Delivering biochemicals with precision using bioelectronic devices enhanced with feedback control.

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.

A system for bioelectronic delivery of treatment directed toward wound healing.

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[Formula: see text] 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[Formula: see text]-treated wounds compared with control wounds, indicating the potential of the platform to improve wound healing.

Picroscope: low-cost system for simultaneous longitudinal biological imaging.

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.

The multi-channel potentiostat: Development and evaluation of a scalable mini-potentiostat array for investigating electrochemical reaction mechanisms.

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.

A Microfluidic Ion Sensor Array.

A balanced concentration of ions is essential for biological processes to occur. For example, [H+ ] gradients power adenosine triphosphate synthesis, dynamic changes in [K+ ] and [Na+ ] create action potentials in neuronal communication, and [Cl- ] contributes to maintaining appropriate cell membrane voltage. Sensing ionic concentration is thus important for monitoring and regulating many biological processes. This work demonstrates an ion-selective microelectrode array that simultaneously and independently senses [K+ ], [Na+ ], and [Cl- ] in electrolyte solutions. To obtain ion specificity, the required ion-selective membranes are patterned using microfluidics. As a proof of concept, the change in ionic concentration is monitored during cell proliferation in a cell culture medium. This microelectrode array can easily be integrated in lab-on-a-chip approaches to physiology and biological research and applications.

A non-enzymatic glucose sensor enabled by bioelectronic pH control.

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.

A Soft Exosuit for Flexible Upper-Extremity Rehabilitation.

For stroke survivors and many other people with upper-extremity impairment, daily life can be difficult without properly functioning arms. Some modern physical therapy exercises focus on rehabilitating people with these troubles by correcting patients' perceptions of their own body to eventually regain complete control and strength over their arms again. Augmentative wearable robots, such as the upper-extremity exoskeletons and exosuits, may be able to assist in this endeavor. A common drawback in many of these exoskeletons, however, is their inability to conform to the natural flexibility of the human body without a rigid base. We have built one such exosuit to address this challenge: Compliant Robotic Upper-extremity eXosuit (CRUX). This robot is a compliant, lightweight, multi-DoF, portable exosuit that affords its wearer the ability to augment themselves in many unconventional settings (i.e. outside of a clinic). These attributes are largely achieved by using a modified tensegrity design situated according to measured lines of minimal-extension, where a network of tension members provide a foundation to apply augmentative forces via precisely placed power-lines. In this paper, we detail the design process of CRUX, the report on CRUX's prototypical composition, and describe the mimetic control algorithm used. We also discuss the results of three studies that illustrate the efficacy of CRUX's mimetic controller, CRUX's flexibility and compliance, and the metabolic cost reduction when users exercise with assistance from CRUX as opposed to without. We conclude this paper with a summary of our findings, potential use cases for this technology, and the direction of future related work.

CRUX: A compliant robotic upper-extremity exosuit for lightweight, portable, multi-joint muscular augmentation.

Wearable robots can potentially offer their users enhanced stability and strength. These augmentations are ideally designed to actuate harmoniously with the user's movements and provide extra force as needed. The creation of such robots, however, is particularly challenging due to the underlying complexity of the human body. In this paper, we present a compliant, robotic exosuit for upper extremities called CRUX. This exosuit, inspired by tensegrity models of the human arm, features a lightweight (1.3 kg), flexible multi-joint design for portable augmentation. We also illustrate how CRUX maintains the full range of motion of the upper-extremities for its users while providing multi-DoF strength amplification to the major muscles of the arm, as evident by tracking the heart rate of an individual exercising said arm. Exosuits such as CRUX may be useful in physical therapy and in extreme environments where users are expected to exert their bodies to the fullest extent.