An Unexpected iPhone App – in vivo Microscopy for Cancer Screening
Fortunately, recent improvements in technical performance and cost efficiency of consumer-grade electronic imaging devices have set the stage for a low-cost alternative to conventional imaging modalities. Rebecca Richards-Kortum, the Stanley C. Moore Professor of Bioengineering at Rice University, and collaborators from the University of Texas M. D. Anderson Cancer Center and the Mount Sinai School of Medicine wanted to offer healthcare providers an imaging device that is inexpensive yet provides high diagnostic accuracy. They designed a portable microscope that can be inserted into a body cavity, such as the mouth, esophagus, or cervix. The battery-operated device, termed a fiber-optic microendoscope, consists of an LED light, a microscope objective lens, a wire-thin, flexible fiber-optic bundle, and a consumer-grade digital camera.
To visualize cells, a non-toxic fluorescent dye that stains cell nuclei is applied to the suspicious area and the thin fiber-optic bundle is inserted into the body. The other end of the fiber-optic bundle is connected to the rest of the microendoscope (objective lens, camera, and LED light), which remains outside the body. The fluorescent dye glows green when illuminated with light of a specific color. Within seconds of applying the dye and inserting the fiber-optic bundle, a magnified image of the cells that are in contact with the tip of the bundle is displayed on the camera’s LCD screen in real-time, eliminating the need for additional image processing hardware. Cancerous tissue can be readily distinguished from healthy tissue by the presence of dense, disorganized nuclei. (In healthy tissue, cells are typically layered in an orderly fashion.) Pathologists use the same approach to visualize tissue architecture in biopsy samples.
“We could use a scientific CCD [charge-coupled device] camera and a laptop computer and build a system like that for under $4,000,” says Richards-Kortum. To reduce costs even further, the digital camera component might be replaced with an iPhone, which also would enable sending images to a central location for expert analysis. Alternatively, digital image analysis algorithms could be built into the system to interpret images at the point of care. This feature could be particularly useful in developing countries “so you can train someone who is not a physician to identify suspicious regions,” explains Richards-Kortum.
Biopsy Without a Knife or Needle
Although the microendoscope provides much of the same information as could be gained from a biopsied tissue, it is not intended to eliminate the need for biopsies, states Richards-Kortum. However, the technology might reduce the number of painful biopsies physicians must take to make a diagnosis. Doctors often randomly select areas to biopsy, hoping they do not miss a malignant lesion if a patient has one. “We have to take a lot of negative biopsies to find one positive area. We are hoping that [this] technology will have a very high negative predictive value so that we don’t need to take unnecessary biopsies,” says Richards-Kortum’s collaborator Sharmila Anandasabapathy, Associate Professor of Medicine and Gastroenterology, Mount Sinai School of Medicine.
A second limitation is the microscope’s narrow field of view, about 1 mm in diameter. Anandasabapathy explains that it would take hours to image the full length of the esophagus (200 times longer than the microendoscope’s field of view), for example. To overcome this limitation, she uses the microendoscope in combination with high-definition white light endoscopy, chromoendoscopy (a newer technique that stains specific structures in a tissue during the endoscopy procedure), and narrow-band imaging (a technique that uses different colors of light to enhance fine structure of tissue without stains). Although they have a lower resolution than the microendoscope provides, these advanced techniques have a wider field of view than the microendoscope and reveal more tissue detail than conventional endoscopy.
Improving Performance, Broadening Applications
“We have been using this technology in surveillance, as an optical approach to increase diagnostic yield and also potentially to determine whether we removed an area completely during endoscopic therapy,” says Anandasabapathy. She adds that with the use of optical markers at the tissue surface, the device could help guide prognosis or treatment.
The microendoscope is currently being tested in clinical trials in China – where there is a high incidence of esophageal cancer – as well as Guatemala and Botswana – two countries that have a high incidence of cervical cancer. “We and other groups in the world are working on ways to expand the range of molecular changes that you could image with microscopes like this,” says Richards-Kortum. For example, the device has recently been improved to take images of multiple fluorescent dyes, each labeling a different structure inside cells.
To further develop this technology, Richards-Kortum and Anandasabathy formed an academic-industrial partnership with Pentax. “We’re developing a wide-field technology that could be used through the endoscope to help direct the fiber-optic microendoscope. We’ll be comparing the performance of the fiber-optic microendoscope to the Pentax confocal microendoscope,” says Richards-Kortum. In parallel with those efforts, the Richards-Kortum lab is developing a microscope small enough to fit in a biopsy needle. The microendoscope would potentially provide the same information as a biopsy, only in real-time, allowing patients to be diagnosed and begin treatment at the time of their clinical visit. This feature would be particularly important in developing countries, where remote location of clinics and poverty prevents patients for coming back for test results and treatment.
This research is supported in part by the National Institute of Biomedical Imaging and Bioengineering and the National Cancer Institute.
Shin D, Pierce MC, Gillenwater AM, Williams MD, Richards-Kortum RR. A fiber-optic fluorescence microscope using a consumer-grade digital camera for in vivo cellular imaging. PLoS One. 2010 Jun 23;5(6):e11218.
Muldoon TJ, Thekkek N, Roblyer D, Maru D, Harpaz N, Potack J, Anandasabapathy S, Richards-Kortum R. Evaluation of quantitative image analysis criteria for the high-resolution microendoscopic detection of neoplasia in Barrett's esophagus. J Biomed Opt. 2010 Mar-Apr;15(2):026027.