Brain implants that measure neural magnetic fields, rather than electrical potentials, are expected to confer significant clinical advantages related to implant longevity and signal fidelity due to the elimination of the electrode-tissue interface. However, the informational differences between neural electrical potentials and magnetic fields remain poorly understood. Using a mathematical formalism based on neuronal current sources, we directly establish the complementary informational content of extracellular magnetic fields and electrical potentials. This formalism also reveals that extracellular magnetic fields generated by spiking neurons inherently exhibit one order lower spatial polarity than electric fields, resulting in more favorable distance-scaling characteristics. We then use computational modeling to illustrate how dense networks of neurons are easier to distinguish and spike sort on the basis of their magnetic, rather than electrical, spike templates. Lastly, we show how the solenoidal nature of neural magnetic fields facilitates approximate morphological reconstruction, even with sparse sensor arrays. Our findings highlight the unique experimental advantages of neural magnetic field sensing, motivating the development of compact, low-noise devices capable of meeting the stringent sensitivity requirements for cortical recordings.

Cadaveric islet and stem cell-derived transplantation hold promise as treatments for type 1 diabetes (T1D). To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques that utilize diffusion to transport insulin across an immunoisolating barrier have been developed. However, despite several devices progressing to human clinical trials, none have successfully attained physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with on-demand insulin delivery and physiologic glucose regulation, when solely reliant on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical evidence and experimental validation that applying pressure, at levels comparable to physiological diastolic blood pressure, significantly enhances insulin flux across immunoisolation membranes—increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pumpbased extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation.

Point-of-care (PoC) biomolecular sensing enables rapid diagnosis and prognosis to significantly improve medical accessibility. Wireless electrochemical sensing strategies typically use dedicated RFID or Bluetooth chips for wireless transmission along with a microcontroller and potentiostat to convert chemical signals into electrical outputs. However, integrating chips and multiple active components into a sensor limits its miniaturization, power efficiency, and usage in disposable applications. We therefore propose a minimalistic yet sensitive and efficient sensor design using only one active component: an LED. The LED, paired with a photoresistor, converts currents from analyte concentrations into resistive changes, which are directly transmitted via inductive coupling. This pairing further functions as a buffer, isolating the electrochemical cell from the inductive link for stable wireless transmission. LED and electrochemical cell power is derived from a galvanic cell consisting of a pair of electrodes activated upon contact with bodily fluids. The integrated sensor was characterized with H2O2 measurement and incorporated into a diaper to demonstrate usability by measuring uric acid in artificial urine. The proposed approach to sensor design enables battery-free amperometry to be integrated with chip-free wireless data transmission, a promising step towards cost-effective and disposable electrochemical sensing.

This study explores the potential of utilizing β-cells, exemplified with R7T1 β-cell pseudoislets, as a transplantable cell factory for on-demand recombinant protein therapeutic delivery. While mammalian cell lines are widely used for in vitro protein production, the commonly utilized constitutive secretion pathway poses challenges to in vivo cell therapy, especially for delivering proteins requiring precise exposure kinetics. The proposed approach capitalizes on unique aspects of β -cells, including substantial vesicular protein storage capacity and electrochemically-regulated protein release, to facilitate timely and titratable in vivo therapeutic delivery. Examining a variety of strategies to acheive β-cell glucagon or glucagon-like peptide 1 (GLP-1) storage and secretion, we devised a flexible β-cell-based expression platform for efficient cellular peptide production and on-demand release. This platform utilizes the preproinsulin coding sequence as a template, wherein therapeutic peptides of interest (glucagon or GLP-1) are substituted for C-peptide while the A- and B-peptide insulin chains are mutated to prevent bio-active insulin production. This approach overcomes the challenge of efficient bio-active peptide expression by leveraging the endogenous β -cell peptide expression, translation, processing, storage and secretion machinery. Furthermore, β-cells provide a mechanism for scalable electyrochemnically-triggered peptide delivery. This transformative strategy, which may be extended to other proteins and peptide expression cassettes, holds significant promise for targeted and temporally controlled in vivo production and release of recombinant protein therapeutics. The study suggests potential applications in addressing challenges in metabolic disorders, blood disorders, and oncology. Future refinements may focus on optimizing vector design, peptide production, and in vivo adaptation. ### Competing Interest Statement E. A. T., R. A. L.,, J. P. A., and A.S.Y.P. are co-inventors of a patent covering the work described in the manuscript filed by Stanford.

