Conductive gradient hydrogels allow spatial control of adult stem cell fate.

Electrical gradients are fundamental to physiological processes including cell migration, tissue formation, organ development, and response to injury and regeneration. Current electrical modulation of cells is primarily studied under a uniform electrical field. Here we demonstrate the fabrication of conductive gradient hydrogels (CGGs) that display mechanical properties and varying local electrical gradients mimicking physiological conditions. The electrically-stimulated CGGs enhanced human mesenchymal stem cell (hMSC) viability and attachment. Cells on CGGs under electrical stimulation showed a high expression of neural progenitor markers such as Nestin, GFAP, and Sox2. More importantly, CGGs showed cell differentiation toward oligodendrocyte lineage (Oligo2) in the center of the scaffold where the electric field was uniform with a greater intensity, while cells preferred neuronal lineage (NeuN) on the edge of the scaffold on a varying electric field at lower magnitude. Our data suggest that CGGs can serve as a useful platform to study the effects of electrical gradients on stem cells and potentially provide insights on developing new neural engineering applications.

Wirelessly Powered-Electrically Conductive Polymer System for Stem Cell Enhanced Stroke Recovery.

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.

Pressure-Driven Insulin Release Overcomes Limitations of Diffusion for Encapsulated Islet Cell Therapy.

Cadaveric islet and stem cell-derived transplantation show great promise as therapeutic approaches for type 1 diabetes. To address the immunocompatibility challenge, numerous cellular macroencapsulation techniques, which rely upon diffusion to transport insulin across the immunoprotective barrier, have been proposed. Although several of these devices were advanced to human clinical trials, they uniformly failed to achieve physiologic glucose control or insulin independence. Indeed, based upon mathematical modeling and empiric evidence, diffusion-based encapsulation devices are fundamentally incompatible with homeostatic on-demand insulin delivery and physiologic glucose regulation. To realize the potential of achieving insulin independence through macroencapsulated cell-based therapy, we propose the necessity of a second driving force. Herein, we provide both theoretical proof and experimental demonstration that modest (11-kPa) micropump-applied pressure considerably enhances insulin flux across immunoisolation membranes by nearly three orders of magnitude, enabling precise delivery of both bolus and basal insulin. Furthermore, pressure-driven insulin efflux from encapsulated mouse and human islets is fast and repeatable. As such, we urge caution against further advancement of diffusion-based immune-isolating macroencapsulation devices that do not incorporate a secondary driving force for precise temporal regulation of peptide delivery. One Sentence Summary: Diffusion-based insulin delivery from macroencapsulated islet cells is incompatible with physiologic glucose control, a constraint addressed through pressure-based insulin delivery.

Remotely controlled near-infrared-triggered photothermal treatment of brain tumours in freely behaving mice using gold nanostars.

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.

Activation of UCP1-Independent Ca2+ Cycling Thermogenesis by Wireless Optogenetics.

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.

Novel Pathogenic De Novo INS p.T97P Variant Presenting With Severe Neonatal DKA.

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.

High-specific-power flexible transition metal dichalcogenide solar cells.

Semiconducting transition metal dichalcogenides (TMDs) are promising for flexible high-specific-power photovoltaics due to their ultrahigh optical absorption coefficients, desirable band gaps and self-passivated surfaces. However, challenges such as Fermi-level pinning at the metal contact-TMD interface and the inapplicability of traditional doping schemes have prevented most TMD solar cells from exceeding 2% power conversion efficiency (PCE). In addition, fabrication on flexible substrates tends to contaminate or damage TMD interfaces, further reducing performance. Here, we address these fundamental issues by employing: (1) transparent graphene contacts to mitigate Fermi-level pinning, (2) MoOx capping for doping, passivation and anti-reflection, and (3) a clean, non-damaging direct transfer method to realize devices on lightweight flexible polyimide substrates. These lead to record PCE of 5.1% and record specific power of 4.4 W g-1 for flexible TMD (WSe2) solar cells, the latter on par with prevailing thin-film solar technologies cadmium telluride, copper indium gallium selenide, amorphous silicon and III-Vs. We further project that TMD solar cells could achieve specific power up to 46 W g-1, creating unprecedented opportunities in a broad range of industries from aerospace to wearable and implantable electronics.

Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis.

Cold stimuli and the subsequent activation of ß-adrenergic receptor (ß-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the ß3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the ß-AR pathway and triggers Ca2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.

Optimization of Sine-Wave Clocking for High-Frequency AC-DC Conversion.

