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Intravascular ultrasound (IVUS) imaging catheters are significant tools for cardiovascular interventions, and their use can be expanded by realizing IVUS imaging guidewires and microcatheters. The miniaturization of these devices creates challenges in SNR due to the need for higher frequencies to provide adequate resolution. An integrated IVUS system with transmit beamforming can mitigate these limitations. This work presents the first practical highly integrated system-on-a-chip (SoC) with plane wave transmit beamforming at 40 MHz for IVUS on guidewire or microcatheters. The front-end circuitry has a 20-channel ultrasound transmitter (Tx) and receiver (Rx) array interfaced with a capacitive micromachined ultrasound transducer (CMUT) array. During each firing, all 20 Tx are excited with the same analog delay with respect to each other, which can be continuously adjusted between ~0 and 10 ns in two directions, generating a steerable plane wave in a range of ±/-50° for a phased array at 40 MHz. The unit delays are generated via a voltage-controlled delay line (VCDL), which only needs two external controls, one tuning the unit delay and the other determining the steering direction. The SoC is fabricated using a 180-nm high-voltage (HV) CMOS process and features a slender active area of 0.3 mm × 3.7 mm. The proposed SoC consumes 31.3 mW during the receiving mode. The beamformer's functionality and the SoC's overall performance were validated through acoustic characterization and imaging experiments.

An acousto-optic (AO)-based electric field sensor is presented for time domain measurement under magnetic resonance imaging (MRI). A fully MR-compatible sensor is designed and fabricated using a phase-shifted fiber Bragg grating mechanically coupled to a piezoelectric transducer. Mechanical resonance of the piezoelectric transducer is matched to the operating frequencies of commonly used MRI systems to increase the sensitivity of the sensor. Sensitivity of the sensor is measured as 1.27 mV/V/m, with a minimum detectable electric field of 4.4 mV/m/√/Hz. Directivity of the sensor is measured with a 18 dB orthogonal component rejection. The dynamic range of the sensor is calculated as 117 dB/Hz, which allows the measurement of electric fields up to 3.2 kV/m. In MRI studies, the AO sensor was able detect local hot spots around a reference implant accurately with high signal-to-noise ratio. AO sensor exhibited similar or better performance when compared with commercially available MRI compatible electric field sensors. Furthermore, the small size of the sensor with the flexible fiber optic link could allow in situ measurements of electric fields during critical interventional procedures such as pacemaker lead or deep brain stimulator placement as an MRI dosimeter during diagnostic scans., Competing Interests: Disclosures The authors do not have any financial interest to disclose.

Despite the challenges in treating glioblastomas (GBMs) with immune adjuvants, increasing evidence suggests that targeting the immune cells within the tumor microenvironment (TME) can lead to improved responses. Here, we present a closed-loop controlled, microbubble-enhanced focused ultrasound (MB-FUS) system and test its abilities to safely and effectively treat GBMs using immune checkpoint blockade. The proposed system can fine-tune the exposure settings to promote MB acoustic emission-dependent expression of the proinflammatory marker ICAM-1 and delivery of anti-PD1 in a mouse model of GBM. In addition to enhanced interaction of proinflammatory macrophages within the PD1-expressing TME and significant improvement in survival ( P  < 0.05), the combined treatment induced long-lived memory T cell formation within the brain that supported tumor rejection in rechallenge experiments. Collectively, our findings demonstrate the ability of MB-FUS to augment the therapeutic impact of immune checkpoint blockade in GBMs and reinforce the notion of spatially tumor-targeted (loco-regional) brain cancer immunotherapy.

This paper demonstrates hybrid sub-aperture beamforming (SAB) with time-division multiplexing (TDM) for massive interconnect reduction in ultrasound imaging systems. A single-chip front-end system prototype has been fabricated in 180-nm HV BCD technology that combines 5×1 SAB with 8×1 TDM to efficiently reduce the number of receive signal interconnects by a factor of 40. The system includes on-chip high-voltage (HV) pulsers capable of generating unipolar pulses up to 70 V in transmit (TX) mode. The receiver (RX) chain consists of a T/R switch, a variable-gain low-noise amplifier (VG-LNA) with 4-step gain control (15-32 dB) for time-gain compensation followed by a programmable switched-capacitor analog delay-and-sum beamformer. The proof-of-concept prototype operates at a 200-MHz clock frequency and the SAB provides 32-step fine delays with a maximum delay of 310 ns corresponding to better than λ/20 delay quantization at 5 MHz. With these specifications, the SAB is capable of beam steering from 0 ° to 45 ° for a 5-element subarray with 150-micron pitch ( λ/2), providing a near-ideal phased array imaging performance. The sub-aperture beamformer is followed by the TDM system where each of the 8 channels is sampled at a rate of 25 MS/s after an anti-aliasing bandpass filter. The full functionality of the prototype chip is validated through electrical and acoustic measurements on a 1-D capacitive micromachined ultrasonic transducer (CMUT) array designed for intracardiac echocardiography (ICE).

This paper presents an active impedance matching scheme that tries to optimize electrical power transfer and acoustic reflectivity in ultrasound transducers. Leveraging negative capacitance-based impedance matching would potentially improve the bandwidth and electrical power transfer while minimizing acoustic reflection of transducer elements and improve uniformity while reducing acoustic crosstalk of transducer arrays. A 16-element transceiver front-end is designed which employs an element-level active capacitive impedance cancellation scheme using an element-level negative impedance converter. The ASIC fabricated in 180-nm HVBCD technology provides high-voltage pulses up to 60 V consuming 3.6 mW and occupying 2.5 mm 2 . The front-end ASIC is used with a 1-D capacitive micromachined ultrasonic transducer (CMUT) array and its acoustical reflectivity reduction and imaging capabilities have successfully been demonstrated through pulse-echo measurements and acoustic imaging experiments.

Brain tumors are particularly challenging malignancies, due to their location in a structurally and functionally distinct part of the human body - the central nervous system (CNS). The CNS is separated and protected by a unique system of brain and blood vessel cells which together prevent most bloodborne therapeutics from entering the brain tumor microenvironment (TME). Recently, great strides have been made through microbubble (MB) ultrasound contrast agents in conjunction with ultrasound energy to locally increase the permeability of brain vessels and modulate the brain TME. As we elaborate in this review, this physical method can effectively deliver a wide range of anticancer agents, including chemotherapeutics, antibodies, and nanoparticle drug conjugates across a range of preclinical brain tumors, including high grade glioma (glioblastoma), diffuse intrinsic pontine gliomas, and brain metastasis. Moreover, recent evidence suggests that this technology can promote the effective delivery of novel immunotherapeutic agents, including immune check-point inhibitors and chimeric antigen receptor T cells, among others. With early clinical studies demonstrating safety, and several Phase I/II trials testing the preclinical findings underway, this technology is making firm steps towards shaping the future treatments of primary and metastatic brain cancer. By elaborating on its key components, including ultrasound systems and MB technology, along with methods for closed-loop spatial and temporal control of MB activity, we highlight how this technology can be tuned to enable new, personalized treatment strategies for primary brain malignancies and brain metastases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tight integration of capacitive micromachined ultrasonic transducer (CMUT) arrays with integrated circuits can make active impedance matching feasible for practical imaging devices. In this article, negative capacitance-based impedance matching for CMUTs is investigated. Simple equivalent circuit model-based calculations show the potential of negative capacitance matching for improving the bandwidth along with electrical power transfer and acoustic reflectivity, but the model has limitations especially for acoustic reflectivity evaluation. For more realistic results, an experimentally validated CMUT array model is applied to a small 1-D CMUT array operating in the 5-15 MHz range. The results highlight the difference between electrical power transfer and acoustic reflectivity as well as the tradeoffs in signal-to-noise ratio (SNR). According to the results, ideal negative capacitance termination matched to the CMUT capacitance provides the broadest bandwidth and highest SNR if acoustic or electrical reflections are of no concern. On the other hand, negative capacitance and resistance matching to minimize acoustic reflectivity provides both lower reflection and closer to ideal SNR as compared with electrical power matching. It is observed that acoustic matching also reduces acoustic crosstalk and improves array uniformity. While several challenges for integrated circuit implementation are present, negative capacitance-based impedance matching can be a viable broadband active impedance matching method for CMUTs operating in conventional and collapsed mode as well as other ultrasound transducers with mainly capacitive impedance.

