SENTRI: Single-Particle Energy Transducer for Radionuclide Injections for Personalized Targeted Radionuclide Cancer Therapy.

PURPOSE: Targeted radionuclide therapy (TRT), whereby a tumor-targeted molecule is linked to a therapeutic beta- or alpha-emitting radioactive nuclide, is a promising treatment modality for patients with metastatic cancer, delivering radiation systemically. However, patients still progress due to suboptimal dosing, driven by the large patient-to-patient variability. Therefore, the ability to continuously monitor the real-time dose deposition in tumors and organs at risk provides an additional dimension of information during clinical trials that can enable insights into better strategies to personalize TRT. METHODS AND MATERIALS: Here, we present a single beta-particle sensitive dosimeter consisting of a 0.27-mm3 monolithic silicon chiplet directly implanted into the tumor. To maximize the sensitivity and have enough detection area, minimum-size diodes (1 µm2) are arrayed in 64 × 64. Signal amplifiers, buffers, and on-chip memories are all integrated in the chip. For verification, PC3-PIP (prostate-specific membrane antigen [PSMA]+) and PC3-flu (PSMA-) cell lines are injected into the left and right flanks of the mice, respectively. The devices are inserted into each tumor and measure activities at 5 different time points (0-2 hours, 7-9 hours, 12-14 hours, 24-26 hours, and 48-50 hours) after 177Lu-PSMA-617 injections. Single-photon emission computed tomography/computed tomography scans are used to verify measured data. RESULTS: With a wide detection range from 0.013 to 8.95 MBq/mL, the system is capable of detecting high tumor uptake as well as low doses delivered to organs at risk in real time. The measurement data are highly proportional (R2 > 0.99) to the 177Lu-PSMA-617 activity. The in vivo measurement data agree well with the single-photon emission computed tomography/computed tomography results within acceptable errors (±1.5%ID/mL). CONCLUSIONS: Given the recent advances in clinical use of TRT in prostate cancer, the proposed system is verified in a prostate cancer mouse model using 177Lu-PSMA-617.

Translational opportunities and challenges of invasive electrodes for neural interfaces.

Invasive brain-machine interfaces can restore motor, sensory and cognitive functions. However, their clinical adoption has been hindered by the surgical risk of implantation and by suboptimal long-term reliability. In this Review, we highlight the opportunities and challenges of invasive technology for clinically relevant electrophysiology. Specifically, we discuss the characteristics of neural probes that are most likely to facilitate the clinical translation of invasive neural interfaces, describe the neural signals that can be acquired or produced by intracranial electrodes, the abiotic and biotic factors that contribute to their failure, and emerging neural-interface architectures.

Piezoelectric-based optical modulator for miniaturized wireless medical implants.

Optical links for medical implants have recently been explored as an attractive option primarily because it provides a route to ultrasmall wireless implant systems. Existing devices for optical communication either are not CMOS compatible, require large bias voltages to operate, or consume substantial amounts of power. Here, we present a high-Q CMOS-compatible electro-optic modulator that enables establishing an optical data uplink to implants. The modulator acts as a pF-scale capacitor, requires no bias voltage, and operates at CMOS voltages of down to 0.5V. We believe this technology would provide a path towards the realization of millimeter (mm)- and sub-mm scale wireless implants for use in bio-sensing applications.

Wireless Measurements Using Electrical Impedance Spectroscopy to Monitor Fracture Healing.

There is an unmet need for improved, clinically relevant methods to longitudinally quantify bone healing during fracture care. Here we develop a smart bone plate to wirelessly monitor healing utilizing electrical impedance spectroscopy (EIS) to provide real-time data on tissue composition within the fracture callus. To validate our technology, we created a 1-mm rabbit tibial defect and fixed the bone with a standard veterinary plate modified with a custom-designed housing that included two impedance sensors capable of wireless transmission. Impedance magnitude and phase measurements were transmitted every 48 h for up to 10 weeks. Bone healing was assessed by X-ray, µCT, and histology. Our results indicated the sensors successfully incorporated into the fracture callus and did not impede repair. Electrical impedance, resistance, and reactance increased steadily from weeks 3 to 7-corresponding to the transition from hematoma to cartilage to bone within the fracture gap-then plateaued as the bone began to consolidate. These three electrical readings significantly correlated with traditional measurements of bone healing and successfully distinguished between union and not-healed fractures, with the strongest relationship found with impedance magnitude. These results suggest that our EIS smart bone plate can provide continuous and highly sensitive quantitative tissue measurements throughout the course of fracture healing to better guide personalized clinical care.

