Angle-insensitive amorphous silicon optical filter for fluorescence contact imaging.

We introduce a novel amorphous silicon absorption filter that has high rejection for all angles of incident light for wavelengths below approximately 700 nm. This filter is used for microscopic cancer tissue detection in a small intraoperative contact fluorescence imaging system that requires excitation light at oblique angles. Our 15 µm thick filter presents over five orders of magnitude rejection at 633 nm, making it compatible with several clinically tested fluorophores, including IR700DX. We have demonstrated imaging of fluorescently labeled human epidermal growth factor receptor 2+ breast cancer tissue using the filter, and we can reliably detect microscopic clusters of breast cancer cells with only a 75 ms integration time.

Chip-Scale Angle-Selective Imager for In Vivo Microscopic Cancer Detection.

We present an image sensor incorporating angle-selective gratings for resolution enhancement in contact imaging applications. Optical structures designed in the CMOS metal layers above each photodiode form the angle-selective gratings that limit the sensor angle of view to ±18 °, rejecting background light and deblurring the image. The imager is based on a high-gain capacitive transimpedance amplifier pixel using a custom 11fF MOM capacitor, achieving [Formula: see text] sensitivity. The pixel includes a leakage current minimization circuit to remove signal-dependent reset switch leakage and the corresponding dark current is [Formula: see text]. The resulting 4.7 mm by 2.25 mm sensor (80 by 36 pixels) is designed specifically for intraoperative cancer imaging in order to solve the pervasive challenge of identifying microscopic residual cancer foci in vivo, where they can be removed. We demonstrate imaging and detection of foci containing less than 200 cancer cells labeled with fluorescent biomarkers in 50 ms with signal-to-noise ratios greater than 15 dB and the detection of microscopic residual tumor in mice models. The absence of large optical elements enables extreme miniaturization, allowing manipulation within a small, morphologically complex, tumor cavity.

Real-time cancer detection with an integrated lensless fluorescence contact imager.

Microscopic tumor cell foci left in a patient after surgery significantly increase the chance of cancer recurrence. However, fluorescence microscopes used for intraoperative navigation lack the necessary sensitivity for imaging microscopic disease and are too bulky to maneuver within the resection cavity. We have developed a scalable chip-scale fluorescence contact imager for detecting microscopic cancer in vivo and in real-time. The imager has been characterized under simulated in vivo conditions using ex vivo samples, providing strong evidence that our device can be used in vivo. Angle-selective gratings enhance the resolution of the imager without impacting its physical size. We demonstrate detection of cancer cell clusters containing as few as 25 HCC1569 breast cancer cells and 400 LNCaP prostate cancer cells with integration times of only 50 ms and 70 ms, respectively. A cell cluster recognition algorithm is used to achieve both a sensitivity and specificity of 92 % for HCC1569 cell samples, indicating the reliability of the imager. The signal-to-noise ratio (SNR) degradation with increased separation is only 1.5 dB at 250 µm. Blood scattering and absorption reduce the SNR by less than 2 dB for typical concentrations. Moreover, HER2+ breast cancer tissue taken from a patient is distinguished from normal breast tissue with an integration time of only 75 ms.

Imaging of IR700DX Labeled Mouse Breast Tumor Using a Custom Angle-Selective Fluorescence Contact Imaging System.

Cancer treatment faces the challenge of identifying small clusters of residual tumor cells in the resection cavity after the gross section of tumor is surgically removed. Despite the introduction of targeted fluorescent probes to guide cancer surgeries, large, bulky, optical components restrict the ability of fluorescence imaging devices to detect small clusters of tumor cells in the complex surgical cavity. We have developed a small size-scale contact fluorescence image sensor that incorporates angle-selective gratings and a thin 15 m amorphous silicon optical wavelength filter for detecting residual cancer tissue in vivo. Using a custom fluorescent probe combining a fluorescent dye, IR700DX, with a targeted antibody, Trastuzumab, we label and visualize breast tissue in in vivo mouse models of breast cancer. When imaging tumorbearing mice injected with the probe, HER2+ breast cancer tissue intensity is 3.80.8 times brighter than other tissue. Excised cancer tumors and residual cancer attached to healthy tissue are imaged using the custom image sensor. Residual cancer tissue can be detected in real-time and is imaged with a high SNR of 45 dB using an integration time of only 40 ms.

Rodent wearable ultrasound system for wireless neural recording.

Advances in minimally-invasive, distributed biological interface nodes enable possibilities for networks of sensors and actuators to connect the brain with external devices. The recent development of the neural dust sensor mote has shown that utilizing ultrasound backscatter communication enables untethered sub-mm neural recording devices. These implanted sensor motes require a wearable external ultrasound interrogation device to enable in-vivo, freely-behaving neural interface experiments. However, minimizing the complexity and size of the implanted sensors shifts the power and processing burden to the external interrogator. In this paper, we present an ultrasound backscatter interrogator that supports real-time backscatter processing in a rodent-wearable, completely wireless device. We demonstrate a generic digital encoding scheme which is intended for transmitting neural information. The system integrates a front-end ultrasonic interface ASIC with off-the-shelf components to enable a highly compact ultrasound interrogation device intended for rodent neural interface experiments but applicable to other model systems.

Ultrasonic Fingerprint Sensor With Transmit Beamforming Based on a PMUT Array Bonded to CMOS Circuitry.