Purpose: This work aims to demonstrate the use of an "active" acousto-optic marker with enhanced visibility and reduced radiofrequency (RF) -induced heating for interventional MRI., Methods: The acousto-optic marker was fabricated using bulk piezoelectric crystal and π-phase shifted fiber Bragg grating (FBGs) and coupled to a distal receiver coil on an 8F catheter. The received MR signal is transmitted over an optical fiber to mitigate RF-induced heating. A photodetector converts the optical signal into electrical signal, which is used as the input signal to the MRI receiver plug. Acousto-optic markers were characterized in phantom studies. RF-induced heating risk was evaluated according to ASTM 2182 standard. In vivo real-time tracking capability was tested in an animal model under a 0.55T scanner., Results: Signal-to-noise ratio (SNR) levels suitable for real-time tracking were obtained by using high sensitivity FBG and piezoelectric transducer with resonance matched to Larmor frequency. Single and multiple marker coils integrated to 8F catheters were readout for position and orientation tracking by a single acousto-optic sensor. RF-induced heating was significantly reduced compared to a coax cable connected reference marker. Real-time distal tip tracking of an active device was demonstrated in an animal model with a standard real-time cardiac MR sequence., Conclusion: Acousto-optic markers provide sufficient SNR with a simple structure for real-time device tracking. RF-induced heating is significantly reduced compared to conventional active markers. Also, multiple RF receiver coils connected on an acousto-optic modulator can be used on a single catheter for determining catheter orientation and shape., (© 2020 International Society for Magnetic Resonance in Medicine.)

A power-efficient bridge-to-digital sensing interface is proposed, which also offers immunity against power supply noise. The interface utilizes duty-cycling to reduce the static power consumption of resistive bridge sensors, which are commonly used in implantable, wearable, and internet of things (IoT) applications, such as intracranial pressure (ICP) sensing and blood pressure (BP) monitoring. The proposed interface uses a revised version of the pseudo-pseudo differential (PPD) topology with the ping-pong technique to reduce the complexity of traditional fully-differential counterparts. A proof-of-concept prototype has been fabricated in 0.35- μ m CMOS and occupies an active area of 0.48 mm 2 . It achieves 9.13 effective number of bits (ENOB) at 3.72 kHz sampling rate and improvement of more than 50 dB in the power supply rejection ratio (PSRR) by employing the ping-pong technique. It reduces the power consumption of a 5-kΩ Wheatstone bridge by 99.6% compared to a traditional interface, down to 2.53 μ w at 1.8 V supply. The functionality of the system has also been demonstrated in an experimental setup in conjunction with an embedded resistive bridge pressure sensor.

In this article, we present a highly integrated guidewire ultrasound (US) imaging system-on-a-chip (GUISoC) for vascular imaging. The SoC consists of a 16-channel US transmitter (Tx) and receiver (Rx) electronics, on-chip power management IC (PMIC), and quadrature sampler. Using a synthetic aperture imaging algorithm, a Tx/Rx pair, connected to capacitive micromachined ultrasound transducers (CMUTs), can be activated at any time. The Tx generates acoustic waves by driving the CMUT, while the Rx picks up the echo signal and amplify it to be delivered through an interconnect that is driven by a buffer. On-chip logic controls the pulsers that generate the high-voltage (HV)-pulse for Tx. An on-chip PMIC provides 1.8-, 5-, 39-, and 44-V supplies and a clock signal from the two interconnects besides GND. A quadrature sampler down-converts the Rx echo signal to baseband, reducing its bandwidth requirement for the output interconnect. The system design, including transimpedance amplifier (TIA) optimization, based on the equivalent circuit of a specific CMUT is presented. The SoC was fabricated by a 0.18- μ m HV CMOS process, occupying 1.5-mm2 active area and consuming 25.2 and 44 mW from 1.8 to 44 V supplies, respectively. The US Tx and Rx show bandwidths of 32-42 and 32.7-37.5 MHz, respectively. The input-referred noise of the system was measured as 9.66 nA in band with 2-m-long 52 American Wire Gauge (AWG) wire interconnects. The functionality of the GUISoC was verified in vitro by imaging wire targets.

Fiber Bragg grating (FBG) based sensors have recently been introduced to the field of magnetic resonance imaging (MRI). Real-time MRI applications demand highly amplitude and phase sensitive MRI compatible sensors. Thus, a model and detailed analysis of FBG based ultrasound detection are required for designing better performing sensors. A hybrid FBG model incorporating numerical and FEA methods was developed and used for sensitivity and linearity analysis. The transfer matrix method was used for the modeling of optical modulation whereas FEA was used for pressure field calculations within the grating. The model was verified through reflection spectrum and acoustic pressure sensitivity testing of two π -phase shifted FBGs in a side slope read-out configuration. The sensitivity curves with respect to the operation point on the side slope was characterized in terms of amplitude and phase, and nonlinearity of the phase response has been quantified. Lastly, the impact of phase linearity of the FBG based acousto-optic sensor was tested under MRI when the sensor was used as a position marker and an analog phase shifter based solution was demonstrated.

A combined supply-inverted bipolar pulser and a Tx/Rx switch is proposed to drive capacitive micromachined ultrasonic transducers (CMUTs). The supply-inverted bipolar pulser adopts a bootstrap circuit combined with stacked transistors, which guarantees high voltage (HV) operation above the process limit without lowering device reliability. This circuit generates an output signal with a peak-to-peak voltage that is almost twice the supply level. It generates a bipolar pulse with only positive supply voltages. The Tx/Rx switch adopts a diode-bridge structure with the protection scheme dedicated to this proposed pulser. A proof- of-concept ASIC prototype has been implemented in 0.18- μ m HV CMOS/DMOS technology with 60 V devices. Measurement results show that the proposed pulser can safely generate a bipolar pulse of -34.6 to 45 V, from a single 45 V supply voltage. The Tx/Rx switch blocks the HV bipolar pulse, resulting in less than 1.6 V at the input of the receiver. Acoustic measurements are performed connecting the pulser to CMUTs with 2 pF capacitance and 8 MHz center frequency. The variation of acoustic output pressures for different pulse shapes were simulated with the large signal CMUT model and compared with the experimental results for transmit pressure optimization. A potential implementation of the methods using MEMS fabrication methods is also described.