Columnar Localization and Laminar Origin of Cortical Surface Electrical Potentials.

Electrocorticography (ECoG) methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. To address this gap, we recorded from rat auditory cortex using customized µECoG, and simulated cortical surface electrical potentials with a full-scale, biophysically detailed cortical column model. Experimentally, µECoG-derived auditory representations were tonotopically organized and signals were anisotropically localized to less than or equal to ±200 µm, that is, a single cortical column. Biophysical simulations reproduce experimental findings and indicate that neurons in cortical layers V and VI contribute ∼85% of evoked high-gamma signal recorded at the surface. Cell number and synchrony were the primary biophysical properties determining laminar contributions to evoked µECoG signals, whereas distance was only a minimal factor. Thus, evoked µECoG signals primarily originate from neurons in the infragranular layers of a single cortical column.SIGNIFICANCE STATEMENT ECoG methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. We investigated the localization and origins of sensory-evoked ECoG responses. We experimentally found that ECoG responses were anisotropically localized to a cortical column. Biophysically detailed simulations revealed that neurons in layers V and VI were the primary sources of evoked ECoG responses. These results indicate that evoked ECoG high-gamma responses are primarily generated by the population spike rate of pyramidal neurons in layers V and VI of single cortical columns and highlight the possibility of understanding how microscopic sources produce mesoscale signals.

Optical voltage sensor based on a piezoelectric thin film for grid applications.

Continuous monitoring of voltages ranging from tens to hundreds of kV over environmental conditions, such as temperature, is of great interest in power grid applications. This is typically done via instrument transformers. These transformers, although accurate and robust to environmental conditions, are bulky and expensive, limiting their use in microgrids and distributed sensing applications. Here, we present a millimeter-sized optical voltage sensor based on piezoelectric aluminum nitride (AlN) thin film for continuous measurements of AC voltages <350kVrms (via capacitive division) that avoids the drawbacks of existing voltage-sensing transformers. This sensor operated with 110µW incident optical power from a low-cost LED achieved a resolution of 170mVrms in a 5kHz bandwidth, 0.04% second harmonic distortion, and a gain deviation of +/-0.2% over the temperature range of ~20-60°C. The sensor has a breakdown voltage of 100V, and its lifetime can meet or exceed that of instrument transformers when operated at voltages <70kVrms with capacitive division. We believe that our sensor has the potential to reduce the cost of grid monitoring, providing a path towards more distributed sensing and control of the grid.

A Method and Analysis to Enable Efficient Piezoelectric Transducer-Based Ultrasonic Power and Data Links for Miniaturized Implantable Medical Devices.

Acoustic links for implantable medical devices (implants) have gained attention primarily because they provide a route to wireless deep-tissue systems. The miniaturization of the implants is a key research goal in these efforts, nominally because smaller implants result in less acute tissue damage. Implant size in most acoustic systems is limited by the piezoelectric bulk crystal used for power harvesting and data communication. Further miniaturization of the piezocrystal can degrade system power transfer efficiency and data transfer reliability. Here, we present a new method for packaging the implant piezocrystal; the method maximizes power transfer efficiency ( η ) from the acoustic power at the piezo surface to the power delivered to the electrical load and information transfer across the acoustic link. Our method relies on placing piezo-to-substrate anchors to the piezo regions where the vibrational displacement of the mode of interest is zero. To evaluate our method, we investigated packaged 1×1×1 mm3 piezocrystals assembled with different sized anchors. Our results show that reducing the anchor size decreases anchor loss and thus improves piezo quality factor (Q). We also demonstrate that this method improves system electromechanical coupling. A strongly coupled, high-Q piezo with properly sized and located anchors is demonstrated to achieve significantly higher η and superior data transfer capability at resonance. Overall, this work provides an analysis and generic method for packaging the implant piezocrystal that enables the design of efficient acoustic power and data links, which provides a path toward the further miniaturization of ultrasonic implants to submillimeter scales.