Wireless energy harvesting devices convert received AC energy into DC voltages suitable to power the back-end functionality of the devices. The low energy available to the devices require high AC-DC conversion efficiency in order for enough power to be delivered to the load. This paper presents a model to characterize loss through charge pump cells in wireless energy harvesting devices. The proposed model includes the time-domain effects of the input radio-frequency (RF) energy wave and provides additional insight into how clock and switch parameters along with architecture considerations can be used to improve the efficiency of AC-DC conversion. Results are verified using simulation in a 0.18-µm CMOS technology. We show the impact of threshold voltage on reverse conduction and the limitations on increasing transistor switch sizes to support high current loads. Design examples use the presented model to optimize design parameters to decrease loss in the charge pump. We compare the performance between sine-wave and square-wave clocked charge pumps to show the trade-off between charge pump loss and clock generation power consumption. Furthermore, the benefits of easily computing architectural changes is demonstrated using the proposed model showing how the calculated equivalent resistance can be used to determine the benefits of mixed-mode clocking.

Conformal phased surfaces for wireless powering of bioelectronic microdevices.

Wireless powering could enable the long-term operation of advanced bioelectronic devices within the human body. Although both enhanced powering depth and device miniaturization can be achieved by shaping the field pattern within the body, existing electromagnetic structures do not provide the spatial phase control required to synthesize such patterns. Here, we describe the design and operation of conformal electromagnetic structures, termed phased surfaces, that interface with non-planar body surfaces and optimally modulate the phase response to enhance the performance of wireless powering. We demonstrate that the phased surfaces can wirelessly transfer energy across anatomically heterogeneous tissues in large animal models, powering miniaturized semiconductor devices (<12 mm3) deep within the body (>4 cm). As an illustration of in vivo operation, we wirelessly regulated cardiac rhythm by powering miniaturized stimulators at multiple endocardial sites in a porcine animal model.

High-performance wireless powering for peripheral nerve neuromodulation systems.

Neuromodulation of peripheral nerves with bioelectronic devices is a promising approach for treating a wide range of disorders. Wireless powering could enable long-term operation of these devices, but achieving high performance for miniaturized and deeply placed devices remains a technological challenge. We report the miniaturized integration of a wireless powering system in soft neuromodulation device (15 mm length, 2.7 mm diameter) and demonstrate high performance (about 10%) during in vivo wireless stimulation of the vagus nerve in a porcine animal model. The increased performance is enabled by the generation of a focused and circularly polarized field that enhances efficiency and provides immunity to polarization misalignment. These performance characteristics establish the clinical potential of wireless powering for emerging therapies based on neuromodulation.

A Millimeter-Wave Digital Link for Wireless MRI.

A millimeter (mm) wave radio is presented in this work to support wireless MRI data transmission. High path loss and availability of wide bandwidth make mm-waves an ideal candidate for short range, high data rata communication required for wireless MRI. The proposed system uses a custom designed integrated chip (IC) mm-wave radio with 60 GHz as radio frequency carrier. In this work, we assess performance in a 1.5 T MRI field, with the addition of optical links between the console room and magnet. The system uses ON-OFF keying (OOK) modulation for data transmission and supports data rates from 200 Mb/s to 2.5 Gb/s for distances up-to 65 cm. The presence of highly directional, linearly polarized, on-chip dipole antennas on the mm-wave radio along with the time division multiplexing (TDM) circuitry allows multiple wireless links to be created simultaneously with minimal inter-channel interference. This leads to a highly scalable solution for wireless MRI.

Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice.

To enable sophisticated optogenetic manipulation of neural circuits throughout the nervous system with limited disruption of animal behavior, light-delivery systems beyond fiber optic tethering and large, head-mounted wireless receivers are desirable. We report the development of an easy-to-construct, implantable wireless optogenetic device. Our smallest version (20 mg, 10 mm(3)) is two orders of magnitude smaller than previously reported wireless optogenetic systems, allowing the entire device to be implanted subcutaneously. With a radio-frequency (RF) power source and controller, this implant produces sufficient light power for optogenetic stimulation with minimal tissue heating (<1 °C). We show how three adaptations of the implant allow for untethered optogenetic control throughout the nervous system (brain, spinal cord and peripheral nerve endings) of behaving mice. This technology opens the door for optogenetic experiments in which animals are able to behave naturally with optogenetic manipulation of both central and peripheral targets.

Wireless power transfer to deep-tissue microimplants.