Conductive gradient hydrogels (CGGs) allow preferential differentiation of human mesenchymal stem cells (hMSCs) toward oligodendrocyte lineage in the center while neuronal lineage at the edge of the scaffold under electrical stimulation.

Cadaveric islet and stem cell-derived transplantations hold promise as treatments for type 1 diabetes. To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques have been developed that utilize diffusion to transport insulin across an immunoisolating barrier. However, despite several devices progressing to human clinical trials, none have successfully managed to attain physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with homeostatic, on-demand insulin delivery and physiologic glucose regulation, when reliant solely on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical proof and experimental validation that applying pressure at levels comparable to physiological diastolic blood pressure significantly enhances insulin flux across immunoisolation membranes-increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pump-based extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, effectively replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation. One Sentence Summary:Towards improved glucose control, applying sub-minute pressure at physiological levels enhances therapeutic insulin transport from macroencapsulated islets.

Wireless passive sensors, being battery-free and simple, are suitable for disposable use across various applications, from tracking food and monitoring the environment to clinical diagnostics. However, their utilization is hampered by the complexity of existing readout techniques and the absence of memory functionality within the sensor. Here, we present a reader technique that can automatically lock to the sensor value wirelessly through inductive coupling, significantly reducing the reader complexity. By integrating a high-frequency audio link and wireless powering, we demonstrate a battery-free and flexible reader. We integrated this reader for wireless temperature logging, which logs temperature data based on the irreversible geometric change of low-melting-point metal during phase transitions, resulting in non-volatile resistance change. As a whole, these results establish the feasibility of a simplistic reader and a passive non-volatile thermistor sensor, opening up new possibilities for disposable and ubiquitous temperature monitoring as well as a range of other applications.

Background:Stroke is one of the most common neurological conditions that often leads to upper limb motor impairments, significantly affecting individuals' quality of life. Rehabilitation strategies are crucial in facilitating post-stroke recovery and improving functional independence. Functional Electrical Stimulation (FES) systems have emerged as promising upper limb rehabilitation tools, offering innovative neuromuscular reeducation approaches. Objective:The main objective of this paper is to provide a comprehensive systematic review of the start-of-the-art functional electrical stimulation (FES) systems for upper limb neurorehabilitation in post-stroke therapy. More specifically, this paper aims to review different types of FES systems, their feasibility testing, or randomized control trials (RCT) studies. Methods:The FES systems classification is based on the involvement of patient feedback within the FES control, which mainly includes "Open-Loop FES Systems" (manually controlled) and "Closed-Loop FES Systems" (brain-computer interface-BCI and electromyography-EMG controlled). Thus, valuable insights are presented into the technological advantages and effectiveness of Manual FES, EEG-FES, and EMG-FES systems. Results and discussion:The review analyzed 25 studies and found that the use of FES-based rehabilitation systems resulted in favorable outcomes for the stroke recovery of upper limb functional movements, as measured by the FMA (Fugl-Meyer Assessment) (Manually controlled FES: mean difference = 5.6, 95% CI (3.77, 7.5), P < 0.001; BCI-controlled FES: mean difference = 5.37, 95% CI (4.2, 6.6), P < 0.001; EMG-controlled FES: mean difference = 14.14, 95% CI (11.72, 16.6), P < 0.001) and ARAT (Action Research Arm Test) (EMG-controlled FES: mean difference = 11.9, 95% CI (8.8, 14.9), P < 0.001) scores. Furthermore, the shortcomings, clinical considerations, comparison to non-FES systems, design improvements, and possible future implications are also discussed for improving stroke rehabilitation systems and advancing post-stroke recovery. Thus, summarizing the existing literature, this review paper can help researchers identify areas for further investigation. This can lead to formulating research questions and developing new studies aimed at improving FES systems and their outcomes in upper limb rehabilitation.

Correction for “Wireless power transfer to deeptissue microimplants,” by John S. Ho, Alexander J. Yeh, Evgenios Neofytou, Sanghoek Kim, Yuji Tanabe, Bhagat Patlolla, Ramin E. Beygui, and Ada S. Y. Poon, which was first published May 19, 2014; 10.1073/ pnas.1403002111 (Proc. Natl. Acad. Sci. U.S.A. 111, 7974–7979). The authors note that their competing interest statement was omitted during publication. The authors declare the following: “J.S.H., A.J.Y., S.K., Y.T., and A.S.Y.P. are the coinventors of a patent covering this study filed by Stanford University. A.J.Y., Y.T., and A.S.Y.P. cofounded Vivonda Medical commercializing wireless powering technology. All the other authors have no competing interests.”

