Single-photon avalanche diode (SPAD) arrays are solid-state detectors that offer imaging capabilities at the level of individual photons, with unparalleled photon counting and time-resolved performance. This fascinating technology has progressed at a very fast pace in the past 15 years, since its inception in standard CMOS technology in 2003. A host of architectures have been investigated, ranging from simpler implementations, based solely on off-chip data processing, to progressively “smarter” sensors including on-chip, or even pixel level, time-stamping and processing capabilities. As the technology has matured, a range of biophotonics applications have been explored, including (endoscopic) FLIM, (multibeam multiphoton) FLIM-FRET, SPIM-FCS, super-resolution microscopy, time-resolved Raman spectroscopy, NIROT and PET. We will review some representative sensors and their corresponding applications, including the most relevant challenges faced by chip designers and end-users. Finally, we will provide an outlook on the future of this fascinating technology.

We present a 1 Mpixel single-photon avalanche diode camera featuring 3.8 ns time gating and 24 kfps frame rate, fabricated in 180 nm CMOS image sensor technology. We designed two pixels with a pitch of 9.4 µm in 7 T and 5.75 T configurations respectively, achieving a maximum fill factor of 13.4%. The maximum photon detection probability is 27%, median dark count rate is 2.0 cps, variation in gating length is 120 ps, position skew is 410 ps, and rise/fall time is < 550 p s , all FWHM at 3.3 V excess bias. The sensor was used to capture 2D/3D scenes over 2 m with resolution (least significant bit) of 5.4 mm and precision better than 7.8 mm (rms). We demonstrate extended dynamic range in dual exposure operation mode and show spatially overlapped multi-object detection in single-photon time-gated time-of-flight experiments.

In this paper, we report on SwissSPAD2, an image sensor with 512 × 512 photon-counting pixels, each comprising a single-photon avalanche diode (SPAD), a 1-b memory, and a gating mechanism capable of turning the SPAD on and off, with a skew of 250 and 344 ps, respectively, for a minimum duration of 5.75 ns. The sensor is designed to achieve a frame rate of up to 97 700 binary frames per second and sub-40 ps gate shifts. By synchronizing it with a pulsed laser and using multiple successive overlapping gates, one can reconstruct a molecule's fluorescent response with picosecond temporal resolution. Thanks to the sensor's number of pixels (the largest to date) and the fully integrated gated operation, SwissSPAD2 enables widefield fluorescence lifetime imaging microscopy with an all-solid-state solution and at relatively high frame rates. This was demonstrated with preliminary results on organic dyes and semiconductor quantum dots using both decay fitting and phasor analysis. Furthermore, pixels with an exceptionally low dark count rate and high photon detection probability enable uniform and high-quality imaging of biologically relevant fluorescent samples stained with multiple dyes. While future versions will feature the addition of microlenses and optimize firmware speed, our results open the way for low-cost alternatives to commercially available scientific time-resolved imagers.

We present the architecture and three applications of the largest resolution image sensor based on single-photon avalanche diodes (SPADs) published to date. The sensor, fabricated in a high-voltage CMOS process, has a resolution of 512 × 128 pixels and a pitch of 24 μm. The fill-factor of 5% can be increased to 30% with the use of microlenses. For precise control of the exposure and for time-resolved imaging, we use fast global gating signals to define exposure windows as small as 4 ns. The uniformity of the gate edges location is ∼140 ps (FWHM) over the whole array, while in-pixel digital counting enables frame rates as high as 156 kfps.

Fluorescence lifetime imaging microscopy (FLIM) is a key technology that provides direct insight into cell metabolism, cell dynamics and protein activity. However, determining the lifetimes of different fluorescent proteins requires the detection of a relatively large number of photons, hence slowing down total acquisition times. Moreover, there are many cases, for example in studies of cell collectives, where wide-field imaging is desired. We report scan-less wide-field FLIM based on a 0.5 MP resolution, time-gated Single Photon Avalanche Diode (SPAD) camera, with acquisition rates up to 1 Hz. Fluorescence lifetime estimation is performed via a pre-trained artificial neural network with 1000-fold improvement in processing times compared to standard least squares fitting techniques. We utilised our system to image HT1080—human fibrosarcoma cell line as well as Convallaria. The results show promise for real-time FLIM and a viable route towards multi-megapixel fluorescence lifetime images, with a proof-of-principle mosaic image shown with 3.6 MP.

Single-photon avalanche diodes (SPADs) have become the sensor of choice in many applications whenever high sensitivity, low noise, and sharp timing performance are required, simultaneously. Recently, SPADs designed in CMOS technology, have yielded moderately good performance in these parameters, but never equaling their counterparts fabricated in highly customized, non-standard technologies. The arguments in favor of CMOS-compatible SPADs were miniaturization, cost and scalability. In this paper, we present the first CMOS SPAD with performance comparable or better than that of the best custom SPADs, to date. The SPAD-based design, fully integrated in 180 nm CMOS technology, achieves a peak photon detection probability (PDP) of 55% at 480 nm with a very broad spectrum spanning from near ultraviolet (NUV) to near infrared (NIR) and a normalized dark count rate (DCR) of 0.2 cps/ $\mu$ m $^2$ , both at 6 V of excess bias. Thanks to a dedicated CMOS pixel circuit front-end, an afterpulsing probability of about 0.1% at a dead time of $\sim$ 3 ns were achieved. We designed three SPADs with a diameter of 25, 50, and 100 $\mu$ m to study the impact of size on the timing jitter and to create a scaling law for SPADs. For these SPADs, a single-photon time resolution (SPTR) of 12.1 ps, 16 ps, and 27 ps (FWHM) was achieved at 6 V of excess bias, respectively. The SPADs operate in a wide range of temperatures, from −65 $^{\circ }$ C to 40 $^{\circ }$ C, reaching a normalized DCR of 1.6 mcps/ $\mu$ m $^2$ at 6 V of excess bias for the 25 $\mu$ m at −65 $^{\circ }$ C. The proposed SPADs are ideal for a wide range of applications, including (quantum) LiDAR, super-resolution microscopy, quantum random number generators, quantum key distribution, fluorescence lifetime imaging, time-resolved Raman spectroscopy, to name a few. All these applications can take advantage of the vastly improved performance of our detectors, while enjoying the opportunities of megapixel resolutions promised by the economy of scale that is offered by CMOS technologies.