacement sensitivity which are flexible and transparent remains a challenge. Here, we present the simple and efficient assembly of highly sensitive, flexible and transparent resistive strain sensors formed from sheets of reduced graphene oxide (RGO) assembled at the interface between immiscible solvents.
Previous work on graphene based strain sensors relied on the percolation of electrical current through a network of overlapping graphene flakes deposited on a flexible substrate. As the substrate is strained the stiffer graphene flakes slide past each other and change the resistivity of the network leading to stable and repeatable strain gauges with gauge factors (GF) in the range 100 – 300. [1,2] Thin film sensors with gauge factors around 1000 have been fabricated that exploit networks of cracks that form in thin conductive films, these have GF of around 1000 but the conductive films are opaque to light. [3,4]
In this work, nanoflakes of electrochemically exfoliated graphene oxide (EGO)[5] were assembled at the interface of immiscible solvents to generate an ultrathin film of EGO. By initiating gradients of interfacial tension at the liquid/liquid interface, the EGO film is placed in compression and this generates efficient packing and flake edge contact without significant flake overlap. The ultrathin film was transferred onto flexible and transparent substrates of polydimethyl siloxane and the resulting thin film is a monolayer of EGO flakes with minimal overlap and predominantly edge to edge contact between flakes. The packing density of the transferred films is high (92 %). After chemical reduction, the resulting RGO thin films were highly transparent (transmittance 88 % at 550 nm) and conductive (10000 S/m).
The thin films of RGO on flexible substrate were analysed for their mechanosensing capabilities. To our knowledge, the gauge factor of the strain gauges is the highest reported for graphene oxide based sensors (>2000 over 2% strain). The extremely high gauge factor is enabled by the formation of nanoscale cracks perpendicular to the direction of strain which cause disconnection and reconnection of the RGO film.

References
1. L.Q. Tao et al (2017) Nanoscale 9, 8226.
2. C. Casiraghi et al. (2018) Carbon 129, 462.
3. Y.F. Yang et al Nanoscale (2018) 10, 11524.
4. M. Choi et al Nature (2014) 516, 222.
5. J. Cao et al J. Am. Chem. Soc. (2017) 139, 17446.

Electronic skin patch represents one of the mainstream innovations in human/Internet of Things (IoTs) interfaces technologies, enabling communication of bio-information obtained from the skin to computing machines. For the long-term communication without damping of the device performance during an extraction of the body information as well as transmission of the data, an interface-stable, conformal contact of the electronic patch on the skin has been developed. Surprisingly, amid this sweeping trend, human skin has been treated mostly as a curvlinear surface for mounting electronic patches to monitor health of internal organs and neglects to recognize how these may affect the biological functions of the skin. Skin is the outmost and the largest organ covering the entire body surface, protecting inner organs from various external hazards and perspiration through the skin pores are essential for preserving the homeostasis of the human body via temperature regulation and water retention. However, non-breathable electronic skin induces degradation of physical properties of skin, more importantly, deterioration of barrier functionality against viruses will lead to secondary infections and complications with physiological problems. Therefore, the electronic skin patch should possess open-spaces that do not block sweat and maintain a persipiration for long-term health monitoring with securing homeostasis of the skin.
Here we introduce a platform of breathable electronic skin that can permeable to sweat as well as vapors, showing ~100% breathability on the skin, via a sweat pore-inspired through-holes on thin-film electric modules and skin-like, soft patch. We have engineered through-hole structures by forming ‘dumbbell’ patterns that include kirigami patterns (auxetic fractal cuts) at the patches with drilling the circular holes at the sharp edges of fractal cuts. Such kirigami fractal cuts enhance conformability of the patches on the skin by increasing biaxial expandability while rounded hinges of the cuts prevent stress-localization-induced crack. Dumbbell patterns also drive skin-like elastic modulus of patches, resulting in an imperceptible lamination onto the skin. More importantly, dumbbell hole patterns form open-space onto sweat pore, enabling sweat penetration through the electronic skin in addition to the vapor, thereby long-term attachment without sweat trapping at skin/patch interface. Additionally, such dumbbell-patterned patch system exhibits excellent mechanical endurance (1,000,000 fatigue cycles with 5% strain cyclic loadings). With this precisely engineered skin patches and interconnects, we have developed the method to heterointegrate single-crystalline freestanding semiconductors on them to maximize the sensitivity of the electronic skin. As a sample case for an ultrasensitive sensor, we have integrated 200-nm-thick single-crystalline GaN freestanding membranes on our advanced skin patch. GaN has been selected as it is bio-compatible while its piezoelectric properties can be maximized when it is free from substrate clamping. Thus, high quality GaN epitaxial films are prepared by remote epitaxial growth on graphene-coated GaN wafers followed by mechanical exfoliation from graphene surface. GaN sensor arrays exhibit ultrahigh strain sensitivity with ~5000 of gauge factor (GF) and 0.001% of strain sensing limit without a signal amplifier. This enables monitoring a nanometer-scale mechanical deformation of stratum corneum that contains clinical information such as dehydration and skin complications, unravelling a kinetics of natural skin movement. Our breathable electronic skin system with freestanding single-crystalline sensors lay foundation for developing ultrasensitive electronic skins for monitoring various biomarkers from human body by applying variety of single-crystalline functional materials as active parts in the breathable electronic skins.

Graphene has been spotlighted as a promising nanomaterials for biological applications such as bioelectronics, imaging, drug delivery, and tissue engineering because of its unique and outstanding optical, electrical, mechanical, and biological characteristics. Especially, regenerative properties of graphene and its derivatives let them broadly used for tissue engineering and regenerative medicine area. Among its tissue applications, it is very interesting for skeletal muscle with graphene because it can effect on the adhesion, proliferation, and myogenesis. Skeletal muscles, serving the primary actuator in animals, have been used for biohybrid actuators in the soft robotics field. Integration of a three dimensional (3D) engineered skeletal muscle embedded in extracellular matrix (ECM) with 3D printed hydrogel skeleton ranging from mm to cm scale enabled a locomotion from electrical or optical stimulation for walking or pumping functions. If the biohybrid machine can integrate with electronics, it can be very synergetic for various functions with electrical applications such as electrical actuation control and sensing.

In this regard, the integration of the conductive graphene electrode with a 3D skeletal muscle tissue has a great potential for electrical applications of biological systems due to its biocompatibility and significant electrical properties. However, its applications for skeletal muscle have been limited on 2D cultured cellular system not for 3D due to the 2D nature of graphene. Although 3D structured graphene systems as a tissue scaffold have been reported using 3D printing or dry spinning with graphene derivatives such as reduced graphene oxide or graphene oxide, they have limited electrical conductivity due to the presence of insulating polymer. In addition, the reduced graphene oxide has a worse uniformity compared with chemcal vapor depostion (CVD) synthesized graphene. Several previous work has been reported for the 3D integration using CVD grown graphene using a thin poly (methyl methacrylate) (PMMA) as a supportive layer. However, the PMMA based wet transfer is limited for the biological application due to its cytotoxicity. Although the PMMA layer was removed after graphene transfer, it is difficult to remove the layer perfectly and the remained residue can be problematic for biological applications.

Here, we report a novel 3D graphene transfer method using a poly (ethyelne glycol) diacrylate (PEGDA) supportive layer and its integration with 3D skeletal muscle ring. A softer PEGDA layer enabled the conformal integration of graphene with a millimeter scaled 3D printed PEGDA pillars. The softer PEGDA supportive layer which has a 10⁵ times lower Young’s modulus compared with PMMA made a conformal integration with 3D printed pillars, followed by integrated with the muscle ring. Considering the PEG is an FDA approved biocompatible material, it can be a good candidate for 3D biological application with electronics. The 3D integrated graphene on the 3D printed pillars was characterized using Raman spectroscopy and electrical conductivity was measured. As an electrical application with 3D electrode integrated tissue system, the 3D muscle ring on the integrated structure was actuated by electrically with different voltages and frequencies through the transferred graphene which contacts to muscle ring. We believe that it can be a potential integration platform of electronics with 3D in-vitro tissue for electrical applications in the soft robotics or tissue-on-a-chip areas.

In recent years, polymer matrices loaded with ionic liquids - namely iongels - have emerged as promising materials for long-term cutaneous electrophysiology. Iongels display high ionic conductivity, negligible vapor pressure and can be designed on demand. Despite the attractive properties, the availability of biocompatible and biodegradable iongels remains scarce. In this work, biodegradable polycarbonate-based iongels were prepared by organo-catalyzed ring-opening polymerization of N-substituted cyclic carbonate monomers in the presence of imidazolium lactate ionic liquid. Our iongels were able to incorporate up to 30 wt% of ionic liquid without compromising the mechanical properties. The ionic conductivity of these iongels increased with the amount of free ionic liquid, up to 5×10^-4 S cm^-1. Additionally, we showed that the polycarbonate matrix of the iongel can undergo hydrolytic bond cleavage, returning non-toxic degradation products. The iongels reduced the impedance of gold electrodes placed on the skin, and were used to record physiologic signals with accuracy levels similar to that of commercial Ag/AgCl electrodes. The low toxicity and biodegradability of polycarbonate-based iongels make these materials highly attractive for cutaneous electrophysiology applications.

Human skin recognizes the information of shape and texture of various objects by sensing tactile and pressure changes in space over a wide dynamic range. In order to mimic such functionalities, artificial skin should not only be sensitive in low pressure range (e.g. tactile stimulation and measure of artery pulse, etc. ) but also should be able to detect mid-to-high pressure change. In addition, it is desired to be thin enough to be applicable to various objects. For this reason, film-type pressure sensors using a variety of materials and structures have been widely studied in recent years. However, it has been challenging to realize a wide pressure sensing range and high flexibility at the same time, because there is a trade-off relationship between wide range and thickness of the pressure sensors. Furthermore, the problem becomes more severe when one tries to realize a multi-modal sensor having high sensitivity in low pressure region as well.

In this study, we propose a flexible capacitive pressure sensor based on topographically patterned arrays of concaved ionic gels as a dielectric layer whose capacitance is responsive to applied pressure, which are positioned in between two substrates having electrodes. The ionic gel film is electrically suitable for high sensitivity due to ultra-high capacitance based on electric double layers, and it is also promising in terms of mechanical properties as a pressure sensing material because it has low Young’s modulus similar to that of rubber. By structuring the surface of the ionic gel film with concave shape of several micro-meter scale to utilize compression of air confined between the structure and an electrode, linear response to large pressure range of over 100 kPa has been obtained. In addition, the complete pressure sensor can be highly flexible because the thickness of the ionic gel film can be reduced near or even below 10 μm. By using an appropriate surface structure of ionic gel film, the sensor shows distinctive responses to low and high pressure regions, respectively, thus demonstrating a multimodal sensing capability for both tactile and pressure signals.

With the overall thickness of the proposed pressure sensor being as low as ca. 15 μm, it exhibits a high degree of mechanical flexibility. Together with this, multi-modal sensing capability, the proposed pressure sensors are expected to be highly beneficial as a key element for artificial skin, which can be important in human-machine interfaces and healthcare products for disabled people.

One major conundrum that impedes the development and application of the emerging soft and stretchable electronics lies in the integration of electronic components with soft substrates for rational combination of various device functionalities into a single wearable state, since the rigid, nondeformable electronics tend to detach from the deformable substrate under mechanical loadings like stretch. Modulating the stiffness of soft materials in a spatially controllable manner provides a promising solution to this rigid-soft coupling challenge, by shielding the local strain of rigid components while maintaining the stretchable property of soft substrates. Hydrogels with superb biocompatibility and skin-like mechanical features are ideal candidates to interface human body and electronic functionalities for the cutting-edge wearable uses, where there exists a major challenge of spatially modulating stiffness of hydrogel to meet the application demands.

In the present work, we develop a facile and straightforward scheme to spatially modulate hydrogel stiffness through local stiffening of the hydrogel. Locally stiffened patterns on hydrogel featuring highly increased stiffness compared to that of the raw hydrogel can be easily achieved via additional crosslinking the hydrogel. For example, the polyacrylamide-alginate (PAAm-alginate) hydrogel demonstrated here is locally stiffened through additional crosslinking with multi-valent ions in specifically designed areas. The local stiffness of hydrogel can be controllably adjusted by tuning ion concentration and the time of additional ionic crosslinking, providing one order of magnitude enhancement of hydrogel stiffness. The locally stiffened hydrogel shows excellent strain shielding efficacy with only ~12% actual strain observed in the stiffened area, relative to a 100% strain applied to the whole hydrogel substrate. With this strategy, rigid electronic components can be directly mounted onto the locally stiffened sites on hydrogel to isolate strains as induced by substrate stretch. We further develop a hydrogel-based multifunctional integrated electronic device and its satisfactory performance in monitoring temperature, UV exposure and EMG signals unveils the brilliant prospect for advanced wearable healthcare applications.

Imparting self-healing capabilities into soft electronic devices and sensors has been of outmost importance for increasing long-term reliability and sustainability. Though some advances have been made in this endeavor, the use of self-healing electronics in environment of wet and/or (under)water has been most challenging. Herein, we report on a new self-healing thermoplastic elastomer having high stretchability and mechanical strength that can reach 1000% and ~ 6 MPa, respectively. The elastomer exhibits high (>90%) self-healing efficiency in harsh humidity and/or (under)water conditions without the assistance of any external physical and/or chemical triggers. Flexible electronic devices, chemical and electrochemical sensing platforms were demonstrated to operate in extreme wet or underwater conditions (e.g., salty sea water). Moreover, the healing process eliminates significant electrical leakages that would have been caused by structural damages. The healing process can reach ~90% efficiency, in terms of mechanical strength, within ~ 24 hr even after multiple harsh mechanical scratches or cuts. These highly-efficient and self-healing properties would serve as a shuttling pad for extending the use of flexible electronics outside lab applications and for widening the spectrum into wide variety of wet (implants) and sub-marine applications.

Soft and healable structures mimicking biological systems have received great attention due to their applications in flexible electronics, soft robotics and bioelectronics. The layer- by-layer technique is a simplified, elegant way to form nanostructures having molecular level thickness control, and homogeneous dispersions of materials for the formation of multifunctional nanocomposites. Thereafter, poly(ethyleneimine) (PEI) and poly(acrylic acid) (PAA) LbL matrices have been extensively explored in this task due to its intrinsic self-healing ability when in contact with water at ambient conditions. Here, we studied the incorporation of conductive materials (metallic nanoparticles, PEDOT:PSS and reduced graphene oxides) in the (PEI/PAA) LbL matrix in order to check a balance between healing and electrical properties. The main motivation has been the fact that the increase in the electrical conduction of the composites implies in a decrease in the healing ability. Electrical and mechanical characterizations were performed in distinct molecular architectures, with multiple healing cycles verified in one case that presented high electrical transport.
Acknowledgment: Capes, CNPq, INEO, Fapesp (2017/19862-3 and 2017/11277-4) and NanoTech Institute at the University of Texas in Dallas.

Organic electrochemical transistors (OECTs) are highly attractive for applications ranging from circuit elements, neuromorphic devices to transducers for biological sensing and the archetypal channel material is poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS. The operation of OECTs involves the doping and de-doping of a conjugated polymer due to ion intercalation under the application of a gate voltage. The major challenges in developing self-healable conjugated polymers for organic electrochemical transistors (OECTs) lie in maintaining good mixed electronic/ionic transport and the need for fast restoration to the original electronic and structural properties after the self-healing process.

Herein, we demonstrate ionic liquid doped PEDOT:PSS that shows good mechanical properties, robust towards physical deformation and further capable of showing high transconductance, fast transient response and high device stability over 3600 switching cycles.[1] Next, we provide the first report of an all solid state OECT that is self-healable and possess good electrical performance, by utilizing a matrix of PEDOT:PSS and non-ionic surfactant as channel, and ion conducting poly(vinyl alcohol) hydrogel as a quasi-solid-state polymer electrolyte. The fabricated OECT exhibits high transconductance (maximum 54 mS), on/off current ratio of ~1.5×10³, fast response time of 6.8 ms and good operational stability after 68 days of storage. Simultaneously, the OECT showed remarkable self-healing and ion-sensing behaviors and recovered ~95% of its ion sensitivity after healing. These findings will contribute to the development of high performing and robust OECTs for wearable bioelectronic devices.

[1] X. Wu, A. Surendran, J. Ko, O. Filonik, E.M. Herzig, P. Muller-Buschbaum, W. L. Leong, "Ionic Liquid Doping Enables High Transconductance, Fast Response time, and High Ion Sensitivity in Organic Electrochemical Transistors", Advanced Materials, 31(2), 1805544 (2018).

In this study, we have developed a sheet-type biosignal voltage amplifier integrated with fully flexible electronic components. The biosignal amplifier comprises from thin-film resistors and CMOS circuits with organic thin-film transistors (OTFTs). All electronic components were integrated on a single 1-μm-thick polymeric foil, therefore showing high mechanical flexibility and conformability to attach on a soft human skin surface. The sheet-type amplifier shows high signal gain over 55 dB that can be tunable by the resistance control of feedback thin-film resistors. The use of such flexible voltage amplifier would play a significant role as an analog-front-end of wearable bioelectrical interfaces for processing human physiological activities.
Flexible and bio-conformable organic circuits are expected to build active electronic components of wearable medical and healthcare applications. In this sense, various kinds of fabrication processes and materials have been intensively studied to realize high performance OTFTs[1,2]. However, electronic circuits with OTFTs such as voltage amplifier are not still satisfactory to condition weak biological information with high signal integrity due to the substantial electrical variations in OTFTs and the lack of flexible passive components such as resistors and/or capacitors with high yield.
The developed circuit is based on an instrumentation amplifier with integration of organic CMOS operational amplifier circuits and film metal resistors. The organic operational amplifier comprises from p-type and n-type OTFTs, and exhibits the high amplification gain of 2,185 ± 272 with the low supply voltage below 3 V. Parylene dielectrics with the surface modification of thermally-evaporated triptycene layer were used for the gate dielectrics, enabling field-effect mobility of 0.68 cm²/Vs for p-type OTFTs and 0.12 cm²/Vs for n-type OTFTs. Thin-film resistors were realized by the 3-nm-thick and 14 μm-wide nichrome layers with the sheet resistance of 765 Ω/square. We also implemented compensation techniques on the organic circuit utilizing top-gate structures to reduce the electrical variations in the amplifier, enabling low input offset voltage ~ 0 V.

[1] Kaltenbrunner, M. et al., Nature 499, 458–463 (2013).
[2] Wang, S. et al. Nature 555, 83–88 (2018).

This work reports on ultrathin and transparent organic electrochemical transistors (OECTs) fabricated with printing technologies of selective wetting and thermal lamination. The printed OECTs exhibit high transconductance of g_m = ~0.97 mS, high stability to diluted-water washing (~8.7% change in g_m), and mechanical durability to crumpling. Furthermore, the biosignal amplification using the printed OECTs can be demonstrated. These features of printability, high gain, washability, and flexibility would be suitable for disposable and soft bioelectrical interfaces.
OECTs are attracting interest as ideal bioelectrical interfaces because of many advantages such as low-voltage operation, high transconductance, and biocompatibility [1–3]. Recently, the OECTs have been constructed in ultrathin design with 2–4 µm thickness and used as soft bioelectrical interfaces to evaluate brain and heart activities [2, 3]. Until now, the ultrathin OECTs have required the complicated fabrication process such as photolithography, but they could be more cost-effective by manufacturing with low-cost and high-throughput printing technologies. However, the ultrathin OECTs are still limitted to inert gold electrodes prepared with thermal vacuum evaporation, because O² plasma process to prepare through holes in OECTs encapsulation layers can easily dysfunction most printable electrodes such as metal nanomaterials, nanocarbons, and conductive polymers.
Here, this work introduces the thermal lamination process for encapsulation of printed ultrathin OECTs. First in the fabrication, transparent silver-nanowires (AgNWs) electrodes and PEDOT:PSS active layers are printed by using a selective-wetting method with hydrophilic/hydrophobic surface patterns. Then, for the encapsulation, a parylene film with through holes is thermally laminated onto a base parylene film with AgNWs and PEDOT:PSS. This thermal lamination allows us for the low gate-leakage current, and for the narrow ion-electron interaction sites (= channel areas with ~100 µm width) between PEDOT:PSS and electrolytes. The completed OECTs achieve stable low-voltage operation < 0.6 V with negligible changes in g_m after diluted-water washing (~8.7% change) and under white-light illumination (~0.35% change). Furthermore, the OECTs exhibit high transconductance of g_m = ~0.97 mS, comparable to OECTs fabricated with inert gold electrodes [2, 3], and mechanical durability to crumpling (~25% change) due to the ultrathin design with total 2 µm thick. This presentation will show the detailed information on the printing technologies, the OECTs properties, and biosignal (ie. EEG, ECG) amplification demonstration.
[1] J. Rivnay et al. Nat. Rev. Mater. 3, 17086 (2018).
[2] D. Khodagholy et al. Nat. Commun. 4, 1575 (2013).
[3] S. Park et al. Nature 561, 516 (2018).

Building high-performance field-effect transistors (FETs) is the foundation towards using CNTs in future high-performance logic circuits, flexible sensors and diagnostic platforms. In particular, aligned CNT arrays with both parallel orientation and evenly small spacings promote on-state performance and accelerate on-off switching. Conventional thin-film approaches produce inter-CNT spacings down to 2 nm, on the cost of wide orientation and crossing CNT junctions, which lead to large subthreshold swing (slow on/off switching) around 500 mV/dec.

Self-assembled biomolecular templates, especially DNA, exhibit complex in silico designed morphologies and atomic-precise dimensions. Using biomolecule-templated fabrication, CNT FETs have been constructed with prescribed CNT orientations. However, surface charges and metal ions within biomolecular templates surround the assembled CNTs, which screen the gate modulation and increase the scattering of charge carriers. As results, the biomolecule-templated FETs typically exhibit one order of magnitude worse on-state performance and on/off switching compared to those fabricated from non-biomolecule approaches.

We here develop a general strategy in constructing high-performance FETs at biomolecule (DNA)-CNT interface. CNTs aligned onto self-assembled DNA templates exhibit uniform inter-CNT spacing down to 8 nm. Next, we explore the impact of DNA at the FET channel area. Within a top-gated PMOS FET, high-concentration DNAs negatively shift the threshold voltage, and increase the doping level at n-region. Furthermore, we invent a method that eliminate DNA templates without affecting the CNT alignment after DNA removal. Using this method, we finally construct multi-channel CNT FETs with record-high transport performance in biomolecule-templated FETs (10 folds better than previous records). Both high on-state conductance (exceeding 0.3 mS/um) and fast on/off switching (less than 150 mV/dec) have been simultaneously demonstrated within a same FET, which is still challenging via conventional thin-film-based approaches.