Objective: The objective of this paper is to introduce an acousto-optic optical fiber sensor for tracking catheter position during interventional magnetic resonance imaging (MRI) to overcome RF induced heating of active markers., Methods: The sensor uses a miniature coil coupled to a piezoelectric transducer, which is in turn mechanically connected to an optical fiber. The piezoelectric transducer converts the RF signal to acoustic waves in the optical fiber over a region including a fiber Bragg grating (FBG). The elastic waves in the fiber modulates the FBG geometry and hence the reflected light in the optical fiber. Since the coil is much smaller than the RF wavelength and the signal is transmitted on the dielectric optical fiber, the sensor effectively reduces RF induced heating risk. Proof of concept prototypes of the sensor are implemented using commercially available piezoelectric transducers and optical fibers with FBGs. The prototypes are characterized in a 1.5 T MRI system in comparison with an active tracking marker., Results: Acousto-optical sensor shows linear response with flip angle and it can be used to detect signals from multiple coils for potential orientation detection. It has been successfully used to detect the position of a tacking coil in phantom in an imaging experiment., Conclusion: Acousto-optical sensing is demonstrated for tracking catheters during interventional MRI. Real-time operation of the sensor requires sensitivity improvements like using a narrow band FBG., Significance: Acousto-optics provides a compact solution to sense RF signals in MRI with dielectric transmission lines.

With Capacitive Micromachined Ultrasound Transducers (CMUTs) increasingly being used for high intensity, large signal ultrasound applications and several drive methods being proposed, the efficiency of these devices in this operation regime have not been quantitatively evaluated. Since well-known frequency and capacitance-based coupling coefficients definitions are not valid for large signal, nonlinear operation, an energy-based definition should be used. In this paper, an expression for mechanical energy in a CMUT is obtained based on the assumption that CMUT is a linear time varying capacitor in all regimes of operation. This expression is evaluated by the help of an experimentally verified nonlinear CMUT model to define an energy conversion ratio (ECR) which can be considered as a coupling coefficient valid for all regimes of operation. This parameter is validated in the small signal regime and then used to evaluate CMUT performance with various large drive signals. The quantitative modeling results show that CMUTs do not need DC bias to achieve high efficiency large signal transduction: AC only signals at half the operation frequency with amplitudes beyond the collapse voltage can provide efficiencies (ECR) above 0.9 with harmonic content below -25 dB. Based on these results, ECR variation with membrane geometry and parasitic capacitance are given as examples for device optimization. The overall modeling approach is also qualitatively validated by experiments.

High-frequency ultrasound imaging arrays are important for a broad range of applications, from small animal imaging to photoacoustics. Capacitive micromachined ultrasonic transducer (CMUT) arrays are particularly attractive for these applications as low noise receiver electronics can be integrated for an overall improved performance. In this paper, we present a comprehensive analysis of high-frequency CMUT arrays based on an experimentally verified CMUT array simulation tool. The results obtained on an example, a 40-MHz 1-D CMUT array for intravascular imaging, are used to obtain key design insights and tradeoffs for receive only and pulse-echo imaging. For the receiver side, thermal mechanical current noise, plane wave pressure sensitivity, and pressure noise spectrum are extracted from simulations. Using these parameters, we find that the receiver performance of CMUT arrays can be close to an ideal piston, independent of gap thickness, and applied dc bias, when coupled to low noise electronics with arrays utilizing smaller membranes performing better. For pulse-echo imaging, thermal mechanical current noise limited signal-to-noise ratio is observed to be dependent on the maximum available voltage and gap thickness. In terms of bandwidth, we find that the Bragg resonance of the array, related to the fill factor, is a significant determinant of the high frequency limit and the fluid loaded single membrane resonance determines the lower limit. Based on these results, we present design guidelines requiring only fluid loaded single membrane simulations and membrane pitch to achieve a desired pulse-echo response. We also provide a design example and discuss limitations of the approach.

A sensor interface circuit based on impulse radio pulse width modulation (IR-PWM) is presented for low power and high throughput wireless data acquisition systems (wDAQ) with extreme size and power constraints. Two triple-slope analog-to-time converters (ATC) convert two analog signals, each up to 5 MHz in bandwidth, into PWM signals, and an impulse radio (IR) transmitted (Tx) with an all-digital power amplifier (PA) combines them while preserving the timing information by transmitting impulses at the PWM rising and falling edges. On the receiver (Rx) side, an RF-LNA followed by an envelope detector recovers the incoming impulses, and a T-flipflop reverts the impulse sequence back to PWM to be digitized by a time-to-digital converter (TDC). Detailed analysis and design guideline on ATC was introduced, and a proof-of-concept prototype was fabricated for a capacitive micromachined ultrasound transducer (CMUT) imaging system in a 0.18- μ m HV CMOS process, occupying 0.18 mm 2 active area and consuming 3.94 mW from a 1.8 V supply. The proposed TDC in this prototype yielded 7-bit resolution, while the entire wDAQ achieved 5.8 effective number of bits (ENOB) at 2 × 10 MS/s.

This paper presents a single chip reduced-wire active catheter application-specific integrated circuit (ASIC), equipped with programmable transmit (Tx) beamforming and receive (Rx) time-division multiplexing (TDM). The proposed front-end ASIC is designed for driving a 64-channel one-dimensional transducer array in intracardiac echocardiography (ICE) ultrasound catheters. The ASIC is implemented in 60 V 0.18-μm HV-BCD technology, integrating Tx beamformers with high voltage pulsers and Rx front end in the same chip, which occupies 2.6 × 11 mm 2 that can fit in the catheter size of 9 F (<3 mm). The proposed system reduces the number of wires from >64 to only 22 by integrating Tx beamformer that is programmable using a single low-voltage differential signaling data line. In Rx mode, the system uses 8:1 TDM with direct digital demultiplexing providing raw channel data that enables dynamic Rx beamforming using individual array elements. This system has been successfully used for B-mode imaging on standard ultrasound phantom with 401 mW of average power consumption. The ASIC has a compact element pitch-matched layout, which is also compatible with capacitive micromachined ultrasound transducer on CMOS application. This system addresses cable number and dimensional restrictions in catheters to enable ICE imaging under magnetic resonance imaging by reducing radio frequency induced heating.