Monitoring deep-tissue oxygenation with a millimeter-scale ultrasonic implant.

Vascular complications following solid organ transplantation may lead to graft ischemia, dysfunction or loss. Imaging approaches can provide intermittent assessments of graft perfusion, but require highly skilled practitioners and do not directly assess graft oxygenation. Existing systems for monitoring tissue oxygenation are limited by the need for wired connections, the inability to provide real-time data or operation restricted to surface tissues. Here, we present a minimally invasive system to monitor deep-tissue O2 that reports continuous real-time data from centimeter-scale depths in sheep and up to a 10-cm depth in ex vivo porcine tissue. The system is composed of a millimeter-sized, wireless, ultrasound-powered implantable luminescence O2 sensor and an external transceiver for bidirectional data transfer, enabling deep-tissue oxygenation monitoring for surgical or critical care indications.

Ceramic packaging in neural implants.

The lifetime of neural implants is strongly dependent on packaging due to the aqueous and biochemically aggressive nature of the body. Over the last decade, there has been a drive towards neuromodulatory implants which are wireless and approaching millimeter-scales with increasing electrode count. A so-far unrealized goal for these new types of devices is an in-vivo lifetime comparable to a sizable fraction of a healthy patient's lifetime (>10-20 years). Existing, approved medical implants commonly encapsulate components in metal enclosures (e.g. titanium) with brazed ceramic inserts for electrode feedthrough. It is unclear how amenable the traditional approach is to the simultaneous goals of miniaturization, increased channel count, and wireless communication. Ceramic materials have also played a significant role in traditional medical implants due to their dielectric properties, corrosion resistance, biocompatibility, and high strength, but are not as commonly used for housing materials due to their brittleness and the difficulty they present in creating complex housing geometries. However, thin-film technology has opened new opportunities for ceramics processing. Thin films derived largely from the semiconductor industry can be deposited and patterned in new ways, have conductivities which can be altered during manufacturing to provide conductors as well as insulators, and can be used to fabricate flexible substrates. In this review, we give an overview of packaging for neural implants, with an emphasis on how ceramic materials have been utilized in medical device packaging, as well as how ceramic thin-film micromachining and processing may be further developed to create truly reliable, miniaturized, neural implants.

A Millimeter-scale Single Charged Particle Dosimeter for Cancer Radiotherapy.

This paper presents a millimeter-scale CMOS 64×64 single charged particle radiation detector system for external beam cancer radiotherapy. A 1×1 µm2 diode measures energy deposition by a single charged particle in the depletion region, and the array design provides a large detection area of 512×512 µm2. Instead of sensing the voltage drop caused by radiation, the proposed system measures the pulse width, i.e., the time it takes for the voltage to return to its baseline. This obviates the need for using power-hungry and large analog-to-digital converters. A prototype ASIC is fabricated in TSMC 65 nm LP CMOS process and consumes the average static power of 0.535 mW under 1.2 V analog and digital power supply. The functionality of the whole system is successfully verified in a clinical 67.5 MeV proton beam setting. To our' knowledge, this is the first work to demonstrate single charged particle detection for implantable in-vivo dosimetry.

An Automated System for Reactive Accelerated Aging of Implant Materials with In-Situ Testing.

The efficacy of implantable medical devices is limited by the longevity of devices in the body environment. Due to the aqueous and mobile-ion rich environment of tissue, robust and long-lasting encapsulation materials are critical for chronic implants. Assessing the reliability of medical devices is commonly performed through saline soak tests with reactive oxidative species at elevated temperatures and lifetime data are fit to an Arrhenius model to predict lifetime under physiological conditions. While effective, these systems often require frequent human involvement to maintain system temperature and reactive oxidative species concentration, as well as monitor sample lifetime, which makes long term testing of multiple samples difficult. Here we present an automated, low-cost, low-solution volume, and high-throughput reactive accelerated aging system to assay many thin film samples in an easy and low maintenance manner. The efficacy of up to 16 thin film coating samples can be assessed by our system through in-situ current leakage tests in a mock biological environment. We validate our system by aging thermal oxide and a-SiC thin films at 93 °C with 20 mM H2O2. Our system shows early failure of the thermal oxide compared to the a-SiC, in agreement with the current literature.