More generally, current strategy could be used to construct diverse devices at biology-electronics interface, including bio-compatible or bio-implantable optoelectronics and multiplexed sensors. It could also be used to construct 3D device architectures over wafer scale, thus building a bridge between precise biomolecular self-assembly and high-performance electronics.

Organic electrochemical transistors (OECTs) become suitable candidates for biological interfacing and logic circuitry applications due to the synthetic tunability, facile fabrication, and bio-compatibility¹. Our group has demonstrated stretchable OECTs can be stretched up to 30% strain while maintaining identical transistor characteristics via optimizing the processing conditions during device fabrication². However, some circumstances, such as heart beating monitoring, require electronics to withstand larger strain comparing with wearable electronics on the skin (30% strain). In this talk, we show that the addition of polyethylene glycol (PEG) can greatly enhance the stretchability of conducting polymer films on the elastomer. With the formation of microcracks at a pre-set strain, the conducting polymer can maintain a stable current during high strain stretching cycles. As a result, the OECTs using highly stretchable conducting polymers as the channel material can keep the same performance during stretching even at strain higher than 30%. This work paves the way for OECTs applications as conformable biosensors or bio-electronics which need to endure high strain, such as heartbeat monitoring.

References
1. Zhang, S.; Hubis, E.; Tomasello, G.; Soliveri, G.; Kumar, P.; Cicoira, F., Patterning of Stretchable Organic Electrochemical Transistors. Chem. Mat. 2017, 29 (7), 3126-3132.
2. Zhang, S.; Li, Y.; Tomasello, G.; Anthonisen, M.; Li, X.; Mazzeo, M.; Genco, A.; Grutter, P.; Cicoira, F., Tuning the Electromechanical Properties of PEDOT: PSS Films for Stretchable Transistors And Pressure Sensors. Advanced Electronic Materials 2019, 1900191.

The use of conducting polymer PEDOT:PSS for the development of flexible organic bioelectronic devices, such as organic electrochemical transistors (OECTs), is growing fast [1] [2]. However, direct manipulation of PEDOT:PSS thin films on flexible substrates remains challenging [1] [3]. Transfer printing films from glass to flexible substrates offers an alternative solution. In this communication, we report that PEDOT:PSS thin films on glass substrates, once mixed with surfactants such as dodecylbenzene sulfonic acid (DBSA), can be delaminated with hydrogels and thereafter transferred to flexible substrates without any further treatments. The proposed method allows easy, fast, and reliable transfer of patterned PEDOT:PSS thin films from glass substrates to various soft substrates, facilitating their application for soft organic bioelectronics. We take advantage of this method and demonstrate a skin-attachable OECT prototype, which is relevant for conformable, lightweight, and wearable biosensing.

[1] S. Zhang, E. Hubis, G. Tomasello, G. Soliveri, P. Kumar and F. Cicoira: Patterning of Stretchable Organic Electrochemical Transistors. Chemistry of Materials. 29, 7 (2017).
[2] S. Zhang, Y. Li, G. Tomasello, M. Anthonisen, X. Li, M. Mazzeo, A. Genco, P. Grutter and F. Cicoira: Tuning the Electromechanical Properties of PEDOT:PSS Films for Stretchable Transistors And Pressure Sensors. Advanced Electronic Materials. p. 1900191 (2019).
[3] S. Zhang, E. Hubis, C. Girard, P. Kumar, J. DeFranco and F. Cicoira: Water stability and orthogonal patterning of flexible micro-electrochemical transistors on plastic. Journal of Materials Chemistry C. 4, 7 (2016).

Organic Electrochemical Transistor (OECT) is a voltage to current transducer with high transconductance (~1 mS) and low operating voltage (< 1 Volt). These features make OECT a good candidate as biosensor. Instead of typical solid dielectric material used in Organic Field Effect Transistor (OFET), electrolyte is used to couple gate and channel in OECT. In particular, ions which injected from electrolyte to channel will either dope or de-dope the channel conducting polymer (CP) and modulate the bulk conductivity of channel. The ion injection lies in the center of all OECT applications. If ions can’t diffuse into CP channel, the OECT will operate as an electrolyte-gated OFET with smaller transconductance. To date, the most common used CP material in OECT is Poly(3,4-ethylenedioxythiophene): Poly(styrenesulfonate) (PEDOT:PSS) due to its high conductivity and solution processability. PEDOT:PSS based OECT had been used for cation detection as well as detecting metabolites and protein biomarker concentration in Phosphate-buffered Saline (PBS) solution. However, when tackling with human serum or plasma, albumin and other proteins will non-specifically attach onto channel CP surface. This may hinder the ion injection and cause the false detection results for PEDOT:PSS based OECT biosensor.
In this work, we covalently link a roughly 30 nm thick copolymer with carboxybetaine functional group on top of PEDOT:PSS based OECT device. We then investigate the device ion sensing ability after the surface is exposed to 5 Wt% Bovine Serum Albumin (BSA) solution or human serum. The copolymer used is PCB_(EtOH), poly(Carboxybetaine acrylamide (CBAA) -co- n-butyl methacrylate (BMA) -co- N-(4-benzoylphenyl) acrylamide (BPAA)), with CBAA, BMA and BPAA at 7:2:1 ratio. While in contact with aqueous solution, the carboxybetaine functional group will flip onto surface and prevent the non-specific adsorption. The BMA functional group helps the copolymer to attach onto the surface while the BPAA functional group reacts with alkyl backbone of CP after UV light (312 nm) irradiation. The gold electrode with designed pattern was first deposited on glass by thermal evaporation. The PEDOT:PSS (PH1000) solution with 5 vol% ethylene glycol and 1 vol% (3-Glycidyloxypropyl)trimethoxysilane was then spin-cast on the defined channel area to have width and length equal to 0.5 mm and 5 mm, respectively. The thickness of PEDOT:PSS layer is about 225 nm. After annealing at 140 °C for 30 minutes, the device was soaked in DI water overnight to remove any remaining small molecules. The PCB solution was further spin-cast on top of PEDOT:PSS layer and cured under UV light. The device was soaked in DI water overnight to remove unbound PCB molecules before further testing and characterization. The covalent binding between PEDOT:PSS and PCB was confirmed by the absorption peak of benzoylphenyl group (320 nm) in UV-Vis spectroscopy compared with bare PEDOT:PSS film. With the specific design, the transconductance of both devices are able to reach mS or even 10 mS level. Though the devices are still under testing, we strongly believe the transfer characteristic curve will shift downward in bare PEDOT:PSS device due to the adsorption of BSA and other proteins while the transfer characteristic curve remain the same for an additional PCB layer device. The downshift level of transfer characteristic curve is very crucial since it has been used for biomolecules quantification in OECT based biosensor. We also expect the decreasing of sensitivity and speed for cation detection in bare PEDOT:PSS device after BSA and other proteins adsorption. Either gold, platinum or silver/silver chloride wire are used as gate electrode. The other advantage of PCB layer is its ability to further link biorecognition molecules though the carboxybetaine functional group. We believe the additional PCB layer on top of PEDOT:PSS based OECT could pave the way for OECT application in the real world.

Biocompatible microbatteries have a high potential as energy sources for a wide range of applications—electronic medical implants, health monitoring devices, and environmental sensors. One concrete example of the application of such microbatteries is in ingestible electronic devices. These devices can be employed for regular monitoring of vital body functions such as core body temperature, pH level, for controlled drug release, and for checking of medication adherence. Presently, ingestible electronic devices are usually powered by relatively large batteries that often contain toxic materials. As a consequence, the whole battery necessitates encapsulation to avoid any leakage of potentially harmful substances into the body, but this also makes the devices difficult to swallow and increases the risk of retention inside the body. Moreover, fabrication of the batteries is mainly based on conventional, macroscale techniques and therefore possesses only limited prospects for miniaturization and mass production. Previously, we developed a primary biocompatible microbattery that was entirely realized by conventional microfabrication techniques. However, the thin film electrodes (thickness about 2–3 µm) had only limited capacities of about 0.5–0.8 µA h, enabling operating times of about 10–25 minutes.
To overcome these limitations and to increase the capacities, we have developed microbatteries that can be realized by a combination of conventional microfabrication and direct printing of the active materials using functional inks. The device consists of two main parts: A Si microreservoir that is filled with the electrolyte (gastric acid) once the device is swallowed, and the microbattery itself. The Si microreservoir was fabricated by dry etching in Si, which was then bonded to a glass wafer that contained the microbattery. For the fabrication of the cathode and anode, Au thin films were first deposited as current collectors (nominal size 0.7 × 3.2 mm²), using standard photolithography followed by sputtering. The anode ink consisted of Zn powder that was mixed with ethyl cellulose as binder and acetylene black to increase the conductivity, while Ag/AgCl ink was used for the cathode. Both Ag/AgCl cathodes and Zn anodes were printed directly on the current collectors using a custom-made 3D printing system, allowing electrode thicknesses of the order of 100–150 µm. The performance of the microbatteries was assessed by galvanostatic testing in simulated gastric fluid (pH 1.2) at current levels ranging from 2 to 10 μA. Compared to the sputtered thin film electrodes, the printed electrodes enabled increasing the capacities to about 10 µA h. It is expected that by optimizing the ink composition, especially the content of the active materials, that the capacities can be increased further. The combination of established microfabrication techniques with direct printing is expected to enable more complex microbattery architectures, allowing customized and easier-to-integrate energy sources in future electronic devices aimed at medical and environmental sensing applications.

Recent advances in soft electronics have enabled a class of bio-integrated sensors that combine advanced sensing functionality with skin-compliant form factors that reduces contact resistances and motion artifacts. Research efforts have yielded a range of biophysical and biochemical sensors for measurements of motion, electrophysiology, sweat biomarkers, temperature and several other clinically relevant quantities.

Here, we demonstrate the use of arrays of thermal sensors and actuators to map out heat transfer through soft tissue and extract properties such as thermal conductivity, thermal diffusivity and volumetric heat capacity. The low thermal masses and contact resistances of these sensors are uniquely suited to making these precise, quantitative thermal measurements to extract depth-dependent tissue properties as they correlate to vascular perfusion, skin hydration and overall activity level. We will discuss three broad areas where we have made significant recent progress:

1. Measurements of skin thermal transport properties for a range of clinical conditions: The thermal transport properties of skin are determined by its constituent materials, including vasculature and free and bound water molecules. These constituents change in response to activity levels and changes in ambient thermal conditions, a critical mechanism for thermoregulation. We present materials, mechanics and thermal transport considerations to map out heat transfer as a correlate for each of the above, with systematic validations in the form of benchtop studies, finite element analyses and on-body testing. These sensors can also be used to map directional, anisotropic thermal transfer in the presence of flow through large blood vessels or implanted catheters. We discuss the potential of these materials advances to in the creation of a class of wearable flow sensors to fundamentally improve the care and treatment of patients suffering from hydrocephalus, a neurological condition caused by the buildup of cerebrospinal fluid in the ventricles of the brain.

2. Fully implantable flow sensors to map vascular changes through peripheral nerves: The peripheral nervous system represents a large research area for materials scientists and neuroscientists alike, presenting challenges due the mechanical mismatch between soft, deformable nerves and traditional rigid, metallic recording electrodes. Here, we discuss our recent work in creating a class of soft, tissue-compliant nerve ‘cuffs’ formed via a novel buckling process of pre-strained elastomer bilayers, that are instrumented with the thermal characterization electronics discussed above. These sensors are capable of measuring blood perfusion through peripheral nerves in a manner that can be correlated with overall nerve health.

3. Wireless powering and data transfer schemes: Wireless power and data transfer are critical for the deployment of these sensors for continuous, real-time monitoring. We discuss two paradigms for wireless operation that offer the advantages of soft, tissue-compliant materials, while allowing for high-precision data transfer and completely wireless powering. The first involves the use of near-field communication (NFC) while the second involves Bluetooth-low energy (BLE) protocols. We demonstrate the utility of these materials integration schemes for measurements of skin hydration and flow.

In minimally invasive endoscopic intraventricular surgeries, very small robotic surgical tools such as a grasper and cutter can be designed and miniaturized to a size of less than 2 mm while maintaining its dexterity and force required to resect brain tumors without open-skull surgery. However, due to remote control the robotic systems, there are very limited haptics namely tactile and kinesthetic information being received by the surgeons, leading to loss of control over tissue and causing unexpected slippage and trauma. This study presents the design of a small and highly sensitive smart material-based sensor being integrated to the tool shaft, known as the concentric tube manipulators, to provide instrument-tissue interaction force feedback for this tool. A 100 μm-ultrathin layer of micropatterned resistive carbon-filled polyvinylidene fluoride (PVDF) conductive polymer is wrapped spirally around the 2 mm-diameter concentric tube for static and quasi-static force sensing. A layer of interdigitated electrodes, connecting with a high-frequency, real time data acquisition (DAQ) system, is designed to achieve pressure readings with both directional and locational information. These pressure readings are visual pressure profile displays generated based on concentric tube-brain tissue contact mechanics with assumption of cylinder-sphere contact model. Optimizations are performed on the size, pitch and shape of the microstructures as well as the width and spacing of the electrodes to improve sensitivity with reduced hysteresis. The finalized design can sense a pressure from as low as 0.55 kPa to 5.5 kPa with an accuracy of 93%. The sensor demonstrates excellent proportionality between the acquired signal and force applied with 91% consistency under small loads while retaining its flexibility, biocompatibility and sterilizability. The sensor will also enhance more intuitive force feedback for surgeons to use the dexterous neurosurgical tool, ensuring the safety and quality of operations for minimally invasive surgeries involving brain tumor and epilepsy practice.

Progress in highly conformal epidermal electronics led electrophysiology recording based on dry electrodes which breakthrough critical problems such as low skin-electrode impedance and motion artifact issues. These astonishing advances give a new opportunity to Brain-Computer Interface (BCI) which is using non-invasive electroencephalography (EEG) recording. Nevertheless, researches so far have just reported electrical and mechanical performance of electrode or suggested elementary exemplification about recording EEG. Here, we introduce a comprehensive wireless BCI system which can be used in daily life such as driving situation, based on depth study about Event-Related Potential (ERP) and tattoo-like epidermal electrode. P300, which is one of the main components of ERP, is considerably used in BCI application and occurred from brain when a person recognizes unexpected stimulus. In this study, P300 wave was thoroughly analyzed from 10 different subjects, three different oddball paradigm tests, both epidermal and conventional electrode simultaneously and motion induced situations to ensure compatibility of epidermal electronics and P300-based BCI. In addition, we present device structures and fabrications, electrical and artifact characteristics of epidermal electrode, epidermal electrode positioning strategy, skin mounting methods, P300 wave recording procedures, and design of miniaturization FPCB chip to measure EEG and communicate wirelessly. As a proof-of-concept, mobile RC car was used as target platform and we compared braking distance between BCI based autonomous driving car and manually controlled driving car in the emergency situations.

Hand gesture recognition based on muscle activity monitoring has been implemented in robust human-machine interactions, bionic prosthetics, and prognosis of neuromuscular disorders. Muscle activities involve myoelectrical trigger of motor neurons at neuromuscular junctions and the mechanical actuation of muscle fibers. Monitoring the functionality of either single event has been fulfilled with various electromyogram electrodes or skin-mountable strain sensors. However, the patterns of myoelectrical triggers and mechanical shortening of myofibers can be different spatiotemporally, intrinsically arising from the excitation-contraction coupling process. Hence, the fidelity of interpretation muscle activities by retrieving either single event is disputed. There is an unmet demand on establishing the electromechanical coupling of the myoelectrical triggers and mechanical responses in muscle for the high-fidelity hand gesture recognition. To address this, we developed the hybrid electrode to spatiotemporally couple the surface electromyogram (sEMG) signals and the mechanical strain of local skin. By resembling the transmembrane architecture of cytoadhesion, the electrode utilized discrete “adhesion plaques” to mechanically and electrically integrate the microcracked metallic nanofilms for strain sensing at a gauge factor, and the ionic gel with low contact impedance for sEMG collection at a high signal-to-noise ratio. By establishing the electromechanical patterns of forearm muscle contraction, the electrode was able to distinguish loose and tight fist clenching, as well as the flexion of different fingers. In addition, the electrode was able to orthogonally recognize the hand gesture dynamics, which could be transferred to robotic hands for recapitulating human grip gestures with varying dynamics.

Smart contact lenses—contact lenses with built-in electronics—are a next-generation wearable product with capabilities beyond simple vision correction. Since the electrical lenses are in continuous contact with the eyeball surface, they have three main applications: (i) biomedical sensing of tears to monitor health conditions, (ii) wearable displays for augmented reality (AR), and (iii) actively regulating eye accommodation to ensure perfect vision. Thus, a smart contact lens has substantially greater functionality than an electrical eyeglass. Here we demonstrate electrochemically (EC) printing a wireless-powered circuit onto a moist, soft contact lens. EC printing involves adding a conductive polymer at the interface between a metal contact and a hydrogel-based contact lens, resulting in strong adhesion of the circuit to the lens without losing high power transfer efficiency (50%) from an eyeglass transmitter to the printed receiver lens. Our wireless powered system is combined with an AC/DC rectifier circuit for a single LED display and for electrochromic filter applications.

Different from normal wounds, chronic wounds often have a large and deep wound area and patients often experience long-term suffering from inflammation and bacterial infection. In chronic wounds healing process, pH is a key parameter, indicating the state of bacterial infections. For a healthy skin, the typical pH is 5.5-6.5, while in chronic wounds, the pH can be above 8 due to the by-products created by bacteria in the process of cell proliferation. In order to treat wound promptly and effectively, pH monitoring requires multiple measurements from the wound area with high spatial resolutions. However, current wound sensors are mostly in solid forms and cannot detect in different depth of wound area comprehensively, while some flexible sensors are costly and with some chemical-based fabrication methods or materials that could be potentially harmful in human body. Herein we proposed an eco-friendly fabrication of, flexible and highly sensitive pH sensor for chronic wounds based on bio-derived materials. The resulting composite sensor has near Nernst limit pH sensitivity in the pH range from 4-10, with low Young’s modulus, and also has a long-term sensitivity lasting for at least 24 hours. This renders its applications in flexible bio-sensors and smart wound dressings.

Advanced nano-science and patterning technologies are constantly evolving to meet the ever-growing expectations for improved flexible optical MEMS. In this work, for the first time to our knowledge, we compare state-of-art commercially available photo-definable optical polymers, namely Ormoclear FX and Ormocomp (hybrid polymers called ormocers), IP-Dip (UV resin) and Epocore (an improved SU8-like epoxy) and explore their suitability for design of flexible bio-optoelectronics. We demonstrate micro- and nano-technologies to pattern optical films on polymer substrates and evaluate their characteristics such as optical transmission and clarity, in vivo lifetime and resistance to photodamage.
Flexible optical materials can be used for applications ranging from waveguide circuits in optical interconnects to micro-lens for CCD/CMOS imagers to optical sensors in bioimplants and wearables. The advantages of polymers include lightweight, flexibility, thin film formation at lower temperatures and wide range of molecular designs. Unlike semiconductor material growth and deposition approaches which are carried out at higher temperatures, polymers can be spun at room temperature and cured at relatively lower temperatures to achieve wide range of thicknesses. With the aid of computational models, polymer molecular formations can be synthetized to tune in optimal physical properties like elasticity, tensile strength and so forth. However, common drawbacks of polymers are narrow range of controllable optical properties such as transmittance, transparency, durability and high moisture absorption. Recently, nano-hybridization of polymers with metallic or inorganic nano-particles has been proposed as a promising technique to overcome polymers’ drawbacks without reducing their inherent advantages. Our results show that hybrid polymers Ormoclear FX and Ormocomp are indeed most flexible (1-1.2 GPa Young’s modulus) with highest transmissivity in visible and near infrared spectrum, high optical transparency and good photodamage resistance. These characteristics make ormocers most preferable for polymer optics including long-term biomedical applications such as waveguiding and imaging. Epocore and IP-Dip are comparable to polyimide and parylene in flexibility (~3GPa of Young’s modulus) but exhibit lower optical transmission in UV/near-UV range with average optical clarity. All polymers withstand a 6-month equivalent accelerated saline soak with only 2-6% decrease in transmissivity over 300-800nm spectral range demonstrating appreciable resistance to in vivo degradation. The results conclude that unique polymer characteristics combined with compatible patterning technologies can be applied to target different optoelectronic applications. While nanoscribe printing (with IP-Dip and Ormocomp) was found suitable for high precision 3D printing of microstructures like diffractive optical elements, optical bonds and hollow guides; 2D microfabrication (with Ormoclear FX and Epocore) was better suited for reliable design of continuous and longer optical structures such as waveguides.

Color is a signature visual feature in nature; however, the ability to trigger color change in the presence of different environmental stimuli is unique to only a handful of species in the animal kingdom. We exploit the natural color changing properties of the predominant pigment in arthropods and cephalopods - xanthommatin (Xa) - and describe its utility as a new broad-spectrum electrochromic material. To accomplish this goal, we explored the spectroelectrochemical properties of Xa adsorbed to an indium-doped tin oxide (ITO) coated substrate chemically modified with poly (3,4-ethylene dioxythiophene) doped with poly(styrenesulfonate) (PEDOT:PSS). We identified a synergistic role between PEDOT:PSS and Xa that contributed to its absorption profile which could be modulated across multiple cycles. This bio pigment was encapsulated into polymeric material and investigated color tunability in response to pH and electrochemical reaction. Enhanced visible through SWIR scattering makes this nano material as a potential candidate for IR colorant.

Conjugated polymers have great potential as flexible, electroactive materials for cell stimulation, but their application is often hindered by their limited processability in non-toxic solvents. A promising solution lies in conjugated polyelectrolytes (CPEs) bearing ionizable pendant groups; these materials are processable in water and exhibit “self-doping” behaviour without the need for external dopants or dispersants. We report the synthesis and characterization of a novel CPE, poly(ethylenedioxythiophene) functionalized with ionizable phosphonate groups (PEDOT-Phos), which is soluble in several solvents including deionized water, phosphate-buffered saline, and dimethylformamide. Raman spectroscopy confirms the presence of both the conjugated PEDOT backbone and the phosphonate pendant groups. The polymer undergoes changes in ultraviolet-visible light absorption and photoluminescence spectra as a function of pH, indicating polaron formation. This pH-dependence is attributed to the tunable ionization behaviour of the phosphonate pendant groups. The polymer is readily processed directly from aqueous solution into semi-crystalline films, which exhibit strong visible-light photoluminescence and reversible redox behaviour. The morphology of cast films can be controlled by modifying the casting solvent and performing thermal annealing. With its intriguing optoelectronic properties and easy processing from aqueous media, PEDOT-Phos has significant potential as a novel, electroactive substrate material for bioelectronic devices.