There is an increasing interest in wireless power transfer for medical implants, sensor networks, and consumer electronics. A passive capacitive parametric ultrasonic transducer (CPUT) can be suitable for these applications as it does not require a dc bias or a permanent charge. In this paper, we present a 1-D lumped parameter model of the CPUT to study its operation and investigate relevant design parameters for power transfer applications. The CPUT is modeled as an ultrasound-driven piston coupled to an RLC resonator resulting in a system of two coupled nonlinear ordinary differential equations. Simulink is used along with an analytical approximation of the system to obtain the voltage across the capacitor and displacement of the piston. Parametric resonance threshold and ultrasound-to-electrical conversion efficiency are evaluated, and the dependence of these performance metrics on the load resistance, input ultrasound intensity, forcing frequency, electrode coverage area, gap height, and the mechanical Q-factor are studied. Based on this analysis, design guidelines are proposed for highly efficient power transfer. Guided by these results, practical device designs are obtained through COMSOL simulations. Finally, the feasibility of using the CPUT in air is predicted to set the foundation for further research in ultrasonic wireless power transfer, energy harvesting, and sensing.

This paper reports an improved CMOS compatible low temperature sacrificial layer fabrication process for Capacitive Micromachined Ultrasonic Transducers (CMUTs). The process adds the fabrication step of silicon oxide evaporation which is followed by a lift-off step to define the membrane support area without a need for an extra mask. This simple addition improves reliability by reducing the electric field between the top and bottom electrodes everywhere except the moving membrane without affecting the vacuum gap thickness. Furthermore, the parasitic capacitance which degrades the CMUT receive performance is reduced. A 1-D CMUT array suitable for Intracardiac Echocardiography (ICE) imaging with 9MHz center frequency is fabricated using this method. Detailed electrical and acoustic testing indicates adequate performance of the devices for ICE in agreement with simulations. Long term output pressure testing with more than 2×10 11 pulsing cycles and environmental testing demonstrate the efficacy of the approach for improved reliability as compared to devices without the additional membrane support layer.

A supply-doubled pulse-shaping high voltage (HV) pulser is presented for medical ultrasound imaging applications, particularly those that use capacitive micromachined ultrasonic transducers (CMUT). The pulser employs a bootstrap circuit combined with dynamically-biased stacked transistors, which allow HV operation above process limit without lowering device reliability. The new pulser overcomes supply voltage limitation of conventional unipolar pulsers by generating output signals that are almost twice the supply level. It also can generate three-level pulses to further optimize the transmit pressure signals. A proof-of-concept prototype has been implemented in 0.18-μm HV CMOS/DMOS technology with 60 V devices. Measurement results show that the HV pulser can safely generate controllable three-level pulses with up to 85 V pp from 45 V supply. Acoustic measurements are conducted connecting the pulser to a CMUT with 2 pF capacitance and 8.3 MHz center frequency. The pulse shape has been adjusted for the CMUT under test to generate maximum pressure output and the results are in good agreement with a large signal CMUT model.

Delivery of large and structurally complex target molecules into cells is vital to the emerging areas of cellular modification and molecular therapy. Inadequacy of prevailing in vivo (viral) and in vitro (liposomal) gene transfer methods for delivery of proteins and a growing diversity of synthetic nanomaterials has encouraged development of alternative physical approaches. Efficacy of injury/diffusion-based delivery via shear mechanoporation is largely insensitive to cell type and target molecule; however, enhanced flexibility is typically accompanied by reduced gene transfer effectiveness. We detail a method to improve transfection efficiency through coordinated mechanical disruption of the cell membrane and electrophoretic insertion of DNA to the cell interior. An array of micromachined nozzles focuses ultrasonic pressure waves, creating a high-shear environment that promotes transient pore formation in membranes of transmitted cells. Acoustic Shear Poration (ASP) allows passive cytoplasmic delivery of small to large nongene macromolecules into established and primary cells at greater than 75% efficiency. Addition of an electrophoretic action enables active transport of target DNA molecules to substantially augment transfection efficiency of passive mechanoporation/diffusive delivery without affecting viability. This two-stage poration/insertion method preserves the compelling flexibility of shear-based delivery, yet substantially enhances capabilities for active transport and transfection of plasmid DNA.

A hybrid boundary element model is proposed for the simulation of large piezoelectric micromachined ultrasonic transducer (PMUT) arrays in immersion. Multiphysics finite element method (FEM) simulation of a single-membrane structure is used to determine stiffness and piezoelectrically induced actuation loading of the membranes. To simulate the arrays of membranes in immersion, a boundary element method is employed, wherein membrane structures are modeled by a surface mesh that is coupled mechanically by mass, stiffness, and damping matrices, and acoustically by a mutual impedance matrix. A multilevel fast multipole algorithm speeds up computation time and reduces memory usage, enabling the simulation of thousands of membranes in a reasonable time. The model is validated with FEM for a small 3 3 matrix array for both square and circular membrane geometries. Two practical optimization examples of large PMUT arrays are demonstrated: membrane spacing of a 7 7 matrix array with circular membranes, and material choice and top electrode coverage of a 32-element linear array with 640 circular membranes. In addition, a simple analytical approach to electrode optimization based on normal mode theory is verified.

Having intravascular ultrasound (IVUS) imaging capability on guide wires used in cardiovascular interventions may eliminate the need for separate IVUS catheters and expand the use of IVUS in a larger portion of the vasculature. High frequency capacitive micro machined ultrasonic transducer (CMUT) arrays should be integrated with interface electronics and placed on the guide wire for this purpose. Besides small size, this system-on-a-chip (SoC) front-end should connect to the back-end imaging system with a minimum number of wires to preserve the critical mechanical properties of the guide wire. We present a 40 MHz CMUT array interface SoC, which will eventually use only two wires for power delivery and transmits image data using a combination of analog-to-time conversion (ATC) and an impulse radio ultra-wideband (IR-UWB) wireless link. The proof-of-concept prototype ASIC consumes only 52.8 mW and occupies 4.07 [Formula: see text] in a 0.35- [Formula: see text] standard CMOS process. A rectifier and regulator power the rest of the SoC at 3.3 V from a 10 MHz power carrier that is supplied through a 2.4 m micro-coax cable with an overall efficiency of 49.1%. Echo signals from an 8-element CMUT array are amplified by a transimpedance amplifier (TIA) array and down-converted to baseband by quadrature sampling using a 40 MHz clock, derived from the power carrier. The ATC generates pulse-width-modulated (PWM) samples at 2 × 10 MS/s with 6 bit resolution, while the entire system achieved 5.1 ENOB. Preliminary images from the prototype system are presented, and alternative data transmission and possible future directions towards practical implementation are discussed.

A boundary element model provides great flexibility for the simulation of membrane-type micromachined ultrasonic transducers (MUTs) in terms of membrane shape, actuating mechanism, and array layout. Acoustic crosstalk is accounted for through a mutual impedance matrix that captures the primary crosstalk mechanism of dispersive-guided modes generated at the fluid-solid interface. However, finding the solution to the fully populated boundary element matrix equation using standard techniques requires computation time and memory usage that scales by the cube and by the square of the number of nodes, respectively, limiting simulation to a small number of membranes. We implement a solver with improved speed and efficiency through the application of a multilevel fast multipole algorithm (FMA). By approximating the fields of collections of nodes using multipole expansions of the free-space Green's function, an FMA solver can enable the simulation of hundreds of thousands of nodes while incurring an approximation error that is controllable. Convergence is drastically improved using a problem-specific block-diagonal preconditioner. We demonstrate the solver's capabilities by simulating a 32-element 7-MHz 1-D capacitive MUT (CMUT) phased array with 2880 membranes. The array is simulated using 233280 nodes for a very wide frequency band up to 50 MHz. For a simulation with 15210 nodes, the FMA solver performed ten times faster and used 32 times less memory than a standard solver based on LU decomposition. We investigate the effects of mesh density and phasing on the predicted array response and find that it is necessary to use about seven nodes over the width of the membrane to observe convergence of the solution-even below the first membrane resonance frequency-due to the influence of higher order membrane modes.

