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Precision medicine endeavors to personalize treatments, considering individual variations in patient responses based on factors like genetic mutations, age, and diet. Integrating this approach dynamically, bioelectronics equipped with real-time sensing and intelligent actuation present a promising avenue. Devices such as ion pumps hold potential for precise therapeutic drug delivery, a pivotal aspect of effective precision medicine. However, implementing bioelectronic devices in precision medicine encounters formidable challenges. Variability in device performance due to fabrication inconsistencies and operational limitations, including voltage saturation, presents significant hurdles. To address this, closed-loop control with adaptive capabilities and explicit handling of saturation becomes imperative. Our research introduces an enhanced sliding mode controller capable of managing saturation, adept at satisfactory control actions amidst model uncertainties. To evaluate the controller's effectiveness, we conducted in silico experiments using an extended mathematical model of the proton pump. Subsequently, we compared the performance of our developed controller with classical Proportional Integral Derivative (PID) and machine learning (ML)–based controllers. Furthermore, in vitro experiments assessed the controller's efficacy using various reference signals for controlled Fluoxetine delivery. These experiments showcased consistent performance across diverse input signals, maintaining the current value near the reference with a relative error of less than 7% in all trials. Our findings underscore the potential of the developed controller to address challenges in bioelectronic device implementation, offering reliable precision in drug delivery strategies within the realm of precision medicine. [ABSTRACT FROM AUTHOR]

The development of wearable bioelectronic systems is a promising approach for optimal delivery of therapeutic treatments. These systems can provide continuous delivery of ions, charged biomolecules, and an electric field for various medical applications. However, rapid prototyping of wearable bioelectronic systems for controlled delivery of specific treatments with a scalable fabrication process is challenging. We present a wearable bioelectronic system comprised of a polydimethylsiloxane (PDMS) device cast in customizable 3D printed molds and a printed circuit board (PCB), which employs commercially available engineering components and tools throughout design and fabrication. The system, featuring solution-filled reservoirs, embedded electrodes, and hydrogel-filled capillary tubing, is assembled modularly. The PDMS and PCB both contain matching through-holes designed to hold metallic contact posts coated with silver epoxy, allowing for mechanical and electrical integration. This assembly scheme allows us to interchange subsystem components, such as various PCB designs and reservoir solutions. We present three PCB designs: a wired version and two battery-powered versions with and without onboard memory. The wired design uses an external voltage controller for device actuation. The battery-powered PCB design uses a microcontroller unit to enable pre-programmed applied voltages and deep sleep mode to prolong battery run time. Finally, the battery-powered PCB with onboard memory is developed to record delivered currents, which enables us to verify treatment dose delivered. To demonstrate the functionality of the platform, the devices are used to deliver H + in vivo using mouse models and fluoxetine ex vivo using a simulated wound environment. Immunohistochemistry staining shows an improvement of 35.86% in the M1/M2 ratio of H + —treated wounds compared with control wounds, indicating the potential of the platform to improve wound healing. [ABSTRACT FROM AUTHOR]

The peripheral nerves (PNs) innervate the dermis and epidermis, and are suggested to play an important role in wound healing. Several methods to quantify skin innervation during wound healing have been reported. Those usually require multiple observers, are complex and labor-intensive, and the noise/background associated with the immunohistochemistry (IHC) images could cause quantification errors/user bias. In this study, we employed the state-of-the-art deep neural network, Denoising Convolutional Neural Network (DnCNN), to perform pre-processing and effectively reduce the noise in the IHC images. Additionally, we utilized an automated image analysis tool, assisted by Matlab, to accurately determine the extent of skin innervation during various stages of wound healing. The 8 mm wound is generated using a circular biopsy punch in the wild-type mouse. Skin samples were collected on days 3, 7, 10 and 15, and sections from paraffin-embedded tissues were stained against pan-neuronal marker- protein-gene-product 9.5 (PGP 9.5) antibody. On day 3 and day 7, negligible nerve fibers were present throughout the wound with few only on the lateral boundaries of the wound. On day 10, a slight increase in nerve fiber density appeared, which significantly increased on day 15. Importantly, we found a positive correlation (R2 = 0.926) between nerve fiber density and re-epithelization, suggesting an association between re-innervation and re-epithelization. These results established a quantitative time course of re-innervation in wound healing, and the automated image analysis method offers a novel and useful tool to facilitate the quantification of innervation in the skin and other tissues. [ABSTRACT FROM AUTHOR]