Effective stroke recovery therapeutics remain limited. Stem cell therapies have yielded promising results, but the harsh ischemic environment of the post-stroke brain reduces their therapeutic potential. Previously, we developed a conductive polymer scaffold system that enabled stem cell delivery with simultaneous electrical modulation of the cells and surrounding neural environment. This wired polymer scaffold proved efficacious in optimizing ideal conditions for stem cell mediated motor improvements in a rodent model of stroke. To further enable preclinical studies and enhance translational potential, we identified a method to improve this system by eliminating its dependence upon a tethered power source. We have herein developed a wirelessly powered, electrically conductive polymer system that eases therapeutic application and enables full mobility. As a proof of concept, we demonstrate that the wirelessly powered scaffold is able to stimulate neural stem cells in vitro, as well as in vivo in a rodent model of stroke. This system modulates the stroke microenvironment and increases the production of endogenous stem cells. In summation, this novel, wirelessly powered conductive scaffold can serve as a mobile platform for a wide variety of therapeutics involving electrical stimulation.

EEG recording has been widely used in a variety of applications, including sleep studies, mental health monitoring, brain–computer interfaces (BCIs), etc. However, mainstream clinical recording systems are still tethered with wet electrodes that require special preparation, limiting the setup to well-equipped labs and preventing the collection of longitudinal data. In this article, we summarize the special characteristics of EEG signals and review key circuit design techniques in EEG signal acquisition and data telemetry. With careful system optimization, a wireless distributed recording setup is possible for nonintrusive EEG data collection, which will enable long-term mental health monitoring and other important applications.

Fully passive sensors (FPS) consist of a sensing element $(\mathrm{R}_{\mathrm{s}}$ or $\mathrm{C}_{2}$ in Fig. 1) and an inductor forming an RLC tank. Compared to legacy sensors (NFC, BLE, RFID), FPSs offer a simple chipless solution with battery-free operation and extremely low cost for scenarios such as implantable, biodegradable, biocompatible, and stretchable applications where legacy sensors cannot be deployed. Typically, sensor measurement is performed through near-field inductive coupling (NFIC) of a reader coil to the sensor with the goal of measuring $\mathrm{R}_{\mathrm{s}}$ or $\mathrm{C}_{2}$ (Fig. 1). Unlike the sensor, the reader remains the bottleneck due to its large size, high power consumption and distance-dependency of the results due to NFIC and may require extensive calibration. As such, existing readers [1]–[4] are not well-suited for handheld low-power operation with non-fixed readout distance. We utilize the properties of coupled resonators and a dual-mode LC-VCO as the reader to address the challenges discussed above for resistive FPS measurement.

Fully passive sensors (FPS) are widely used as a simple and inexpensive alternative of their active counterparts in many applications. However, measurement of FPSs relies on extremely bulky and complicated reader circuitry. In some cases the readout method depends on measurement distance. In this paper, we propose a readout technique based on a two-mode LC-oscillator formed with two coupled resonators, i.e., the FPS and the LC tank in the reader. We show that such a configuration can offer robust measurement of fully passive resistive and capacitive sensors provided that the system operates under strong coupling. We examine measurement errors due to non-idealities of the system (finite coil Q and frequency mismatch) and provide design guidelines to ameliorate these unwanted effects. Although applied to sensing in this work, this analysis can be extended to wireless power transfer and impedance transformation.

Current clinical brain tumour therapy practices are based on tumour resection and post-operative chemotherapy or X-ray radiation. Resection requires technically challenging open-skull surgeries that can lead to major neurological deficits and, in some cases, death. Treatments with X-ray and chemotherapy, on the other hand, cause major side-effects such as damage to surrounding normal brain tissues and other organs. Here we report the development of an integrated nanomedicine-bioelectronics brain-machine interface that enables continuous and on-demand treatment of brain tumours, without open-skull surgery and toxicological side-effects on other organs. Near-infrared surface plasmon characteristics of our gold nanostars enabled the precise treatment of deep brain tumours in freely behaving mice. Moreover, the nanostars' surface coating enabled their selective diffusion in tumour tissues after intratumoral administration, leading to the exclusive heating of tumours for treatment. This versatile remotely controlled and wireless method allows the adjustment of nanoparticles' photothermal strength, as well as power and wavelength of the therapeutic light, to target tumours in different anatomical locations within the brain.