In real-time catheter-based 3-D ultrasound imaging applications, gathering data from the transducer arrays is difficult, as there is a restriction on cable count due to the diameter of the catheter. Although area and power hungry multiplexing circuits integrated at the catheter tip are used in some applications, these are unsuitable for use in small sized catheters for applications, such as intracardiac imaging. Furthermore, the length requirement for catheters and limited power available to on-chip cable drivers leads to limited signal strength at the receiver end. In this paper, an alternative approach using analog time-division multiplexing (TDM) is presented, which addresses the cable restrictions of ultrasound catheters. A novel digital demultiplexing technique is also described, which allows for a reduction in the number of analog signal processing stages required. The TDM and digital demultiplexing schemes are demonstrated for an intracardiac imaging system that would operate in the 4- to 11-MHz range. A TDM integrated circuit (IC) with an 8:1 multiplexer is interfaced with a fast analog-to-digital converter (ADC) through a microcoaxial catheter cable bundle, and processed with a field-programmable gate array register-transfer level simulation. Input signals to the TDM IC are recovered with -40-dB crosstalk between the channels on the same microcoax, showing the feasibility of this system for ultrasound imaging applications.

Conventional amplitude and phase modulated pulse sequences for selective imaging of nonlinear tissue and ultrasound contrast agents are designed for piezoelectric transducers that behave linearly. Inherent nonlinearity of capacitive micromachined ultrasonic transducers (CMUTs), especially during large-signal operation, renders these methods inapplicable. In this paper, we present different pulse sequences for nonlinear imaging that are valid for small- and large-signal CMUT operations. For small-signal operation, two-pulse amplitude and phase modulation methods for microbubble and tissue harmonic imaging are presented, where CMUT nonlinearity is compensated via subharmonic excitation. In the large-signal regime, using a nonlinear model, we first show that there is a simple linear relationship between the phases of each harmonic distortion component generated and the input drive signal. Based on this observation, we demonstrate a pulse sequence using N+1 consecutive phase modulated transmit events to extract N harmonics of the nonlinear contrast agent echo content uncorrupted by CMUT nonlinearity. The proposed methods assume no apriori information about the transducer and, therefore, are applicable to any CMUT. The phase modulation method is also valid for piezoelectric transducers and systems with nonlinearities described by Taylor series where the same phase relationship between the input signal and the harmonic content is valid. The proof of principle experiments using a commercial contrast agent validates the phase modulated pulse sequences for CMUTs, operating in a highly nonlinear collapse-snapback mode and for piezoelectric transducers.

We present a nonlinear lumped model that predicts the electrical input-output behavior of an ultrasonic system using CMUTs with arbitrary array/membrane/electrode geometry in different transmit-receive configurations and drive signals. The receive-only operation, where the electrical output signal of the CMUT array in response to incident pressure field is calculated, is included by modifying the boundary elementbased vibroacoustic formulation for a CMUT array in rigid baffle. Along with the accurate large signal transmit model, this formulation covers pitch-catch and pulse-echo operation when transmit and receive signals can be separated in time. In cases when this separation is not valid, such as CMUTs used in continuous wave transmit-receive mode, pulse-echo mode with a nearby hard or soft wall or in a bounded space such as in a microfluidic channel, an efficient formulation based on the method of images is used. Some of these particular applications and the overall modeling approach have been validated through comparison with finite element analysis on specific examples including CMUTs with multiple electrodes. To further demonstrate the capability of the model for imaging applications, the two-way response of a partial dual-ring intravascular ultrasound array is simulated using a parallel computing cluster, where the output currents of individual array elements are calculated for given input pulse and compared with experimental results. With its versatility, the presented model can be a useful tool for rapid iterative CMUT-based system design and simulation for a broad range of ultrasonic applications.

Monolithic integration of capacitive micromachined ultrasonic transducer arrays with low noise complementary metal oxide semiconductor electronics minimizes interconnect parasitics thus allowing the measurement of thermal-mechanical (TM) noise. This enables passive ultrasonics based on cross-correlations of diffuse TM noise to extract coherent ultrasonic waves propagating between receivers. However, synchronous recording of high-frequency TM noise puts stringent requirements on the analog to digital converter's sampling rate. To alleviate this restriction, high-frequency TM noise cross-correlations (12-25 MHz) were estimated instead using compressed measurements of TM noise which could be digitized at a sampling frequency lower than the Nyquist frequency.

A lattice Boltzmann (LB) formulation, which is consistent with the phase-field model for two-phase incompressible fluid, is proposed to model the interface dynamics of droplet impingement. The interparticle force is derived by comparing the macroscopic transport equations recovered from LB equations with the governing equations of the continuous phase-field model. The inconsistency between the existing LB implementations and the phase-field model in calculating the relaxation time at the phase interface is identified and an approximation is proposed to ensure the consistency with the phase-field model. It is also shown that the commonly used equilibrium velocity boundary for the binary fluid LB scheme does not conserve momentum at the wall boundary and a modified scheme is developed to ensure the momentum conservation at the boundary. In addition, a geometric formulation of the wetting boundary condition is proposed to replace the popular surface energy formulation and results show that the geometric approach enforces the prescribed contact angle better than the surface energy formulation in both static and dynamic wetting. The proposed LB formulation is applied to simulating droplet impingement dynamics in three dimensions and results are compared to those obtained with the continuous phase-field model, the LB simulations reported in the literature, and experimental data from the literature. The results show that the proposed LB simulation approach yields not only a significant speed improvement over the phase-field model in simulating droplet impingement dynamics on a submillimeter length scale, but also better accuracy than both the phase-field model and the previously reported LB techniques when compared to experimental data. Upon validation, the proposed LB modeling methodology is applied to the study of multiple-droplet impingement and interactions in three dimensions, which demonstrates its powerful capability of simulating extremely complex interface phenomena.