Flexible thermal sensing devices have shown great potential towards many biomedical applications and robotic/machine interfaces in which direct conformal measurement over complicated geometry is necessary. However, conventional inorganic materials widely used to fabricate the sensory element either inherently lacks flexibility and sensitivity, or often requires high temperature processing steps which complicates their integration with flexible plastic substrates. Recently, we have demonstrated that organic thin films composed of plant-derived polysaccharide, pectin, can detect temperature changes with more than two order of magnitude higher sensitivity compared to those state-of-art temperature sensing layers. However, the characteristics of these natural products are complex and their properties can vary widely. In addition, pectin films exhibit poor mechanical properties over repeated stress and bending solicitations. Here we report a multifunctional polymer scaffold inspired by pectin. The chemical structure and mechanical properties of the polymer are tailored to retain the thermal response with flexible functionality. Through impedance characterization as a function of temperature, we show that the ionic conductivity within the polymer film is strongly related to temperature and demonstrate its ultra-high temperature responsivity and reproducibility that also allows device scalability for large scale integration.

We have been investigating the electrochemical deposition of functionalized polythiophenes around neural cells with the goal of creating stable, directly biointegrated electronic devices. Our previous efforts have primarily focused on the well-studied 3,4-ethylenedioxythiophene monomer (EDOT). While the corresponding polymer (PEDOT) has shown considerable potential, its highly hydrophobic character leads to issues when depositing it around living cells. Here, we discuss recent efforts to examine the potential of an EDOT monomer with a pendant carboxylic acid moiety (EDOT-acid). We have examined the cell viability of EDOT-acid relative to EDOT and have found that EDOT-acid solutions are much more cytocompatible. We have also seen variations in the growth mechanisms when P(EDOT-acid) is deposited around living cells. P(EDOT-acid) grows in a manner that is more attached directly to the cell surfaces, rather than to the electrodes as seen with PEDOT. Most recently, we have been examining the deposition of a bifunctional monomer that combines EDOT with dopamine, creating what we call EDOT-dopamide. P(EDOT-dopamide) polymers can also be grown electrochemically and show low impedances over a broad frequency range. The morphological, physical and chemical characterization of these materials with optical and electron microscopy, spectroscopy, and other techniques will be discussed and compared with PEDOT.

Although peripheral nerves possess the inherent ability to regenerate, nerve transections require surgical intervention to optimize functional recovery. While small gaps (≤5 mm) may be directly coapted without tension, larger gaps may require interposition grafting with nerve auto- or allografts or conduits to provide tension-free mechanical support, axon guidance, and protection from fibrous tissue ingrowth. Conduits avoid the substantial disadvantages of autografts, i.e. a second surgical site, donor site morbidity, limited availability, high treatment cost, but current FDA approved devices are limited to use in defects ≤30 mm. Cadaveric nerve allografts are used only for defects ≤70 mm due to the limited regenerative capacity of neurons through such grafts. Thus, autografts remain the gold standard and outcomes remain suboptimal with only 50% of patients with mixed nerve injuries regaining meaningful motor and sensory function, and less than 15% regaining full functionality.
Nerve guidance scaffolds (NGS), in which piezoelectric nanoparticles (PNPs) are homogeneously distributed enable the possibility of fractionated stimulation of the PNPs using ultrasound (US) to aid speed and quality of regeneration over several weeks and months. Innovative are the application of a straightforward, benign processing technique, freeze casting, to the manufacture of multifunctional scaffolds from a novel PNP composite. The freeze-cast scaffold architecture emulates that of the natural tissue and, through composition and processing parameters, can be custom-designed in its structural, mechanical, and piezoelectric properties. Presented will be a summary of key experimental and modeling results, and correlations obtained during the design, manufacture and testing of the piezoelectric NGS, from the poling of the PNP to enhance their piezoelectric conversion to their structural and piezoelectric characterization, and finally in vitro and in vivo testing. The results suggest that piezoelectric scaffolds and their US stimulation offer a very promising approach for neuroregenerative devices with comparative ease of translation into clinical application.

Organic electrochemical devices, which use conjugated polymers in contact with an electrolyte, have applications in bioelectronics, energy storage, electrocatalysis, and sensors. Their operation relies on the oxidation (electron loss) or reduction (electron gain) of the polymer, which are traditionally described as Faradaic processes that transfer charge. However, recent evidence from various devices based on poly(3,4-ethylenedioxythiophene) chemically doped with poly(styrene sulfonate) (PEDOT:PSS) is consistent with a purely capacitive process that stores charge. To clarify whether PEDOT:PSS is an exception or the rule and determine which processes are capacitive and which are Faradaic, solid-state physics methodology developed to understand the operation of organic light-emitting diodes can be used. Such studies can pave the way for device optimization.

Within 1.3L of human brain billions of neurons connected by trillions of synapses are continuously exchanging signals. These signals govern the inner workings of the nervous system, and the aberrations in communication between neurons and other cells within the brain are manifested as the neurological and mental conditions that increasingly affect our aging society. While clinically available devices lack the finesse of the neural circuits and drugs often come with unwanted side effects, our team leverages the principles of optoelectronics and magnetism to develop tools matching the signaling complexity of the nervous system and cause minimal disruption to natural physiological function.
My talk will discuss how multimaterial fiber technology can be leveraged to produce compliant and miniature devices capable of electrical and optical recording and stimulation of neural activity, and delivery and sensing of neurochemicals. I will further highlight how multimaterial fibers can be employed for neural repair following traumatic injury as well as the potential candidates for artificial muscles with future applications in prosthetics. The second half of my talk will focus on using iron-containing nanomaterials as transducers of magnetic fields to biologically relevant stimuli such as heat and force. By tuning magnetic nanomaterials properties in conjunction with magnetic field conditions, it is possible to independently control multiple heat- or force-dependent biological processes. Finally, iron-containing nanomaterials can be used to aid minimally-invasive delivery of neurochemicals via magnetothermal and electrocatalytic means.

The auditory brainstem implant (ABI) is a neuroprosthesis that provides sound awareness to deaf individuals who are not candidates for the cochlear implant. The ABI electrically stimulates the surface of the cochlear nucleus (CN) in the brainstem. The complex anatomy and physiology of the CN together with the poor spatial selectivity of electrical stimulation and inherent stiffness of contemporary implants lead to only modest auditory outcomes in ABI users.
We propose a soft conformable ABI electrode array to improve the biomechanical match of the man-made implant to the curved CN surface. The conformable implant provides stable positioning of the implant in vivo and enables higher selectivity of electrical stimulation. The soft neurotechnology leverages miniaturization, high performance thin-film materials, and engineered mechanical compliance to produce implants compatible with the demanding ABI surgical insertion and conformability to the curvature of the brainstem. We developed elastic micro-structured multilayers, a soft electrode coating, and transient surgical features that allowed the fabrication of a scalable ABI from miniaturized mouse implants to human-size arrays.
This talk will report on the microfabrication and scaling process, mechanical and electrochemical characterization of the compliant ABIs. The soft electrode specifications are very similar to those measured in clinical ABIs with average impedance at 1 kHz of 5.78 ± 0.62 kΩ (electrodes of 0.385 mm² surface area). In a mouse model, we show that soft neurotechnology can be implemented to reliably activate auditory neurons in vivo for up to 4 weeks, a mandatory step before evaluating longer, chronic use of the technology. In a human cadaveric model, we demonstrate that the soft ABI is robust to surgical manipulation and insertion into the lateral recess of the IVth ventricle, and displays improved electrochemical performance compared to current clinical devices.

Aim: This study aimed to compare the chronic in vivo charge transfer properties of conductive hydrogel (CH) coated cochlear implant (CI) electrodes to traditional platinum (Pt) CI electrodes.

Background: CIs can improve quality of life in profoundly deaf people by restoring sound perception. Ideally, bionic devices should safely operate for a lifetime; however, host responses such as protein adsorption, inflammation and fibrosis can impact electrode impedance. These host responses can lead to inefficient stimulation and formation of toxic byproducts. CH coatings, based on poly(vinyl alcohol) (PVA) anti-fouling polymers modified with conductive polymers (CPs), can provide enhanced electrical properties, superior to those of traditional Pt electrodes. This technology can be directly coated onto metallic substrate of state-of-the-art bionic devices¹. This study tested the hypothesis that PVA conductive hydrogels can enhance safe charge injection and improve the quality of neural recordings.

Methods: CIs with 4 electrodes specifically designed for the rat cochlea were implanted for up to 5 weeks. The CH coating was fabricated using PVA hydrogel modified with 20 taurine groups for electrical doping and 5 methacrylate groups for crosslinking. The CP poly(ethylene dioxythiophene) (PEDOT) was galvanostatically grown through the hydrogel and arrays were ethylene oxide-sterilized (ETO) prior to implantation. Electrochemical impedance (EI), charge injection limits (CIL) and charge storage capacity (CSC) of electrodes was compared before and after implantation using a 3-electrode cell (vs Ag/AgCl). Sprague Dawley rats were unilaterally implanted with CH coated or uncoated Pt CIs. The animals were chronically stimulated using charge balanced biphasic pulses for ~20 hrs/week over the implantation period. To evaluate electrode performance in vivo, voltage transient impedance was measured 5 days/week, and EI, CIL and CSC was also recorded over the implantation period. Explanted electrodes were imaged using scanning electron microscopy (SEM) for evaluation of the CH attachment and for signs of Pt oxidation.

Results: Before implantation, EI of CH coated electrodes over a frequency range of 10Hz-50kHz was more than 3 times lower than uncoated Pt implants. CSC and CIL of CH-coated electrodes was over one and two orders of magnitude higher than Pt electrodes, respectively. During implantation periods, common ground impedance of CH-coated electrodes increased from ~4kW in the first week, and stabilized thereafter at ~6kW. In contrast, the impedance of Pt electrodes was approximately double that of CH immediately after surgery at ~8kW and after 2 weeks at ~13kW. Following implantation electrochemical impedance was maintained at close to pre-implantation levels in CH coated electrodes, which was significantly lower than in Pt. CSC and CIL decreased by ~40% and ~60% in CH coated electrodes following implantation, but both were still ~10 times higher than the Pt CSC and CIL. Preliminary observations of SEM images (n=2) showed that the CH coat remained attached to the cochlear implant throughout studies. However, further histological analysis will assess potential CH residues in cochleae tissue. Following removal of CH no signs of Pt oxidation were observed.

Conclusion: CH-coated cochlear arrays maintained enhanced electrical properties during and after implantation. These results support the potential of CH as an advanced electrode coating for cochlear implants with superior electrochemical performance than Pt electrodes.

1. Hassarati, R. T. et al. Improving Cochlear Implant Properties Through Conductive Hydrogel Coatings. IEEE Trans. Neural Syst. Rehabil. Eng. 22, 411–418 (2014).

Microelectronic devices placed in the nervous system present tremendous potentials for mapping neural circuits and treating neurological disorders. Currently, these devices often experience failures in part due to the electrical, mechanical, and biochemical, mismatch between the artificial device and neural tissue. Quantitative histology and 2 photon imaging have revealed neuronal damage and degeneration, inflammatory gliosis, blood brain barrier leakage and oxidative stress at the site of implants which may compromise the intended recording/stimulation/neurochemical sensing function. We use several biomaterial strategies to minimize these mismatches in order to achieve seamless and stable device-tissue interface. First, various conducting polymer based nanocomposites have been investigated as electrode coatings and facilitate the signal transduction/charge transfer between the ionically conductive tissue and the electrical device. Nanostructuring is employed to improve the adhesion, stability and charge injection and drug delivery capability of the conducting polymers to meet the material challenges in chronic interface. Secondly, to minimize the mechanical mismatch at the device-brain tissue interface, novel soft and elastomeric electrode materials have been developed with Young’s modulus approaching that of neural tissue (less than 1 MPa). Soft implants demonstrated reduced inflammatory tissue response in both CNS and PNS compared to stiff implants of similar geometry and surface chemistry. Thirdly, bioactive approaches are being developed to modulate the biological responses. One approach is to modify the implant surface with biomolecules or biomimics. Surface immobilization with these bioactive molecules significantly improved neuronal health and inhibited the inflammatory tissue response around the implants. Alternatively, therapeutics that control inflammation, neurodegeneration and oxidative stress have been delivered systemically or locally. These bioactive approaches have demonstrated significant benefit in neural recording quality and longevity. The ultimate solution to a seamless device/tissue interface may be a combinatorial approach that takes advantage of multiple biomimetic strategies discussed above and beyond.

In recent years, implantable bioelectronics has raised huge interest, especially for neural diseases. Among them, devices with a nerve guidance to guide neuron growth can enhance neural regeneration for traumatic peripheral nerve injury. However, the commonly used nerve conduit cannot provide a spatiotemporal regulation and in-situ monitoring for localized neurons. Accordingly, in this study, an implantable neural device that is built with microelectrode arrays on transparent and flexible substrate was developed to enhance cell growth through applying electrical stimulation and neural signals recording in a tissue-mimicked microenvironment. A new type of flexible substrate, nanoporous Parylene C, was designed and fabricated to exhibit tissue-mimic structural and mechanical properties. The microelectrode array, iridium oxide electrode for both neural stimulation and recording, was pre-deposited on a water-soluble sacrificial layer of poly acrylic acid (PAA) prior to the transfer print process. Such transfer printed tissue-mimic neural microelectrode array enabled conformable adhesion on a curvilinear nerve surface and electrical signals transduction from the microelectrode site, which is expected to provide higher performance of peripheral nerve regeneration. In addition, we characterized and evaluated the microelectrode array of iridium oxide film, including charge storage capacity, charge injection capability, and electrochemical impedance.

Various bioelectronic devices have attracted broad attentions and they inevitably require stable integration with biological tissues to ensure their reliable functions without compromising their electrical performance. Due to the intrinsic wet, dynamic, and deformable nature of biological tissues, the poor combination and the potential tissue damages during integration is undoubtably interfered with the accuracy and reliability of electrical communication between biological tissues and bioelectronics. Here, we present a new family of conductive tissue-adhesive (CTA) interface capable of offering a general strategy for integrating various bioelectronics with wet and dynamic tissues to develop stable electrical communication between them seamlessly and instantly. The soft, stretchable, patternable and biocompatible CTA interface can adhere diverse materials of electronics and different biological tissues, as well as provides stable electrical properties in wet physiological environment and under deformation ex vivo and in vivo. The study provides a new powerful platform for diverse bioelectronics to address the long-standing challenges in human-machine interface.

Efficiently powering the next generation of highly miniaturized bio-sensors, implantable drug delivery systems and bio-electronic devices for the human body defines a new era of medicine to track, support and operate body functions. Here, glucose fuel cells have seen a renaissance in recent years as an implantable power source harvesting energy from readily available fuels in the human blood stream.¹ Compared to existing implantable batteries, glucose fuel cells do not require frequent replacement surgery, due to the abundance and perpetual availability of glucose inside the human body. However, state-of-the-art glucose fuel cells are primarily based on polymer electrolytes being relatively bulky, suffer from long-term stability issues and exhibit low power densities. Here, we innovate a miniaturized glucose fuel cell, which is fully composed of solid state materials based on thin film processing.² This all-solid-state glucose fuel cell can be scaled down to the sub-micrometer range for unprecedented miniaturization and is built on a Si-chip using standard semiconductor fabrication methods suitable for integrated and direct powering of bio-electronic devices and implants. Through the use of abiotic catalysts instead of conventional biological catalysts such as enzymes and microbes, long term stability and increased power density are in perspective. Free-standing fuel cell membranes based on a proton conducting oxide on Si-chips were assembled using a microfabrication route with standard semiconductor processing techniques. Oxide thin films were prepared via pulsed laser deposition.³ The anode is in contact with glucose in phosphate buffered saline solution to mimic blood, whereas the cathode is in contact with oxygen. Performance characterizations were carried out via electrochemical impedance spectroscopy and galvanostatic polarization curve measurements. During this presentation we will present that the proposed cell is electrochemically active and reproducibly functions as the first all-solid-state glucose fuel cell with a roughly 100-fold lowered thickness of the device (only 250 nm) compared to polymer-based glucose fuel cells. In addition, we will present our recent efforts in developing a new, cheap and scalable route of fabricating our newly invented glucose fuel cell using spray pyrolysis.
References
[1] S. Kerzenmacher, J. Ducrée, R. Zengerle, F. von Stetten. J. Power Sources, 182 (2008) 1-17.
[2] P. Simons & J.L.M. Rupp. US Patent Application US 15/901,732 (2018)
[3] Y. Shi, A.H. Bork, S. Schweiger, J.L.M. Rupp. Nat. Mater., 14 (2015) 721-727.

Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS, has been regarded as one of the most successful semiconductor polymers for organic electrochemical transistors (OECTs) due to their solution-processability and aqueous stability. The ability to operate in aqueous environments make OECTs excellent candidates for a variety of applications, especially in the area of sensing. Incorporation of plasticizers or pre-treatment, such as ethylene glycol or sulfuric acid，have been done to boost the electrical performance of PEDOT:PSS-based OECTs by changing the PEDOT domain, crystallinity and nanostructure. In our previous work, we have introduced ionic-liquids in PEDOT:PSS induced a highly ordering molecular packing, and enable good device characteristics, including high transconductance, controllable operating window and fast response time with long-term stability.^[1] Here, we expand our work further to study the various ionic liquids in PEDOT:PSS and their effects in the structural realignments of PEDOT and therefore on OECT performance. In addition, we demonstrate a facile patterning method via spray-coating to fabricate ionic liquid doped PEDOT:PSS-based OECTs, instead of the conventional complicated photolithography process, with great electrical performance and excellent device stability. More importantly, this facile technique makes it possible to fabricate high-performance OECTs on diverse substrates such as biodegradable flexible substrates based on ethyl-cellulose and natural leaf, wearable type substrate based on the commercial adhesive bandage, and deformable elastic substrate based on polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS) elastomer. Using these substrates, the fabricated OECTs maintained high electrical performance with a transconductance of ~3.7 – 7.4 mS at V_G = 0 V. Overall, the results indicate that the spray-deposition technique provides a convenient route to prepare high performing OECT channels and exhibits great prospects in various ubiquitous electronics and bio-integrated organic electronics, such as flexible, conformal biological sensors and foldable wearable integrated circuits.

Reference
[1] X. Wu, A. Surendran, J. Ko, O. Filonik, E. M. Herzig, P. Müller-Buschbaum, W. L. Leong, Adv. Mater. 2019, 31, 1805544.

The tight coupling between ions and electronic charges, along with several unique physical and chemical features, makes the conducting polymers a unique material platform in bridging the signaling gap between biology and technology. Here, different organic bioelectronic sensor and delivery devices will be reported that can operate as distributed and autarchic nodes within a body area network. The resulting system, the BioComLab, can be applied to the human body and has been explored in different healthcare-relevant settings. The BodyComLab technology has been developed to enable fast diagnostics, decision-making and delivery of targeted compounds.

A stretchable and transparent sensor enables to monitor electroencephalogram (EEG) with less psychological stress. Here, an Au-plated Ag nanowire (AgNW/Au) is reported to enhance properties of a conductive track in the sensor on conductivity, stretchability, and electrochemical durability without the loss of transparency. With a newly-developed dry bioelectrode, the sensor wirelessly records EEG with low noise less than 1 microvolt and can contribute to diagnose brain disorders in relaxed state.
Recently, stretchable and transparent conductive electrodes (stretchable TCE) including conductive tracks have been demonstrated to be applicable in biosensors. [1] The softness, as being closely equal to biological body, steps forward to long lasting therapeutic.[2,3] However, there is a challenge on recording small biopotential such as EEG having amplitude of 1–100 microvolt using stretchable TCE. Signal to noise ratio is impacted from an exogenous noise that is usually related high skin-electrode contact impedance.
Here, conductive materials that show biocompatibility meeting the ISO standards and exhibit low skin contact impedance less than 50 kilo-ohm are reported and integrated in a stretchable and transparent sensor. AgNW/Au-based TCE shows an improved sheet resistance by 20–30% and stretchability up to 100 cycles between 0–60% strains although pristine AgNW-based TCE could not achieve them. No severe change of electrical resistance is also confirmed under accelerated test by high current on AgNW/Au-based TCE in the presence of water. Meanwhile, a stretchable and transparent adhesive as the dry bioelectrode is developed based on anisotropic conduction mechanism in order to reduce cross-talk. Finally, EEG is successfully recorded under wireless communication with low noise during continuous 12 h usage of the developed sensor. The technologies that lead to the development of the stretchable and transparent sensor will provide a new way for long therapeutic system.

Reference
[1] S. Park et al., Nanoscale, 5, 2013. [2] I. R. Minev et al., Science, 347, 159, 2015. [3] S. Lee et al., Nature Comm., 5, 5898, 2014.

Recent advances in medical technologies have enabled a new generation of implantable devices to treat neurological disorders, restore and repair lost functions, and to modulate neural circuitry to control mood and behavior. Tapping into the nervous system to monitor its state and achieve the desired output, however, requires understanding the fundamental neural processes underlying function, behavior, and disease. The rapid development of neural microelectrodes operating in close proximity with neural circuits, has enabled mapping and modulating neural dynamics at fine spatial and temporal scales. Yet, establishing a stable, safe, long-term functional interface between these man-made artificial components and the host neural tissue, still remains and unsolved challenge. Furthermore, while the brain naturally operates across multiple domains, neural microelectrodes can only transduce either electrical, chemical or optical signals, thus completely missing the interplay between the different signaling modalities.
Nanostructured materials are uniquely positioned to address these challenges because they combine high electrical conductivity with intrinsically high mass-specific surface area and mechanical flexibility. Furthermore, they can interact with biological systems on a molecular scale and can be processed into thin films with tunable optical properties, thus opening new and exciting opportunities for neuroelectronic interfaces. In this talk I will present the ongoing work in my lab leveraging the unique properties of nanostructured materials, such as nanocarbons and MXenes, to engineer novel devices for neural recording and stimulation at high spatial and temporal resolution, as well as for integrating multiple mapping modalities within the same platform. I will also present examples of applications in animal models of neurologic disorders and discuss the potential for future translation of these technologies in the clinical domain.

