Butrus T. Khuri-Yakub

Carbon nanotubes as photoacoustic molecular imaging agents in living mice

Photoacoustic imaging of living subjects offers higher spatial resolution and allows deeper tissues to be imaged compared with most optical imaging techniques. As many diseases do not exhibit a natural photoacoustic contrast, especially in their early stages, it is necessary to administer a photoacoustic contrast agent. A number of contrast agents for photoacoustic imaging have been suggested previously, but most were not shown to target a diseased site in living subjects. Here we show that single-walled carbon nanotubes conjugated with cyclic Arg-Gly-Asp (RGD) peptides can be used as a contrast agent for photoacoustic imaging of tumours. Intravenous administration of these targeted nanotubes to mice bearing tumours showed eight times greater photoacoustic signal in the tumour than mice injected with non-targeted nanotubes. These results were verified ex vivo using Raman microscopy. Photoacoustic imaging of targeted single-walled carbon nanotubes may contribute to non-invasive cancer imaging and monitoring of nanotherapeutics in living subjects.

Surface micromachined capacitive ultrasonic transducers

The current state of novel technology, surface microfabricated ultrasonic transducers, is reported. Experiments demonstrating both air and water transmission are presented. Air-coupled longitudinal wave transmission through aluminum is demonstrated, implying a 110 dB dynamic range for transducers at 2.3 MHz in air. Water transmission experiments from 1 to 20 MHz are performed, with a measured 60 dB SNR at 3 MHz. A theoretical model is proposed that agrees well with observed transducer behavior. Most significantly, the model is used to demonstrate that microfabricated ultrasonic transducers constitute an attractive alternative to piezoelectric transducers in many applications.

Capacitive micromachined ultrasonic transducers: next-generation arrays for acoustic imaging?

Piezoelectric materials have dominated the ultrasonic transducer technology. Recently, capacitive micromachined ultrasonic transducers (CMUTs) have emerged as an alternative technology offering advantages such as wide bandwidth, ease of fabricating large arrays, and potential for integration with electronics. The aim of this paper is to demonstrate the viability of CMUTs for ultrasound imaging. We present the first pulse-echo phased array B-scan sector images using a 128-element, one-dimensional (1-D) linear CMUT array. We fabricated 64- and 128-element 1-D CMUT arrays with 100% yield and uniform element response across the arrays. These arrays have been operated in immersion with no failure or degradation in performance over the time. For imaging experiments, we built a resolution test phantom roughly mimicking the attenuation properties of soft tissue. We used a PC-based experimental system, including custom-designed electronic circuits to acquire the complete set of 128/spl times/128 RF A-scans from all transmit-receive element combinations. We obtained the pulse-echo frequency response by analyzing the echo signals from wire targets. These echo signals presented an 80% fractional bandwidth around 3 MHz, including the effect of attenuation in the propagating medium. We reconstructed the B-scan images with a sector angle of 90 degrees and an image depth of 210 mm through offline processing by using RF beamforming and synthetic phased array approaches. The measured 6-dB lateral and axial resolutions at 135 mm depth were 0.0144 radians and 0.3 mm, respectively. The electronic noise floor of the image was more than 50 dB below the maximum mainlobe magnitude. We also performed preliminary investigations on the effects of crosstalk among array elements on the image quality. In the near field, some artifacts were observable extending out from the array to a depth of 2 cm. A tail also was observed in the point spread function (PSF) in the axial direction, indicating the existence of crosstalk. The relative amplitude of this tail with respect to the mainlobe was less than -20 dB.

Ultrahigh Sensitivity Carbon Nanotube Agents for Photoacoustic Molecular Imaging in Living Mice

Photoacoustic imaging is an emerging modality that overcomes to a great extent the resolution and depth limitations of optical imaging while maintaining relatively high-contrast. However, since many diseases will not manifest an endogenous photoacoustic contrast, it is essential to develop exogenous photoacoustic contrast agents that can target diseased tissue(s). Here we present a novel photoacoustic contrast agent, Indocyanine Green dye-enhanced single walled carbon nanotube (SWNT-ICG). We conjugated this contrast agent with cyclic Arg-Gly-Asp (RGD) peptides to molecularly target the alpha(v)beta(3) integrins, which are associated with tumor angiogenesis. Intravenous administration of this tumor-targeted contrast agent to tumor-bearing mice showed significantly higher photoacoustic signal in the tumor than in mice injected with the untargeted contrast agent. The new contrast agent gave a markedly 300 times higher photoacoustic contrast in living tissues than previously reported SWNTs, leading to subnanomolar sensitivities. Finally, we show that the new contrast agent can detect approximately 20 times fewer cancer cells than previously reported SWNTs.

Fabricating capacitive micromachined ultrasonic transducers with wafer-bonding technology

Introduces a new method for fabricating capacitive micromachined ultrasonic transducers (CMUTs) that uses a wafer bonding technique. The transducer membrane and cavity are defined on an SOI (silicon-on-insulator) wafer and on a prime wafer, respectively. Then, using silicon direct bonding in a vacuum environment, the two wafers are bonded together to form a transducer. This new technique, capable of fabricating large CMUTs, offers advantages over the traditionally micromachined CMUTs. First, forming a vacuum-sealed cavity is relatively easy since the wafer bonding is performed in a vacuum chamber. Second, this process enables better control over the gap height, making it possible to fabricate very small gaps (less than 0.1 /spl mu/m). Third, since the membrane is made of single crystal silicon, it is possible to predict and control the mechanical properties of the membrane to within 5%. Finally, the number of process steps involved in making a CMUT has been reduced from 22 to 15, shortening the device turn-around time. All of these advantages provide repeatable fabrication of CMUTs featuring predictable center frequency, bandwidth, and collapse voltage.