Electrostatic Energy Harvesting from Human Interactions with Smart Paper Electronics.

Smart devices are quickly becoming ubiquitous with the rise of portable biosensors and the internet of things. There exists particular interest in enhancing common objects to have smart capabilities and finding inexpensive solutions for diagnostic tools. One such example is transforming paper items into interactive devices and point-of-care analytic products. Due to the lightweight, flexible, and cost-efficient qualities of paper, unobtrusively powering these devices remains an outstanding problem. In this paper, we demonstrate an electrostatic human-touch powered energy harvesting system, integrated with flexible painted conductive electrodes on paper. This system harvests 8.5 nJ of energy and reaches a voltage of 1.3 V on a 10 nF energy storage capacitor. This technology not only provides a method of powering paper-based products with routine human gestures but can also detect human touch for input communication to sensors.

Wireless User-Generic Ear EEG.

In the past few years it has been demonstrated that electroencephalography (EEG) can be recorded from inside the ear (in-ear EEG). To open the door to low-profile earpieces as wearable brain-computer interfaces (BCIs), this work presents a practical in-ear EEG device based on multiple dry electrodes, a user-generic design, and a lightweight wireless interface for streaming data and device programming. The earpiece is designed for improved ear canal contact across a wide population of users and is fabricated in a low-cost and scalable manufacturing process based on standard techniques such as vacuum forming, plasma-treatment, and spray coating. A 2.5 × 2.5 cm2 wireless recording module is designed to record and stream data wirelessly to a host computer. Performance was evaluated on three human subjects over three months and compared with clinical-grade wet scalp EEG recordings. Recordings of spontaneous and evoked physiological signals, eye-blinks, alpha rhythm, and the auditory steady-state response (ASSR), are presented. This is the first wireless in-ear EEG to our knowledge to incorporate a dry multielectrode, user-generic design. The user-generic ear EEG recorded a mean alpha modulation of 2.17, outperforming the state-of-the-art in dry electrode in-ear EEG systems.

A wireless millimetre-scale implantable neural stimulator with ultrasonically powered bidirectional communication.

Clinically approved neural stimulators are limited by battery requirements, as well as by their large size compared with the stimulation targets. Here, we describe a wireless, leadless and battery-free implantable neural stimulator that is 1.7 mm3 and that incorporates a piezoceramic transducer, an energy-storage capacitor and an integrated circuit. An ultrasonic link and a hand-held external transceiver provide the stimulator with power and bidirectional communication. The stimulation protocols were wirelessly encoded on the fly, reducing power consumption and on-chip memory, and enabling protocol complexity with a high temporal resolution and low-latency feedback. Uplink data indicating whether stimulation occurs are encoded by the stimulator through backscatter modulation and are demodulated at the external transceiver. When embedded in ex vivo porcine tissue, the integrated circuit efficiently harvested ultrasonic power, decoded downlink data for the stimulation parameters and generated current-controlled stimulation pulses. When cuff-mounted and acutely implanted onto the sciatic nerve of anaesthetized rats, the device conferred repeatable stimulation across a range of physiological responses. The miniaturized neural stimulator may facilitate closed-loop neurostimulation for therapeutic interventions.

Correction: Ion concentration polarization (ICP) of proteins at silicon micropillar nanogaps.

[This corrects the article DOI: 10.1371/journal.pone.0223732.].

Design of Ceramic Packages for Ultrasonically Coupled Implantable Medical Devices.