With the development of low power neuromorphic systems, novel paradigms based on combining artificial intelligence (AI) and machine learning with local adaptive biological systems can be envisioned. This could have applications in a variety of smart “trainable” devices, notably in adaptive prosthetics. However, to achieve a feedback mechanism between the biological systems and AI, a neuromorphic memory must act as an adaptive mechanism that is responsive to biological systems and can close the loop. In this talk, I will bridge the gap between artificial and biological synapses by creating a neurotransmitter-sensitive organic neuromorphic device. We combine microfabricated neuromorphic devices in a microfluidic channel to form a neuromorphic-neurotransmitter biohybrid interface. Voltage pulses at the pre-synaptic electrode drive the oxidation of the excitatory neurotransmitter dopamine (DA), leading to both a short-term potentiation of the channel from ionic drift as well as a long-term potentiation due to the chemical reaction with dopamine at the biohybrid interface. This demonstrates the direct translation of dopamine secreted by PC12 neuron-like cells to a change in memory state in artificial synapses. These results are opening the pathway to combine artificial neural networks with biological systems and develop biohybrid and bidirectional closed-loop sensing platforms.

Synaptic devices that can emulate biological neuron functionality and be reliably programmed to a continuum of resistance states at low energy cost are highly desirable for neuromorphic computing. Despite recent progress in demonstrating neuromorphic arrays using conventional inorganic resistive memories, no architecture to date can operate with comparable efficiencies to that of the human brain due to limitations at the device level. State-of-the-art filament-forming metal oxides (FFMOs) and phase change memory (PCM) based synaptic devices still suffer from excessive write-noise and device non-linearities, preventing massively parallel information processing at a comparable efficiency to that of the human brain. We show that polymer-based devices relying on mixed ionic-electronic conduction are highly promising to address these challenges [1].

To demonstrate this, we have developed a new class of polymer-based devices which can be linearly and symmetrically programmed over 100× distinct states by low voltage pulses (<1 V) at low power (<1 pJ per write) while retaining low write noise. Reversible switching in our devices relies on controlled insertion/extraction of ions into a transistor-like channel, similar to the synaptic cleft in the brain, whereas device non-volatility is enabled by a supercapacitor-like architecture. Our devices can be reliably programmed using <1 μs pulses and endure >10⁸ write-read events without notable deterioration in device performance, thus exceeding the endurance of conventional FLASH memories, subject to oxide stresses. This shows that polymer-based devices can meet the stringent speed, endurance and linearity requirements necessary for efficient neuromorphic computing.

As a proof of concept integration into synaptic arrays, we have combined our polymer-based device with an inorganic diffusive memristor, serving as an access device. Using this two-device combination as an adressable memory cell, we built prototype 3×3 organic/inorganic neuromorphic arrays [1]. The linear switching characteristics of our polymer-based devices allowed the arrays to be programmed in parallel, resulting in an n² latency advantage compared to conventional crossbar memories, where n is the array size. Architectural simulations predict that a scaled 1024×1024 organic/inorganic synaptic array would have an energy, latency and area advantages of 476×, 16× and 9.5×, respectively, compared to an optimized 8-bit static random-access memory (SRAM) accelerator, highlighting the yet untapped potential of polymer-based synaptic devices for brain-like computing.

[1] E. Fuller, S. T. Keene*, A. Melianas*, et al. Science 364 (6440), 570-574 (2019)

Organic electronic materials have been widely investigated as a valid complement to conventional electronic technologies, owing to their mechanical properties and large area printability ^1,2. Green electronics recently opened new research avenues to use bio-sourced, biocompatible (possibly biodegradable) materials to limit the environmental impact of the electronics sector³. Within bio-sourced carbon-based materials, eumelanin, a black-brown conjugated biopigment, emerged as an excellent candidate for green electronics.
A rapid interest grew around eumelanin due to its fascinating physicochemical properties (e.g. broadband optical absorption^4,5, metal-ion chelation⁶, mixed ionic/electronic conductivity^7–9) and biocompatibility^1,10. The conjugated sp² backbone of eumelanin suggests that it would be a naturally occurring semiconductor. The amorphous semiconductor model (ASM) was proposed for the first time in the 70s after the reports on resistive switching behavior in wet melanin pellets¹¹. Recent investigations on the role of adsorbed water on eumelanin charge carrier transport challenged the ASM by proposing mixed electronic/protonic and proton membrane models^8,9,12. None of the current models can provide a comprehensive understanding of the charge carrier transport properties of eumelanin.
In this work we fabricated wet and dry sepia melanin pellets included between Cu and stainless-steel electrodes. We report for the first time the electrical response of dry eumelanin pellets. As opposed to previous studies that indicated dry eumelanin as an insulating material^11,13 , dry pellets switch. Surprisingly, the electrical response of dry pellets features a quasi-linear, metallic-like behaviour. On the other hand, wet pellets show a reversible and reproducible resistive switching, in agreement with McGinness et al¹¹.
Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), X-Ray Photoemission Spectroscopy (XPS) and Raman Spectroscopy did not reveal neither the formation of metallic filaments bridging the electrodes nor a phase transformation (i.e. amorphous to graphitic carbon) possibly induced by Joule heating. We can, therefore, exclude the formation of metallic filaments or graphitic carbon in the interpretation of the electrical response. These findings suggest that dry pellets would be predominant electronic conductors. Our results show that despite huge effort, certain fundamental aspects of eumelanin’s transport physics need to be radically reconsidered and confirm the tremendous potential of the biopiments for green electronics and bioelectronics.

References
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2. Gomez, E. F. & Steckl, A. J. Green Materials for Electronics. Green Materials for Electronics (Wiley-VCH, 2018).
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4. Micillo, R. et al. Sci. Rep., 7(41532), (2017).
5. Tran, M. L., Powell, B. J. & Meredith, P. Biophys. J. 90, 743–752 (2006).
6. Hong, L. & Simon, J. D. J. Phys. Chem. B 111, 7938–7947 (2007).
7. Mostert, A. B., Powell, B. J., Gentle, I. R. & Meredith, P. Appl. Phys. Lett 100, 093701 (2012).
8. Mostert, A. B. et al. Proc. Natl. Acad. Sci., 109 (23), 8943-8947 (2012).
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12. Sheliakina, M., Mostert, A. B. & Meredith, P. Adv. Funct.Mater., 1805514 (2018).
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Recent advances in biodegradable electronics exhibit a huge potential to transform the conventional implantable biomedical devices into transient ones by obviating many challenges associated with chronic implants. Biocompatible/biodegradable packaging materials, naturally-sourced electronic components, or biodegradable charge storages would be the ideal building block to fabricate these types of devices. Recent researches have shown that eumelanin pigments can be served as promising electrode materials due to the exceptional biodegradability, the ease of processing, and the capability of binding various cations. Coordination boding with cations can be formed mostly with semiquinone radicals that are induced by comproportionation reaction of indoles. These electrochemical properties are largely dependent upon the chemical functional groups as well as the structural characteristics. Eumelanins are mainly composed of the aggregated network of oligomers that include two subunits of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in various ratios. These subunits are randomly crosslinked into planar protomolecules by Pmel17 proteins that are further p-stacked to form spherical nanostructures. The protomolecules of natural eumelanins have been known as the unique structural feature that cannot be observed in the synthetic counterparts synthesized from the template free autoxidation. Despite numerous efforts with a wide range of techniques, little has been known about the macromolecular topography that links the configuration of two subunits. Furthermore, the structural effect on charge transport is still elusive due to the disordered nature during melanogenesis. We report herein the presence of the meso-scale protomolecule structures of natural eumelanins using x-ray scattering, electrochemical techniques and spectroscopic analysis. Increased understanding of structure-property relationship can provide insight into the template-assisted self-assembly in melanosome. In addition, controlling the charge transport would be advantageous to design the device quality bioinspired materials as well as the high performance energy storage devices for biodegradable transient biomedical electronics.

The effective treatment of pain remains a challenge as current therapeutics still lack desired levels of efficacy and tolerability. Around 80 protein ion channels have strong links to pain sensation, but only a small number of these channels have been successfully drugged for pain management. One reason for the bottleneck in discovery is the inadequacy of conventional platforms for drug discovery that monitors modulation in ion channel activity. Current methods require a skilled hand, yet are still very laborious, time-consuming, and low throughput. There is an urgent need to develop faster, authentic, and high throughput assays that give direct and quantitative information on ion channel function, drug interactions, and insight on the efficacy of a developed therapy.
The platform presented here features a biomimetic membrane that provides an authentic lipid environment, native cell membrane material to support the natural transmembrane ion channel function, and a sensor made from an electroactive polymer surface upon which the biomembrane is supported. Of focus here is the ATP-gated P2X family ion channels. These protein ion channels are considered important therapeutic targets for multiple pain modalities including neuropathic, inflammatory, and chronic pain states. This biomembrane sensor is capable of reading and transducing ion channel activity as it depends on the availability of ATP. Critically, this platform captures these essential features: 1) it preserves native plasma membrane, protein orientation, fluidity, and activity; 2) is robust and long-lasting; and 3) is compatible with high throughput expansion. Given the considerable amount of research focus and development on identifying drug targets and engineering new drugs for the treatment of pain, this new biosensing platform may prove to be a useful new approach for ion channel research and drug screening.

Implantable bioelectronics has drawn huge attention in recent years since they can monitor the levels of biomarker(s) continuously. For example, the implantable glucose sensor is highly desired for diabetic people. Implantable sensors were used to monitor electrical signal and bio-analytes in the brain and they can be coupled with implantable drug delivery system for controlled release of drugs. The performance and lifetime of implantable sensors are significantly influenced by interfacial phenomena at the interface of the sensor/biological system, including biofouling, foreign body reaction, loss of structural integrity, and infection. In electrochemical bioelectronics, bioelectrodes are a core component for the delivery of charge and recording of an electrical signal. Conventional electrodes are fabricated from platinum and gold, which require surface modification to increase their integration with biological tissue and minimize foreign body encapsulation at the electrode/tissue interface. As emerging biomaterials, conjugated polymers have attracted significant interests for bioelectronics; however, traditional conjugated polymers, which were originally designed for non-biological applications, lack biocompatibility, functionality to conjugate biomolecules, tunable mechanical properties and antimicrobial properties to prevent infection. In the past five years, we have developed a versatile zwitterionic conjugated polyelectrolyte (CP) platform to address key challenges of conjugated polymers for biomedical applications. Zwitterionic CPs, consisting of conjugated backbones and multifunctional zwitterionic side chains, integrate all essential functions and tunable properties into one material at monomer level. Zwitterionic materials gain tunable conducting, optical and antimicrobial properties through conjugated backbones. Low-biocompatible conjugated polymers obtain outstanding biocompatibility, controllable antifouling properties, enhanced ionic conductivity, sensitivity to environmental stimuli, functionality for bioconjugation and tunable mechanical properties via zwitterionic side chains. In this presentation, I will show you why and how we designed the zwitterionic conjugated polyelectrolytes and how we synthesized and characterized this versatile platform. In the end, I will show you how we used this zwitterionic CP platform to improve the performance of bioelectronics using the glucose sensor as an example.

In recent years, nanotechnology developed into a promising field in cancer research by using various kind of magnetic nanoparticles such as magnetite (Fe₃O₄) in early diagnosis and prompt treatment of cancer. In this context, nanomaterials loaded with different biomolecules and imaging agents contribute to the improved delivery of drug at the target site and minimizing its exposure to the healthy tissues. At this point, active surface chemistry is considered essential for the specific uptake of nanoparticles to the cancer cells. Nevertheless, surface grafted molecules and their quantification is an immense challenge in nanoparticle surface modification but indispensable in regard of their possible medical applications. Nearly all known quantification methods of surface-bound molecules including direct and indirect methods are affected by their size, surface consistency, composition or charge distributions of particles, resulting in scattering of measurement results.
To fill up this knowledge gap, we present a novel quantification method in which freely accessible hydroxide groups located on the surface of SiO₂ particles, utilizing the electrokinetic sonic amplitude (ESA) effect supported by simultaneous conductivity measurements. ESA techniques itself became one of the most innovative methods for analyzing particle-ligand interactions. The zeta potential of charged particles located in an alternating electric field is calculated from the resulting sound wave, opening insights into the surface chemistry of nanoparticles. Furthermore, the degree of surface functionalization of phase-pure quasi-cubic hematite (Fe₂O₃) particles with a zeta potential value of +50 mV was monitored through their reaction with 10-undecynoic acid and citric acid as ligand molecules, paving a profound approach of ligand quantification. Thereby, all results highlight the usage of ESA techniques by its high potential as quantification method in nanoparticle surface modification.

Nanopore sensing technology has been developed for detection of various biomolecules such as DNA, RNA, proteins, and metabolites in order to exploit the single-molecule discrimination capability of a nanopore. Succinct device structure, easy fabrication process, and simple electrical readout facility are additional features for this technology [1]. Solid-state nanopores are usually formed in a solid-state membrane such as SiN_x, SiO₂, graphene, MoS₂, etc., to benefit from the mechanical robustness and fabrication compatibility with traditional semiconductor processes. As such, they offer great potential for low-cost, large-scale, high-throughput sensing applications [2, 3]. Here, we present a novel asymmetric nanopore with a truncated-pyramid shape (TPP) realized in silicon-on-insulator wafers. This unique pore structure facilitates the formation of electroosmotic vortex in the nanopore and offers a unique platform to study the interaction between analytes and the pore through the corresponding apparent translocation behaviors.
In general, two forces simultaneously act on an analyte in an electric field formed inside a nanopore under external bias voltage. They are electrophoresis force, F_ele=Eq, and viscosity drag force by electroosmotic flow, referred to as electroosmotic force, F_EOF=6πηrv, where, E is electric field intensity, q charge on the analyte, η electrolyte viscosity, r analyte radius, v velocity of the analyte. The direction and intensity of the two forces determine the translocation direction, which are further influenced by carried charge on the analyte, surface charge density of the pore sidewall, size and shape of the nanopore, concentration and pH of the electrolyte, etc. [4]. In our experiments, DNA and protein IgG₁ are selected to perform the translocation in TPPs. DNA is a long strand and heavily charged. Therefore, the electrophoresis force is expected to dominate the translocation. IgG₁ is disk-like with low density of charge. Thus, the electroosmotic force dominates. In addition, by varying pH, the polarity and amounts of charge for a protein can change, which may lead to alternation of direction and intensity of the electrophoresis force. Changing pH can also tune the surface charge density of the pore sidewall, which can further influence the velocity of electroosmotic flow, as well as the size and intensity of the aforementioned electroosmotic vortex. Hence, the electroosmotic force is affected. Comprehensively considering the effects of many related factors, reflected as the competition between F_ele and F_EOF, the translocation behavior of analytes can be understood. By clarifying the kinetic mechanism of analyte translocation, it paves the way to practices of versatile applications of nanopore sensing.
[1] Shi W., et al. Anal. Chem. 2017, 89, 157−188.
[2] Dekker C. Nat. Nanotechnol. 2007, 2, 209-215.
[3] Magierowski S., et al. Biosensors. 2016, 6, 42.
[4] Campos E. J., et al. Sensor. Ancuat. B-Chem. 2018, 155, 2032-2049.

Solid-state nanopores have been recognized as a versatile tool for single-molecule detection with high sensitivity. They have been extensively studied for analysis by nanopore translocation of biomolecules, such as DNA, RNA, and proteins. As a complement to the electrical sensing readout, optical sensing of labeled molecules on a solid-state nanopore array can notably enhance the sensing capacity with high throughput. However, the widely used silicon nitride (SiN_x) nanopore produces significant photoluminescence (PL) background under blue-green laser illumination, which can severely limit, e.g., multicolor sensing for DNA barcode discrimination. In addition, the occasionally occurring irreversible DNA clogging in a solid-state nanopore, because of DNA molecules interacting with the nanopore channel wall during translocation, can seriously affect the sensing efficacy and accuracy. To address these problems, we have developed an optical sensing system dedicated to nanopore arrays fabricated in a free-standing silicon membrane with its surface functionalized by lipid bilayer coating.
A silicon nanopore array with pores of sub-20 nm diameter is fabricated in a silicon-on-insulator wafer using electron beam lithography in combination with anisotropic etching. The 55 nm thick free-standing silicon membrane shows negligible PL emission in the 550 to 800 nm spectral range under blue-green laser illumination, which greatly improves the optical signal-to-background ratio for single-molecule detection in comparison with standard SiN_x devices. The formation of a lipid bilayer on the nanopore walls is successful as inferred by monitoring in situ the stepwise reduction of the nanopore conductance of ionic current and subsequently by observing ex situ the homogenous fluorescence emitted from a labeled lipid bilayer. As a demonstration, we perform the optical sensing measurements with a conventional wide-field microscope to detect the translocation of fluorophore-labeled DNA strands (120 kbp). With the low background PL of the silicon membrane, the optical signal of individual DNA translocation events is more clearly identified than when using similarly processed SiN_x nanopore devices. Moreover, the coated fluidic lipid bilayer provides a nonstick surface to minimize the non-specific interaction of DNA molecules with the silicon pore walls. The results show that the DNA clogging is substantially reduced in the lipid bilayer coated nanopores as compared to uncoated nanopores. These results demonstrate that using silicon nanopores coated by a lipid bilayer is a promising strategy to realizing massively-parallel single-molecule optical detection.

This talk describes how single layer graphene functionalized with thin metal films was functionalized to form piezoresistive (increasing resistance with strain) sensors capable of resolving 10ppm strain. Our group has demonstrated the strong bio-compatibility, substrate flexibility, and exceptional piezoresistive capability of graphene/gold films by monitoring contractions of stem-cell derived human cardiomyocyte cells and fabricating wearable heart rate sensors. These sensors exhibit a dynamic range of 9% strain with a sensitivity of 10ppm. By utilizing image analysis software, the relationship between fractional metal film coverage and thermal coefficient of resistivity (TCR) was studied. A sensor with near-zero TCR was created, mounted on flexible tape, and affixed to a subject’s wrist for non-invasive heart rate monitoring. While these composite films have demonstrated notable mechanical and electrical properties, the mechanisms for piezoresistance have not been thoroughly studied. To understand the mechanisms for strain sensing, graphene was replaced with hexagonal boron nitride (hBN). This semiconducting 2D material has gained interest in recent years due to its near insulator bandgap and exceptional chemical stability. Image analysis of ultra-thin gold films on hBN and graphene demonstrate the effect of the 2D scaffold on the metal film morphology (i.e. surface coverage and density of discrete islands). In replacing graphene with hBN, thus removing the conduction path through the 2D scaffold, the piezoresistance of percolated gold films could be compared to intrinsic graphene and graphene decorated with gold. Electromechanical characterization of strain sensor devices comprising these composite films determined the morphologies with highest strain sensitivity. By optimizing the gold film morphology that gives the highest piezoresistive sensitivity, we were able to fabricate piezoresistive sensors capable of resolving 1ppm strain.

Recent research progress of relieving the discomfort between electronics and human body involves serpentine designs, ultra-thin films and extraordinary properties of nanomaterials. However, these strategies addressed thus far each face own limitation for achieving desired form of electronic-skin (E-skin) applications. Evenly-matched mechanical properties anywhere on the body and imperceptibility of electronics are two essentially required characteristics for E-skin devices. Yet accomplishing these two main properties simultaneously is still very challenging. Hence, we propose a novel fabrication method borrowing an idea from kirigami, Japanese ancient cutting art, to pattern highly conductive and transparent electrode into diverse shapes of stretchable electronics with multi-variable configurability for E-skin applications. These kirigami engineered patterns impart tunable elasticity to the electrodes, which can be stretched over 400% tensile strain with strain-invariant electrical property and show excellent strain reversibility even after 10,000 cycles of 400% stretching while exhibiting high optical transparency (more than 80%). The transparent kirigami electrodes with customizable elasticity pave the way of offering facile construction and providing appropriate geometries for achieving multi-functional transparent and wearable electronic skin applications. The versatility of this work is demonstrated by ultra-stretchable transparent kirigami heater for personal thermal management and conformal transparent kirigami electrophysiology (EP) sensor for continuous health monitoring of human body conditions. Finally, by integrating E-skin sensors with a quadrotor drone, we have successfully demonstrated human-machine interface using our stretchable transparent kirigami electrodes.

The remarkable mechanical robustness and excellent electrical/thermal properties make graphene a strong candidate for future flexible, stretchable and bio-integrated electronics. In practice, many soft electronics such as the graphene electronic tattoos (GETs) demand the chemical vapor deposited (CVD) graphene to be supported by a deformable substrate. Moreover, various conductive overlayers need to directly laminate on graphene to make electrical contacts. In such cases, the overall device performance relies dominantly on the substrates and the interfaces, especially when subjected to deformations. To investigate the mechanical reliability of CVD graphene in these situations, we fabricated CVD monolayer graphene supported by 300-nm-thick poly(-methyl methacrylate) (PMMA) substrate and also placed gold/polyethylene terephthalate (Au/PET) and graphene/PMMA (Gr/PMMA) overlayers on graphene. The stretchability of the Gr/PMMA and the overlayer-Gr/PMMA interface was characterized by electrical resistance change during uniaxial tensile tests. Combined with semi-in situ microstructure and Raman investigation, we identified four deformation/fracture stages of Gr/PMMA – elastic deformation, microcracking in graphene, macrocracking in PMMA, and full rupture. While microcracks emerged in graphene at very small strain (~0.9%), electrical conductivity of the Gr/PMMA specimen remained up to tensile strains of ~14.5%. In contrast, 100-nm-thick Au film supported by the same PMMA substrate fully ruptured after tensile strains of ~1%. When laminating Au/PET and Gr/PMMA over Gr/PMMA, we found that the Au/PET- Gr/PMMA interface is very vulnerable but the Gr/PMMA- Gr/PMMA interface behaves very similar to intact Gr/PMMA electromechanically. The present experimental study provides fundamental insight into the fracture and interface behaviors of polymer-supported graphene, which is critical for designing future graphene-based soft electronics.