A surface micromachined electrostatic ultrasonic air transducer

We describe a technique to fabricate an electrostatic transducer using silicon surface micromachining. Using these techniques to fabricate arrays of transducers with small electrode spacing, we make efficient and broadband ultrasonic air transducers. These transducers are made using standard silicon processing techniques allowing them to be integrated, in the future, with control electronics for the fabrication of electronically scanned systems with large transducer arrays. The air transducer described in this paper operates at 1.9 MHz with an insertion loss of 26 dB (slightly worse than a reference piezoelectric transducer) and a 20% bandwidth (-4 times better than the piezoelectric transducer). The impulse response of the transducer has a short ringdown time due to the fact that the transducer has a single resonance. We present here the theory of operation, the fabrication technique used, and the characterization of the device

Capacitive micromachined ultrasonic transducers: fabrication technology

Capacitive micromachined ultrasonic transducer (MUT) technology is a prime candidate for next generation imaging systems. Medical and underwater imaging and the nondestructive evaluation (NDE) societies have expressed growing interest in cMUTs over the years. Capacitive micromachined ultrasonic transducer technology is expected to make a strong impact on imaging technologies, especially volumetric imaging, and to appear in commercial products in the near future. This paper focuses on fabrication technologies for cMUTs and reviews and compares variations in the production processes. We have developed two main approaches to the fabrication of cMUTs: the sacrificial release process and the recently introduced wafer-bonding method. This paper gives a thorough review of the sacrificial release processes, and it describes the new wafer-bonding method in detail. Process variations are compared qualitatively and quantitatively whenever possible. Through these comparisons, it was concluded that wafer-bonded cMUT technology was superior in terms of process control, yield, and uniformity. Because the number of steps and consequent process time were reduced (from six-mask process to four-mask process), turn-around time was improved significantly.

Integration of 2D CMUT arrays with front-end electronics for volumetric ultrasound imaging

For three-dimensional (3D) ultrasound imaging, connecting elements of a two-dimensional (2D) transducer array to the imaging systems front-end electronics is a challenge because of the large number of array elements and the small element size. To compactly connect the transducer array with electronics, we flip-chip bond a 2D 16 times 16-element capacitive micromachined ultrasonic transducer (CMUT) array to a custom-designed integrated circuit (IC). Through-wafer interconnects are used to connect the CMUT elements on the top side of the array with flip-chip bond pads on the back side. The IC provides a 25-V pulser and a transimpedance preamplifier to each element of the array. For each of three characterized devices, the element yield is excellent (99 to 100% of the elements are functional). Center frequencies range from 2.6 MHz to 5.1 MHz. For pulse-echo operation, the average -6-dB fractional bandwidth is as high as 125%. Transmit pressures normalized to the face of the transducer are as high as 339 kPa and input-referred receiver noise is typically 1.2 to 2.1 rnPa/ radicHz. The flip-chip bonded devices were used to acquire 3D synthetic aperture images of a wire-target phantom. Combining the transducer array and IC, as shown in this paper, allows for better utilization of large arrays, improves receive sensitivity, and may lead to new imaging techniques that depend on transducer arrays that are closely coupled to IC electronics.

Fabrication and characterization of surface micromachined capacitive ultrasonic immersion transducers

In this paper, several innovative steps used in fabricating surface micromachined capacitive ultrasonic immersion transducers are reported. The investigation is focused on major steps in the device fabrication processes necessary to optimize transducer performance. Such steps include membrane formation, vacuum sealing, and electrode metallization. Three transducer membrane structures are evaluated: a nitride membrane with an oxide sacrificial layer; a polysilicon membrane with an oxide sacrificial layer; and a nitride membrane with a polysilicon sacrificial layer. Three vacuum sealing mechanisms are compared, each of which requires a different degree of lithographic sophistication, uses a particular sealing mechanism, and results in a sealed cavity. Submicrometer via sealing requires sophisticated lithography but is amenable to LPCVD nitride, LTO, and other sealing procedures. Standard g-line lithography results in vies which seal only with high sticking coefficient species, such as LTO. A novel etch channel structure, which results in lateral sealing and requires neither sophisticated lithography nor a particular sealing material, is demonstrated. Finally, the impact of electrode metallization on the impedance, bandwidth, and efficiency of the transducers is discussed. The experiments in the paper are guided by theoretical analysis and computer simulations when applicable. The new process results in optimized devices which have a broad-band 50-/spl Omega/ real part impedance in the megahertz range. A transducer dynamic range in excess of 100 dB is achieved around 4.5 MHz. An untuned transducer exhibits more than 100% bandwidth when connected to electronics with 50-/spl Omega/ input impedance. In addition, beam pattern measurement shows the immersion devices behave like uniform piston transducers and are readily suitable for array applications. The fabrication techniques and results herein reported indicate that surface micromachined ultrasonic immersion transducers are an attractive alternative to piezoelectric transducers in immersion applications.

Nozzleless droplet formation with focused acoustic beams

We report the use of focused acoustic beams to eject discrete droplets of controlled diameter and velocity from a free‐liquid surface. No nozzles are involved. Droplet formation has been experimentally demonstrated over the frequency range of 5–300 MHz, with corresponding droplet diameters from 300 to 5 μm. The physics of droplet formation is essentially unchanged over this frequency range. For acoustic focusing elements having similar geometries, droplet diameter has been found to scale inversely with the acoustic frequency. A simple model is used to obtain analytical expressions for the key parameters of droplet formation and their scaling with acoustic frequency. Also reported is a more detailed theory which includes the linear propagation of the focused acoustic wave, the coupling of the acoustic fields to the initial surface velocity potential, and the subsequent dynamics of droplet formation. This latter phase is modeled numerically as an incompressible, irrotational process using a boundary integra...