Srikant Vaithilingam

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.

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.

Three-dimensional photoacoustic imaging using a two-dimensional CMUT array

In this paper, we describe using a 2-D array of capacitive micromachined ultrasonic transducers (CMUTs) to perform 3-D photoacoustic and acoustic imaging. A tunable optical parametric oscillator laser system that generates nanosecond laser pulses was used to induce the photoacoustic signals. To demonstrate the feasibility of the system, 2 different phantoms were imaged. The first phantom consisted of alternating black and transparent fishing lines of 180 μm and 150 μm diameter, respectively. The second phantom comprised polyethylene tubes, embedded in chicken breast tissue, filled with liquids such as the dye indocyanine green, pig blood, and a mixture of the 2. The tubes were embedded at a depth of 0.8 cm inside the tissue and were at an overall distance of 1.8 cm from the CMUT array. Two-dimensional cross-sectional slices and 3-D volume rendered images of pulse-echo data as well as photoacoustic data are presented. The profile and beamwidths of the fishing line are analyzed and compared with a numerical simulation carried out using the Field II ultrasound simulation software. We investigated using a large aperture (64 x 64 element array) to perform photoacoustic and acoustic imaging by mechanically scanning a smaller CMUT array (16 x 16 elements). Two-dimensional transducer arrays overcome many of the limitations of a mechanically scanned system and enable volumetric imaging. Advantages of CMUT technology for photoacoustic imaging include the ease of integration with electronics, ability to fabricate large, fully populated 2-D arrays with arbitrary geometries, wide-bandwidth arrays and high-frequency arrays. A CMUT based photoacoustic system is proposed as a viable alternative to a piezoelectric transducer based photoacoustic systems.

Deep Tissue Photoacoustic Imaging Using a Miniaturized 2-D Capacitive Micromachined Ultrasonic Transducer Array

In this paper, we demonstrate 3-D photoacoustic imaging (PAI) of light absorbing objects embedded as deep as 5 cm inside strong optically scattering phantoms using a miniaturized (4 mm × 4 mm × 500 μm), 2-D capacitive micromachined ultrasonic transducer (CMUT) array of 16 × 16 elements with a center frequency of 5.5 MHz. Two-dimensional tomographic images and 3-D volumetric images of the objects placed at different depths are presented. In addition, we studied the sensitivity of CMUT-based PAI to the concentration of indocyanine green dye at 5 cm depth inside the phantom. Under optimized experimental conditions, the objects at 5 cm depth can be imaged with SNR of about 35 dB and a spatial resolution of approximately 500 μm. Results demonstrate that CMUTs with integrated front-end amplifier circuits are an attractive choice for achieving relatively high depth sensitivity for PAI.

An endoscopic imaging system based on a two-dimensional CMUT array: real-time imaging results

Real-time catheter-based ultrasound imaging tools are needed for diagnosis and image-guided procedures. The continued development of these tools is partially limited by the difficulty of fabricating two-dimensional array geometries of piezoelectric transducers. Using capacitive micromachined ultrasonic transducer (CMUT) technology, transducer arrays with widely varying geometries, high frequencies, and wide bandwidths can be fabricated. A volumetric ultrasound imaging system based on a two-dimensional, 16×16-element, CMUT array is presented. Transducer arrays with operating frequencies ranging from 3 MHz to 7.5 MHz were fabricated for this system. The transducer array including DC bias pads measures 4 mm by 4.7 mm. The transducer elements are connected to flip-chip bond pads on the array back side with 400-µm long through-wafer interconnects. The array is flip-chip bonded to a custom- designed integrated circuit (IC) that comprises the front-end electronics. Integrating the front-end electronics with the transducer array reduces the effects of cable capacitance on the transducers performance and provides a compact means of connecting to the transducer elements. The front-end IC provides a 27-V pulser and 10-MHz bandwidth amplifier for each element of the array. An FPGA-based data acquisition system is used for control and data acquisition. Output pressure of 230 kPa was measured for the integrated device. A receive sensitivity of 125 mV/kPa was measured at the output of the amplifier. Amplifier output noise at 5 Mhz is 112 nV/√Hz. Volumetric images of a wire phantom and vessel phantom are presented. Volumetric data for a wire phantom was acquired in real-time at 30 frames per second. Keywords-ultrasound imaging, catheter, capacitive micromachined ultrasonic transducer, CMUT, integrated electronics, volumetric, real-time

CMUT fabrication based on a thick buried oxide layer

We introduce a versatile fabrication process for direct wafer-bonded CMUTs. The objective is a flexible fabrication platform for single element transducers, 1D and 2D arrays, and reconfigurable arrays. The main process features are: A low number of litho masks (five for a fully populated 2D array); a simple fabrication sequence on standard MEMS tools without complicated wafer handling (carrier wafers); an improved device reliability; a wide design space in terms of operation frequency and geometric parameters (cell diameter, gap height, effective insulation layer thickness); and a continuous front face of the transducer (CMUT plate) that is connected to ground (shielding for good SNR and human safety in medical applications). All of this is achieved by connecting the hot electrodes individually through a thick buried oxide layer, i.e. from the handle layer of an SOI substrate to silicon electrodes located in each CMUT cell built in the device layer. Vertical insulation trenches are used to isolate these silicon electrodes from the rest of the substrate. Thus, the high electric field is only present where required — in the evacuated gap region of the device and not in the insulation layer of the post region. Array elements (1D and 2D) are simply defined be etching insulation trenches into the handle wafer of the SOI substrate.