Intravascular ultrasound (IVUS) and intracardiac echography (ICE) catheters with real-time volumetric ultrasound imaging capability can provide unique benefits to many interventional procedures used in the diagnosis and treatment of coronary and structural heart diseases. Integration of capacitive micromachined ultrasonic transducer (CMUT) arrays with front-end electronics in single-chip configuration allows for implementation of such catheter probes with reduced interconnect complexity, miniaturization, and high mechanical flexibility. We implemented a single-chip forward-looking (FL) ultrasound imaging system by fabricating a 1.4-mm-diameter dual-ring CMUT array using CMUT-on-CMOS technology on a front-end IC implemented in 0.35-μm CMOS process. The dual-ring array has 56 transmit elements and 48 receive elements on two separate concentric annular rings. The IC incorporates a 25-V pulser for each transmitter and a low-noise capacitive transimpedance amplifier (TIA) for each receiver, along with digital control and smart power management. The final shape of the silicon chip is a 1.5-mm-diameter donut with a 430-μm center hole for a guide wire. The overall front-end system requires only 13 external connections and provides 4 parallel RF outputs while consuming an average power of 20 mW. We measured RF A-scans from the integrated single- chip array which show full functionality at 20.1 MHz with 43% fractional bandwidth. We also tested and demonstrated the image quality of the system on a wire phantom and an ex vivo chicken heart sample. The measured axial and lateral point resolutions are 92 μm and 251 μm, respectively. We successfully acquired volumetric imaging data from the ex vivo chicken heart at 60 frames per second without any signal averaging. These demonstrative results indicate that single-chip CMUT-on-CMOS systems have the potential to produce realtime volumetric images with image quality and speed suitable for catheter-based clinical applications.

Effective intracellular delivery is a significant impediment to research and therapeutic applications at all processing scales. Physical delivery methods have long demonstrated the ability to deliver cargo molecules directly to the cytoplasm or nucleus, and the mechanisms underlying the most common approaches (microinjection, electroporation, and sonoporation) have been extensively investigated. In this review, we discuss established approaches, as well as emerging techniques (magnetofection, optoinjection, and combined modalities). In addition to operating principles and implementation strategies, we address applicability and limitations of various in vitro, ex vivo, and in vivo platforms. Importantly, we perform critical assessments regarding (1) treatment efficacy with diverse cell types and delivered cargo molecules, (2) suitability to different processing scales (from single cell to large populations), (3) suitability for automation/integration with existing workflows, and (4) multiplexing potential and flexibility/adaptability to enable rapid changeover between treatments of varied cell types. Existing techniques typically fall short in one or more of these criteria; however, introduction of micro-/nanotechnology concepts, as well as synergistic coupling of complementary method(s), can improve performance and applicability of a particular approach, overcoming barriers to practical implementation. For this reason, we emphasize these strategies in examining recent advances in development of delivery systems.

We present a system-on-a-chip (SoC) for use in high-frequency capacitive micromachined ultrasonic transducer (CMUT) imaging systems. This SoC consists of trans-impedance amplifiers (TIA), delay locked loop (DLL) based clock multiplier, quadrature sampler, and pulse width modulator (PWM). The SoC down converts RF echo signal to baseband by quadrature sampling which facilitates modulation. To send data through a 1.6 m wire in the catheter which has limited bandwidth and is vulnerable to noise, the SoC creates a pseudo-digital PWM signal which can be used for back telemetry or wireless readout of the RF data. In this implementation, using a 0.35-μm std. CMOS process, the TIA and single-to-differential (STD) converter had 45 MHz bandwidth, the quadrature sampler had 10.1 dB conversion gain, and the PWM had 5-bit ENoB. Preliminary results verified front-end functionality, and the power consumption of a TIA, STD, quadrature sampler, PWM, and clock multiplier was 26 mW from a 3 V supply.

A large-signal, transient model has been developed to predict the output characteristics of a CMUT array operated in the non-collapse mode. The model is based on separation of the nonlinear electrostatic voltage-to-force relation and the linear acoustic array response. For modeling of linear acoustic radiation and crosstalk effects, the boundary element method is used. The stiffness matrix in the vibroacoustics calculations is obtained using static finite element analysis of a single membrane which can have arbitrary geometry and boundary conditions. A lumped modeling approach is used to reduce the order of the system for modeling the transient nonlinear electrostatic actuation. To accurately capture the dynamics of the non-uniform electrostatic force distribution over the CMUT electrode during large deflections, the membrane electrode is divided into patches shaped to match higher order membrane modes, each introducing a variable to the system model. This reduced order nonlinear lumped model is solved in the time domain using commercial software. The model has two linear blocks to calculate the displacement profile of the electrode patches and the output pressure for a given force distribution over the array. The force-to-array-displacement block uses the linear acoustic model, and the Rayleigh integral is evaluated to calculate the pressure at any field point. Using the model, the time-domain transmitted pressure can be simulated for different large drive signal configurations. The acoustic model is verified by comparison to harmonic FEA in vacuum and fluid for high- and low-aspect-ratio membranes as well as mass-loaded membranes. The overall software model is verified by comparison to transient 3-D finite element analysis and experimental results for different large drive signals, and an example for a phased array simulation is given.

A new method of actuating atomic force microscopy (AFM) cantilevers is proposed in which a high frequency (>5 MHz) wave modulated by a lower frequency (~300 kHz) wave passes through a contact acoustic nonlinearity at the contact interface between the actuator and the cantilever chip. The nonlinearity converts the high frequency, modulated signal to a low frequency drive signal suitable for actuation of tapping-mode AFM probes. The higher harmonic content of this signal is filtered out mechanically by the cantilever transfer function, providing for clean output. A custom probe holder was designed and constructed using rapid prototyping technologies and off-the-shelf components and was interfaced with an Asylum Research MFP-3D AFM, which was then used to evaluate the performance characteristics with respect to standard hardware and linear actuation techniques. Using a carrier frequency of 14.19 MHz, it was observed that the cantilever output was cleaner with this actuation technique and added no significant noise to the system. This setup, without any optimization, was determined to have an actuation bandwidth on the order of 10 MHz, suitable for high speed imaging applications. Using this method, an image was taken that demonstrates the viability of the technique and is compared favorably to images taken with a standard AFM setup.

The authors describe a method for biomolecular force clamp measurements using atomic force microscope (AFM) cantilevers and micromachined membrane-based electrostatic actuators. The actuators comprise of Parylene membranes with embedded side actuation electrodes and are fabricated on a silicon substrate. The devices have a displacement range of 1.8 μm with 200 V actuation voltage, and displacement uncertainty is 0.8 nm, including the noise and drift. The settling time, limited by the particular amplifier is 5 ms, with an inherent range down to 20 μs. A force clamp measurement setup using these actuators in a feedback loop has been used to measure bond life-times between human IgG and anti-human IgG molecules to demonstrate the feasibility of this method for biological experiments. The experimental findings are compared with a molecular pulling experiment and the results are found to be in good agreement., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We designed and fabricated a dynamic receive beamformer integrated circuit (IC) in 0.35-μm CMOS technology. This beamformer IC is suitable for integration with an annular array transducer for high-frequency (30-50 MHz) intravascular ultrasound (IVUS) imaging. The beamformer IC consists of receive preamplifiers, an analog dynamic delay-and-sum beamformer, and buffers for 8 receive channels. To form an analog dynamic delay line we designed an analog delay cell based on the current-mode first-order all-pass filter topology, as the basic building block. To increase the bandwidth of the delay cell, we explored an enhancement technique on the current mirrors. This technique improved the overall bandwidth of the delay line by a factor of 6. Each delay cell consumes 2.1-mW of power and is capable of generating a tunable time delay between 1.75 ns to 2.5 ns. We successfully integrated the fabricated beamformer IC with an 8-element annular array. Experimental test results demonstrated the desired buffering, preamplification and delaying capabilities of the beamformer.

