Abstract
Surgery remains one of the key treatment options for tumour removal, and surgeons primarily rely on eye and touch to assess the boundary between healthy and cancerous tissue with no cellular information as guidance. There is therefore a need for a device or instrument that can be used by the surgeon in real-time during the surgical procedure to ensure as many of the cancerous cells and as few of the healthy cells have been removed as possible. Fluorescence approaches have previously demonstrated significant promise in this application, but clinical take-up has been limited and much more characterization of critical parameters needed before robotic surgery can be contemplated. Here we investigate two time-correlated single-photon counting (TCSPC) fluorescence lifetime systems for the detection of phantom tumour margins derived from silica sol-gels. A simple and low-cost liquid light guide system (LLG) incorporating a single photomultiplier detection channel and translational stage was developed. This provided a useful reference for a compact single-photon avalanche diode (SPAD) array camera system for fluorescence lifetime imaging microscopy (FLIM) which permits up to ∼25 000 in-pixel timing measurements at video rates in ambient light using only low energy (∼30 pJ) diode laser pulses to minimize cell and dye degradation. Measurements of phantom margins with sol-gel doped Rhodamine 6G (R6G) of fluorescence lifetime ∼4 ns using the LLG system demonstrates that for 7 mm excitation diameter and over 5–15 mm sol-gel LLG separation the sol-gel only region could be clearly identified 1 mm after the margin position, a widely accepted minimum surgical resolution. A comparison between measurements with the LLG and SPAD FLIM system using the sub-ns fluorescence lifetime of the FDA-approved dye indocyanine green (ICG) demonstrates that the minimum workable spatial resolution and sufficient speed are only achievable with such faster lifetimes using the SPAD FLIM system.
Highlights
Cancer is one of the leading causes of death worldwide, with over 18 million cases diagnosed globally in 2018 [1]
Measurements were taken of the Rhodamine 6G (R6G) phantom margin sample at 1 mm increments until the light guides approached the margin, where measurements were taken at 1/2 mm increments to see how the fluorescence decay changed over such small distances as the margin was passed under the light guides
Silica alcogels have been utilized for creating phantom tumour margins to test the ability of a liquid light guide system (LLG) and translational stagebased fluorescence lifetime system as well as a single-photon avalanche diode (SPAD) fluorescence lifetime imaging microscopy (FLIM) array system for determining the margin position
Summary
Cancer is one of the leading causes of death worldwide, with over 18 million cases diagnosed globally in 2018 [1]. During cancer surgery it is important that as much of the cancerous tissue is removed as possible while preventing unnecessary damage to surrounding healthy tissue [3] To accomplish this surgeons primarily rely on visual inspection, palpation and previous experience in order to determine the cancerous tissue. While this can be effective for bulk tumour it lacks sensitivity in detecting cancer at the cellular level [4], potentially leading to the patient requiring further surgery if cancerous cells remain in the body. The margin between the cancerous cells and the cut tissue edge is known as the surgical margin, where the current gold standard for margin assessment is slide-based histology This has to be completed post-operatively, and is often a time-consuming and laborious process [5]. New technologies for intraoperative margin assessment need to be able to match the diagnostic accuracy of post-operative histology and bring further benefits such as reduced turnover times, practicality and reduced cost before they can be considered for routine clinical practice [9]
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