Healthcare monitoring devices assess the state of a person by detecting the physiological signals such as heart beat, respiration rate, and temperature measured directly or in relation to the deformation and vibrations of the human body. The body deformation strains provide useful information about the body movement, which helps people optimize their performance in sports and physical activities as well as provide warnings to avoid serious injuries especially in athletes and the elderly population. The body temperature is one of the most important vital signal since it reflects the overall health condition of a person. An abnormal rise or drop in body temperature may indicate infections and /or diseases in a patient. However, conventional rigid physiological measuring devices could not achieve complete and efficient contacts with the skin of the human body without the use of additional interfacing gels due their non-deformable configuration that also limits the mobility of the patient. Hence, many researchers have struggled to make these physiological sensors into conformable and stretchable wearable devices as part of non-invasive diagnostic system that enables remote and continuous healthcare monitoring outside the clinical settings. In this work, we fabricated both capacitive strain sensors patterning Ag nanowire networks (AgNWs) and capacitive temperature sensor using pyroelectric polymer P(VDF-TrFE) as dielectric material. The AgNWs were patterned using capillary force lithography (CFL) method and were embedded onto the surface of the elastomeric polydimethylsiloxane (PDMS) substrate. The strain sensor was patterned as the interdigitated shape, while the temperature sensor was patterned as the serpentine shape. The interdigitated capacitive strain sensor (ICSS) had a -2 gauge factor (GF) at 30% strain (ε), which is much higher than the sensitivity of conventional parallel plate-type capacitive strain sensors. The ICSS had no hysteresis behavior up to ε of 15% and showed stable ε sensing performance during the repeated stretching test at ε of 10% for 1000 cycles. Furthermore, there was no crosstalk between the ε and pressure sensing in the AgNW-based ICSS, which was found to be insensitive to externally applied pressure. The ICSS was then used to detect the finger and wrist muscle motions of the human body in order to simulate its application to large and small ε sensing. The pyroelectric capacitive temperature sensor (PCTS) had 0.23 %/^oC sensitivity in the range of 25 to 40 ^oC. This sensitivity was maintained under mechanical stretching under 10% strain although the initial value of the strain is changed. Using those strain sensor and temperature sensor, we could successfully measure the physiological breathing rate and body temperature.

Electronic devices with high degrees of flexibility have been attracting considerable amount of attention, owing to their potential novel applications such as electronics skins, wearable textiles, and real-time health monitors. Flexible electronic devices have been demonstrated by combining electrically conductive materials, including metals and carbon-based materials, with flexible substrates, such as polydimethylsiloxane (PDMS), polyimide (PI), and natural rubber. Various fabrication techniques have been developed to fabricate such composite structures for flexible devices applications, such as transfer printing techniques, lithography techniques, as well as laser-based techniques. Recently, our group reported the fabrication of electrically conductive structures composed of crystalline silicon carbide (β-SiC) directly on the surface of PDMS by femtosecond-laser-based-modification of PDMS. The degradation of PDMS into β-SiC is hypothesized to be a result of photolysis, due to the high laser energy, as well as thermal degradation, due to the thermal effects resulting from the high repetition rate. To investigate the potential of the fabricated structures for future flexible device applications, the effects of strain on the electrical conductance of the fabricated structures were investigated in the present study. Electrically conductive structures, 8 mm x 3 mm, were patterned on the surface of a PDMS thin-film by focusing laser pulses onto the surface and raster scanning the beam over the surface. Two types of structures were individually fabricated by different raster scanning directions, longitudinal scanning and transverse scanning, respectively. Both structures were bent in the longitudinal direction, and the structures showed changes in electrical conductance with bending. However, the structures showed different sensitivity to bending, i.e. the change in electrical conductance with bending was significantly less for the structures fabricated with transverse scanning, indicating anisotropic directional sensitivity to strain. SEM observations revealed the generation of micro-cracks on the surface when the structures were bent parallel to the laser scanning direction, while significantly less generation of micro-cracks when the structures were bent perpendicular to the laser scanning direction. The changes in electrical conductance of the fabricated structures could be attributable to the formation of such cracks on the surface. The findings of this study indicate that the structures fabricated by femtosecond-laser-based direct modification of PDMS can be applied for strain sensing, and could allow for a simple one-step method to fabricate directional strain sensors. Furthermore, by focusing the femtosecond pulses into bulk PDMS, arbitrary 3D electrically conductive structures could be directly written inside PDMS via multiphoton process.

Graphene-based materials have been attracting a great deal of attention as candidates for a variety of applications, from electronics to biology, thanks to its unique set of properties. Therefore, patterning graphene-based materials is of foremost relevance for the development of devices. Novel transferring/printing methods have been developed for fabricating high-resolution patterns, such as direct laser writing (DLW), as alternatives to standard lithographic processes. In this direction, Laser Induced Forward Transfer (LIFT) has been attracting considerable attention because it allows patterning different materials, from metals to polymers, to distinct types of substrates. In the LIFT technique, a laser pulse with enough intensity is focused onto the donor material, which is ejected towards the receiver substrate, allowing the production of micro-scale patterns.

In this work, we used fs-LIFT to fabricated graphene oxide functionalized silk fibroin micrometric patterns on a glass substrate. In such structures, graphene oxide is dispersed in silk fibroin, which is a natural biopolymer that has numerous applications due to its excellent biocompatibility, chemical stability, and mechanical properties. Scanning electron and atomic force microscopy results revealed a localized, controllable and reproducible deposition, with lines widths on the order of 1 µm, when the proper parameters are employed. Furthermore, Raman spectroscopy reveals the reduction of graphene oxide upon fs-LIFT, which is in agreement with the observed increase in the electrical conductivity of the transferred material. It is worth mentioning that femtosecond pulses offer advantages to LIFT in terms of resolution and transferring of intact material, thanks to the reduced thermal effects and minimal collateral damage resulting from the nonlinear light-matter interaction. Such results offer novel perspectives on the use of graphene/biopolymer composites for the development of electronic and biomedical devices.

Patterning three-dimensional (3D) architectures into elastomeric substrates can advance development of stretchable bioelectronics, sensors, and data storage devices. Block copolymer (BCP) self-assembly under topographical confinement has shown promise in generating 3D nanostructures down to sub-10 nm scale. Experimental efforts in directed BCP assembly, however, have focused on using hard pre-patterned substrates that require top-down processing, which limits scalability for large-area patterning. Also, the fabrication steps involving BCP film casting and thermal/solvent annealing typically deform polymeric substrates and damage complex 3D geometries. Here we present an all-soft templated assembly of PS-b-PDMS BCPs using polymeric nanowrinkle confinement. We precisely structured BCPs in highly aligned, densely packed arrays on the wrinkled substrate. We also selectively tuned the BCP alignment parallel or perpendicular to the wrinkle orientation by manipulating the pre-strain. Furthermore, self-consistent field theory modeling revealed that wrinkle curvature and surface affinity drove the aligning behavior. Controlled BCP structuring was demonstrated with complex wrinkle geometry, various copolymer molecular weights, and functional skin layers such as graphene and gold. This integration of BCP patterning with flexible 3D architectures will serve useful in lithographic applications for nano-bio interfaces and next-generation soft electronics.

Although research in bio-integrated electronics has been advancing at a rapid pace, the substrates of these systems haven’t been fully optimized for their developed applications (e.g., on-skin, cardiac, and neural lamination). Current wearable electronics rely on impenetrable, non-porous platforms that obstruct the natural diffusive and convective fluid flow and gas transfer, which consequently increase inflammation, contributes to device delamination, and sensor inaccuracies. Furthermore, the microspatial mechanical mismatch at the interface between flexible electronics and soft biological tissue continuously evokes shear stress and thus further exacerbates biomedical complications. To solve critical challenges in soft bioelectronics, we have developed a device capable of being fully breathable, an open-mesh structural design with comparable mechanics to the epidermis (e.g., elastic modulus = 10–500 kPa, 30% ≥ strain).

Polydimethylsiloxane (PDMS), a common substrate material because of its soft mechanics and ability to be used in soft lithography makes it a desirable material for breathable electronics. Here, we developed an elastomeric network of PDMS fibers by utilizing coaxial electrospinning, where a non-spinnable material, PDMS was encapsulated with a spinnable polymer of polyvinylpyrrolidone (PVP). Coaxial electrospinning was capable of producing a core-shell structure of PDMS-PVP fibers. Post electrospinning the PVP encapsulation was able to be fully removed through submergence in ethanol, leaving behind a fibrous network of PDMS micro sized fibers. The fibrous mesh presented a fiber diameter (1.99 ± 0.56 µm) and mechanically biomimicry structure similar to native tissue, with a viscoelastic response, nonlinear region, and a soft elastic modulus response (129.07 ± 14.85 kPa) comparable to the epidermis. Furthermore, performing mechanical testing under wet conditions the fibrous mat was capable of exhibiting dynamic properties, a more prominent non-linear region, and viscoelastic effect. The water was capable of expanding the fiber pores and decrease the fiber-fiber interaction. To establish biocompatibility, human keratinocyte (HaCaT) immortalized cells were seeded in static culture over a film of PDMS and the PDMS fibrous mesh. The fibrous PDMS demonstrated greater cell viability and proliferation in comparison to the PDMS film. In application, this PDMS fibrous mat can be utilized for implantable biomedical devices where cell integration is required. Furthermore, through soft lithography techniques, microfabricated sensors were capable of fully bonding to the PDMS micromesh and conformally laminating onto the skin while enabling biopotential (e.g. electrocardiogram (ECG)) measurement. Applying this elastomeric mesh platform to stretchable electronics can attribute to the development of the next class of wearable electronics for innovation in chronic health diagnostics, multifunctional sensing, and a more quantitative understanding of dynamic physiochemical biological microenvironments.

Stretchable electronics for seamless implant integration attracted increased attention in the last years, by overcoming the mechanical miss-match between implant and soft organic tissues such as the brain. Enhancement of the implant-tissue interface to both reduce the foreign body response as well as achieve improved electrode properties has been the main focus of many new devices. However, with the increased focus on non-invasive techniques such as in vivo optical recordings , new challenges arise to incorporate temporal and spatial resolution in future brain monitoring implants. Especially for basic neuroscience, where the interplay between single neurons and complete neuronal networks are crucial to understand origins of diseases such as Parkinson and Epilepsy.
Here, we present the combination of optical and electrical recording using PDMS based electronic implants to gain scattering free optical recordings through this transparent base material. The highly porous platinum electrodes allow for electrical recording with high temporal resolution while the PDMS insulator is sufficiently transparent for 2-photon imaging of neural activity with single cell resolution. We were able to generate multimodal neuronal recordings in living animals in first proof-of-concept experiments. By fabricating PDMS based electronic implants with a newly generated protocol, new designs, sizes and unconventional shapes can be incorporated within a short time frame and show distinct electrical performance for electrode sizes between 30-100 μm. This approach shows promising results for the versatile use of PDMS based implants for complex brain activity recordings.

Next-generation brain-machine interfaces may use thin-film metals or non-metallic materials (e.g. carbon) for electrical connection to the brain. However, thin-films are not robust to electrical stimulation and carbon is not a low impedance material. Thus, improving the electrical and mechanical stability of neural microelectrodes is a major challenge facing chronic brain interfaces. Electrochemical deposition of a rough, robust material onto an electrode surface is a promising technique that increases real surface area, which facilitates charge transfer, while maintaining geometric area for targeted recording from and stimulation of small neural populations.
In this study, a Pt-Ir alloy is electrodeposited on two different multi-electrode arrays to investigate the impedance, durability and morphology at both the surface and within the film. Polyimide electrodes array consisted of a 4 µm base and top layer of polyimide 2611, a middle layer of a metal stack of 20/80/400 nm of Ti-Pt-Au, respectively. Standard photolithography was used to define 17 circular gold electrodes with a diameter ranging from 30 to 200 µm. Carbon fiber arrays consist of 8 fibers (~8 µm diameter) of 2 or 5 mm length, coated with parylene-C [1, 2]. Pt-Ir was deposited using a potential cycling technique following the process in Petrossians et al. that utilizes sonication to improve the surface coating rate [3].
Electrode impedance was measured with the electrochemical impedance spectroscopy (EIS) method. EIS consistently was decreased after coating, for example a carbon fiber probe showed decreases in impedance modulus of 96 % @10 Hz, 89 % @1 kHz and 10 % @ 1 MHz. The surface morphology of the Pt-Ir coated electrodes was characterized using both scanning and transmission electron microscopy (SEM, TEM). The chemical composition analysis was then acquired with the energy-dispersive X-ray spectroscopy (EDS) on both microscopy systems. An average percentage of 65 – 35 % of Pt-Ir composition was measured in selected regions up to 10 x 7 µm² and up to 200 x 200 µm² for the carbon fiber probes and gold probes, respectively. Further, inspection of images, delineating Pt and Ir with false colors, show uniformity with respect to distribution of Pt and Ir across the electrode surface. To analyze the interface between the base electrode and the Pt-Ir coating, a focused ion beam (FIB) was used to cut a thin region of the interface to be examined at the TEM. It was then possible to establish the coating thickness and the distribution of the Pt-Ir molecules on the coating surface using EDS analysis. The FIB cut performed on one carbon fiber showed a ~400 nm thick and well homogenous Pt-Ir coating closely adherent to the carbon fiber surface.
A heated soak test was performed on the carbon fibers arrays to mimic an in vivo environment by immersing the fiber tips in PBS by 1mm at 50 °C for 36 days. Some probes electrically failed after 10 days, but still showed the Pt-Ir coating on the surface, indicating a connector failure. Other fibers displayed an impedance increase of 8 % after 36 days.
Overall, from the electrochemical characterization, a low electrode impedance has been achieved while having a homogenous and well distributed Pt-Ir coating on two different material testing arrays. Further analysis will be performed to characterize the stability of the coated arrays by the means of electrical pulsing tests.

Patel et al., Journal of neural engineering, 2016
Patel et al., Journal of neural engineering, 2015
Petrossians et al., J. Electrochem. Soc., 2011


Dr. James D. Weiland has a commercial interest in Pt-Ir electrode materials.

Biological electron transfer represents critical processes upon which many essential biological functions depend. Its seamless integration with artificial electronics offers tremendous potential in various engineering applications including biosensing, biocomputing, and bioenergy conversion. The effective coupling at their interface, however, remains challenging, the active redox centers involved in biological electron transfer are typically buried inside the insulating protein matrix, creating large contact resistance with inorganic electrodes. To overcome this challenge, we explored a bottom-up, bio-synthetic strategy to actively “wire” these redox centers to the electronics. In this approach, graphene oxide (GO) were exploited as the solid-state electron acceptors, which can be reduced by G. sulfurreducens as a result of extracellular electron transfer through their membrane cytochrome C (cytCs). Since EET can only occur within the tunnelling distance of cytCs, reduced graphene oxide (rGO) can naturally link the redox centers of cytCs to the external electrodes to facilitate the interfacial charge transport. Through this strategy, the contact resistance at the biofilm-electrode interface can be effectively reduced by 90%, which enables unambiguous characterization of the inherent DC and AC transport across the electroactive biofilm independent of the contact barrier. The current work represents a strategically new approach to seamlessly interface the charge transfer between biological and artificial electronic systems, which is expected to open-up new opportunities for tackling the fundamentals and implications of biological charge transfer.

Dry electrodes are an important component of organic-electronic wearable devices for future human-centric Internet of Things (IOT) applications such as health monitoring and diagnostic; measuring brain, heart, and muscle bio potentials can allow early diagnosis of diseases relating to these organs as well as prevention, treatment, and therapy. In addition, they may provide means to monitor auxiliary brain-related information when used, for example, together with OLED-based photo biomodulation (PBM) devices that activate brain activity by light; as well as in electrical impedance tomography (EIT), an emerging imaging technology used to detect brain injury and stroke. Likewise, they may allow one to realize a wearable device combining both electrocardiogram (ECG) and photoplethysmography (PPG), the latter of which can be realized with OLEDs and organic photodiodes. Similarly, they can be part of human-machine interfaces (HMI) used to control organic fiber strands for muscle-like actuators. If realized, such devices will deliver continuously measured vital information beyond only heart rate in a way that diminishes any disturbances on everyday life.

Existing clinical-use electrodes have limited wearable and external use capabilities due to the use of gels, a long time to set up the electrodes, and lack of comfort. Dry electrodes have shown to improve on these issues, but still lack the signal quality of gel electrodes required for accurate and relevant measurements. Some research has been done on dry electrodes based on soft polymers with different structures on the surface, and covered by metallic layers and nanowires, as well as carbon nanotubes among other conductive materials; these approaches are successful in measuring bio potentials but are often bulky and show high electrode-skin impedance compared to gel electrodes, this directs to a lower signal performance.

In this study, we propose microneedle array dry electrodes that demonstrate decreased electrode-skin impedance compared with current dry electrodes in a flexible substrate and able to be fitted on wearable devices; as well as comparable characteristics to gel electrodes. The proposed electrodes were fabricated using a biocompatible conductive-filled polymer on top of an also biocompatible flexible substrate, reducing skin irritation and increasing the comfort of the electrode. By constructing the electrode with a microneedle array structure, we provide a better contact over hairy skin and an enhanced conformality to different places on the body, ensuring the reduction of the electrode-skin impedance while keeping the electrode comfortable to wear due to the absence of skin preparation. The proposed electrodes are characterized by impedance and signal quality; to be compared with clinical-use gold cup electrodes, and Ag/AgCl standard-use electrodes. The impedance of the electrodes is measured using impedance spectrometry over typical bio potential frequencies in a two-electrode configuration; and the signal quality is determined by recording EEG, ECG, and EMG, to later calculate the signal-to-noise ratio (SNR) of the recorded data. We believe the proposed electrodes can be used on wearable health monitoring applications requiring long-term measurement, comfort, and high performance, and can do the groundwork for future Internet of Humans devices, such as active electrodes for remote health data monitoring.

Cardiovascular disease is the leading cause of death in the US, accounting for 630,00 deaths in the US each year. Ischemic stresses substantially alter cardiac electrophysiology, yet there are few tools that enable multiplexed, real-time studies of cardiac function under controlled ischemia-like conditions. Such a platform would have substantial implications for disease modeling and drug screening. Herein, we present an integrated microfluidic and bioelectronic platform that exposed cultured HL-1 cells to controlled hypoxic stresses while simultaneously providing extra- or intracellular electrophysiological readouts from up to 16 distinct recording sites. Planar device arrays provided extracellular readouts which allowed for construction of isochronal maps and calculation of signal propagation velocities. Vertical nanopillar arrays entered the cytosol following localized electroporation, enabling direct readouts of the intracellular action potential.

Immunohistochemical analysis of HIF-1a expression demonstrated that HL-1 cells became hypoxic upon exposure to deoxygenated media (1.0 – 1.3% O2). During a five-hour window of hypoxia HL-1 cells exhibited episodes of tachycardia followed by bradycardia and arrhythmia. During that same window the action potential shortened from 4.89 ±1.54 to 1.68 ±3.34 ms (APD50). Normal cardiac function resumed after exposure to normoxic medium. Our microfluidic platform enabled rapid modulation of media profiles to achieve acute hypoxic stresses similar to those present during a cardiac infarct. Our ability to simultaneously read electrophysiological activity—including intracellular action potentials—provides information not readily achievable using other electrophysiological techniques. The noninvasive nature of our platform enables a wide range of long-term studies, including hypoxic conditioning or chronic hypoxia and is also amenable to more complex biological systems including 3D tissue models. Ultimately, these advances could provide new insights into the role of hypoxia in cardiac function.

The measurement of electrolytes has a high value in the clinical routine. Ions are present in all body fluids with variable concentrations and are involved in multiple pathologies such as heart failures and chronic kidney disease. In the case of dissolved potassium, although a high concentration in the blood (hyperkalemia) is relatively uncommon in the general population, it is one of the most frequent acute electrolyte abnormalities. In recent years, the integration of thin films technologies in this field has allowed the development of highly sensitive biosensors with ultra-low limits of detection for the assessment of metals in liquid samples. However, despite the current efforts in the miniaturization of sensitive devices and their integration into portable systems, only a limited number of successful examples used commercially can be found. This fact can be attributed to a high cost involved in their production and the sustained degradation of the electrodes over time, which causes a signal drift in the measurements. Thus, there is an unmet necessity for the development of low-cost and robust sensors for the real-time monitoring of analyte concentrations in patients to allow the early detection and diagnosis of diseases. This work reports a thin film ion-selective sensor for the evaluation of potassium ions in aqueous samples. As an alternative for this fabrication method, aerosol assisted chemical vapor deposition (AACVD), was applied due to cost-effectivity and fine control over the film deposition. Such a technique does not require vacuum and is suitable for the coating of large surface areas and structures with complex geometries. This approach allowed the fabrication of highly homogeneous surfaces with well-defined microstructures onto 50 nm thin gold layers. The degradative processes of the ubiquitously employed poly(vinyl chloride) membranes in contact with a biological solution were studied, including the polymer leaching process, mechanical desorption of nanoparticles and chemical degradation over time. A rational design of a protective coating based on an organosilicon material in combination with cellulose to improve the long-term stability of the sensors was then carried out, showing an improvement in the performance after 5 weeks. The antifouling properties of such coating were assessed using a cutting-edge quartz microbalance sensor, allowing the quantification of the adsorbed proteins in the nanogram range. A correlation between the microstructural properties of the films with the surface energy and biomolecules adhesion was then found and used to optimize the protective film.

Advances in organic bioelectronics have urged to bridge the gap between interfacial compatibility and electrical charge transfer. Establishing communication between the electronic device and bio-entities surfaces the challenge of complexity involved in translating a biological event into an electronic signal. The goal of this project is to learn how to electrically communicate with virus particles. The virus particles of interest are M13 bacteriophage that have been engineered to recognize and bind a protein disease marker. This capability will provide the basis for a new type of biosensor in which M13 bacteriophage (or “phage”) supplant antibodies for the detection of protein disease markers in bodily fluids, such as urine.
It is demonstrated that M13 phage particles (dimensions 6 nm (w) x 1 mm (l)) can be wired into an electrical circuit by first embedding them in an electronically conductive polymer composed of poly(3,4-ethylene dioxythiophene) or PEDOT. This virus-PEDOT composite material, which is prepared by electrodeposition, acts as a resistor, and its resistance is increased when the entrained virus particles recognize and bind a target protein. The virus-PEDOT material provides a convenient means for electrically communicating with virus particles which are electrically insulating. An increase in resistance of the virus-PEDOT material signals the presence of the target protein and the amplitude of the resistance change allows its concentration in the contacting solution to be measured.
More information is obtained by measuring an electrical impedance spectrum for the virus-bioresistor (VBR), across a frequency range from 1 Hz to 40 kHz. These semi-circular Nyquist plots can be interpreted in terms of an equivalent circuit with three circuit elements: A channel resistance (R_VBR), a solution resistance (R_sol) and an interfacial capacitance (C_VBR). Information on target binding is extracted from R_VBR that increases upon target recognition and binding, producing a signal DR_VBR.
The VBR concept is tested on a model system in which a dynamic range of 7.5 nM – 900 nM human serum albumin (HSA, 66kDa) is detected in phosphate buffer solution. The high DR_VBR (»200 W) induced by HSA binding capacitates the sensor to achieve a coefficient of variation <15% for a total of 20 devices tested for 7 different protein concentrations. The reliability of signals is testified by the control experiments; followed by real-time sensing measurements. The VBR does not employ a redox probe or reagents for signal amplification. The Nyquist plot also allows the electrical resistance of the solution, R_soln, to be deconvoluted from the electrical resistance of the virus-PEDOT channel which contains information about the target concentration. This means that the VBR is able to detect and measure the concentration of a target protein irrespective of the salt concentration of the solution, and this capability will be demonstrated.
Higher sensitivity for the VBR can be achieved by reducing the conductivity of the PEDOT-PSS base layer in order to force maximum current through an ultra-thin (<80 nm) virus-composite channel. This modification enabled pico-molar detection of a 22kDa cancer biomarker, DJ-1 in synthetic urine. The signal produced by the modified VBR for 10 pM DJ-1 is 50 – 60 W, compared to the 5 W signal generated by the controls accounting for non-specific binding. The new VBR with the inherited ability to distinguish between the R_soln and R_VBR, produces maximum signal 500-600 W for DJ-1 in synthetic urine which has a total concentration of 160 mM. VBRs are characterized by extreme sensor-to-sensor reproducibility of 2-9% across the entire binding curve for DJ-1. Response time for sensing of 1.0 min. is also demonstrated. The mechanism of VBR transduction will also be discussed.