The ability to implant electronic systems in the human body has led to many medical advances. Progress in semiconductor technology paved the way for devices at the scale of a millimeter or less ("microimplants"), but the miniaturization of the power source remains challenging. Although wireless powering has been demonstrated, energy transfer beyond superficial depths in tissue has so far been limited by large coils (at least a centimeter in diameter) unsuitable for a microimplant. Here, we show that this limitation can be overcome by a method, termed midfield powering, to create a high-energy density region deep in tissue inside of which the power-harvesting structure can be made extremely small. Unlike conventional near-field (inductively coupled) coils, for which coupling is limited by exponential field decay, a patterned metal plate is used to induce spatially confined and adaptive energy transport through propagating modes in tissue. We use this method to power a microimplant (2 mm, 70 mg) capable of closed-chest wireless control of the heart that is orders of magnitude smaller than conventional pacemakers. With exposure levels below human safety thresholds, milliwatt levels of power can be transferred to a deep-tissue (>5 cm) microimplant for both complex electronic function and physiological stimulation. The approach developed here should enable new generations of implantable systems that can be integrated into the body at minimal cost and risk.

Mass fabrication and delivery of 3D multilayer µTags into living cells.

Continuous monitoring of in vivo biological processes and their evolution at the cellular level would enable major advances in our understanding of biology and disease. As a stepping stone towards chronic cellular monitoring, we demonstrate massively parallel fabrication and delivery of 3D multilayer micro-Tags (µTags) into living cells. Both 10 µm × 10 µm × 1.5 µm and 18 µm × 7 µm × 1.5 µm devices containing inductive and capacitive structures were designed and fabricated as potential passive radio-frequency identification tags. We show cellular internalization and persistence of µTags over a 5-day period. Our results represent a promising advance in technologies for studying biology and disease at the cellular level.

Midfield wireless powering of subwavelength autonomous devices.

We obtain an analytical bound on the efficiency of wireless power transfer to a weakly coupled device. The optimal source is solved for a multilayer geometry in terms of a representation based on the field equivalence principle. The theory reveals that optimal power transfer exploits the properties of the midfield to achieve efficiencies far greater than conventional coil-based designs. As a physical realization of the source, we present a slot array structure whose performance closely approaches the theoretical bound.

A mm-sized wirelessly powered and remotely controlled locomotive implant.

A wirelessly powered and controlled implantable device capable of locomotion in a fluid medium is presented. Two scalable low-power propulsion methods are described that achieve roughly an order of magnitude better performance than existing methods in terms of thrust conversion efficiency. The wireless prototype occupies 0.6 mm × 1 mm in 65 nm CMOS with an external 2 mm × 2 mm receive antenna. The IC consists of a matching network, a rectifier, a bandgap reference, a regulator, a demodulator, a digital controller, and high-current drivers that interface directly with the propulsion system. It receives 500 µW from a 2 W 1.86 GHz power signal at a distance of 5 cm. Asynchronous pulse-width modulation on the carrier allows for data rates from 2.5-25 Mbps with energy efficiency of 0.5 pJ/b at 10 Mbps. The received data configures the propulsion system drivers, which are capable of driving up to 2 mA at 0.2 V and can achieve speed of 0.53 cm/sec in a 0.06 T magnetic field.

Miniaturization of implantable wireless power receiver.

Implantable medical devices will play an important role in modern medicine. To reduce the risk of wire snapping, and replacement and corrosion of embedded batteries, wireless delivery of energy to these devices is desirable. However, current autonomous implants remain large in scale due to the operation at very low frequency and the use of unwieldy size of antennas. This paper will show that the optimal frequency is about 2 orders of magnitude higher than the conventional wisdom; and thereby the power receiving coils can be reduced by more than 100 fold without sacrificing either power efficiency or range. We will show that a mm-sized implant can receive 100's microW of power under safety constraints. This level of power transfer is sufficient to enable many functionalities into the micro-implants for clinical applications.

Locomotive micro-implant with active electromagnetic propulsion.

An active locomotive technique requiring only an external power source and a static magnetic field is presented, and its operation is analyzed and simulated. For a modest static MRI magnetic field of 1 T, the results show that a 1-mm cube achieves roughly 3 cm/sec of lateral motion using less than 20.4 microW of power. Current-carrying wires generate the forces, resulting in highly controllable motion. Existing solutions trade off size and power: passive solutions are small but impractical, and mechanical solutions are inefficient and large. The presented solution captures the advantages of both systems, and has much better scalability.

Optimal operating frequency in wireless power transmission for implantable devices.

This paper examines short-range wireless powering for implantable devices and shows that existing analysis techniques are not adequate to conclude the characteristics of power transfer efficiency over a wide frequency range. It shows, theoretically and experimentally, that the optimal frequency for power transmission in biological media can be in the GHz-range while existing solutions exclusively focus on the MHz-range. This implies that the size of the receive coil can be reduced by 10(4) times which enables the realization of fully integrated implantable devices.