Recent Advances in Fluorescence Lifetime Analytical Microsystems: Contact Optics and CMOS Time-Resolved Electronics

Abstract

Fluorescence spectroscopy has become a prominent research tool with wide applications in medical diagnostics and bio-imaging. However, the realization of combined high-performance, portable, and low-cost spectroscopic sensors still remains a challenge, which has limited the technique to the laboratories. A fluorescence lifetime measurement seeks to obtain the characteristic lifetime from the fluorescence decay profile. Time-correlated single photon counting (TCSPC) and time-gated techniques are two key variations of time-resolved measurements. However, commercial time-resolved analysis systems typically contain complex optics and discrete electronic components, which lead to bulkiness and a high cost. These two limitations can be significantly mitigated using contact sensing and complementary metal-oxide-semiconductor (CMOS) implementation. Contact sensing simplifies the optics, whereas CMOS technology enables on-chip, arrayed detection and signal processing, significantly reducing size and power consumption. This paper examines recent advances in contact sensing and CMOS time-resolved circuits for the realization of fully integrated fluorescence lifetime measurement microsystems. The high level of performance from recently reported prototypes suggests that the CMOS-based contact sensing microsystems are emerging as sound technologies for application-specific, low-cost, and portable time-resolved diagnostic devices.

Keywords: CMOS; TCSPC; contact sensing; fluorescence spectroscopy; lab-on-a-chip; microsystems; time-gated; time-resolved.

Figure 1

The two methods of time-gated fluorescence detection. (a) The fluorescence decay curve detected using two time gates with equal width; (b) the time gate scanning method.

Figure 2

Time-correlated single photon counting (TCSPC) operation principle. (a) System schematic; (b) timing diagram of the start-stop watch mode [29].

Figure 3

Schematic and photo of a conventional optical system of time-resolved fluorescence system (MF32). LASP is the motherboard of the SPAD array daughterboard. © (2010) Optical Society of America. Adapted, with permission, from [57].

Figure 4

(a) The cross section and top view of the fluidic channel. The excitation light is coupled into the fluidic channel and the imager records the fluorescence emission of the analytes while they move along the channel. Reproduced from [63] with permission from The Royal Society of Chemistry. (b) The prototype of the ARROW chip for sample preparation and single nucleic acid measurement. Reproduced from [64] with permission from The Creative Commons Attribution 4.0 International License.

Figure 5

On-chip lens-free holographic fluorescent imaging platform with a wide field-of-view of 2.5 cm × 3.5 cm. Adapted from [24] with permission from The Royal Society of Chemistry.

Figure 6

The cross section of the integrated time-gated fluorescence microsystem. The fluorescent sample is sandwiched between a micro-cavity slide and a cover slip. The long-pass filter eliminates the excitation light. © (2010) IEEE. Adapted, with permission, from [34].