The development of wearable bioelectronic systems is a promising approach for optimal delivery of therapeutic treatments. These systems can provide continuous delivery of ions, charged biomolecules, and an electric field for various medical applications. However, rapid prototyping of wearable bioelectronic systems for controlled delivery of specific treatments with a scalable fabrication process is challenging. We present a wearable bioelectronic system comprised of a polydimethylsiloxane (PDMS) device cast in customizable 3D printed molds and a printed circuit board (PCB), which employs commercially available engineering components and tools throughout design and fabrication. The system, featuring solution-filled reservoirs, embedded electrodes, and hydrogel-filled capillary tubing, is assembled modularly. The PDMS and PCB both contain matching through-holes designed to hold metallic contact posts coated with silver epoxy, allowing for mechanical and electrical integration. This assembly scheme allows us to interchange subsystem components, such as various PCB designs and reservoir solutions. We present three PCB designs: a wired version and two battery-powered versions with and without onboard memory. The wired design uses an external voltage controller for device actuation. The battery-powered PCB design uses a microcontroller unit to enable pre-programmed applied voltages and deep sleep mode to prolong battery run time. Finally, the battery-powered PCB with onboard memory is developed to record delivered currents, which enables us to verify treatment dose delivered. To demonstrate the functionality of the platform, the devices are used to deliver H + in vivo using mouse models and fluoxetine ex vivo using a simulated wound environment. Immunohistochemistry staining shows an improvement of 35.86% in the M1/M2 ratio of H + —treated wounds compared with control wounds, indicating the potential of the platform to improve wound healing. [ABSTRACT FROM AUTHOR]

Proton conductivity is important in many natural phenomena including oxidative phosphorylation in mitochondria and archaea, uncoupling membrane potentials by the antibiotic Gramicidin, and proton actuated bioluminescence in dinoflagellate. In all of these phenomena, the conduction of protons occurs along chains of hydrogen bonds between water and hydrophilic residues. These chains of hydrogen bonds are also present in many hydrated biopolymers and macromolecule including collagen, keratin, chitosan, and various proteins such as reflectin. All of these materials are also proton conductors. Recently, our group has discovered that the jelly found in the Ampullae of Lorenzini- shark’s electro-sensing organs- is the highest naturally occurring proton conducting substance. The jelly has a complex composition, but we proposed that the conductivity is due to the glycosaminoglycan keratan sulfate (KS). Here we measure the proton conductivity of hydrated keratan sulfate purified from Bovine Cornea. PdHx contacts at 0.50 ± 0.11 mS cm -1, which is consistent to that of Ampullae of Lorenzini jelly at 2 ± 1 mS cm -1. Proton conductivity, albeit with lower values, is also shared by other glycosaminoglycans with similar chemical structures including dermatan sulfate, chondroitin sulfate A, heparan sulfate, and hyaluronic acid. This observation supports the relationship between proton conductivity and the chemical structure of biopolymers. [ABSTRACT FROM AUTHOR]

The growing number of multicampus interdisciplinary projects in academic institutions expedites a necessity for tracking systems that provide instantly accessible data associated with devices, samples, and experimental results to all collaborators involved. This need has become particularly salient with the COVID pandemic when consequent travel restrictions have hampered in person meetings and laboratory visits. Minimizing post-pandemic travel can also help reduce carbon footprint of research activities. Here we developed a Quick Response (QR) code tracking system that integrates project management tools for seamless communication and tracking of materials and devices between multicampus collaborators: one school of medicine, two engineering laboratories, three manufacturing cleanroom sites, and three research laboratories. Here we aimed to use this system to track the design, fabrication, and quality control of bioelectronic devices, in vitro experimental results, and in vivo testing. Incorporating the tracking system into our project helped our multicampus teams accomplish milestones on a tight timeline via improved data traceability, manufacturing efficiency, and shared experimental results. This tracking system is particularly useful to track device issues and ensure engineering device consistency when working with expensive biological samples in vitro and animals in vivo to reduce waste of biological and animal resources associated with device failure. [ABSTRACT FROM AUTHOR]

