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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]

Hydrogels have become the material of choice in bioelectronic devices because their high‐water content leads to efficient ion transport and a conformal interface with biological tissue. While the morphology of hydrogels has been thoroughly studied, systematical studies on their ionic conductivity are less common. Here, an easy‐to‐implement strategy is presented to characterize the ionic conductivity of a series of polyelectrolyte hydrogels with different amounts of monomer and crosslinker and correlate their ionic conductivity with microstructure. Higher monomer increases the ionic conductivity of the polyelectrolyte hydrogel due to the increased charge carrier density, but also leads to excessive swelling that may cause device failure upon integration with bioelectronic devices. Increasing the amount of crosslinker can reduce the swelling ratio by increasing the crosslinking density and reducing the mesh size of the hydrogel, which cuts down the ionic conductivity. Further investigation on the porosity and tortuosity of the swollen hydrogels correlates the microstructure with the ionic conductivity. These results are generalizable for various polyelectrolyte hydrogel systems with other ions as the charge carrier and provide facile guidance to design polyelectrolyte hydrogel with desired ionic conductivity and microstructure for applications in bioelectronic devices. [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]

Bioelectronic ion pumps deliver ions and biomolecules from a source to a target biological system with high spatiotemporal control for bioengineering and regenerative medicine applications. A voltage between a working electrode and a reference/counter electrode delivers the charged ions and biomolecules from a source to the desired target. The source and the target are separated by an ion exchange membrane so that only the charged molecules of interest are delivered. Future wearable and implantable applications require high efficiency of delivery to minimize power consumption. The majority of recent efforts on improving ion pump efficiency have focused on optimizing the ion exchange membrane. However, the contribution of the working electrode material to the ion pump efficiency has been mostly overlooked. This work identifies how changing the working electrode material greatly affects the efficiency of delivery in ion pumps. With an electrical circuit model analysis, voltammetry studies on silver, platinum, and palladium hydride working electrodes, and implementation of the Butler–Volmer equation, results show that the material‐dependent equilibrium potential at the working electrode surface has a large impact on ion pump efficiency. With this knowledge, a simple predictive model to optimize the working electrode material for delivering each specific ion or molecule of interest is designed. [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]

In article number 2100687 by Marco Rolandi and co-workers, the ionic conductivity and microstructure of a series of polyelectrolyte hydrogels are investigated to provide simple guidance for hydrogel design. B Front Cover b : Polyelectrolyte hydrogels have received increasing attention in bioelectronics because they allow ion transport and form a conformal interface with biological tissue. [Extracted from the article]

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]

[Display omitted] • Morphology and composition of an internal shell have been studied for the first time. • The internal shell is organized in layers that control calcite nucleation and growth. • Diverse morphologies of calcite crystals were observed on the two pages of the shell. • The two faces of the shell might act as short- and long- term calcium reserve. A slug is a shell-less terrestrial gastropod mollusk. During evolution, slugs have lost their mineralized external shell but some of them have retained an internal shell (IS). Unlike external shells, which have been widely investigated, the ISs have been poorly studied. We report for the first time the compositional and complete morphological characterization of Ariolimax californicus' IS. According to literature, this shell calcifies and decalcifies depending on the animal's needs. Its composition is mostly organic, consisting of proteins and β-chitin. The internal shell is organized in layers and membranes in which CaCO 3 crystal formation occurs in specific areas. In the two faces of the IS we observed different morphologies and aggregations of calcite bio-crystals along with a different organization of the organic matrix. Dorsally, the mineral forms a thick layer composed of misaligned crystal aggregates of large dimensions, separated by thin organic layers. This suggests a protective purpose and the use of this layer as a long-term calcium storage system. Ventrally, the mineral phase is organized in small crystal aggregates of comparable size, separated by thin organic layers, and quite aligned one to the other. The whole ventral mineral layer is covered by a membrane, identified as the hypostracum. This face is proposed to be a short-term calcium storage system. In vitro crystallization experiments suggest massive calcium ions sequestration from the solution for the precipitation of calcite crystals inside the organic matrix. In conclusion, this research provides new information on the dynamic of biomineralization on mollusk evolved in calcium-poor environments. [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]

The top working electrode (WE) interfaces with the source solution, while the bottom reference/counter electrode (RE/CE) interfaces with the target solution. Bioelectronics, electrode materials, ion delivery, ion pumps, ions and biomolecules Keywords: bioelectronics; electrode materials; ion delivery; ion pumps; ions and biomolecules EN bioelectronics electrode materials ion delivery ion pumps ions and biomolecules 1 1 1 07/14/23 20230710 NES 230710 B Bioelectronic Ion Pumps b An example of an ion pump for delivering therapeutic ions and biomolecules is demonstrated in article 2201996, by Marco Rolandi and co-workers. [Extracted from the article]