This PDF file contains the front matter associated with SPIE Proceedings Volume 12356, including the Title Page, Copyright information, Table of Contents, and Conference Committee information.

High grade serous ovarian cancer is the most deadly gynecological cancer, and it is now believed that most originate in the fallopian tubes (FTs). We developed a FT endoscope, the falloposcope, as a method for detecting ovarian cancer. The falloposcope clinical prototype is being implemented in a pilot study with 20 volunteers (12 enrolled to date) to evaluate the safety and feasibility of FT imaging prior to standard of care salpingectomy in normal-risk volunteers. The falloposcope is approximately 0.8 mm in diameter and is introduced via a minimally invasive approach through a commercially available hysteroscope and introducing catheter. To date, FT navigation video, multispectral reflectance and fluorescence images, and optical coherence tomography (OCT) of human FT have successfully been acquired. This manuscript describes the fabrication improvements and iterative design changes that have been introduced to improve usability and reduce failure points based on clinical implementation. We discuss falloposcope improvements made with respect to the following subjects: improving perceived image quality with the fiber bundle, GRIN lens stray light, and improving the proximal imaging system. Navigation and MFI are limited by the 3,000 element fiber bundle and lens working distance (WD). A future system is being developed with a 10,000 element fiber bundle, more uniform illumination, a closer WD lens, and wire cytology instead of OCT probe.

Ovarian cancer is the deadliest gynecological cancer, with most cases of high-grade serous ovarian carcinoma originating as serous tubal intraepithelial carcinoma (STIC) lesions in the fallopian tube epithelium. The Cell-Acquiring Fallopian Endoscope (CAFE) was designed to optically detect these STIC lesions and collect cells from the suspicious site for further analysis. While approximately 0.93 mm in diameter, the CAFE is able to perform multispectral fluorescence imaging (MFI), white light imaging for navigation, and cell collection. Each of these modalities is useful to locating potentially pathological areas. To find these regions, the CAFE looks for alterations of the autofluorescence of the tissue. Upon identification of a potential STIC lesion, a scrape biopsy collects cells from the region of interest. The prototype CAFE achieved an imaging resolution of 88 μm at a 5 mm distance, and 45° full field of view in air. When tested on ex vivo porcine tissue, hemocytometry counts determined that on the order of 10⁵ cells per scrape biopsy could be collected. Current progress on the CAFE includes cell collection testing on ex vivo porcine and human tissue, and improvements in the imaging resolution.

Microbiological imaging in compact and integrated devices allows for a variety of applications such as endomicroscopy or neuroscience. Typically, such devices require a large field-of-view with a high resolution to visualize cellular details and a high light collection efficiency to improve the signal-to-noise ratio and reduce exposure times. Thus, high numerical apertures are required. Miniature objectives with a numerical aperture of 0.7, a field-of-view diameter of 264 μm in the sample plane and color correction for a wide spectral range (450 nm – 900 nm) are offered by the company GRINTECH GmbH. However, while these accept curved sample fields as a degree of freedom, many demanding applications in the area of endo- and point-of-care-microscopy desire a field as flat as possible.

In the scope of this work a broad optical design study was conducted to minimize the optical curvature of the object field. After having worked out 16 design approaches, the three best designs were shortlisted and investigated considering optical and mechanical design tolerances. The best as-built design was chosen and prototypes made of 6 lenses were manufactured. The diameter of the mounted objective is 2.2 mm with a total length of 13 mm. The performance of the novel micro system was experimentally evaluated by means of a confocal laser-scanning-microscope.

Single-use endoscopes show a steady growth in medical applications due to the advantage of omitted cross-patient infections. The devices benefit in terms of the imaging optics from the developments in wafer-level-optics (WLO) which was once considered to become the fabrication technique for all high volume applications. However, the restrictions in achievable vertex heights of the lenses, the necessity of the glass wafers within the optical path and the limited number of lenses per stack are still obstacles when targeting resolutions beyond HD.

We have developed a new and fully scalable fabrication method for monolithic aspherical polymer lenses similar to those originating from optical injection molding. In contrast to the later, high-temperature resistant UV-curing materials as in WLO are used, which are even compliant to reflow-soldering processes. In consequence, a new tool-set for low-cost, high-volume and high-resolution imaging optics becomes available. It overcomes the restrictions of WLO-based lens techniques and thus provides new degrees of freedom in lens design and manufacturing. Furthermore, in contrast to WLO and injection molding, low initial fabrication costs enable cost-effective demonstrators, prototypes, and small series products. Thanks to the scalability of the processes, also high-volume applications can be addressed cost-efficiently. In this paper we present the benefits of our new technology and show some endoscopy camera module demo systems we realized with our optics so far.