Ultrasound contrast agents (UCAs) have tremendous potential for in vivo molecular imaging because of their high sensitivity. However, the diagnostic potential of UCAs has been difficult to exploit because current UCAs are based on pre-formed microbubbles, which can only detect cell surface receptors. Here, we demonstrate that chemical reactions that generate gas forming molecules can be used to perform molecular imaging by ultrasound in vivo. This new approach was demonstrated by imaging reactive oxygen species in vivo with allylhydrazine, a liquid compound that is converted into nitrogen and propylene gas after reacting with radical oxidants. We demonstrate that allylhydrazine encapsulated within liposomes can detect a 10 micromolar concentration of radical oxidants by ultrasound, and can image oxidative stress in mice, induced by lipopolysaccharide, using a clinical ultrasound system. We anticipate numerous applications of chemically-generated microbubbles for molecular imaging by ultrasound, given ultrasound's ability to detect small increments above the gas saturation limit, its spatial resolution and widespread clinical use.

When capacitive micromachined ultrasonic transducers (CMUTs) are monolithically integrated with custom-designed low-noise electronics, the output noise of the system can be dominated by the CMUT thermal-mechanical noise both in air and in immersion even for devices with low capacitance. Because the thermal-mechanical noise can be related to the electrical admittance of the CMUTs, this provides an effective means of device characterization. This approach yields a novel method to test the functionality and uniformity of CMUT arrays and the integrated electronics when a direct connection to CMUT array element terminals is not available. Because these measurements can be performed in air at the wafer level, the approach is suitable for batch manufacturing and testing. We demonstrate this method on the elements of an 800-μm-diameter CMUT-on-CMOS array designed for intravascular imaging in the 10 to 20 MHz range. Noise measurements in air show the expected resonance behavior and spring softening effects. Noise measurements in immersion for the same array provide useful information on both the acoustic cross talk and radiation properties of the CMUT array elements. The good agreement between a CMUT model based on finite difference and boundary element methods and the noise measurements validates the model and indicates that the output noise is indeed dominated by thermal-mechanical noise. The measurement method can be exploited to implement CMUT-based passive sensors to measure immersion medium properties, or other parameters affecting the electro-mechanics of the CMUT structure.

The nonlinear relationship between the electrical input signal and electrostatic force acting on the capacitive micromachined ultrasonic transducer (CMUT) membrane limits its harmonic imaging performance. Several input shaping methods were proposed to compensate for the nonlinearity originating from the electrostatic force's dependence on the square of the applied voltage. Here, we analyze harmonic generation in CMUTs with a time-domain model. The model explains the basis of the input shaping methods and suggests that the nonlinearity resulting from gap dependence of the electrostatic force is also significant. It also suggests that the harmonic distortion in the output pressure can be eliminated by subharmonic ac-only excitation of the CMUT in addition to scaling the input voltage with the instantaneous gap. This gap feedback configuration can be approximated by the simple addition of a series impedance to the CMUT capacitance. We analyze several types of series impedance feedback topologies for gap feedback linearization. We show that for subharmonic ac excitation, although resistive and capacitive impedances result in a trade-off between input voltage and harmonic distortion for a desired pressure output, harmonic generation can be suppressed while increasing the Pa/V transmit sensitivity for proper series inductance and resistance feedback. We experimentally demonstrate the feedback method by reducing harmonic generation by 10 dB for the same output pressure at the fundamental frequency by using a simple series resistor feedback with a CMUT operating at a center frequency of 3 MHz. The proposed methods also allow for utilization of the full CMUT gap for transmit operation and, hence, should be useful in high-intensity ultrasonic applications in addition to harmonic imaging., (© 2012 IEEE)

An intravascular ultrasound (IVUS) catheter that can provide forward viewing volumetric ultrasound images would be an invaluable clinical tool for guiding interventions. Single chip integration of front-end electronics with capacitive micromachined ultrasonic transducers (CMUTs) is highly desirable to reduce the interconnection complexity and enable miniaturization in IVUS catheters. For this purpose we use the monolithic CMUT-on-CMOS integration where CMUTs are fabricated directly on top of pre-processed CMOS wafers. This minimizes parasitic capacitances associated with connection lines. We have recently implemented a system design including all the required electronics using 0.35-µm CMOS process integrated with a 1.4-mm diameter CMUT array. In this study, we present the experimental volumetric imaging results from an ex-vivo chicken heart phantom. The imaging results demonstrate that the single-chip forward looking IVUS (FL-IVUS) system with monolithically integrated electronics has potential to visualize the front view of coronary arteries.

Forward-looking (FL) catheter-based imaging systems are highly desirable for guiding interventions in intra- vascular ultrasound (IVUS) applications. One of the main challenges of array-based FL-IVUS systems is the large channel count, which results in increased system complexity. Synthetic phased-array processing with a reduced firing count simplifies the front-end and, hence, can enable 3-D real-time imaging. Recently, we have investigated dual-ring arrays suitable for IVUS imaging, in which the two concentric circular arrays are used separately as transmit (Tx) and receive (Rx) arrays. In this study, we present different optimized array designs based on dual and single circular rings which are suitable for synthetic phased-array processing with a reduced number of firings. To obtain an optimal firing set that produces low side lobes in the wideband response, we use a simulated annealing algorithm. In the simulations, we use 1.2-mm-diameter array configurations with 64 Tx and 58 Rx elements, a center frequency of 20 MHz and fractional bandwidths of 50% and 80%. The results show that optimized dual-ring arrays provide 8 dB improvements in peak near side-lobe level with no widening in the main lobe width when compared with full and other sparse co-arrays.

One of the most important promises of capacitive micromachined ultrasonic transducer (CMUT) technology is integration with electronics. This approach is required to minimize the parasitic capacitances in the receive mode, especially in catheter-based volumetric imaging arrays, for which the elements must be small. Furthermore, optimization of the available silicon area and minimized number of connections occurs when the CMUTs are fabricated directly above the associated electronics. Here, we describe successful fabrication and performance evaluation of CMUT arrays for intravascular imaging on custom-designed CMOS receiver electronics from a commercial IC foundry. The CMUT-on-CMOS process starts with surface isolation and mechanical planarization of the CMOS electronics to reduce topography. The rest of the CMUT fabrication is achieved by modifying a low-temperature micromachining process through the addition of a single mask and developing a dry etching step to produce sloped sidewalls for simple and reliable CMUT-to-CMOS interconnection. This CMUT-to-CMOS interconnect method reduced the parasitic capacitance by a factor of 200 when compared with a standard wire-bonding method. Characterization experiments indicate that the CMUT-on-CMOS elements are uniform in frequency response and are similar to CMUTs simultaneously fabricated on standard silicon wafers without electronics integration. Ex- periments on a 1.6-mm-diameter dual-ring CMUT array with a center frequency of 15 MHz show that both the CMUTs and the integrated CMOS electronics are fully functional. The SNR measurements indicate that the performance is adequate for imaging chronic total occlusions located 1 cm from the CMUT array.

