Fully Integrated Ultra-thin Intraoperative Micro-imager for Cancer Detection Using Upconverting Nanoparticles

Abstract

Purpose Intraoperative detection and removal of microscopic residual disease (MRD) remain critical to the outcome of cancer surgeries. Today’s minimally invasive surgical procedures require miniaturization and surgical integration of highly sensitive imagers to seamlessly integrate into the modern clinical workflow. However, current intraoperative imagers remain cumbersome and still heavily dependent on large lenses and rigid filters, precluding further miniaturization and integration into surgical tools. Procedures We have successfully engineered a chip-scale intraoperative micro-imager array—without optical filters or lenses—integrated with lanthanide-based alloyed upconverting nanoparticles (aUCNPs) to achieve tissue imaging using a single micro-chip. This imaging platform is able to leverage the unique optical properties of aUCNPs (long luminescent lifetime, high-efficiency upconversion, no photobleaching) by utilizing a time-resolved imaging method to acquire images using a 36-by-80-pixel, 2.3 mm $$\times$$ × 4.8 mm silicon-based electronic imager micro-chip, that is, less than 100-µm thin. Each pixel incorporates a novel architecture enabling automated background measurement and cancellation. We have validated the performance, spatial resolution, and the background cancellation scheme of the imaging platform, using resolution test targets and mouse prostate tumor sample intratumorally injected with aUCNPs. To demonstrate the ability to image MRD, or tumor margins, we evaluated the imaging platform in visualizing a single-cell thin section of the injected prostate tumor sample. Results Tested on USAF resolution targets, the imager is able to achieve a resolution of 71 µm. We have also demonstrated successful background cancellation, achieving a signal-to-background ratio of 8 when performing ex vivo imaging on aUCNP-injected prostate tumor sample, improved from originally 0.4. The performance of the imaging platform on single-cell layer sections was also evaluated and the sensor achieved a signal-to-background ratio of 4.3 in resolving cell clusters with sizes as low as 200 cells. Conclusion The imaging system proposed here is a scalable chip-scale ultra-thin alternative for bulky conventional intraoperative imagers. Its novel pixel architecture and background correction scheme enable visualization of microscopic-scale residual disease while remaining completely free of lenses and filters, achieving an ultra-miniaturized form factor—critical for intraoperative settings.

Optical Coherence Tomography Angiography of the Intestine: How to Prevent Motion Artifacts in Open and Laparoscopic Surgery?

“…Conventional technologies of radiation diagnostics (computer tomography and magnetic resonance imaging) do not meet the aforementioned requirements. The main disadvantage is their large size that is related to the use of large lenses and rigid filters that prevent their miniaturization and integration into surgical instruments [ 2 ].…”

Multicolor fluorescence microscopy for surgical guidance using a chip-scale imager with a low-NA fiber optic plate and a multi-bandpass interference filter

“…Despite these advantages, fluorescence contact imaging comes with two unique optical design challenges: (1) integrating high-performance, customizable, multicolor fluorescence emission filters on chip and (2) achieving microscopic resolution without lenses. In this work, we improve on our prior work in chip-based FGS [19][20][21], introducing a novel optical frontend design that addresses both challenges. Our design consists of a multi-bandpass thin-film interference filter directly coated on a low-numerical-aperture fiber optic plate (LNA-FOP).…”