This work presents a penny-sized 1.2-gram (battery included) wearable wireless EEG recorder for continuous long-term mental health monitoring. Each device has two 12-bit Σ-Δ ADCs with 9.4-bit peak ENOB. With 12-channel FDMA transmitter (TX) in the 902-928MHz ISM band, concurrent untethered recording can be achieved at 24 sites. 90µW power consumption enables month-long battery life with a size-10 hearing-aid battery. System functionality has been validated by comparing with clinical-grade instrument in measurements of both eye-closed alpha wave and event-related potential (ERP).

Pathogenic INS gene mutations are causative for mutant INS-gene-induced diabetes of youth (MIDY). We characterize a novel de novo heterozygous INS gene mutation (c.289A>C, p.T97P) that presented in an autoantibody-negative 5-month-old male infant with severe diabetic ketoacidosis. In silico pathogenicity prediction tools provided contradictory interpretations, while structural modeling indicated a deleterious effect on proinsulin folding. Transfection of wildtype and INS p.T97P expression and luciferase reporter constructs demonstrated elevated intracellular mutant proinsulin levels and dramatically impaired proinsulin/insulin and luciferase secretion. Notably, proteasome inhibition partially and selectively rescued INS p.T97P-derived luciferase secretion. Additionally, expression of INS p.T97P caused increased intracellular proinsulin aggregate formation and XBP-1s protein levels, consistent with induction of endoplasmic reticulum stress. We conclude that INS p.T97P is a newly identified pathogenic A-chain variant that is causative for MIDY via disruption of proinsulin folding and processing with induction of the endoplasmic reticulum stress response.

A wireless dual-channel potentiostat is fabricated in TSMC 40-nm CMOS and integrated in a mouthguard format for continuous salivary biosensing of glucose and lactate. Continuous glucose monitoring is required for closed-loop insulin dosing in Type 1 Diabetes. Continuous lactate sensing could improve closed-loop control, by serving as a biomarker of exercise, to help prevent life threatening hypoglycemia. Saliva is an ideal sensing fluid as it is readily and non-invasively available. Glucose sensing range is < 0.6 mM with sensitivity of 2.4 µM and lactate sensing range is < 2 mM with sensitivity of 1.6 µM. Data from both channels is packetized for simultaneous transmission over the 902–928 MHz ISM band. Nominal power is 100 µW, which would allow for operation on a size-10 hearing aid battery for > 1 month.

The identification of non-canonical UCP1-independent thermogenic mechanisms offers new opportunities to target such pathways to improve metabolic health. Based on our recent studies on Ca2+ futile cycling thermogenesis in beige fat, we applied the newly developed implantable wireless optogenetic system to activate Ca2+ cycling in an adipocyte-specific manner without external stimuli, i.e., fat-specific cold mimetics. Here, we describe the detailed methodology and application to the prevention of obesity.

Abstract The rapid growth and development of technology has had significant implications for healthcare, personalized medicine, and our understanding of biology. In this work, we leverage the miniaturization of electronics to realize the first demonstration of wireless detection and communication of an electronic device inside a cell. This is a significant forward step towards a vision of non-invasive, intracellular wireless platforms for single-cell analyses. We demonstrate that a 25 $$\upmu $$ μ m wireless radio frequency identification (RFID) device can not only be taken up by a mammalian cell but can also be detected and specifically identified externally while located intracellularly. The S-parameters and power delivery efficiency of the electronic communication system is quantified before and after immersion in a biological environment; the results show distinct electrical responses for different RFID tags, allowing for classification of cells by examining the electrical output noninvasively. This versatile platform can be adapted for realization of a broad modality of sensors and actuators. This work precedes and facilitates the development of long-term intracellular real-time measurement systems for personalized medicine and furthering our understanding of intrinsic biological behaviors. It helps provide an advanced technique to better assess the long-term evolution of cellular physiology as a result of drug and disease stimuli in a way that is not feasible using current methods.

In this chapter, first a distinction is made between forced (or controlled) oscillating systems, which require an external source to tune or sweep the amplitude and/or frequency of oscillation, and self-oscillating systems that can reach a steady-state oscillation on their own. Next, the chapter discusses the respective measurement methods of such systems, starting with those using a nonresonant primary. Then, methods that add either a forced resonator or oscillator to the reader are detailed; as the forced reader is tuned across a frequency range, changes in the frequency response are monitored as a means of sensing. The chapter provides a system-by-system comparison for the reader in terms of both sensitivity of the system to small coupling strengths and complexity of measurement. Finally, it concludes with some future directions in this area including more real-time approaches that preclude the need for tuning/sweeping and sensing using other different sensor modalities.