Bioelectronic devices that interface electronics with biological systems can actuate and control biological processes. The potassium ion plays a vital role in cell membrane physiology, maintaining the cell membrane potential (Vmem) and generating action potentials. In this work, we present two bioelectronic ion pumps that use an electronic signal to modulate the potassium ion concentration in solution. The first ion pump is designed to integrate directly with six-well cell culture plates for optimal ease of integration with in vitro cell culture, and the second on-chip ion pump provides high spatial resolution. These pumps offer increased ease of integration with in vitro systems and demonstrate K+ concentration distribution with high spatial resolution. We systematically investigate the ion pump's performance using electrical characterization and computational modeling, and we explore closed-loop control of K+ concentration using fluorescent dyes as indicators. As a proof-of-concept, we study the effects of modulating K+ concentration on Vmem of THP-1 macrophages. [ABSTRACT FROM AUTHOR]

Organ-on-a-chip systems combine microfluidics, cell biology, and tissue engineering to culture 3D organ-specific in vitro models that recapitulate the biology and physiology of their in vivo counterparts. Here, we have developed a multiplex platform that automates the culture of individual organoids in isolated microenvironments at user-defined media flow rates. Programmable workflows allow the use of multiple reagent reservoirs that may be applied to direct differentiation, study temporal variables, and grow cultures long term. Novel techniques in polydimethylsiloxane (PDMS) chip fabrication are described here that enable features on the upper and lower planes of a single PDMS substrate. RNA sequencing (RNA-seq) analysis of automated cerebral cortex organoid cultures shows benefits in reducing glycolytic and endoplasmic reticulum stress compared to conventional in vitro cell cultures. [ABSTRACT FROM AUTHOR]

Simultaneous longitudinal imaging across multiple conditions and replicates has been crucial for scientific studies aiming to understand biological processes and disease. Yet, imaging systems capable of accomplishing these tasks are economically unattainable for most academic and teaching laboratories around the world. Here, we propose the Picroscope, which is the first low-cost system for simultaneous longitudinal biological imaging made primarily using off-the-shelf and 3D-printed materials. The Picroscope is compatible with standard 24-well cell culture plates and captures 3D z-stack image data. The Picroscope can be controlled remotely, allowing for automatic imaging with minimal intervention from the investigator. Here, we use this system in a range of applications. We gathered longitudinal whole organism image data for frogs, zebrafish, and planaria worms. We also gathered image data inside an incubator to observe 2D monolayers and 3D mammalian tissue culture models. Using this tool, we can measure the behavior of entire organisms or individual cells over long-time periods. Ly et al. report a multi-well imaging system (the Picroscope) that can perform longitudinal bright-field z-stack imaging for 24 wells simultaneously. They demonstrate its capability by imaging zebrafish embryos, planaria worms, development of Xenopus tropicalis over a 28-h period and embryonic stem cell monolayer and organoids inside an incubator. [ABSTRACT FROM AUTHOR]

A potentiostat is an essential piece of analytical equipment for studying electrochemical devices and reactions. As the design of electrochemical devices evolve, applications for systems with multiple working electrodes have become more common. These applications drive a need for low-cost multi-channel potentiostat systems. We have developed a portable, low-cost and scalable system with a modular design that can support 8 to 64 channels at a cost as low as $8 per channel. This design can replace the functionality of commercial potentiostats which cost upwards of $10k for certain applications. Each channel in the multi-channel potentiostat has an independent adjustable voltage source with a built-in ammeter and switch, making the device flexible for various configurations. The multi-channel potentiostat is designed for low current applications (nA range), but its purpose can change by varying its shunt resistor value. The system can either function as a standalone device or remotely controlled. We demonstrate the functionality of this system for the control of a 24-channel bioelectronic ion pump for open- and closed- loop control of pH. [ABSTRACT FROM AUTHOR]

Biological materials such as chiton tooth, squid beak, and byssal threads of bivalves have inspired the development of new technologies. To this end, we have characterized the acellular components in the buccal mass of the terrestrial slug Ariolimax californicus (banana slug). These components are the radula, the jaw, and the odontophore. In the radula, calcium-rich denticles are tightly interlocked one to the other on top of a nanofibrous chitin membrane. The jaw has a nanostructured morphology made of chitin to achieve compression resistance and is directly linked to the foregut cuticle, which has a protective nanofibrous structure. Finally, in the odontophore, we observed a structurally elastic microstructure that interfaces soft tissues with a highly stressed radula membrane. Based on those observations, we discuss the interaction between these components and highlight how the materials in these task-specific components have evolved. This structure-properties-function study of the A. californicus’ buccal mass may aid in the design and fabrication of novel bioinspired materials. [ABSTRACT FROM AUTHOR]

