10.1117/2.1201605.006500 Single-photon avalanche diodes and advanced digital circuits for improved biomedical imaging Jamal Deen, Zeng Cheng, and Darek Palubiak High-performance detectors that are compatible with mainstream semi- conductor device fabrication deliver high speed, ultra-sensitivity, and good timing resolution. Recent advances in biomedical imaging include the enhance- ment of image contrast, 3D sectioning capability, and compati- bility with specialized imaging modes such as fluorescence life- time imaging (FLIM). 1–3 Compared with other imaging meth- ods, FLIM offers the highest image contrast because it measures the lifetime of the fluorescence, rather than just its intensity or wavelength characteristics. The contrasting fluorescence lifetime attributes can then enable the observer to discriminate between regions, such as identifying healthy and diseased tissue for can- cer detection. In conventional FLIM, a discrete single-photon de- tector, typically based on photomultiplier tube (PMT) technol- ogy, enables the acquisition of a single focal spot. 4 This focal spot is then raster-scanned across the field of view to form an image. This approach, however, requires sequential scanning—pixel by pixel—and thus results in a slow image acquisition rate. In many instances, the image acquisition is critical to the application, e.g., in live cell imaging and in high-content screening for drug dis- covery. Consequently, there is a great need for high-speed imag- ing instruments that would enable next-generation biomedical imaging applications. In current imaging techniques, high-resolution charge- coupled devices or CMOS image sensors are used. Although these imagers have high spatial resolution, their critical lim- itation is their poor temporal resolution. They are thus lim- ited only to the acquisition of fluorescence intensity images. The fluorescence lifetimes of most biological samples are in the nanosecond range. The measurement of fluorescence light on such a short timescale, therefore, requires photodetectors with both very high (single-photon) sensitivity and very high (sub-nanosecond) timing accuracy. To meet these requirements, Figure 1. Schematic illustration of a generalized time-correlated single- photon counting measurement setup. A time-to-digital converter (TDC) is used to measure the inter-arrival time (t) between laser pulses and a photon’s arrival. The results are recorded in a histogram. solid-state single-photon detectors—such as single-photon avalanche diodes (SPADs) 5, 6 —offer a promising solution. SPADs are smaller than PMT alternatives, and are also more ro- bust, consume significantly less power, and are less expensive. We have previously proposed that single-photon detectors, fabricated using CMOS technology, 7 are the ideal sensors for emerging biomedical imaging applications (e.g., which require both single-photon sensitivity and high timing resolution). The main benefits of fabricating such devices with CMOS technol- ogy are the lower power and the faster performances that can be achieved. These benefits can be realized with lower overall system cost and with improved system miniaturization. 8 In our more recent work, we have developed solid-state photon detectors that exploit standard digital CMOS technol- ogy with fast timing electronics (e.g., 130nm CMOS). We have also built a comprehensive and analytical model in a hardware Continued on next page