Antibiotic resistance is one of the most serious threats to global health and food security. Misuse and over-prescription of antibiotics accelerates the promotion of resistant bacteria. To prevent and control this process, the development of new diagnostics which can specifically test for the specific bacterial strain is an urgent need. Graphene field effect transistor (GFET) based label free biosensors have shown great promise due to their highly sensitive Dirac voltage to any chemical/biological modification that occurs on the channel, fast response time, and flexibility to different substrates, which make them capable to be utilized for point of care diagnostics. In this study, the specific probes were synthesized, which are selective to clinical bacterial strains of Staphylococcus aureus (Sa) and Acinetobacter baumannii (Ab). The GFET devices fabricated using CVD monolayer graphene transferred over SiO2/Si substrates were functionalized with these probes in the single step process via non-covalent binding using π-π interaction with the graphene surface. In the talk I will discuss the various controls employed to ensure the selectivitiy of our probes. In addition, I will discuss device fabrication and measurement protocols to reduce the concentration required. These results point to the utility of gFET sensors for future point of care devices to rapidly detect bacteria strain and resistance.

Fast, precise, and reliable detection of cardiac biomarkers is essentially important for early diagnosis and prognosis of cardiovascular diseases, the most common life-threatening illnesses. However, the current commercially available diagnostic methods either lack of the sensitivity needed for the proper detection of cardiac biomarkers at the very early disease development stage or still suffer from the long-term process of enzymatic labeling. In this work, we designed and fabricated liquid-gated single silicon nanowire field-effect transistors (NW FETs) for label-free sensing of cardiac biomolecules. We demonstrate selective and direct detection of C-reactive protein (CRP) and cardiac troponin I (cTnI) proteins as gold standard biomarkers for prediction and detection of cardiovascular diseases at the early stage. A detailed electrical characterization of fabricated nanosensors, as well as the proof-of-principle experiments such as pH response, were performed before sensing measurements. Sensor characteristics reflect high working stability and nearly ideal Nernstian sensitivity confirming the high-quality of fabricated structures. High specific recognition elements like aptamers and antibodies were immobilized on functionalized nanowire surfaces. A novel attachment approach was shown by using dibenzocyclooctyne (DBCO)-linked aptamers for cardiac troponin to azide-functionalized nanowire surface. The approach has several advantages: fast covalent and directed attachment of aptamers to the azide-terminated surface of nanowires, efficient linkage and high-yield covering of nanowire surface with cTnI-specific aptamers. In particular, the DBCO-linked aptamers do not react with amines or hydroxyls presented in most of the biomolecules, which makes functionalization of nanowires more efficient and specific. After covalent immobilization of cTnI-specific aptamers and CRP-specific antibodies on the silicon nanowires surface, the highly sensitive and fast electrical detection was performed. A 1 fg/ml detection limit concentration was achieved for both CRP and cTnI biomolecules. The target biomolecules on the Si NW surface are confirmed by atomic force microscopy (AFM) characterization. Moreover, application of nanowire structures with different sizes allowed us to detect biomarkers in a wide concentration range (from 1 fg/ml to 1 µg/ml). This range covers the dynamic concentration range of CRP and cTnI biomarkers release during the early disease stage and progression. Thus, we demonstrate that our specifically functionalized silicon NW FET biosensors integrated with polydimethylsiloxane (PDMS) microfluidic channels can be effectively used as highly sensitive diagnostic tools for early prediction and prevention of cardiovascular diseases.

Small biomolecules are often recognized as significant biomarker candidates in the field of in vitro diagnostics. In this study, we propose a novel concept of a biointerface, a polymeric nanofilter, for the potentiometric detection of small biomolecules using an extended-Au-gate field-effect transistor (EG-Au-FET). A Au electrode has the potential capability to detect various small biomolecules with high sensitivity at nM levels on the basis of a surface redox reaction, but it exhibits no selective response to such biomolecules. Therefore, a suitable polymeric nanofilter is designed and modified on the Au electrode, so that a small target biomolecule reaches the Au surface, resulting in an electrical signal, whereas low-molecular-weight interferences not approaching the Au surface are captured in the polymeric nanofilter. The polymeric nanofilter is composed of two layers. The first layer is electrografted as an anchor layer by a cyclic voltammetry method [1]. Then a filtering layer is precisely polymerized as the second layer by a photo-mediated surface-initiated atom transfer radical polymerization method [2]. As a model case, serotonin, a well-known stress marker, is detected by filtering a series of stress markers including catecholamine-related small biomarkers using the polymeric nanofilter-grafted EG-Au-FET on the basis of the following mechanism. The phenylboronic acid (PBA) that copolymerizes with the polymeric nanofilter captures catecholamines through diol binding, whereas serotonin reaches the Au surface through the filter layer. The polymeric nanofilter can also effectively prevent the interaction between biomacromolecules, such as amylase and human-serum albumin, and the Au electrode. A platform based on a polymeric nanofilter-grafted EG-Au-FET biosensor is suitable for the ultrasensitive and specific detection of a small biomolecule in biological samples such as tears and sweat, which include small amounts of low-molecular-weight interferences, which generate nonspecific electrical signals.

[1] S. Himori, S. Nishitani, T. Sakata, Langmuir 2019, 35 (10), 3701-3709.
[2] S. Nishitani and T. Sakata, ACS Appl. Mater. Interfaces 2019, 11 (5), 5561-5569.

This research focuses on analyzing the attachment of normal cells (HaCAT) and cancerous cells (A431), and the effects of Ganoderma Lucidum (reishi) treatment on the attachment of HaCAT and A431 cells. Cell attachment is an important property of the cell membrane; cells are held together through direct membrane contact and adhesion to the extracellular matrix. Cell attachment is essential to maintain tissue structure. Cells with poor attachment can detach and enter into the body’s fluid stream, which in cancer results in metastasis. It has been shown by researchers that reishi is commonly used as a nutritional supplement and is known to improve immunity. There have been previous reports that there has been an increase in the rate of apoptosis of cancer calls after being treated with reishi. In this study, attachment of HaCAT and A431 cells has been investigated using an impedance sensing system. An impedance sensing system is used to characterize the cell membrane attachment quantitatively. This technique is noninvasive and allows for observation and analysis of various aspects of cell behavior, particularly attachment and spreading in real time. An impedance sensing system measures changes in impedance with respect to an applied alternating current (AC) in real-time. Cell attachment and the epithelial layer formation limit current flow between the basal membrane and the cell. The attachment of HaCAT cells and A431 cells, and the influence of reishi with various dosages of 0.005, 0.01, 0.02 g/mL on these cells has been examined. The impedance analysis will be used to compare the attachment and the spreading rate of HaCAT cells and A431 cells, and the effect of reishi on the epithelial cell layer. The initial set of data shows that the impedance of HaCAT cells and A431 cells increases with time; cell attachment and spreading impedes current flow. There is a significant difference between the impedances of normal cells and cancer cells detected over time. The time dependent response of HaCAT and A431 cells shows a characteristic behavior and reveals junction formation of these epithelial cells. The impedance of HaCAT and A431 cells continued to increase after 24 hours. The effect of reishi on cell attachment of HaCAT and A431 cells will be compared. The first series of reishi treatment reduced cell attachment of A431 cells. Various dosages of reishi could potentially slow down the rate of cancer cell attachment. Further experimental analysis could reveal the possible therapeutic or unwanted side effects due to reishi, a widely used supplement.

All current implantable pacemakers are powered by batteries which are bulky, contain toxic components, and last for only a few years before a replacement surgery is a necessity. This exposes the patient to repetitive pain, cost, and risk of infection due to the multiple surgeries. Herein, an approach of fabricating nanogenerator-supercapacitor hybrid based on biocompatible graphene-protein nanocomposite that utilizes the patient’s own body fluid is described. This hybrid device has been tested on COS-7 cell culture cells as well as live animal tissue. This unique self-powered system could harvest the body mechanical energy, store it, and power a prototype pacemaker leading to potentially a life-long and miniaturized implantable device. This work is patent pending and under commercialization through our start-up, Energytica.

Electronic implants in the human body present safety challenges when exposed strong external magnetic fields, such as those encountered in magnetic resonance imaging (MRI). Metallic and other conductive interconnects, being ubiquitous in electronic devices, including memories, are susceptible to displacement forces and torques that can result in potentially lethal projectile effects. The Food and Drug Administration (FDA) provides guidance on listing implants as MR safe/unsafe/conditional under ASTM F2503-13. Cancer patients, who may need real-time monitoring of tumor growth offered by implants, as well as MRI scans for charting the progress of the therapy, are sometimes forced to accept less than ideal choices in their treatment as they often make poor candidates for repeated extractive surgeries needed to extract the implants. The cost of implanted electronic devices presents another challenge. In this work, we have developed an exemplar biocompatible memory device that is biodegradable at a specific pH. Cleaned commercial thermal silicon dioxide (500 nm) wafers (University Wafers) were drop cast with ~100 µl of polyvinyl alcohol (PVA), and then heated at 80^○C for 30 minutes (thickness ~600nm). Bottom contacts of the device were next grown using shadow masks using successive DC sputtering (Cr ~200Å) and thermal evaporation (Au ~300Å) at 4 x 10^-6 Torr (Angstrom Engineering). A titania sol was synthesized using the sol-gel method, and spin-coated (spin NXG-P2) was next deposited as the active layer. Top contacts (Ag ~500Å) were thermally deposited to complete the metal-insulator-metal structure. Current-voltage characteristics of the device were acquired using a Keithley 4200-SCS semiconductor parameter analyzer in dual sweep mode with a grounded bottom electrode. Pristine devices were assumed to be in a high resistive state (HRS, off). On the application of bias voltage [-8, 5] V, the device switches to low resistive states (LRS, on) and exhibits a repeatable pinched hysteresis loop. Retention measurements were carried out at a constant readout voltage (0.01 V) to obtain the retention ratio (R_on/R_off) of (~10⁴). After the device characterization, these devices were dipped in three different media: acidic (pH=3), neutral (pH=7) and basic (pH=9). The devices were found to completely vanish (visual inspection) due to PVA dissolution in 15 min, 150 min, and 90 min respectively. As titania, silver and gold are all biocompatible materials, and present in minute quantities in the device, the dissolution of such devices over 150 minutes in neutral blood (modeled with pH ~7.4) presents few health challenges. Further, it was found that PVA films were easily removable from the silica substrate through peeling, thus enabling the use of the flexible memory device directly in the human body. Operationally, such biologically transient devices could be used to monitor patient vitals and permitted to completely dissolve prior to any MRI scans, without any extractive surgery with its deleterious health effects. Owing to the low cost of the implant, a patient can be injected with the device as many times as necessary during treatment.

Targeted drug delivery devices have flourished in recent years due to their superior biocompatibility and lower possibility of side effects compared to systematic drug treatments. Following recent advances of microfluidic ion pumps (µFIPs) [1,2], it has been demonstrated that drugs can be delivered to targeted cells with temporal and spatial precision with applied electric field.

In the µFIP, drugs are electrophoretically pumped from the microfluidic reservoir through an ion exchange membrane into the targeted area. The ion exchange membrane bears fixed charges in the polymer matrix, which allow the membrane to selectively transport oppositely charged ions while blocking ions with the same charge. Hence, µFIPcan actively deliver the drug of interest when electric field is applied while preventing passive drug diffusion when device is switched off.

An ideal µFIP should have a perfectly selective membrane and passive leakage should be minimal. Parameters such as device geometry, fixed charge concentration in the membrane and initial drug concentration in the microfluidic reservoir would all affect the efficiency and performance of µFIP.

Having fundamental knowledge and accurate quantitative models therefore are crucial to the design and optimization of such implantable medical devices. As the range of applications for µFIP continue to expand, there is an urgent need for deeper understanding of their device physics.

Here we report a numerical model for µFIP platforms. The transient behavior of µFIP during operation is described by time-dependent governing equations for the ionic/electronic coupled model. We identified three performance indices to characterize the device performance, namely, the pumping efficiency, amount of drug transported, and the ON/OFF ratio. Performance contour plots for these three indices were obtained by varying two parameters- initial drug concentration in the microfluidic reservoir and fixed charge concentration in the membrane, both by three orders of magnitude.

The parameter space covered in this study encompasses a concentration range far wider than those commonly found in membrane materials and drug molecules used today, thereby giving a comprehensive view of the device performance of µFIPs and possible new avenues for material development and design optimization for such devices.

The model is able to describe both steady state and transient behavior of the ionic and electronic transport across the ion exchange membrane over a wide range of parameter space. Dynamic phenomena, such as electric double layer relaxation within the conducting polymer coated at the electrodes and concentration polarization at the electrolyte-membrane interface, are also captured by the time-dependent numerical model.

The results from this study allow us to design advanced µFIP platforms and push forward the development of targeted drug delivery devices for higher efficiency and extend its range of applications.

References:

1. Uguz, I., Proctor, C.M., Curto, V.F., Pappa, A.M., Donahue, M.J., Ferro, M., Owens, R.M., Khodagholy, D., Inal, S. and Malliaras, G.G., 2017. A microfluidic ion pump for in vivo drug delivery. Advanced Materials, 29(27), p.1701217.
2. Proctor, C.M., Slézia, A., Kaszas, A., Ghestem, A., Del Agua, I., Pappa, A.M., Bernard, C., Williamson, A. and Malliaras, G.G., 2018. Electrophoretic drug delivery for seizure control. Science advances, 4(8), p.eaau1291.

Antibiotic resistance is a growing global health concern in part due to changes in membrane properties and composition of Gram-negative bacteria that affect antibiotic efficacy. The alteration in membrane properties of Gram-negative bacteria influences response to antibiotics and mediates resistance; consequently, the antibiotic is unable to control or kill these bacterial strains, instead, they survive and multiply in the presence of an antibiotic. Therefore, understanding the interactions between bacteria membrane and antibiotics and the transport across the membrane is important for elucidating membrane properties that can be used for the design of novel antimicrobial drugs. The outer membranes of Gram-negative bacteria containing protein and complex liposaccharides that helps to protect them from external harsh conditions. To study outer membrane-antibiotic interactions, we created an electrochemical sensing platform based on a surface-supported planar bacterial outer membrane on an optically transparent conducting polymer surface poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS). The bilayer platform is fabricated using outer membrane vesicles (OMVs) of different clinically-relevant Gram-negative bacteria in order to incorporate native lipids, membrane proteins and liposaccharides to the supported bilayer. The supported bilayer formation and their fluidity are characterized using Fluorescence Recovery After Photobleaching (FRAP) technique, which also enables measurement of the diffusion coefficient using fluorescently labelled molecules/phospholipids. The change in electrical properties of surface-supported bacteria membrane during formation and their interaction with disrupting compounds have been monitored by electrochemical impedance spectroscopy (EIS). The optical transparency and conducting properties of the polymer allowed us to monitor the bilayer formation by both microscopic techniques and changes in ion flux by electrical readout. This sensor platform introduces a method containing biologically-complex membranes to the study of antimicrobial drug testing, a much-needed intermediate between very simple bilayer platforms and whole cell readouts.

One of the challenges in the development of Electrocaloric (EC) based solid state cooing device/heat pump is the involvement of moving parts – either active material or regenerator needs to be moved to extract energy from source (hot end) and releasing it to the sink (cold end). This not only reduces the efficiency but also adds the complexities in the device design limiting its exploitation in small scale applications. In this study, a two-layered solid-state heat pump is being devised in which the EC layers have been sandwiched between source and sink and the heat is pumped from source to sink in a complete silent operation (no moving parts). An electric field cycle is applied on the EC layers alternatively in such a way that it creates a temperature gradient to achieve a directional heat flow in a system of bodies (Sink/ECs/Source) which are otherwise in thermal equilibrium. This transient heat conduction problem has been solved analytically and gives promising results specially for interfaces having lower contacting coefficients. This technique can offer viable solutions to address the cooling issues in high power electronics and other portable medical applications.

3D printing technology has an importance for manufacturing microfluidic chip since it offers high-resolution complex structures. We designed a micromixer chip in which liquid solutions are mixed for detecting hemagglutination. To fabricate the chip, we prepared a mold structure by employing digital light processing (DLP), one of the most popular 3D printing methods. Upon the 3D printed mold, polydimethylsiloxane (PDMS) fluidic device was prepared, which was with another PDMS layer. The assembled micromixer chip consists of multi-level geometry: The first level has meander channels for liquid solution guiding, and the second one has microwell structures to capture blood cell droplets. Inside the micromixer chip, blood cells were initially loaded and captured in the microwells, followed by being mixed with the subsequently loaded antibody solutions, either anti-A or anti-B solutions. As a result, we identified a mixing between blood cell droplets and antibody solutions. In particular, hemagglutination behaviors were identified inside the micromixer chip, which was further characterized by conventional colorimetric microplate-readers. Interestingly, once the hemagglutination occurs, the mixed solution has transparent regions in between the dispersed aggregates of blood cells and antibody solutions. Therefore, the measured absorbance value, optical density (OD), through the channel was significantly decreased. Our method provides an insight for 3D printing technology to be coupled with the existing the benchtop analysis tools.

Ferritin is an intracellular iron-storage protein that maintains iron balance by storing and releasing iron in response to physiological need. It is present in almost all living organisms, which means that it is an environment-friendly material and is easily available. It is a stable protein that remains functional in both solution and solid phases in a wide range of temperatures (up to 85 °C) and pH 4.0–9.0. It sustains its electronic integrity in solid-state condition for a long period of time (about one year). Ferritin has a unique spherical structure, having an 8 nm semiconducting iron oxy-hydroxide core. Ferritin has been suggested for use in wide ranging device applications - the nano-battery, FET, and memory device. Ferritin appears to be a versatile protein as its electron transport properties can be tuned and it can be anchored onto a solid substrate (silicon, Au, Al, ITO, HOPG, glass etc.) as per device requirement by various means of chemisorption and physisorption. In this presentation, the suitability of ferritin as a 3D bio-electronic material is discussed. It is first ensured that the native ferritin and the different reconstituted ferritins along with apoferritin show their electron accessibility and statistically distinct band gap characteristics in the monolayer configuration on heavily doped silicon substrate by using conductive atomic force microscopy and spectroscopy (C-AFM and C-AFS) [1]. Here, ferritin has been treated as an insulator-conductor composite as the core modification results in a change in overall electronic state of the ferritin. The successful tuning of band gap of the different metal core reconstituted ferritins indicate that band gap engineering is possible in case of ferritins which is quite useful in synthetic semiconductor technology. The success with ferritin-monolayer-based bioelectronics on silicon surface prompted us to prepare a purely proteinaceous iron-loaded holoferritin multilayer using layer-by-layer electrostatic deposition of successive cationized and native ferritin layers. This ferritin multilayer is found to be capable of long-range electron transport in solid-state configuration - the maximum range being ~40 nm for vertical transport (across the multilayer) as observed in a C-AFS study and ~40 μm for lateral transport (along the multilayer) as observed by an interdigitated electrode-based measurement [2]. The ferritin multilayer is largely an electronically homogeneous material as found in a KP-AFM study, and it shows less substrate influence than the monolayer configuration. Importantly, the holoferritin multilayer exhibits Z-electronic confinement with a high exciton radius of 45 nm [2]. This is one of the longest exciton radii reported so far. This is also the first report of electronic confinement inside any biomaterial. The bulk electron transport capacity of the ferritin multilayer as presented here indicates its potential for use as a component in futuristic molecular 3D circuit.

References:
[1] Nanoscale on-silico electron transport via ferritins; S. Bera, J. Kolay, S. Banerjee and R. Mukhopadhyay, Langmuir 2017, 33(6), 1951−1958.

[2] Long-range solid-state electron transport through ferritin multilayers, S. Bera, J. Kolay, P. Pramanik, A. Bhattacharyya, and R. Mukhopadhyay J. Mater. Chem. C 2019, 7(29), 9038-9048.

Antimicrobial materials that are less susceptible to evolved resistances are one approach for combatting the rise in antibiotic resistance, which is a growing concern for public health [1]. Metallic materials have been widely used as a biocidal tool since ancient time and copper-based materials are a key component because of their observed ability to generate radicals and cause cell membrane damage. According to reports which discussed the antibacterial activities of elemental copper, copper(II) oxide and copper(I) oxide [2], Cu(I) and metallic Cu show higher antibacterial activity than Cu(II) state, although the mechanism remains unclear. At the same time, it is known that lattice defects in transition-metal oxides donate local charges that can enhance catalytic properties [3]. To test the hypothesis that lattice defects, such as oxide sublattice vacancies, underlie the noted biocidal activity of Cu₂O, initial studies of the relationship between degree of lattice damage and defect concentration in this material were undertaken.

The structural and the electronic states, as revealed by magnetic characterization, were assessed in Cu₂O powders (Alfa Aesar, < 200 mesh powder) that were subjected to cryo-milling for up to two hours. Decreases in the cubic a-lattice parameter, the unit cell volume V and an increase in both the Pauli paramagnetic and the Curie-Weiss susceptibilities with an increase of cryo-milling time were observed. These observations, which are consistent with changes in the defect state of the lattice, will be correlated with the potential catalytic state of the processed material. Clarification of these structure/property correlations demonstrates the relationship between the lattice defects and the potential catalytic state, which may be a promising way to tailor the antibacterial activity of Cu₂O.

