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A 25 micron-thin microscope for imaging upconverting nanoparticles with NIR-I and NIR-II illumination.
Rationale: Intraoperative visualization in small surgical cavities and hard-to-access areas are essential requirements for modern, minimally invasive surgeries and demand significant miniaturization. However, current optical imagers require multiple hard-to-miniaturize components including lenses, filters and optical fibers. These components restrict both the form-factor and maneuverability of these imagers, and imagers largely remain stand-alone devices with centimeter-scale dimensions. Methods: We have engineered INSITE (Immunotargeted Nanoparticle Single-Chip Imaging Technology), which integrates the unique optical properties of lanthanide-based alloyed upconverting nanoparticles (aUCNPs) with the time-resolved imaging of a 25-micron thin CMOS-based (complementary metal oxide semiconductor) imager. We have synthesized core/shell aUCNPs of different compositions and imaged their visible emission with INSITE under either NIR-I and NIR-II photoexcitation. We characterized aUCNP imaging with INSITE across both varying aUCNP composition and 980 nm and 1550 nm excitation wavelengths. To demonstrate clinical experimental validity, we also conducted an intratumoral injection into LNCaP prostate tumors in a male nude mouse that was subsequently excised and imaged with INSITE. Results: Under the low illumination fluences compatible with live animal imaging, we measure aUCNP radiative lifetimes of 600 μs - 1.3 ms, which provides strong signal for time-resolved INSITE imaging. Core/shell NaEr0.6Yb0.4F4 aUCNPs show the highest INSITE signal when illuminated at either 980 nm or 1550 nm, with signal from NIR-I excitation about an order of magnitude brighter than from NIR-II excitation. The 55 μm spatial resolution achievable with this approach is demonstrated through imaging of aUCNPs in PDMS (polydimethylsiloxane) micro-wells, showing resolution of micrometer-scale targets with single-pixel precision. INSITE imaging of intratumoral NaEr0.8Yb0.2F4 aUCNPs shows a signal-to-background ratio of 9, limited only by photodiode dark current and electronic noise. Conclusion: This work demonstrates INSITE imaging of aUCNPs in tumors, achieving an imaging platform that is thinned to just a 25 μm-thin, planar form-factor, with both NIR-I and NIR-II excitation. Based on a highly paralleled array structure INSITE is scalable, enabling direct coupling with a wide array of surgical and robotic tools for seamless integration with tissue actuation, resection or ablation
Hybrid Amperometric and Potentiometric Sensing Based on a CMOS ISFET Array
Potentiometry and amperometry are some of the most important techniques for electroanalytical applications. Integrating these two techniques on a single chip using CMOS technology paves the way for more analysis and measurement of chemical solutions. In this paper, we describe the integration of electrode transducers (amperometry) on an ion imager based on an ISFET array (potentiometry). In particular, this integration enables the spatial representation of the potential distribution of active electrodes in a chemical solution under investigation
On evolution of CMOS image sensors
CMOS Image Sensors have become the principal technology in majority of digital cameras. They started replacing the film and Charge Coupled Devices in the last decade with the promise of lower cost, lower power requirement, higher integration and the potential of focal plane processing. However, the principal factor behind their success has been the ability to utilise the shrinkage in CMOS technology to make smaller pixels, and thereby have more resolution without increasing the cost. With the market of image sensors exploding courtesy their inte- gration with communication and computation devices, technology developers improved the CMOS processes to have better optical performance. Nevertheless, the promises of focal plane processing as well as on-chip integration have not been fulfilled. The market is still being pushed by the desire of having higher number of pixels and better image quality, however, differentiation is being difficult for any image sensor manufacturer. In the paper, we will explore potential disruptive growth directions for CMOS Image sensors and ways to achieve the same
CMOS Image Sensors for High Speed Applications
Recent advances in deep submicron CMOS technologies and improved pixel designs have enabled CMOS-based imagers to surpass charge-coupled devices (CCD) imaging technology for mainstream applications. The parallel outputs that CMOS imagers can offer, in addition to complete camera-on-a-chip solutions due to being fabricated in standard CMOS technologies, result in compelling advantages in speed and system throughput. Since there is a practical limit on the minimum pixel size (4∼5 μm) due to limitations in the optics, CMOS technology scaling can allow for an increased number of transistors to be integrated into the pixel to improve both detection and signal processing. Such smart pixels truly show the potential of CMOS technology for imaging applications allowing CMOS imagers to achieve the image quality and global shuttering performance necessary to meet the demands of ultrahigh-speed applications. In this paper, a review of CMOS-based high-speed imager design is presented and the various implementations that target ultrahigh-speed imaging are described. This work also discusses the design, layout and simulation results of an ultrahigh acquisition rate CMOS active-pixel sensor imager that can take 8 frames at a rate of more than a billion frames per second (fps)
Fluorescence lifetime biosensing with DNA microarrays and a CMOS-SPAD imager
Fluorescence lifetime of dye molecules is a sensitive reporter on local
microenvironment which is generally independent of fluorophores
concentration and can be used as a means of discrimination between molecules
with spectrally overlapping emission. It is therefore a potentially powerful
multiplexed detection modality in biosensing but requires extremely low
light level operation typical of biological analyte concentrations, long
data acquisition periods and on-chip processing capability to realize these
advantages. We report here fluorescence lifetime data obtained using a
CMOS-SPAD imager in conjunction with DNA microarrays and TIRF excitation
geometry. This enables acquisition of single photon arrival time histograms
for a 320 pixel FLIM map within less than 26 seconds exposure time. From
this, we resolve distinct lifetime signatures corresponding to dye-labelled
HCV and quantum-dot-labelled HCMV nucleic acid targets at concentrations as
low as 10 nM
Low Noise and High Photodetection Probability SPAD in 180 nm Standard CMOS Technology
A square shaped, low noise and high photo-response single photon avalanche diode suitable for circuit integration, implemented in a standard CMOS 180 nm high voltage technology, is presented. In this work, a p+ to shallow n-well junction was engineered with a very smooth electric field profile guard ring to attain a photo detection probability peak higher than 50% with a median dark count rate lower than 2 Hz/μm2 when operated at an excess bias of 4 V. The reported timing jitter full width at half maximum is below 300 ps for 640 nm laser pulses
Neutron imaging and tomography with MCPs
A neutron imaging detector based on neutron-sensitive microchannel plates
(MCPs) was constructed and tested at beamlines of thermal and cold neutrons.
The MCPs are made of a glass mixture containing B-10 and natural Gd, which
makes the bulk of the MCP an efficient neutron converter. Contrary to the
neutron sensitive scintillator screens normally used in neutron imaging,
spatial resolution is not traded off with detection efficiency. While the best
neutron imaging scintillators have a detection efficiency around a percent, a
detection efficiency of around 50% for thermal neutrons and 70% for cold
neutrons has been demonstrated with these MCPs earlier.
Our tests show a performance similar to conventional neutron imaging
detectors, apart from the orders of magnitude better sensitivity. We
demonstrate a spatial resolution better than 150 um. The sensitivity of this
detector allows fast tomography and neutron video recording, and will make
smaller reactor sites and even portable sources suitable for neutron imaging.Comment: Submitted to the proceedings of the 19th International Workshop on
Radiation Imaging Detectors (iWoRiD) 2-6 July 2017, Krakow, Polan
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