In applications such as optical coherence tomography, there is a need both to achieve large depth of field by light shaping and to maintain ultracompact form factors. Flat metasurfaces on optical fibers can achieve such requirements, with designs such as encapsulated diffractive axicon masks. They have the advantages of simple fabrication and transfer, scalability to multi-layer structures and ability to wavelength and/or polarization control. We show a method to shape light from optical fibers via diffractive metallic metalenses bonded onto fiber facets. We discuss a novel process for fabrication and, as proof-of-principle, demonstrate Fresnel zone plates and diffractive axicons on optical fiber facets.

Two photon fluorescence imaging microendoscopy is a current research thrust for detailed tissue interrogation and early detection of pre-cancerous lesions. There is a need for miniaturization of endoscopes so that it is minimally invasive for in-vivo optical imaging of cavities in the body inaccessible by existing endoscopes. With the advancements in micro-optics and gradient refractive index (GRIN) lenses, high numerical aperture is achieved at the tissue end with compact lenses. However, GRIN lenses owing to their optical aberrations limit the resolution and thereby image quality. We present the optical design of single fiber microendoscope imaging head with distal beam scanning and diameter of probe optics limited to 1.5mm. We found that positioning of the micro mirror plays a crucial role in controlling the aberrations, diameter of probe and field of view. The effect of gradient constant on aberrations is analyzed with excitation path models at 830 nm. The design is optimized to keep the predominant aberrations such as coma and astigmatism in control when the beam is scanned over the sample by tilting a micro electro mechanical system (MEMS) scan mirror. In addition to the monochromatic aberrations, chromatic focal shift is another major challenge in two photon fluorescence imaging that limits fluorescence collection. The key novelty in this research is the incorporation of phase element in the design for chromatic correction at 830nm and 520nm. A homogenous spot radius of 1.5μm is achieved at multiple tilt angles (±3°) of the scan mirror resulting in a field of view of 142μm.

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.

Here, we present a new handheld multiphoton endomicroscopic system for tumor diagnosis in the head and neck region. It consists of an approx. 25 cm long rigid endomicroscopic probe with two variants (0° and 45° bended tip), connected to a handheld scan-head. The system can achieve a field of view > 600 μm for coherent anti-Stokes Raman scattering (CARS) and other nonlinear imaging techniques by a non-descanned detection channel, and laser confocal imaging with indocyanine green (ICG) by a descanned detection channel. Furthermore, high-power femtosecond laser pulses can be transmitted through the system for precise tissue ablation without the risk of damaging the optical components.

Imaging modalities capable of detecting functional changes over small areas can increase sensitivity and specificity of early cancer detection. Label-free imaging of metabolic activity at cellular level resolution over full thickness of cervix epithelium is possible with 2p imaging. However, low probability of 2p excitation and scattering nature of tissues limit autofluorescence levels in 2p imaging. We present a 2p autofluorescence imaging endoscope system for detection of metabolic changes in cervix in a clinical setting, with an increased collection efficiency in scattering media. Collection of autofluorescence signals is done with a multitude of high NA fibers arranged around a miniaturized excitation objective. By cleaving the collection fibers at a specific angle, we increase the directivity of the collection and the collection efficiency per fiber. The endoscope performs imaging at 775 nm, which is capable of exciting NAD(P)H and FAD molecules. Laser pulses of 100 fs duration are delivered to the sample with an air core photonic bandgap fiber. Fiber is scanned in spiral pattern via a piezo actuator tube. Scanning at different tissue depths is possible with the axial actuation of the endoscope via a linear stepper motor. Benchtop tests indicate that the endoscope system has lateral and axial resolutions of 0.65 μm and 4.33 μm, respectively. Fluorescence images of pollen cores are presented to demonstrate the imaging quality of the endoscope system.

We demonstrate the feasibility of multiphoton fluorescence imaging with high spatial resolution using commercially available single-core 50/125 multimode graded-index fiber. Light propagating forward inside the endoscopic fiber undergoes a non-reciprocal propagation exhibiting a robust nonlinear spatial self-cleaning process. Whereas fluorescence from nonlinear interactions with biological samples linearly propagates backward along the same fiber. The scanner head, located at the distal end of the endoscope and suited for multimode fibers, is based on a ceramic tube where the fiber end follows a spiral course to explore the sample. No knowledge of the fiber transfer matrix is required.