No Lens, No Problem

Although technological advances have taken telepathology forward by leaps and bounds, allowing physicians to remotely access medical data and make diagnoses, there is still an urgent need for a reliable, inexpensive means of imaging and identifying disease. Standard optical microscopy tools unfortunately don’t fit the bill; they are expensive, relatively bulky, and many laboratories – especially in resource-limited settings – have no access to such equipment.

According to Aydogan Ozcan and his research colleagues at the University of California, Los Angeles, the solution may be holographic lens-free microscopy (1). The group’s unique method provides high-throughput imaging of samples with diffraction-limited resolution over large fields of view – but most importantly, it does so without compromising on cost-effectiveness or portability.

Ozcan explains, “We prepare tissue samples using a technique called CLARITY, which makes tissue transparent using a chemical process that removes fat and leaves behind proteins and DNA.” The method typically requires tissue staining via fluorescent dyes, which carry several drawbacks; not only can they be costly, but the staining tends to degrade over time, making it harder for microscopists to gather information from samples. Instead of fluorescent dyes, Ozcan’s team used colorimetric dyes that can be used with regular bright-field microscopy tools without any noticeable signal loss over time.

To image the samples, the team developed a computational imaging device made of components that collectively cost just a few hundred dollars: a holographic lens-free microscope capable of producing 3D pictures with one-tenth of the image data that conventional scanning optical microscopes need. Ozcan talks through the process: “In this computational microscope, the cleared tissue is placed in a small container on a silicon chip that contains millions of photodetectors – the same type of chip found in mobile phone cameras. When we shine light on the sample, low-resolution shadows from the tissue fall on the chip. Those shadows, created by the interference of light scattered by the sample, form holograms of the cleared tissue sample.” Next, the researchers enhance the resolution and enable 3D imaging by shifting the sample relative to the image sensor and capturing holographic shadow again. That allows them to digitally view different cross-sections, or digital slices, of the tissue sample. “To put it simply, through computation- and holography-based algorithms, we converted a standard 10-megapixel imager into a several-hundred-megapixel microscope that can digitally image through different slices of a thick tissue sample.”

Now, Ozcan and his colleagues can image tissue samples up to 0.2 mm thick – over 20 times thicker than a typical sample. It’s especially important for such a device to handle thick samples because, in laboratories without sophisticated equipment, producing thinner tissue slices is difficult. But even well-resourced labs can benefit: “It enables us to study larger sample volumes, which could help us to detect abnormalities earlier than we otherwise would.” In fact, they’re already aiming higher, hoping eventually to develop a version of the microscope that can image even thicker tissue samples.