OBJECTIVE: Ultrasonic acoustic power transfer is an efficient mechanism for coupling energy to millimeter and sub-millimeter implants in the body. To date, published ultrasonically powered implants have been encapsulated with thin film polymers that are susceptible to well-documented failure modes in vivo, including water penetration and attack by the body. As with all medical implants, packaging with ceramic or metallic materials can reduce water vapor transmission and improve biostability to provide decadal device lifetime. In this paper, we evaluate methods of coupling ultrasonic energy to the interior of ceramic packages. METHODS: The classic wave approach and modal expansion are used to obtain analytical expressions for ultrasonic transmission through two different package designs and these approaches are validated experimentally. A candidate package design is demonstrated using alumina packages and titanium lids, designed to be acoustically transparent at ultrasonic frequencies. RESULTS: Bulk modes are shown to be more effective at coupling ultrasonic energy to a piezoelectric receiver than flexural modes. Using bulk modes, packaged motes have an overall link efficiency of roughly 10%, compared to 25% for unpackaged motes. Packaging does not have a significant effect on translational misalignment penalties, but does increase angular misalignment penalties. Passive amplitude-modulated backscatter communication is demonstrated. CONCLUSION: Thin lids enable the use of ultrasonically coupled devices even with package materials of very different acoustic impedance. SIGNIFICANCE: This work provides an analysis and method for designing packages that enable ultrasonic coupling with implantable medical devices, which could facilitate clinical translation.

Ion concentration polarization (ICP) of proteins at silicon micropillar nanogaps.

Fast detection of low-abundance protein remains a challenge because detection speed is limited by analyte transport to the detection site of a biosensor. In this paper, we demonstrate a scalable fabrication process for producing vertical nanogaps between micropillars which enable ion concentration polarization (ICP) enrichment for fast analyte detection. Compared to horizontal nanochannels, massively paralleled vertical nanogaps not only provide comparable electrokinetics, but also significantly reduce fluid resistance, enabling microbead-based assays. The channels on the device are straightforward to fabricate and scalable using conventional lithography tools. The device is capable of enriching protein molecules by >1000 fold in 10 min. We demonstrate fast detection of IL6 down to 7.4 pg/ml with only a 10 min enrichment period followed by a 5 min incubation. This is a 162-fold enhancement in sensitivity compared to that without enrichment. Our results demonstrate the possibility of using silicon/silica based vertical nanogaps to mimic the function of polymer membranes for the purpose of protein enrichment.

An Actuated Neural Probe Architecture for Reducing Gliosis-Induced Recording Degradation.

Glial encapsulation of chronically implanted neural probes inhibits recording and stimulation, and this signal loss is a significant factor limiting the clinical viability of most neural implant topologies for decades-long implantation. We demonstrate a mechanical proof of concept for silicon shank-style neural probes intended to minimize gliosis near the recording sites. Compliant whiskers on the edges of the probe fold inward to minimize tissue damage during insertion. Once implanted to the target depth and retracted slightly, these whiskers splay outward. The splayed tips, on which recording sites could be patterned, extend beyond the typical 50-100 [Formula: see text] radius of a glial scar. The whiskers are micrometer-scale to minimize or avoid glial scarring. Electrically inactive devices with whiskers of varying widths and curvature were designed and monolithically fabricated from a 5- [Formula: see text] silicon-on-insulator (SOI) wafer, and their mechanical functionality was demonstrated in a 0.6% agar brain phantom. Deflection was plotted versus deflection speed, and those that were most compliant actuated successfully. This probe requires no preparation for use beyond what is typical for a shank-style silicon probe.

MEMS-Actuated Carbon Fiber Microelectrode for Neural Recording.

Microwire and microelectrode arrays used for cortical neural recording typically consist of tens to hundreds of recording sites, but often only a fraction of these sites are in close enough proximity to firing neurons to record single-unit activity. Recent work has demonstrated precise, depth-controllable mechanisms for the insertion of single neural recording electrodes, but these methods are mostly only capable of inserting electrodes which elicit an adverse biological response. We present an electrostatic-based actuator capable of inserting individual carbon fiber microelectrodes which elicit minimal to no adverse biological response. The device is shown to insert a carbon fiber recording electrode into an agar brain phantom and can record an artificial neural signal in saline. This technique provides a platform generalizable to many microwire-style recording electrodes.