Visual design, learning sciences, and nanotechnology may be strange bedfellows; yet, as this paper highlights, peer interaction between a designer and a scientist is an effective method for helping scientists acquire visual design skills. We describe our findings from observing twelve sessions at the Design Help Desk, a tutoring center at the University of Washington. At each session, a scientist (who is expert in his own domain but a novice in design) consulted a designer (who is expert in design but a novice in science) in order to receive advice and guidance on how to improve a scientific visualization. At the Design Help Desk, this pairing consistently produced a momentary disequilibrium in the scientist’s thought process: a disequilibrium that led to agency (where the scientist gained ownership of his/her own learning) and conceptual change in the scientist’s understanding of visual design. Scientists who visited the Design Help Desk were satisfied with their experience, and their published work demonstrated an improved ability to visually communicate research findings—a skill critical to the advancement of science. To our knowledge, the Design Help Desk is a unique effort to educate scientists in visual design; we are not aware of any other design-advice/tutoring centers at public or private universities in the United States or abroad. [ABSTRACT FROM AUTHOR]

Hybrid biotic abiotic devices can be used to interface electronics with biological systems for novel therapies or to increase device functionality beyond silicon. Many strategies exist to merge the electronic and biological worlds, one dominated by electrons and holes as charge carriers, the other by ions. In the biological world, lipid bilayers and ion channels are essential to compartmentalize the cell machinery and regulate ionic fluxes across the cell membrane. Here, we demonstrate a bioelectronic device in which a lipid bilayer supported on H+-conducting Pd/PdHx contacts contains carbon nanotubes porin (CNTP) channels. This bioelectronic device uses CNTPs to control of H+ flow across the lipid bilayer with a voltage applied to the Pd/PdHx contacts. Potential applications of these devices include local pH sensing and control. [ABSTRACT FROM AUTHOR]

Continuous glucose monitoring from sweat and tears can improve the quality of life of diabetic patients and provide data for more accurate diagnosis and treatment. Current continuous glucose sensors use enzymes with a one-to-two week lifespan, which forces periodic replacement. Metal oxide sensors are an alternative to enzymatic sensors with a longer lifetime. However, metal oxide sensors do not operate in sweat and tears because they function at high pH (pH > 10), and sweat and tears are neutral (pH = 7). Here, we introduce a non-enzymatic metal oxide glucose sensor that functions in neutral fluids by electronically inducing a reversible and localized pH change. We demonstrate glucose monitoring at physiologically relevant levels in neutral fluids mimicking sweat, and wireless communication with a personal computer via an integrated circuit board. [ABSTRACT FROM AUTHOR]

Bioelectronic devices that modulate pH can affect critical biological processes including enzymatic activity, oxidative phosphorylation, and neuronal excitability. A major challenge in controlling pH is the high buffering capacity of many biological media. To overcome this challenge, devices need to be able to store and deliver a large number of protons on demand. Here, a bioelectronic modulator that controls pH using palladium nanoparticles contacts with high surface area as a proton storage medium is developed. Reversible electronically triggered acidosis (low pH) and alkalosis (high pH) in physiologically relevant buffer conditions are achieved. As a proof of principle, this new platform is used to control the degradation and fluorescence of acid sensitive polymeric microparticles loaded with a pH sensitive fluorescent dye. A bioelectronic modulator controls pH using palladium nanoparticle contacts as a proton storage medium. This powerful tool achieves reversible electronically triggered acidosis and alkalosis in physiologically relevant buffer conditions. [ABSTRACT FROM AUTHOR]

In article number 1800935, Marco Rolandi and co‐workers present a bioelectronic proton pump based on palladium hydride that changes pH in physiological conditions. [ABSTRACT FROM AUTHOR]

Bioelectronic devices that modulate pH can affect critical biological processes including enzymatic activity, oxidative phosphorylation, and neuronal excitability. A major challenge in controlling pH is the high buffering capacity of many biological media. To overcome this challenge, devices need to be able to store and deliver a large number of protons on demand. Here, a bioelectronic modulator that controls pH using palladium nanoparticles contacts with high surface area as a proton storage medium is developed. Reversible electronically triggered acidosis (low pH) and alkalosis (high pH) in physiologically relevant buffer conditions are achieved. As a proof of principle, this new platform is used to control the degradation and fluorescence of acid sensitive polymeric microparticles loaded with a pH sensitive fluorescent dye. [ABSTRACT FROM AUTHOR]