In this paper, we present a single-chip 65 ×42 element ultrasonic pulse-echo fingerprint sensor with transmit (TX) beamforming based on piezoelectric micromachined ultrasonic transducers directly bonded to a CMOS readout application-specific integrated circuit (ASIC). The readout ASIC was realized in a standard 180-nm CMOS process with a 24-V high-voltage transistor option. Pulse-echo measurements are performed column-by-column in sequence using either one column or five columns to TX the ultrasonic pulse at 20 MHz. TX beamforming is used to focus the ultrasonic beam at the imaging plane where the finger is located, increasing the ultrasonic pressure and narrowing the 3-dB beamwidth to [Formula: see text], a factor of 6.4 narrower than nonbeamformed measurements. The surface of the sensor is coated with a poly-dimethylsiloxane (PDMS) layer to provide good acoustic impedance matching to skin. Scanning laser Doppler vibrometry of the PDMS surface was used to map the ultrasonic pressure field at the imaging surface, demonstrating the expected increase in pressure, and reduction in beamwidth. Imaging experiments were conducted using both PDMS phantoms and real fingerprints. The average image contrast is increased by a factor of 1.5 when beamforming is used.

Monolithic ultrasound fingerprint sensor.

This paper presents a 591×438-DPI ultrasonic fingerprint sensor. The sensor is based on a piezoelectric micromachined ultrasonic transducer (PMUT) array that is bonded at wafer-level to complementary metal oxide semiconductor (CMOS) signal processing electronics to produce a pulse-echo ultrasonic imager on a chip. To meet the 500-DPI standard for consumer fingerprint sensors, the PMUT pitch was reduced by approximately a factor of two relative to an earlier design. We conducted a systematic design study of the individual PMUT and array to achieve this scaling while maintaining a high fill-factor. The resulting 110×56-PMUT array, composed of 30×43-µm2 rectangular PMUTs, achieved a 51.7% fill-factor, three times greater than that of the previous design. Together with the custom CMOS ASIC, the sensor achieves 2 mV kPa-1 sensitivity, 15 kPa pressure output, 75 µm lateral resolution, and 150 µm axial resolution in a 4.6 mm×3.2 mm image. To the best of our knowledge, we have demonstrated the first MEMS ultrasonic fingerprint sensor capable of imaging epidermis and sub-surface layer fingerprints.

Ultrasonic beamforming system for interrogating multiple implantable sensors.

In this paper, we present an ultrasonic beamforming system capable of interrogating individual implantable sensors via backscatter in a distributed, ultrasound-based recording platform known as Neural Dust [1]. A custom ASIC drives a 7 × 2 PZT transducer array with 3 cycles of 32V square wave with a specific programmable time delay to focus the beam at the 800mm neural dust mote placed 50mm away. The measured acoustic-to-electrical conversion efficiency of the receive mote in water is 0.12% and the overall system delivers 26.3% of the power from the 1.8V power supply to the transducer drive output, consumes 0.75µJ in each transmit phase, and has a 0.5% change in the backscatter per volt applied to the input of the backscatter circuit. Further miniaturization of both the transmit array and the receive mote can pave the way for a wearable, chronic sensing and neuromodulation system.

Miniaturizing Ultrasonic System for Portable Health Care and Fitness.

We present a miniaturized portable ultrasonic imager that uses a custom ASIC and a piezoelectric transducer array to transmit and capture 2-D sonographs. The ASIC, fabricated in 0.18 µm 32 V CMOS process, contains 7 identical channels, each with high-voltage level-shifters, high-voltage DC-DC converters, digital TX beamformer, and RX front-end. The chip is powered by a single 1.8 V supply and generates 5 V and 32 V internally using on-chip charge pumps with an efficiency of 33% to provide 32 V pulses for driving a bulk piezoelectric transducer array. The assembled prototype can operate up to 40 MHz, with beamformer delay resolution of 5 ns, and has a measured sensitivity of 225 nV/Pa , minimum detectable signal of 622 Pa assuming 12 dB SNR ( 4σ larger than the noise level), and data acquisition time of 21.3 ms. The system can image human tissue as deep as 5 cm while consuming less than 16.5 µJ per pulse-echo measurement. The high energy efficiency of the imager can enable a number of consumer applications.

On-chip magnetic separation of superparamagnetic beads for integrated molecular analysis.

We have demonstrated a postprocessed complementary metal oxide semiconductor (CMOS) integrated circuit (IC) capable of on-chip magnetic separation, i.e., removing via magnetic forces the nonspecifically bound magnetic beads from the detection area on the surface of the chip. Initially, 4.5 mum wide superparamagnetic beads sedimenting out of solution due to gravity were attracted to the detection area by a magnetic concentration force generated by flowing current through a conductor embedded in the IC. After sedimentation, the magnetic beads that did not bind strongly to the functionalized surface of the IC through a specific biochemical complex were removed by a magnetic separation force generated by flowing current through another conductor placed laterally to the detection area. As the spherical bead pivoted on the surface of the chip, the lateral magnetic force was further amplified by mechanical leveraging, and 50 mA of current flowing through the separation conductor placed 18 mum away from the bead resulted in 7.5 pN of tensile force on the biomolecular tether immobilizing the bead. This force proved high enough to break nonspecific interactions while leaving specific antibody-antigen bonds intact. A sandwich capture immunoassay on purified human immunoglobulin G showed strong correlation with a control enzyme linked immunosorbent assay and a detection limit of 10 ngml or 70 pM. The beads bound to the detection area after on-chip magnetic separation were detected optically. To implement a fully integrated molecular diagnostics platform, the on-chip magnetic separation functionality presented in this work can be readily combine with state-of-the art CMOS-based magnetic bead detection technology.