Surgery remains an effective treatment for many cancers and is often the only curative treatment option. This is achieved if the totality of the malignant tissue is resected. During surgery, though, surgeons can only rely on direct visual inspection and, at times, on palpation. Therefore, intra-operative guidance, by which the cancer lesions are highlighted during the surgical procedure, would be of great value for the surgeon to obtain real-time information about the local spread of the disease. To this end, several antibody-based fluorescent contrast agents are currently in different stages of research or clinical trial. These contrast agents are engineered to bind with maximum specificity to the cancer lesions as to clearly highlight them with fluorescent signal. The spectrum of choice for this fluorescence is the near-infrared (NIR) region from 650 nm to 800 nm. In that window, light is minimally absorbed by blood and tissue and can therefore penetrate deeper.
Highlighting these contrast against can be achieved by measuring the specific fluorescence lifetime. The fluorescence lifetime is the decay rate of the fluorescence after excitation by a pulse and is independent of the intensity and can therefore be used for robust and specific tracer detection. When specificity is of great importance like when antibody based contrast agents are used, the need for lifetime imaging is even greater as the fluorescence lifetime adds extra information to the image that can be used to separate specific from non-specific signal. E.g. the fluorescence lifetime of bound tracer can be different from that of unbound tracer. Signal emerging from unbound tracer can therefore be suppressed, increasing the image contrast or measurement specificity.
Fluorescence lifetime imaging requires advanced time-resolved imaging systems in combination with pulsed or modulated laser excitation to resolve the sub-nanosecond lifetimes that are typically encountered for NIR fluorescence. Today this is possible on microscopy platforms (mainly scanned) but no camera system exists that can image such lifetimes at the required video frame rates for fluorescence guided surgery. However, if conventional fluorescence cameras could be replaced by fluorescence lifetime cameras, fluorescence guided surgery could be greatly improved, even more so with specific fluorescent contrast agents emerging.
In recent years, our group has developed a sensor, the Current-Assisted Photon Sampler (CAPS) that can perform the needed gating function, fully implemented in CMOS. This detector can potentially use two gating windows to capture nearly all photons and resolve sub-nanosecond lifetimes with high QE. The CAPS sensor, being a current-assisted device, uses electric fields (generated by a majority carrier current) to gather photo-generated electrons from deep within the substrate and doing so fulfills two important requirements for fluorescence guided surgery image sensors: good NIR QE and fast gating for sub-nanosecond lifetimes. However, the noise performance is not yet adequate because it is limited, as is common for three transistor (3T) pixels, by dark current shot noise and 1/f noise. Both noise sources scale with the photo-integration time and for an integration time of 30 ms (representative for video rate imaging) the noise is around 50 e-, many times higher than the 1.5 e- that can be achieved in scientific CMOS imagers.
In this research we research, in anticipation of the need for video-rate fluorescence lifetime cameras, the combination of the Current-Assisted Photonic Sampler (CAPS) with pinned-photodiode technology, to combine the excellent speed and NIR performance of CAPS with the low-noise capabilities of pinned-photodiode technology to arrive at an image sensor that has all the characteristics needed for fluorescence lifetime imaging at video rates.