Researchers from Harvard Medical School and Mass General Brigham have created a flexible needle-like endoscopic imaging probe that can acquire 3D microscopic images of tissue. A flexible graded index (GRIN) lens, which the researchers also developed, enables the probe’s bendability. The development of the GRIN lens and the demonstration of the probe challenge the conventional belief that GRIN lenses can only be used as rigid imaging probes, which may limit their potential for certain applications, the researchers said. The researchers’ flexible GRIN lens and bendable endoscopic imaging probe hold potential use in a variety of applications. The long-range flexibility of the new GRIN lens could expand the impact of GRIN lens micro-endoscopy in both research and clinical settings. To develop the flexible endoscopic probe, the team custom-designed a GRIN lens 500 μm in diameter and about 100 mm long. The lens’ long, thin shape and its lack of a rigid outer casing give it the flexibility to bend about 10 degrees without breaking. The researchers integrated the bendable GRIN lens into an endoscopic imaging probe and tested it by performing two-photon 3D fluorescence imaging through the lens. A recently developed GRIN-based endoscope is being used with an implantable microdevice designed to quickly evaluate the effectiveness of various cancer therapies. A setup using the lens that is currently being studied in mice could eventually be used in human patients to quickly figure out which treatment options are best for fighting each patient's specific tumor. Courtesy of Guigen Liu/Harvard Medical School and Brigham and Women’s Hospital. The researchers positioned the lens vertically and induced the type of beam deflection the lens would undergo if the probe were being used in the working channel of a needle used for biopsy. In this way, they were able to simulate how the lens would bend in “real life” when it probed deep into tissue. The experiment showed that the resolution and signal level did not obviously deteriorate when one end of the probe was displaced laterally by 6 mm. “When the lens is bent, the signal lanes that carry the image through the rod synergistically adapt by laterally shifting, much like a car tends to shift toward the outside of a slippery curved road,” researcher Guigen Liu said. “While the signal lanes distort a bit while shifting, they largely keep their properties such as order and shape. This allows most of the resolution and signal level to be retained.” The flexible endoscope does not require calibration from the distal end, and thus preserves the small spatial footprint of the probe itself required for minimally invasive clinical integration. According to Liu, the bendable nature of the GRIN probes streamlines measurements in living subjects, such as animals or human patients and makes them much more practical. The bendable GRIN lens for microimaging could support numerous applications that cannot be supported with a rigid GRIN lens. For example, according to the researchers, the GRIN lens is highly desirable for incorporation into a microdevice the team is currently designing for high-throughput cancer drug selection. The team’s new microdevices are designed to be implanted directly into a tumor and carry small amounts of up to 20 drugs. To measure the effectiveness of the various drugs without removing any tumor tissue, the researchers insert a GRIN-based endoscope directly into the microdevice where it can be used to image fluorescence signals inside the tumor. “When a traditional biopsy is performed, it represents a single moment in time and can take days to get results back from the laboratory,” Liu said. “Our bendable imaging probes could shorten the waiting time to minutes and enable new approaches that use imaging to dynamically monitor tissue changes — for instance, how tumors react to treatments over time.” To move the probes toward clinical application, the researchers are developing longer-length bendable GRIN lenses to allow deeper imaging and more flexibility. They also want to enhance the mechanical durability of the optical components using a thin polymer coating that won’t affect flexibility. The research was published in Optics Express (www.doi.org/10.1364/OE.468827).