The authors describe a method of actuation for atomic force microscope (AFM) probes to improve imaging speed and displacement range simultaneously. Unlike conventional piezoelectric tube actuation, the proposed method involves a lever and fulcrum "seesaw" like actuation mechanism that uses a small, fast piezoelectric transducer. The lever arm of the seesaw mechanism increases the apparent displacement range by an adjustable gain factor, overcoming the standard tradeoff between imaging speed and displacement range. Experimental characterization of a cantilever holder implementing the method is provided together with comparative line scans obtained with contact mode imaging. An imaging bandwidth of 30 kHz in air with the current setup was demonstrated.

Distinct regimes of droplet charging, determined by the dominant charge transport process, are identified for an ultrasonic droplet ejector using electrohydrodynamic computational simulations, a fundamental scale analysis, and experimental measurements. The regimes of droplet charging are determined by the relative magnitudes of the dimensionless Strouhal and electric Reynolds numbers, which are a function of the process (pressure forcing), advection, and charge relaxation time scales for charge transport. Optimal (net maximum) droplet charging has been identified to exist for conditions in which the electric Reynolds number is of the order of the inverse Strouhal number, i.e., the charge relaxation time is on the order of the pressure forcing (droplet formation) time scale. The conditions necessary for optimal droplet charging have been identified as a function of the dimensionless Debye number (i.e., liquid conductivity), external electric field (magnitude and duration), and atomization drive signal (frequency and amplitude). The specific regime of droplet charging also determines the functional relationship between droplet charge and charging electric field strength. The commonly expected linear relationship between droplet charge and external electric field strength is only found when either the inverse of the Strouhal number is less than the electric Reynolds number, i.e., the charge relaxation is slower than both the advection and external pressure forcing, or in the electrostatic limit, i.e., when charge relaxation is much faster than all other processes. The analysis provides a basic understanding of the dominant physics of droplet charging with implications to many important applications, such as electrospray mass spectrometry, ink jet printing, and drop-on-demand manufacturing.

The authors describe a method where quantitative ultrasonic atomic force microscopy (UAFM) is achieved during time-resolved interaction force (TRIF) imaging in intermittent contact mode. The method uses a calibration procedure for quantitative UAFM. It improves elasticity measurements of stiff regions of surfaces while retaining the capabilities of the TRIF mode for topography, adhesion, dissipation, and elasticity measurements on soft regions of sample surfaces. This combination is especially advantageous when measuring and imaging samples with broad stiffness range in a nondestructive manner. The experiments utilize an active AFM probe with high bandwidth and the UAFM calibration is performed by measuring the magnitude of the time-resolved UAFM signal at a judiciously chosen frequency for different contact stiffness values during individual taps. Improved sensitivity to stiff surface elasticity is demonstrated on a special sample. The results show that combining UAFM with TRIF provides 2.5 GPa (5%) standard deviation on the silicon surface reduced Young's modulus, representing 5× improvement over using only TRIF mode imaging.

The physical processes governing the transition from purely mechanical ejection to electromechanical ejection to electrospraying are investigated through complementary scaling analysis and optical visualization. Experimental characterization and visualization are performed with the ultrasonically-driven array of micromachined ultrasonic electrospray (AMUSE) ion source to decouple the electrical and mechanical fields. A new dimensionless parameter, the Fenn number, is introduced to define a transition between the spray regimes, in terms of its dependence on the characteristic Strouhal number for the ejection process. A fundamental relationship between the Fenn and Strouhal numbers is theoretically derived and confirmed experimentally in spraying liquid electrolytes of different ionic strength subjected to a varying magnitude electric field. This relationship and the basic understanding of the charged droplet generation physics have direct implications on the optimal ionization efficiency and mass spectrometric response for different types of analytes., (Copyright © 2010. Published by Elsevier Inc.)

Electrochemistry and ion transport in a planar array of mechanically-driven, droplet-based ion sources are investigated using an approximate time scale analysis and in-depth computational simulations. The ion source is modeled as a controlled-current electrolytic cell, in which the piezoelectric transducer electrode, which mechanically drives the charged droplet generation using ultrasonic atomization, also acts as the oxidizing/corroding anode (positive mode). The interplay between advective and diffusive ion transport of electrochemically generated ions is analyzed as a function of the transducer duty cycle and electrode location. A time scale analysis of the relative importance of advective vs. diffusive ion transport provides valuable insight into optimality, from the ionization prospective, of alternative design and operation modes of the ion source operation. A computational model based on the solution of time-averaged, quasi-steady advection-diffusion equations for electroactive species transport is used to substantiate the conclusions of the time scale analysis. The results show that electrochemical ion generation at the piezoelectric transducer electrodes located at the back-side of the ion source reservoir results in poor ionization efficiency due to insufficient time for the charged analyte to diffuse away from the electrode surface to the ejection location, especially at near 100% duty cycle operation. Reducing the duty cycle of droplet/analyte ejection increases the analyte residence time and, in turn, improves ionization efficiency, but at an expense of the reduced device throughput. For applications where this is undesirable, i.e., multiplexed and disposable device configurations, an alternative electrode location is incorporated. By moving the charging electrode to the nozzle surface, the diffusion length scale is greatly reduced, drastically improving ionization efficiency. The ionization efficiency of all operating conditions considered is expressed as a function of the dimensionless Peclet number, which defines the relative effect of advection as compared to diffusion. This analysis is general enough to elucidate an important role of electrochemistry in ionization efficiency of any arrayed ion sources, be they mechanically-driven or electrosprays, and is vital for determining optimal design and operation conditions.

Charge transport and separation in mechanically-driven, droplet-based ion sources are investigated using computational analysis and supporting experiments. A first-principles model of electrohydrodynamics (EHD) and charge migration is formulated and implemented using FLUENT CFD software for jet/droplet formation. For validation, classical experiments of electrospraying from a thin capillary are simulated, specifically, the transient EHD cone-jet formation of a fluid with finite electrical conductivity, and the Taylor cone formation in a perfectly electrically-conducting fluid. The model is also used to investigate the microscopic physics of droplet charging in mechanically-driven droplet-based ion sources, such as array of micromachined ultrasonic electrospray (AMUSE). Here, AMUSE is subject to DC and AC electric fields of varying amplitude and phase, with respect to a time-varying mechanical force driving the droplet formation. For the DC-charging case, a linear relationship is demonstrated between the charge carried by each droplet and an applied electric field magnitude, in agreement with previously reported experiments. For the AC-charging case, a judiciously-chosen phase-shift in the time-varying mechanical (driving ejection) and electrical (driving charge transport) signals allows for a significantly increased amount of charge, of desired polarity, to be pumped into a droplet upon ejection. Complementary experimental measurements of electrospray electrical current and charge-per-droplet, produced by the AMUSE ion source, are performed and support theoretical predictions for both DC- and AC-charging cases. The theoretical model and simulation tools provide a versatile and general analytical framework for fundamental investigations of coupled electrohydrodynamics and charge transport. The model also allows for the exploration of different configurations and operating modes to optimize charge separation in atmospheric pressure electrohydrodynamic ion sources under static and dynamic electrical and mechanical fields., (2010 American Society for Mass Spectrometry. Published by Elsevier Inc. All rights reserved.)