| NSF Org: |
DBI Division of Biological Infrastructure |
| Recipient: |
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| Initial Amendment Date: | August 29, 2011 |
| Latest Amendment Date: | July 3, 2012 |
| Award Number: | 1063315 |
| Award Instrument: | Continuing Grant |
| Program Manager: |
Christopher Sanford
csanford@nsf.gov (703)292-8132 DBI Division of Biological Infrastructure BIO Directorate for Biological Sciences |
| Start Date: | September 1, 2011 |
| End Date: | August 31, 2016 (Estimated) |
| Total Intended Award Amount: | $750,000.00 |
| Total Awarded Amount to Date: | $750,000.00 |
| Funds Obligated to Date: |
FY 2012 = $500,000.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
615 W 131ST ST NEW YORK NY US 10027-7922 (212)854-6851 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
615 W 131ST ST NEW YORK NY US 10027-7922 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
INSTRUMENTAT & INSTRUMENT DEVP, Cross-BIO Activities |
| Primary Program Source: |
01001213DB NSF RESEARCH & RELATED ACTIVIT |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.074 |
ABSTRACT
IDBR: CMOS cameras for high-frame-rate time-correlated single-photon counting
Recent advances in biological imaging techniques, particularly those exploring molecular dynamics, are outpacing technological innovation. Fluorescence lifetime holds great potential as a biomarker that can reveal changes in a fluorophore's local chemical and physical environment, as well as the binding dynamics of single proteins through excited state interactions and Förster resonance energy transfer (FRET). Many of the latest active dyes, molecular probes and even transgenic labeling strategies exploit FRET to enable real-time observation of cellular processes both in-vitro and in-vivo. While FRET can be detected using intensity-only measurements, quantitation can be dramatically impaired by experimental factors such as photobleaching, whereas lifetime-based FRET measurements are significantly more robust. Nevertheless, adoption and widespread use of fluorescence lifetime imaging microscopy (FLIM) for biological research has been hindered by two major factors: the speed with which FLIM images can be acquired and the cost and complexity of the instrumentation required for FLIM. In this multidisciplinary proposal, a novel two-dimensional high-frame-rate complementary metal-oxide-semiconductor (CMOS) fluorescent lifetime camera chip based on single-photon avalanche diodes (SPADs) will be developed. This chip will be applied to both wide-field and laser-scanning-based microscopy techniques to enable several important advances in FLIM imaging. In widefield imaging, this will result in acquisition of images at a incident-photon-limited frame rate as high as 1 kHz.
Solid-state imagers are based primarily on two technologies, charged-coupled device (CCD) and CMOS. Both of these imaging technologies are based on converting photons to electrons and collecting many of these electrons to produce a measurable signal. These imagers are now employed in digital cameras of every type, from cell phone cameras to the high-end cameras employed in biological imaging. Since optical techniques are so pervasive in probing biological systems, cameras represent the fundamental interface between the biological world and the solid-state world. In this effort, an entirely new camera chip will be designed based on a device that, instead of collecting electrons produced by photons, counts them, one-by-one. This enables very high sensitivity for photon detection. At the same time it allows resolution of very short (and dim) optical events (on the order of 10's of ps). Such capabilities will enable new types of biological imaging applications. This project supports the multidisciplinary training of graduate and undergraduate students and a significant K-12 outreach effort.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
In this project, we have developed camera technologies that exploit single-photon avalance diodes (SPADs) that can be integrated with complementary metal-oxide-semiconductor (CMOS) technology. We completed the design of a full-integrated SPAD and time-to-digital converter (TDC) array for high-speed fluorescence lifetime imaging microscopy (FLIM) in a standard 130-nm CMOS technology node. The TDCs use a delay-locked-loop-based architecture and achieve a 62.5 psec resolution wiht up to a 64 ns rane. A data-compression datapath is designed to transfer TDC data to off-chip buffers, which an support a data rate of up to 42 Gbps. These features, combined with a system implementaiton that leverages a x4 PCIe-cabed interface, allow for demonstrated FLIM imager rates up to 100 frames per second.
We have also put these cameras into two unusual form factors. The first is the development of a qPCR lab-on-a-chip that leverages integrated SPADs for detection. The second is a imager in the form of a shank that can be inserted into the brain for imaging. Only superficial layers of the brain can be imaged by free-space microscopy, due to the intrinsic light scattering and absorption limitation in brain tissue. To allow optical fluorescence imaging of deeper layers of the brain with proper signal-to-noise ratio, both discrete optical detectors and discrete light emitters must be distributed on shanks for possible insertion into the brain. In our case, we have developed the detector shanks, in which more than 100 SPAD detectors are arranged down a shank which is 100-um wide, 50-um thick, and 3-mm long. Follow-on work supported by NIH and DARPA will continue the work seeded by this grant.
Several graduate students were trained over the course of this program and students supported by this program helped put together a new outreach summer program for high school students from underserved groups in the New York City public schools at Columbia.
Last Modified: 12/31/2016
Modified by: Kenneth L Shepard
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