Acknowledgement: This research was conducted under the auspices of Northeastern University.

[1] V. M. Villapún, L. G. Dover, A. Cross and S. González, Materials, 2016, 9, 736
[2] S. Meghana, P. Kabra, S. Chakraborty, N. Padmavathy, RSC Adv., 2015, 5, 12293
[3] J. Liu, P. M. Hosseinpour, S. Luo, D. Heiman, L. Menon, D. A. Arena, L. H. Lewis, J. Vac. Sci. Technol. A 33(2), 2015, 021202-1

Wearable electronics has progressed dramatically and has opened the prospective future, including electric circuits, flexible displays, stretchable energy storages, electronic skins, wearable devices, etc. For flexibility and elasticity are hardly a matter, these have to be surmounted beyond convergence of state-of-the-art technologies. Here, we developed simple and cost-effective fabrication method of nanohybrid composites with carbon nanotubes (CNTs) and polydimethylsiloxane (PDMS) elastomer for improving its electrical and mechanical properties for wearable electronics. CNT/PDMS composites provide high flexibility, elasticity, and electrical conductivity itself and are also biocompatible and mechanically stable. The CNT/PDMS composites are demonstrated to create functional materials that are used for effective bio-signal monitoring of brain, heart, and muscle signals, as well as devices with incorporated integrated flexible circuits. This simple and cost-effective fabrication method provides a promising process and material for various applications of flexible, stretchable and wearable electronic devices, particularly considering the growing global interests in wearable healthcare monitoring system.

Electrofluidics is an emerging technology of combining electronics and nanofluidics. One important device in electrofluidics is an ion transistor in which the ionic current through a nanopore is regulated by gate voltage bias. Here, we suggest a fabrication method of nanopore ion transistors by introducing focused ion beam (FIB) and atomic layer deposition (ALD). We deposited 100 nm-thick silicon-nitrite layers on both sides of silicon wafer by low-pressure chemical vapour deposition (LPCVD). We fabricated rectangular patterns by photolithography followed by reactive ion etching (RIE) on the backside of the wafer. Anisotropic silicon etching by KOH was performed. The front side of the chip was patterned by photolithography followed by Ti/Au deposition for the fabrication of electrode structures. We drilled 50 ~ 100 nm pores in the Si₃N₄ membrane by FIB. By the ALD process, we deposited highly-conformal metal film, either Platinum (Pt) or Ruthenium (Ru) to shrink nanopores by a self limiting process. We expect that the gate modulation of ionic current through the nanopore is efficiently controlled by the gate-surrounding structures.

Localized surface plasmon resonance (LSPR) is a highly sensitive platform for detecting biomolecules including protein, nucleotide, and vesicle. Although LSPR signal is easily taken by ultraviolet-visible (UV-Vis) spectroscopy, the shift of LSPR peak by the attachment of target molecules is small, which makes it challenging the precise evaluation of the peak shift. Here, we report an Au LSPR sensor platform in which the Au nanoparticle assists the precise evaluation of LSPR peak shift by offering a stable reference peak in UV-Vis spectroscopy. For LSPR sensor fabrication, we employed a roll-to-roll nanoimprint process to create nanograting structures on polyethylene (PET) film. By angled deposition of Au, we demonstrated double-bent Au structures which have strong LSPR peak at ~740 nm. Upon the Au structures, we introduced IL-10 capture antibody to Au LSPR chip by using cross-linking chemistry. Afterward, we loaded IL-10 target protein for specific adsorption to the IL-10 capture antibody. To form a sandwich assay platform assisted by Au nanoparticle, we conjugated Au nanocube (AuNC) with IL-10 detecting antibody and induced it to bind with IL-10 capture antibody/IL-10 complex specifically. We note that AuNC has a stable peak at ~530 nm in the solution state. By using the characteristic peak of AuNC as a reference, we estimated the red shift of the LSPR peak of Au strip structures with high accuracy, which is caused by the formation of IL-10 capture antibody/IL-10/IL-10 detection antibody sandwich assay. We expect that the Au nanoparticle assisted LSPR sensor platform can be used as diagnostic tools for detecting various biomarkers.

Proton conduction is important in many natural phenomena including oxidative phosphorylation, enzyme reaction, and is extensively studied and developed in bioelectronic technologies and renewable energy, like actuators, sensors, and fuel cells. Recently, with the rapid development of bioelectronics, efforts are expended on developing proton conducting materials to bridge the gap of the biological system and electrical devices. Natural biomolecules, like peptides, glycosaminoglycans, DNA, etc., show great potential to be proton conducting materials because of their intrinsic biological function and biocompatibility. The sulfate group in glycosaminoglycans, amino acid residues in peptides, and the helix structure of two hydrogen-bonded complementary strands of DNA, provide good environments for proton transfer. Here we compare the results of AC electrochemical impedance spectroscopy (EIS) on several proton-conducting natural materials with the DC data obtained with Pd/PdHx proton-conducting electrodes and show that the two techniques are consistent with each other.

An estimated 285 million adults suffered from diabetes mellitus worldwide in 2010, a number that is expected to exponentially grow. Approximately 15% of diabetics develop diabetic foot ulcers (DFU) and one-in-five are estimated to suffer from a lower extremity amputation in their lifetime. While a number of methods have been developed for wound healing, most are not applicable for DFUs due to their unique pathophysiology, especially their impaired immune response during the wound healing process. In healthy patients, macrophages have an integral part in homeostasis and tissue repair and orchestrate the wound healing process through various mechanisms. Unfortunately, a decrease in the number of macrophages is observed in diabetic wounds, and those present tend to be pro-inflammatory (M1s) instead of pro-healing and/or anti-inflammatory macrophages (M2a/c, respectively). As a result, the wound healing progression is delayed, or prevented, which can lead to non-healing wounds and amputations.
To address this challenge, we hypothesized that increasing the number of macrophages at the wound site and redirecting them to a more pro-healing state can enhance healing in diabetic wounds. To this end, we have developed alginate, cryogel bandages to deliver various factors to wounds. The hydrogel bandages can be manufactured on a large scale as off-the-shelf products and be loaded with therapeutics (cells or factors) during or after the manufacturing process.
Using this bandage system, bone marrow derived macrophages were polarized to inflammatory or healing states, loaded into bandages, delivered to diabetic wounds in a murine model of type 2 diabetes, and the wound size was monitored over a 10-day period. Additionally, the wounds’ cellular components were analyzed by immune-histochemistry and immunofluorescence. Wounds treated with macrophage had smaller wound sizes as compared to the empty bandages. Normalized wound size at Day 10 was 23, 18, 22, 19, and 14% of the original wound size for wounds treated with empty bandages, non-polarized (M0), M1, M2a, and M2c macrophages, respectively. Furthermore, wounds treated with M2c loaded bandages were significantly more healed than those treated with M1 loaded macrophages. These results confirmed our hypothesis that the addition of macrophages, especially anti-inflammatory macrophages, to the wound site can enhance healing in diabetic wounds.
Currently, we are exploring the use of therapeutic-loaded bandages for the recruitment of macrophages to the wound site (MCP-1) and their polarization to the pro-healing state (IL-4 and IL-10) to aid in the healing process. This approach can be advantageous over the delivery of cells in several aspects, including processing time, cost, patient compliance, and feasibility. Depending on the therapeutics’ properties such as surface charge, molecular weight, and heparin binding affinities, we have fabricated bandages with different material compositions to create a prolonged therapeutic release prolife for each factor that can be tuned-in to range from a few hours to days and weeks. Using these bandages, we have demonstrated that more immune cells, specially macrophages, are recruited to the wound site as compared to traditional bandages. Here, MCP-1 loaded bandages were placed on wounds over a 3-day period and the cell types and numbers present in the wound were analyzed via flow cytometry. A significantly higher number of macrophages were recruited to the wound site in samples treated with MCP-1 loaded bandages as compared to traditional bandages (approximately four times more). Our next step is to assess the capability of bandages loaded with IL-4 and IL-10 to polarize the local macrophages to the M2 state and, thereby, enhance wound healing. Such bandage systems can potentially provide significant improvement in the lives of diabetic patients by using their body’s own immune system to directly address their impaired healing mechanism.

In this talk I will describe cutting-edge technologies for engineering functional tissues and organs, focusing on the design of new biomaterials mimicking the natural microenvironment, or releasing biofactors to promote stem cell recruitment and tissue protection. In addition, I will discuss the development of patient-specific materials and 3D-printing of personalized vascularized tissues and organs. Finally, I will show a new direction in tissue engineering, where, micro and nanoelectronics are integrated within engineered tissues to form cyborg tissues.

Bioelectronics from edible materials (e.g. food) can be defined as the design of circuits and devices that incorporate edible materials into electronic components and/or uses edible materials to perform the function of electronic components.

I will discuss the (bio-)electronic behaviour of three different types of common food products, i.e. breakfast spreads (Vegemite, Marmite), a vegetable (celery) and a desert (jelly).

The characteristic breakfast spreads Vegemite and Marmite were 3D printed into edible circuitry onto bread substrates. We demonstrated the importance of characterising the rheological behaviour of the food products in retaining the structural integrity of the printed materials (e.g. pyramids on bread). The electrical conductivity (20 +/- 3 mS/cm) of Vegemite and Marmite was used to 3D print edible circuits on “breadboards.”

The edible gelatin product Jell-O (or Aeroplane Jelly) was turned into an electrode structure via the inclusion of table salt during preparation of the hydrogel material. It was shown that the resulting hydrogels prepared using a one-pot synthesis method displayed suitable conductivity values (190 +/- 20 mS/cm) at high water content (70% by weight).

Celery is a marshland plant that has been cultivated as a vegetable. We show that its vascular system (xylem) can be used to facility the uptake of the conducting polymer, poly(3,4-ethylenedioxythiophene) poly(styrene sulfonate) PEDOT:PSS. Our results indicate that PEDOT:PSS is an ideal candidate for enhancing the electrical behavior of the biological system, i.e. celery. The celery-PEDOT:PSS bioelectrical system exhibit conductivity value of 500 +/- 30 mS/cm, suitable to function as components in electrical devices.

Bioelectronics for modulating nervous system, such as the vagus nerve stimulator, demonstrate great promise in treating various neurological diseases. However, their fixed sizes and shapes cannot accommodate the rapid tissue growth and negatively influence normal developmental functions. For infants, children and adolescents, once the implanted devices are ‘outgrown’, additional surgeries are usually needed for device removal, followed by replacement. These tedious processes inevitably lead to repeated intervention and elevated complication rates. Although stretchable electronics with high elasticity is ideal for repeated motion and volumetric expansion of organs, they still cannot adapt to developmental tissue growth, which should not be restricted by any strain. Here, we address this limitation with Morphing Electronics (termed MorphE) which are designed and fabricated to suitably adapt to in vivo nerve tissue growth with zero strain. This is achieved by viscoplastic electronic materials (VEMs) that eliminate the stress and tissue constraint on growing tissue. In addition, water-insensitive self-healing property of the multilayered MorphE consisting of viscoplastic electrodes and a strain sensor allows fora reconfigurable platform for individualized implantation procedures. Animal study demonstrated that the soft and self-adapting MorphE showed no damage to the rat nerve after grown 2.4 times its initial diameter. This stable neural interface allowed chronic electrical stimulation and monitoring without disruption of functional behavior in developing rats. Our MorphE creates a new avenue for adaptive pediatric electronics medicine.

Most mammalian cells will, upon exposure to an extracellular, DC electric field, reorient along the field axis in a process known as ‘electrotaxis’ (or: galvanotaxis). Surprisingly, electrotaxis arises naturally in processes spanning injury healing, organ development, infection, and general cell migration where electrochemical ion gradients (~1 V/cm) within the tissue can act akin to a ‘compass’ signal directing cellular navigation. Excitingly, if bioelectric cues play an important role in tissue assembly and growth, then we should be able to externally manipulate these cues in order to effectively program tissue form and function. This concept underlies a major thrust in our lab where we develop new engineering approaches to harness electrotaxis for applications in tissue engineering and regenerative medicine. Here, we describe our recently developed multi-electrode, electrochemical bioreactor. The bioelectric interface combines layer-based microfluidics, cell-sheet engineering, and multiplexed salt bridge electrodes to allow for interactive manipulation of large, living tissues. Using this system, we are able to interactively steer collective cell migration and growth in engineered skin, kidney, and vascular precursor tissues, and we have so far induced complex maneuvers such as turns, loops, and sculpted tissue outgrowth. Using analytical tools from active matter, we are beginning to relate swarm controllability to bulk material properties such as cell type, cell density, and cell adhesion strength. Finally, we are working on new electrode materials and biomaterials to more precisely and stably couple our stimulation array into living tissue. Together, these approaches are helping us to define a ruleset for how to rationally design bioelectric interfaces to program the behavior of living tissues.

In this work, we demonstrated an innovative method of rapid in-situ fabrication of conductive-bacterial-composite on carbon electrodes. The conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) was electrochemically polymerized by 3D printing the monomer precursor directly onto the surface of electrode submerged in an aqueous suspension of Shewanella oneidensis wild type MR1, creating an electrochemically active biocomposite within 35 min. Using cyclic voltammetry (CV), the biocomposite showed enhanced bio-electrochemical activities, opening up new avenues to the development of bioenergy harvester, biosensor and biomedical device. Ever since the discovery of conductive polymers, their electroactive properties have been extensively examined by researchers and engineers alike. Particularly, the biocompatible conductive polymers have been given significant attention in recent years as a promising bridge between biology and electronics. Applications as microbial fuel cell (MFC), water-quality sensor, glucose sensor, or body-machine interface have shown great potentials in the fields of energy harvesting technology, biosensing, bioelectronics and health care. Bioelectrochemical systems (BES) utilizing conductive polymer and electroactive bacteria biocomposite to directly transduce biological processes to electrical signals are of unique interest as their immediate application in bioenergy harvesting and biosensing. Comparing to the natural biofilms, the electrochemically active biocomposite offers distinctive advantages as enhanced extracellular electron transfer (EET) rate, denser cell attachment onto the electrode, higher signal-to-noise ratio, and more controllable and versatile composite constitution and functions. Yet, current conductive biocomposite formation procedures such as polymer coating over bacteria cells and electrode surface, cell absorption onto polymer matrix, or cell immobilization by polymerization often involve prolonged cell exposure to cytotoxic chemicals, species-specific procedures, or complicated experimental process and setup. Thus, a more rapid, non-specific and simple biocomposite fabrication method is urgently needed to fully unleash the full potential of conductive-polymer-based BES. Using 3D printing, we present a novel, rapid and simple method to fabricate conductive biocomposite by electropolymerization of 3,4-ethylenedioxythiophene (EDOT) in bacteria-containing aqueous solution. The electropolymerization was conducted with plenary 3-electrode electrochemical cells containing S.oneidensis in M9 medium in room environment. While a constant potential (1V versus Ag/AgCl) was applied to the carbon working electrode (WE) by a potentiostat in chronoamperometry (CA) mode, 10mM EDOT (in M9 medium) was patterned over the WE surface by a 3D printer. Cells attached to the WE were entrapped by the in-situ synthesized PEODT whereas their exposure to the cytotoxic monomer was minimized. The dimension of the conductive biocomposite can be controlled by the printing pattern and number of repeated iterates. A settling time of 10 min between each print and iterate repeat of 3 times were selected in this work.

Three-dimensional (3D) printing is one of the most transformative technologies in modern manufacturing that offers unprecedented capabilities of programmable, rapid, and flexible fabrication of materials. Despite their unique benefits and growing importance, conducting polymers have yet remained as an inaccessible class of materials for 3D printing. Here we introduce a 3D printable high-performance conducting polymer based on poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) to take full advantage of advanced 3D printing. Superior 3D printability of the conducting polymer ink enables high resolution (over 30 µm), high aspect ratio (over 20), and reproducible fabrication of conducting polymer in microscale, seamlessly integrable with multi-material printing with other 3D printable materials such as insulating elastomers. The 3D printed conducting polymer structures can readily be converted into highly conductive and flexible pure PEDOT:PSS both in dry and hydrogel states. Both of the 3D printed PEDOT:PSS films and hydrogels exhibit interesting properties that are desirable for optoelectronic and bioelectronic applications, such as high electrical conductivity, low Young's modulus, superior mechanical, electrical and electrochemical stability in wet physiological environments. We further demonstrate various functional applications of the 3D printable conducting polymer including a high-density flexible electronic circuit and a soft neural probe capable of in vivo single-unit recording, all fabricated by 3D printing. This work not only widens the choice of materials for 3D printing but also provides a promising new fabrication strategy for a broad range of applications in flexible electronics, wearable devices, and bioelectronics.

Field-effect transistors (FETs), when functionalized with bioactive receptors (such as antibodies or enzymes), represent a unique platform for real time, specific, label-free transduction of biochemical signals with unprecedented sensitivity and spatiotemporal resolution. However, direct functionalization of bio-receptor on FETs places limitations on reprogrammability, sensor regeneration and sensitive bio-receptor handling. Here we demonstrate a modularized design of FET biosensors with separate recognition module and transducer module, which are capable of reversible assembly and disassembly. Successful detection of penicillin down to 0.25 mM was achieved by integrating penicillinase-encoded hydrogel module onto graphene FETs, demonstrating effective signal transduction across the interface. Moreover, sequential integration of urease- and penicillinase-encoded modules on the same FET device allows us to reprogram sensing modality without cross-contamination. Except for the variation of bio-receptor encoding, the modular design also fosters sophisticated modulation of the biophysical/biochemical microenvironment in the recognition modules for controllable diffusion dynamics. Specifically, the tuning of hydrogel porosity with polyethylene glycol and gelatin enables the selective detection of poly-L-lysine (MW 150-300 kDa). Recognition modules designed with standardized interfacing geometry towards transducer modules have also been shown to be capable of being mass fabricated by 3D printing and batch photopolymerization, demonstrating potential for low cost, ease of storage, multiplexing and great customizability for personalized biosensor arrays. This generic concept presents a unique integration strategy for modularized bioelectronics and could impact broadly hybrid device development.

The interface between biological cells and non-biological materials has profound influences on cellular activities, chronic tissue responses, and ultimately the success of medical implants and bioelectronic devices. For instance, electroactive materials in contact with cells can have very different composition, surface topography and dimensionality. Dimensionality defines the possibility to have planar (2D), pseudo-3D (planar with nano-micropatterned surface)1 and 3D conductive materials (i.e. scaffolds) in bioelectronic devices. Their success for both in vivo and in vitro applications lies in the effective coupling/adhesion of cells/tissues with the devices’ surface. In fact, the tight contact between the cellular membrane and the electrode surface massively affects the quality of the recorded signals or ultimately the stimulation efficiency of a device.
However, it is largely unexplored how the patterning and ultimately the dimensionality of bioelectrodes are enhancing the cell-chip coupling.
Here, we explore how the transition from planar to pseudo-3D nanopatterned materials (i.e. conductive vertical nanostructures, nanogrooves, nanofibers) have introduced a new strategy of integrating with biological cells. Although a spontaneous penetration does not occur, adhesion process are extremely distinct when bioelectronics devices are engineering with those patterned materials. These materials have been further exploited towards fully 3D dimensional solutions, moving closer to complex 3D architectures which could directly resemble tissue-like architectures. In this way, cells recognize the bioelectrodes as being embedded in their own matrix and thus fully integrate with the device.

The human gut microbiome plays an essential role in health and disease. Gastrointestinal disease phenotypes (e.g. coeliac disease (CeD), colorectal cancer), have been linked with an impaired gut microbiome, while increasing evidence suggests that microbiome alteration effects extend beyond the gut, reaching other organs, and particularly, the brain. However, the cross-talk interactions of the ‘gut-brain-microbiome axis’ remain a mystery, mainly due to the lack of a human clinical model. Over the last decade, organ-on-chip technology has arisen as powerful alternative to animal models for studying human (patho-)physiology¹. Integration of this technology with organic electronics can be particularly favourable for delivering robust, biomimetic models, with in-line, multiparametric monitoring².
Here, we report the first version of an in vitro intestinal model integrated with a novel 3D bioelectronic device (i.e. Tubistor), based on scaffolds made from the conducting polymer poly(3,4-ethylenedioxythiphene)poly(styrenesulfonate) (PEDOT:PSS)². To emulate the intestinal epithelial barrier we established co-cultures of enterocytes, along with fibroblasts which are used for their ability to secrete extracellular matrix and render the surface of the scaffolds more appealing for cell adhesion. This co-culture system is generated inside Tubistors, both under static and flow conditions, where PEDOT:PSS scaffolds serve both as cell hosts and as the active material for monitoring cell integrity and activity. During a 25-day growth period, we continuously monitor the model electrically and at the end of this period, these data are cross-validated with traditional optical assays (i.e., Scanning Electron Microscopy and immunofluorescence staining). The soft, tissue-like nature of PEDOT:PSS scaffolds provides a favourable microenvironment for tissue growth and differentiation, exhibiting typical in-vivo-like characteristics of the native tissue (e.g. brush border formation, tight junction and mucin expression). To generate a complete gut-microbiome model, we are currently working on co-culturing bacterial cells – representative of the human microbiome - with our intestinal model.
We anticipate that this bioelectronic platform will serve as a powerful tool for studying host-microbiome interactions, as well as a diagnostic tool for personalised medicine applications.

Hybrid interfaces between living cells and nano/micro-structured scaffolds have been extensively investigated over the latest decades, due to their huge application potential in biotechnology,spanning from regenerative medicine and stem cells therapies to localized drug delivery, from biosensing and tissue engineering to neural computing. In particular, 3D scaffolds based on organic conductors have recently gained increasing interest, due to the combination of excellent biocompatibility properties with versatile fabrication techniques and good electrical conductivity. In this scenario, however, architectures based on semiconducting polymers, endowed with responsivity to visible light as an additional interesting feature, have never been considered.
Here, we originally develop a push-coating technique to realize high aspect ratio (HAR) polymeric pillars, based on polythiophene. The organic semiconducting structures show optimal biocompatibility and allow for the realization of soft, three-dimensional cell cultures, as tested with both primary neurons and cell line models. HEK-293 cells cultured on top of polymer pillars display a remarkable change in the cell morphology. Interestingly, we observe a sizable enhancement of the cell membrane capacitance as due to the cell membrane thinning in correspondence of the pillars’ top surface. Importantly, however, this does not negatively affect cells proliferation. Electrophysiology properties and synapses number of primary neurons are also very well preserved.
HAR semiconducting polymer pillars represent the first necessary step towards the realization of 3D, electro-optically responsive organic structures. In perspective, they may find interesting applications as soft, photoactive elements for cell activity sensing and modulation.

