Rice University researchers have tested a tiny lensless microscope called Bio-FlatScope, capable of producing high levels of detail in living samples. The team imaged plants, hydra, and, to a limited extent, a human. A previous iteration of the technology, FlatCam, was a lensless device that channeled light through a mask and directly onto a camera sensor, aimed primarily outward at the world at large. The raw images looked like static, but a custom algorithm translated the raw data into focused images. The device described in current research looks inward to image micron-scale targets such as cells and blood vessels inside the body, and even through skin. The technology combines a sophisticated phase mask to generate patterns of light that fall directly onto the chip, the researchers said. The mask in the original FlatCam looked like a barcode and limited the amount of light that passes through to the sensor. The lensless Bio-FlatScope is a small, inexpensive camera to monitor biological activity that can’t be captured by conventional instruments. The device could eventually be used to look for signs of cancer or sepsis or become a valuable endoscopy tool. Courtesy of Robinson Lab/Rice University. The phase mask for Bio-FlatScope looks more like a map of a natural landscape, with no straight lines. “Being random allows the mask to be pretty diverse in gathering light from all directions,” said postdoctoral researcher Vivek Boominathan, one of four lead authors of the study. “And then we take the random input, which is called Perlin noise, and do some processing to get these high-contrast contours.” At the sensor, light that comes through the mask appears as a point spread function, a pair of blurry blobs that seems useless but is actually key to acquiring details about objects below the diffraction limit that are too small for many microscopes to see. The blobs’ sizes, shapes, and distances from each other indicate how far the subject is from the focal plane. Software reinterprets the data into an image that can be refocused at will. The researchers first tested the device by capturing cellular structures in a lily of the valley, and then calcium activity in small jellyfish-like hydra. The team then monitored a running rodent, attaching the device to the rodent’s skull and then setting the animal down on a wheel. Data showed fluorescent-tagged neurons in a region of the animal’s brain, connecting activity in the motor cortex with motion and resolving blood vessels as small as 10 µm in diameter. In collaboration with Rebecca Richards-Kortum and research scientist Jennifer Carns from Rice Bioengineering, the team identified vascular imaging as a potential clinical application of the Bio-FlatScope. The team imaged graduate student and co-lead author Jimin Wu’s lower lip to see if light passing through to the camera could deliver structural details of the blood vessels within. “It was kind of an engineering challenge because it’s difficult to position the Bio-FlatScope at the correct position and keep it there,” Wu said. “But it showed us it could be a good tool for seeing signs of sepsis, because pre-sepsis changes the density of the vasculature. Cancer also alters the morphology of the microvasculature.” The team sees potential for a camera that can curve around its subject, such as brain tissue, where the device would match the morphology of the subject, said Jacob Robinson, an electrical and computer engineer at Rice. “Or maybe you could fold it up, stick it in place, and have it unfold and deploy. You could also do really interesting things by bending it for a fisheye effect, or you could curve it inward and have very high light-collection efficiency.” The research was published in Nature Biomedical Engineering (www.doi.org/10.1038/s41551-022-00851-z).