Design of multiphoton microendoscope system for minimally invasive detection of cancer

Abstract

Early detection of cancer is crucial for improving patient survival. High resolution optical imaging is ideal to image cellular abnormalities indicative of early cancer. For tissues located deep within the body, such as the pancreato-biliary ducts, high resolution imaging must be implemented endoscopically due to the limited penetration depth of light. We are developing a minimally invasive high numerical aperture (HNA) microendoscope system capable of simultaneous co-registered multiphoton imaging (two-photon excited fluorescence, second harmonic generation, three-photon excited fluorescence, and third harmonic generation) of small diameter ductal tissues, such as the pancreato-biliary ducts. Imaging of the epithelial layer is achieved via helical scanning of the 1.5 mm diameter endoscope with a fixed focus. The endoscope distal end optics act as both the illumination and collection mechanism, with the core of the dual clad fiber (DCF) carrying femtosecond laser excitation light, and the inner cladding of the DCF carrying multiphoton emission. Designing HNA optics at the 1 mm diameter size scale is challenging, time consuming, and may be expensive. To complete development of the proximal components of the system, we designed a low numerical aperture (LNA) reflectance & single photon fluorescence system using low cost off the shelf optical components to aid in the development of software and the testing of proximal system hardware components. Additionally, rapid, low-cost design and fabrication of HNA optics with 3D printing is presented.

Design of a 1.0mm multiphoton microscopy microendoscope

“…The full optical path and transmission spectra of the filter system within PMT system has been described in previous works. 5,[7][8][9] The MMF can be manually switched from the PMT system to a Photodiode detector (MKS/Newport, 2107-FC-M Balanced Fiber-Optic Receiver) to allow for reflectance imaging with a 561 nm center wavelength (CWL) green laser diode (Laserglow Technologies, R560503FX). This modality is useful primarily for testing purposes.…”

“…To conform with requirements outlined in Section 1 and in previous work 5 the endoscope requires the design of a distal end optical system that is ≤ 10.00mm in axial length, ≤ 1.0mm in diameter, that performs diffraction limited imaging (Wavefront root mean square [RMS] ≤ 0.07) with a lateral resolution that enables imaging at the sub-cellular level (Airy radius ≤ 2µm). The system must also be able to produce appreciable multiphoton excitation.…”

“…We can also design a fold prism that has power on its exit face that makes the endoscope side-viewing, enabling the acquisition of NA ≥ 0.40. 5 As part of the prototyping process, we have developed two intermediary optical systems to evaluate the feasibility of printing a system that follows the proposed design.…”

“…The goal in the design and fabrication of test part 1 was to create a custom part similar to the proposed design but simpler with fewer elements. 5 As such, we opted to have a part <1.0mm in axial length and set no stringent requirement for resolution and NA. We opted for a focus distance, defined in this instance as distance between the vertex of the exit face of the prism and the focal point, to be 0.5mm or greater, to allow for easier benchtop testing.…”

“…Previously, we have discussed the application of MPM for early detection of pancreato-biliary cancers. 5 The MPM system must be miniaturized and implemented in an endoscopic system. For this application we need to create a flexible endoscope ≤ 1.5mm in outer diameter (OD) and with a maximum rigid length of ≤ 10.00 mm.…”