Organic bioelectronic sensors are gaining momentum as they can combine high performance sensing level with flexible and stretchable large-area processable materials. This opens to potentially highly powerful biomarkers sensing systems for point-of-care health monitoring and diagnostics. Prominent to detect biochemical recognition events are the Electrolyte-Gated Organic Field-Effect Transistors (EGOFETs) and Organic ElectroChemical Transistors (OECTs) as they are easy to fabricate and operate. Relevantly, the EGOFETs have been recently shown capable of label-free single-molecule detections even in blood serum.
This lecture aims to provide a critical perspective trough a selected overview of the literature on both EGOFETs and OECTs organic bioelectronic sensors. Attention is paid to correctly attribute them to the potentiometric and amperometric categories which is important to set the right conditions for quantification purposes. Moreover, to deepen the understanding of the sensing mechanisms, also with the support of unpublished data, focus is put on two among the most critical aspects, namely: the capacitance interplay in EGOFETs and the role of faradaic currents in OECTs. The final aim is to provide a general rational encompassing both EGOFETs and OECTs sensors, to improve materials and devices design taking full advantage of the processes that enhance the sensing response enabling the extremely high-performance level resulting in ultimate sensitivity, selectivity and fast response.

Field effect transistor-based electrical biosensors are capable of label-free detection of nucleic acids and proteins by measuring the intrinsic charge of these biomolecules. However, the ultimate detection limit of these sensors is determined by the Debye screening from counter ions in solution, the proximity of the biomolecules to the surface of the sensor, and the operating conditions of the transistor sensor. Here, we use field effect transistors with a deformed monolayer graphene channel for the detection of DNA molecules and DNA/RNA hybridization. We find that these devices with even millimeter scale long channels show an ultra-high sensitivity detection in buffer and human serum sample down to 20 aM in 50 µL, which is equivalent to ~600 DNA/RNA molecules. Molecular dynamic simulations reveal that the nanoscale deformations can result in the formation of ‘electrical hot spots’ in the sensing channel which reduce the charge screening at the concave regions allowing improved detection of the molecular charge. These hot spots also exclude mobile charges, thus exhibiting a high local potential due to the charge of the DNA/RNA. In addition, the deformed monolayer graphene could exhibit a band-gap allowing an exponential change in the source-drain current due to a small number of unscreened biomolecular charges at those hot spots. Collectively, these phenomena can allow for ultrasensitive electronic biomolecular detection in millimeter scale structures, opening the way to many applications in biology and medicine.

In the past decades, wearable biosensors have attracted a great amount of attention due to the increasing demands for affordable, non-invasive, and continuous monitoring of physiological parameters for disease prevention, early medical diagnostics, and personalized medicine. These rapid diagnostic biosensing devices should be sensitive, robust, and compact. They do not require conventional clinical laboratory infrastructures to perform the tests, which potentially contributes to reducing healthcare service costs. Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT: PSS) based organic electrochemical transistors (OECTs) have been demonstrated to have great potentials for customizable biosensors due to their simple device structure, great material stability, capability to operate in aqueous environment with low operation voltage, and most importantly high transconductance (g_m).[1–3] Devices with high g_m show high sensitivities and transduce biological and chemical signals into electrical signals with high signal to noise ratio (SNR).
Functionalization is essential for improving the sensing selectivity and sensitivity, which involves modifying the channel and/or gate surface of OECT with functional groups and linking the desired biomolecules. N-heterocyclic carbene (NHC) forms extremely strong bonds with transition metals and has been demonstrated as surface-ligands on different metal surfaces, which can be used as linkers for the conjugation of needed biological recognition elements.[4]
In this study, we have integrated NHC modified Pt wire as the gate for 3D printed OECTs. The OECTs were printed by Optomec Aerosol Jet 5X system on both rigid and flexible substrates with silver source and drain electrodes, PEDOT:PSS channel, and UV-curable polydimethylsiloxane (PDMS) as the passivation layer. All materials used for OECT printing are commercially available. The printed OECTs exhibit high g_m of 30.63 mS (L = 104 µm, W/L = 4, d = 570 nm) tested with 100 mM NaCl electrolyte and Ag/AgCl gate. A distinctive shift in the transfer characteristic was observed when measuring with the NHC modified Pt gate compared to the pristine Pt wire gate. This is due to the work function change of the Pt wire with NHC functionalization. We have demonstrated biosensing capability of the sensor by attaching biotin to the NHC functional group via click chemistry and then detecting streptavidin.

References:
[1] Wang N, Yang A, Fu Y, Li Y and Yan F 2019 Functionalized Organic Thin Film Transistors for Biosensing Acc. Chem. Res. 52 277–87
[2] Majak D, Fan J and Gupta M 2018 Fully 3D printed OECT based logic gate for detection of cation type and concentration Sensors Actuators B Chem. 286 111–8
[3] Fan J, Montemagno C and Gupta M 2019 3D printed high transconductance organic electrochemical transistors on flexible substrates Org. Electron. 73 122–9
[4] Hopkinson M N, Richter C, Schedler M and Glorius F 2014 An overview of N-heterocyclic carbenes Nature 510 485–96

Poly(3,4-ethylenedioxythiophene), PEDOT, has been widely used in an array of applications spanning from energy storage to biomedical devices due to its high conductivity, good chemical stability, biocompatibility, and feasibility of functionalization. Herein we present a new strategy to copolymerize PEDOT, and its hydroxyl terminated counterpart (PEDOT-OH) through electropolymerization in the presence of different additives. A fixed amount of the monomers is introduced in the presence of ClO₄^- or PSS^- anions. The range of additives spans from MXene, CNTs, Au nanoparticles to ionic liquids such as 1-ethyl-3-methylimidazolium trifluoromethanesulfonate. We study the impact of these components on the physicochemical and electrochemical properties of the resulting films. The roughness and topography amongst the various electrodes are compared by AFM and SEM-FIB and correlated with the results stemmed from electrochemical impedance spectroscopy, cyclic voltammetry and galvanostatic charge-discharge cycling performed in an aqueous environment (0.1 M NaCl). The best performing copolymers are further used to build state-of-the-art electrodes for oxygen reduction and electrodes for neural recordings.

The ability to control the interaction between living systems and electroactive surfaces has been a longstanding goal of many scientific disciplines, ranging from healthcare to clean energy. For bioelectric applications, maintaining the specificity of cell placement while facilitating electron transfer between cells and the surface remains a challenge. DNA is capable of both imbuing specificity through self-recognizing hybridization and wire-like behavior, making it ideal to address key issues with the interfacing of cells with electroactive surfaces. Through DNA hybridization-based cell adhesion, we have captured and monitored non-adherent mammalian cells, yeast, and microbes on DNA-modified electrodes. Importantly, we have applied this method to the rapid assembly of low-density monolayers of current-producing cells. Through DNA-based immobilization, we have found that these cells maintain their electron transfer abilities prior to biofilm formation. We attribute this feature, at least in part, to the conductivity of DNA. This DNA-based technique to interface cells with inorganic surfaces has broad applications, including diagnostic tools and biofuel cells.

The cell membrane is the first point of contact for pathogen entry. It is the interface that defines the inside of the cell from the environment and a surface that presents an array of biological moieties that pathogens can use to recognize a specific host cell target. Pathogens or pathogenic material, such as viruses or bacterial toxins, target these surface moieties, which are often specific proteoglycans or glycolipids. Binding occurs first, then various mechanisms are used to gain entry into the cell by crossing the membrane barrier. Bacterial toxins poke holes in membranes, which causes catastrophic leakage of ions and nutrients from the cell, while allowing external materials enter. Viruses can inject genetic material across the plasma membrane directly or get endocytosed into the cytosol to later release their genetic code after membrane fusion. With the constant evolution of resistant bacteria and viruses that can evade the immune system, being a step ahead of them by defining new ways to disarm them is progressively more difficult. Here we present a new biomembrane sensing platform that mimics host cell membranes and takes advantage of the natural propensity of these pathogens to want to interact with these surfaces. Binding, membrane disruption, or membrane fusion can be sensed using an electroactive polymer film that supports the biomembrane as an element in an electronic circuit that monitors the electrical properties of the membrane when pathogens attack.

Bilayer lipid membranes demonstrates an ultrathin thickness (3~5 nm) and ultrahigh ionic resistivity (>100 GΩ). Here, we propose that by utilizing the outstanding properties of bilayer lipid membranes, functional bio-hybrid membranes can be formed by doping the lipid membrane with organic molecules. In this work, organic molecules Copper (II) 2,9,16,23-tetra-tert-butyl-29H,31H-phthalocyanine (CuPc), which has been widely used in the fields of catalysis, solar cells, and transistors, were used to dope the lipid membranes. It is supposed that hydrophobic CuPc molecules can be inserted into the hydrophobic tails of bilayer lipid membrane, forming a sandwiched binary hybrid membrane structure. Therefore, these nano-scale hybrid membranes can be functionalized by inserting nanoparticles, without disturbing the natural ordered membrane structure. Since the lipid membrane have good insulativity and ultrathin thickness, this hybrid membrane can be used as a basic framework of bio-hybrid devices.
The bio-hybrid membranes composed of lipids and CuPc molecules were formed by using self-assembly at water/air interface. Lipid molecules DPhPC and CuPc were dissolved in organic solvent. At room temperature, the prepared solution was dropped onto water surface. As the solvent evaporated, hybrid membranes immediately formed on the water surface. Finally, the self-assembled hybrid membranes were transferred onto Si substrate by gradually lowering water level.
To investigated the surface morphology, atomic force microscope (AFM) was used. By measuring 74 samples, it is concluded that all the thicknesses of membranes are very close to multiples of 5 nm, such as 10 nm, 15 nm, 20 nm and so on. Therefore, it is highly possible that the hydrophobic CuPc molecules combined hydrophobic tails of two lipid molecules to form a hybrid sandwich structure. X-ray diffraction (XRD) measurement were used to examine the structure of hybrid membranes. The patterns did not show any peak representing the CuPc packing. This result indicated that CuPc molecules did not aggregate to form small crystals in the hybrid membrane. Furthermore, an experiment was designed based on fluorescence resonance energy transfer (FRET) theory by adding fluorescent labeled lipids into hybrid membranes. The experimental results indicated that the CuPc molecules are closer to the tails rather than heads of lipid molecules in the membranes, which is corresponding to former speculation. And these hybrid bilayer membranes can stack up to form multilayer structures whose thicknesses are integral multiples of 5 nm. With this insulator-semiconductor-insulator structure, the hybrid membrane can be used as a framework for novel nano-devices.

Recordings and stimulations of neuronal electrical activity is a topic of great interest in neuroscience. Multiple neurological disorders can benefit from a microelectrode that is flexible, chemically inert, electrically conducting, and preferentially transfers electrons via capacitive charge-injection. Commercial electrodes that currently exist and other electrodes that are being tested with the purpose of facilitating and improving the electron transport between solid electrode materials and biological tissue still have some limitations. This paper discusses a carbon nanotube-based microelectrode from its synthesis, fiber assembly, polymer coating and application as microelectrode for neural recording and stimulation. We compare electron transport capabilities of carbon nanotube fibers to noble metals Au and Ag wire microelectrodes to biological tissue. The recording ability of microelectrodes is demonstrated through Electroretinography (ERG) on Sarcophaga bullata fly eyes, where light stimulation generates potential changes that were detected by our microelectrodes. Stimulation is demonstrated through Au wire and carbon nanotube fiber implants in Madagascar hissing cockroach (Gromphadorhina portentosa) antennas to control their locomotion directions. A comparison of their impedance, charge injection capacity and electrical conductivity demonstrates that carbon nanotube fibers have great potential as microelectrodes in neuroscience.

Bioelectronic devices interact directly with biological systems to monitor cellular electrical activity and promote cell reaction to electrical stimulation. The capabilities of such devices, in terms of recording and stimulation, are affected by the effective cell-platform coupling. Therefore, during the last years, the development of engineered 3D micro and nanostructures has improved the effectiveness of biosensors using protruding structures to achieve a more intimate contact between cells and substrates. In parallel, the rising of carbon-based materials for bioelectronics has gained attention during the last years because of their outstanding chemical properties which allow improved cell-device interface. Given this scenario, 3D out-of-the-plane graphene structures has been designed and grown on planar platforms, exploiting the electrical, mechanical and optical features of this promising material. 3D fuzzy graphene (3DFG) and nanowire-templated 3DFG (NT-3DFG) were realized as electrode surface (1). Here we report a comprehensive study of the interface by using fluorescence and electron microscopy for characterizing cell-materials interactions at micro and nanoscale. First, we investigated the biocompatibility and the adhesion effect (cell stretching) of the diverse graphene-based pseudo-3D surfaces. Then, we examined the membrane deformation and the actual cell-device coupling via scanning electron microscopy/focused ion beam sectioning (2,3). Finally, as outlook we will present preliminary results on how the material surface can affect the recording of spontaneous action potentials from electrogenic cells. We found out an enhanced cells adhesion on the substrates, suggesting that out-of-the-plane platform could improve the coupling between cells and sensors.
References
(1) Garg R., Rastogi S. K., Lamparski M., de la Barrera S. C., Pace G. T., Nuhfer N. T., Hunt B. M., Meunier V., Cohen-Karni T., Nanowire-Mesh-Templated growth out-of-plane three-dimensional fuzzy graphene. ACS Nano, 2017.
(2) Li X., Matino L., Zhang W., Klausen L., McGuire A.F., Lubrano C., Zhao W., Santoro F., Cui B., A nanostructure plaform for live-cell manipulation of membrane curvature. Nature Protocols, 2019
(3) Santoro, F., Zhao, W., Joubert, L.-M., Duan, L., Schnitker, J., van de Burgt, Y., Lou, H.-Y., Liu, B., Salleo, A., Cui, L., Cui Y., Cui B., Revealing the Cell–Material Interface with Nanometer Resolution by Focused Ion Beam/Scanning Electron Microscopy, ASC Nano, 2017.

Bioelectronic devices should optimally merge a soft, biocompatible tissue interface with capacity for local, advanced signal processing. Here, we introduce an organic mixed-conducting particulate composite material (MCP) that can form functional electronic components by varying particle size and density. We created MCP-based high performance anisotropic films, independently-addressable transistors, resistors, and diodes that are pattern-free, scalable, and biocompatible. MCP enabled facile and effective electronic bonding between soft and rigid electronics, permitting recording of neurophysiological data at the resolution of individual neurons from freely moving rodents and from the surface of the human brain through a small opening in the skull. We also acquired high spatiotemporal resolution electrophysiological signals non-invasively by directly interfacing MCP with human skin. MCP provides a single material solution to facilitate development of bioelectronic devices that can safely acquire, transmit, and process complex biological signals.

The control of ion concentration gradients and ionic currents is ubiquitous in tissue-level and cell-level processes such as enzyme activation, oxidative phosphorylation, neuronal excitation, and immune response. Bioelectronic devices with functional materials that can transduce between electronic and ionic signals allow researchers to use existing knowledge of electronics to perform unique tasks with ions in solution. Devices of this nature are well-suited to these biological ion-driven applications. Here, I report on recent progress towards developing and using iontronic devices for activating metal oxide catalysis in aqueous solutions with the application of glucose sensing.

Cellular membranes represent an obvious, yet relatively neglected target for fundamental understanding of the mechanisms of disease and for therapeutic optimization. Existing membrane models suffer from incompatibility at the biotic/abiotic interface and lack molecular complexity, compromising their reliability. To address these issues we have developed human membrane models by fusing native extracellular material on top of conducting polymer transducers. This unique platform rises above the state of the art by providing a physiologically relevant biomimetic environment close to that of native membranes, as well as by providing integrated functionality to transduce biological events at the molecular level. The use of conducting polymers and in particular poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), overcomes the issue of the commonly used solid substrates (ie., glass, Au) for signal transduction, by facilitating mobility of the transmembrane proteins, enhancing the native structural and functional properties of the membrane. Simultaneously, it allows for the electrical characterization of the membrane properties and its interactions, by transducing the ionic flux to an electronic signal. In this work, we demonstrate the formation of native cell membranes from human embryonic kidney 293 cells (HEK) in the form of supported lipid bilayers (SLBs) on top of PEDOT:PSS electrodes and transistors. We monitor the formation of the native SLBs and characterize them using both optical and electronic methods. We show dynamics of membrane fusion by electrically monitoring the changes on the membrane properties. Finally, we show that the h-TREK-1 potassium ion channel overexpressed in HEK cells can be monitored within its native membrane context. We show that our devices can transduce the action of clinically important molecules that are able to open or block these channels. Our results suggest that this platform could be an excellent in vitro assay for drug testing, providing a scalable and cost-efficient alternative to using whole cells e.g. patch clamp assays.

Ultra-thin conducting fibres possess unique mechanical, optical and electrical properties due to the high aspect-ratio, low bending stiffness and transparency. Those fibre arrays made with different conducting materials could enable a variety of novel applications, ranging from transparent textile-based circuits to bio-sensors. Current fibre fabrication techniques usually deposit fibres onto substrates, and the optomechanical properties of substrates largely compromise the advantages of ultra-thin fibres. Herein, we present an efficient fibre printing method to produce conducting and substrate-free sub-micron fibres arrays. The fibre printing and fibre to circuit connection are completed in one step under a sub-80°C mild temperature, without needing post processing steps such as annealing. With this printing method, we demonstrate the capability to print conducting polymer based (PEDOT:PSS, (poly(3,4-ethylenedioxythiophene) polystyrenesulfonate)) fibres. The high resolution fibres can span across a freestanding distance up to 10mm, having both ends attached to outer circuit with negligible contact resistance. Floating electronics are demonstrated where small electronics such as LEDs and photodiodes can be mechanically supported and electrically connected by suspended fibre arrays. Cell attachment and viability results with the PEDOT:PSS fibre arrays also show their potential use as biosensors.

Traditional electronics is based on the silicon transistors for a number of decades. However, the emergence of organic, conductive polymers leading to organic transistors has allowed for research into non-traditional electronic devices that combine organic and inorganic material. Organic transistors [3,4] have shown many benefits and applications, by using organic semiconductors, devices can be flexible, solution processable, 3D printable and economical. Organic Electrochemical Transistors (OECTs)- a specific subset of organic transistors - are perfectly suited for biological sensing. OECTs have specifically been used to sense dopamine, DNA, pH, lactate, glucose, ion concentration and more. OECTs operate in a similar manner to traditional silicon transistors but the channel is made of an organic polymer and uses the ions in an electrolyte as part of the gate contact. OECTs operate with both electrical and ionic current, meaning they can be driven at lower voltages and have lower power consumption. In addition, they have built-in amplification, which means higher sensitivity and lower power consumption. By operating with ionic current, OECTs can be used for bio-sensing as they can detect ions present in biological environments.
Canada is the first nation in the G7, and the second in the world to legalize the recreational use of cannabis. However, despite legalization, a number of challenges remain that need to be solved. One of the main issues is the detection, and quantization of impairment. The psychoactive cannabinoid, Δ⁹-Tetrahydrocannabinol (THC), is the cause of impairment, however the extent of it is difficult to determine because THC remains in blood, urine and other bodily fluids long after exposure and therefore does not correlate to impairment.
Currently, all the Δ9-THC detection techniques are based on either utilising mass spectroscopy or gas chromatography (GC) for oral fluids. Both of these techniques are accurate but require extensive measurement equipment and are not cheap. The other Δ9-THC measurements are based on blood or urine pathological measurements which also require more sampling equipment along with the issues of hygiene and can take several hours to obtain results. A better approach is to test the concentration of THC present in the saliva [1, 2] of the user, as THC concentrations in saliva can more closely be correlated with cognitive and motor impairment. OECTs are perfectly suited for this application, due to the high transconductance and sensitivity. Our 3D printed OECTs [6-8] can detect concentrations down to 0.05 nM, in DI water, without functionalization of the OECT. This limit of detection is well within the required level to be able to detect the THC levels present in cannabis users’ saliva. These sensors are entirely 3D printed, which means that they can be easily and cost effectively fabricated, as compared to traditional nano and micro fabrication methods. These sensors show repeatable results with low drift (<3.6%), as well as a fast response (163s average). The next step is to improve the detection capability of the sensors in saliva rather than water and this can be achieved by functionalization of the gate electrode to detect only the Δ9-THC. Results from this study will be presented.

[1] Milman. G., et.al., Anal Bioanal Chem., 401,2, (2011).
[2] Lee. D., et.al., Drug Test Anal., 6, (2014).
[3] Y. Seekaew, et. al., Org. Electron., 15, 11, 2971–2981, (2014).
[4] H. S. White, et.al., J. Am. Chem. Soc., 106, 18, 5375–5377, (1984).
[6] J. Fan et al., Org. Electron. 73, 122–129 (2019).
[7] J. Fan et al., Org. Electron. 66, 148–155 (2019).
[8] D. Majak et al., Sensors Actuators B Chem. 286, 111–118 (2019).

Neurodegenerative processes in the brain became an important challenge with increased age of the population. Usually, relatively bulky optical methods are used to detect Amyloid β peptides, which are linked to the pathogenesis of Alzheimer disease. To prolong effective and healthy memory and thinking capability as well as to stop the factors resulting in Alzheimer’s disease new high-sensitive and direct methods for the early detection of peptides involved in Alzheimer’s disease have to be developed. In this contribution, we report on successful demonstration of a new label-free approach for detection of amyloid beta proteins by high-selective aptamers immobilized onto the SiO₂ surface. A nucleotide aptamer was synthesized to detect the target Amyloid beta-40 sequence. Functionalized structures based on thin SiO₂ dielectric layer has been developed to detect ultra-low concentrations of the target protein. The detection technique utilizes high-efficient aptamer immobilization on the SiO₂ surface of the sensor system configured with a liquid-gate. The introduction of amyloid beta protein of different concentrations in a wide range from 0.1 pM to 1 μM to the surface of the sensor results in a change of surface potential. Obtained experimental data demonstrate high-sensitive and reliable detection of ultra-low concentrations of the amyloid beta protein, which opens the perspective for the development of real-time electrical sensors for studies and understanding of different stages of Alzheimer’s disease utilizing nanostructures fabricated on the basis of cost-efficient CMOS-compatible technology.