Multi-row linear cMUT array using cMUTs and multiplexing electronics

A large area reconfigurable imaging array for research purposes is being developed with co-integrated cMUTs and control electronics. The goal is a 2.5cm 2D tileable module with ≫16,000 transducer sub-elements spaced at a pitch of 185um in X and Y dimensions. As a prototype demonstration of some of the goals of this effort, a multi-row linear array using cMUTs and external multiplexing electronics was designed and fabricated. In this paper the challenges of trenched cMUT attach to a laminate interposer as part of a tileable module will be discussed. The architecture of the tileable module build-up for manufacturability, reliability, acoustic planarity, and reduced spacing between tiles and cMUT chips will also be addressed. Finally, a first prototype will be shown and experimental acoustic results with the new cMUT-based probe will be presented.

Capacitive micromachined ultrasonic transducers (CMUTs) for photoacoustic imaging

In photoacoustic (optoacoustic) medical imaging, short laser pulses irradiate absorbing structures found in tissue, such as blood vessels, causing brief thermal expansions that in turn generate ultrasound waves. These ultrasound waves which correspond to the optical absorption distribution were imaged using a two dimensional array of capacitive micromachined ultrasonic transducers (CMUTs). Advantages of CMUT technology for photoacoustic imaging include the ease of integration with electronics, ability to fabricate large two dimensional arrays, arrays with arbitrary geometries, wide-bandwidth arrays and high-frequency arrays. In this study, a phantom consisting of three 0.86-mm inner diameter polyethylene tubes inside a tissue mimicking material was imaged using a 16 x 16 element CMUT array. The center tube was filled with India-ink to provide optical contrast. Traditional pulse-echo data as well as photoacoustic image data were taken. 2D cross-sectional slices and 3D volume rendered images are shown. Simple array tiling was attempted, whereby a 48 x 48 element array was simulated, to illustrate the advantages of larger arrays. Finally, the sensitivity of the photoacoustics setup to the concentration of ink in the tube was also explored. For the sensitivity experiment a different phantom consisting of only one 1.14-mm inner diameter polyethylene tube inside a tissue mimicking material was used. The concentration of the ink inside the tube was varied and images were taken.

Integrated ultrasound imaging systems based on capacitive micromachined ultrasonic transducer arrays

Capacitive micromachined ultrasonic transducers (CMUTs) overcome many limitations of existing ultrasound transducer technologies enabling new applications of ultrasound, especially for medical imaging and treatment. Some of the most important of these advancements are the ability to fabricate transducer arrays with two dimensional geometries and high operating frequencies. Over the past decade, extensive research has been conducted on the fabrication, characterization, and modelling of CMUTs. Current research efforts focus on the integration of CMUTs in systems for new medical imaging tools. This paper briefly reviews CMUT technology and presents imaging results from two CMUT-based imaging systems. The first system is designed for use within a 5-mm endoscopic channel and is based on a two dimensional, 16-element times 16-element, 5-MHz CMUT array. To provide a means of integrating the CMUT array with electronics, each element of the array is connected to a flip-chip bond pad on the back side of the array via a through-wafer interconnect. The array is flip-chip bonded to a custom-designed integrated circuit (IC) that comprises the frontend circuitry for the transducer elements. The array and IC are connected to an FPGA-based data acquisition system that can acquire volumetric imaging data in real time. Volumetric pulse-echo and photoacoustic images obtained with this system are presented. The second system is based on a 64-element, 20-MHz, 2-mm diameter CMUT ring array. This array is also designed for use in catheter-based imaging applications. Ring arrays have the advantage of providing space in the center for a guidewire or other catheter-based instrument. Volumetric images obtained with the ring-array system are also presented

CMUTs for air coupled ultrasound with improved bandwidth

We present the design, fabrication and characterization of a multi-purpose capacitive micromachined ultrasonic transducer (CMUT) for air coupled ultrasound (~300-500 kHz), with a focus on improved bandwidth. The focus of this work is to investigate whether and how wafer-bonded CMUTs can be improved in terms of bandwidth for airborne ultrasound by intentionally varying the cell radii across the entire device. Further, we consider the differences in terms of static d.c. operation point for improved frequency response and predictability by using a sensitivity-weighted distribution of cell radii groups. The pitch-catch results from one of our designs, compared to a reference device (all cell radii identical), show that the -6 db fractional bandwidth (FBW) can be improved from 1% up to 2.5%. For many applications, in which the -14 db duration signal (ASTM E1065) plays a role, the improvement goes from 1% to 18.9%. The observed improvements support the argument that such CMUTs will be beneficial for ultrasonic transit-time detection based applications.