Optical microscope without lenses produces high-resolution 3-D images on a chip

Apr 22, 2011
Schematic diagram of the lens-free tomography setup showing the angles of rotation for the light source to illuminate a sample.

(PhysOrg.com) -- UCLA researchers have redefined the concept of a microscope by removing the lens to create a system that is small enough to fit in the palm of a hand but powerful enough to create three-dimensional tomographic images of miniscule samples.

The advance, featured this week in the early online edition of the journal , represents the first demonstration of lens-free optical tomographic imaging on a chip, a technique capable of producing high-resolution 3-D images of large volumes of microscopic objects.

"This research clearly shows the potential of lens-free computational microscopy," said Aydogan Ozcan, senior author of the research and an associate professor of electrical engineering at UCLA's Henry Samueli School of Engineering and Applied Science. "Wonderful progress has been made in recent years to miniaturize life-sciences tools with microfluidic and lab-on-a-chip technologies, but until now optical microscopy has not kept pace with the miniaturization trend."

An optical imaging system small enough to fit onto an opto-electronic chip provides a variety of benefits. Because of the automation involved in on-chip systems, scientific work could be sped up significantly, which might have a great impact in the fields of cell and developmental biology. In addition, the small size not only has great potential for miniaturizing systems but also leads to cost savings on equipment.

The optical , invented more than 400 years ago, has tended to grow larger and more complex as it has been modified to image ever-smaller objects with better resolution. To address this lack of progress in miniaturization, Ozcan's research group — with graduate student Serhan Isikman and postdoctoral scholar Waheb Bishara as lead researchers — developed the new tomographic microscopy platform through the next evolution of a lens-free imaging technology the group created and has been improving for years.

Ozcan, a researcher at the California NanoSystems Institute at UCLA, makes the analogy that a traditional is like a huge set of pipes delivering content, in the form of images, to the user. Over years of development, bottlenecks occur that impede further improvement. Even if one part of the system — that is, one bottleneck — is improved, other bottlenecks keep that improvement from being fully realized. Not so with the lens-free system, according to Ozcan.

Artistic rendering of a sample being tomographicaly imaged, showing the individual sections.

"Lens-free imaging removes the pipes altogether by utilizing an entirely new design," he said.

The system takes advantage of the fact that organic structures, such as cells, are partially transparent. So by shining a light on a sample of cells, the shadows created reveal not only the cells' outlines but details about their sub-cellular structures as well.

"These details can be captured and analyzed if the shadow is directed onto a digital sensor array," Isikman said. "The end result of this process is an image taken without using a lens."  

Ozcan envisions this lens-free imaging system as one component in a lab-on-a-chip platform. It could potentially fit beneath a microfluidic chip, a tool for the precise control and manipulation of sub-millimeter biological samples and fluids, and the two tools would operate in tandem, with the microfluidic chip depositing and subsequently removing a sample from the lens-free imager in an automated, or high-throughput, process.

The platform's 3-D images are created by rotating the light source to illuminate the samples from multiple angles. These multiple angles also allow the system to utilize tomography, a powerful imaging technique. Through the use of tomography, the system is able to produce 3-D images without sacrificing resolution.

"The field of view of lens-based microscopes is limited because the lens focuses on a narrow area of a sample," Bishara said. "A lens-free microscope has both a much larger field of view and depth of field because the imaging is done by the digital sensor array and is not constrained by a lens."

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More information: Lens-free optical tomographic microscope with a large imaging volume on a chip, PNAS Published online before print April 19, 2011, doi: 10.1073/pnas.1015638108

Abstract
We present a lens-free optical tomographic microscope, which enables imaging a large volume of approximately 15 mm3 on a chip, with a spatial resolution of < 1 μm ×  < 1 μm ×  < 3 μm in x, y and z dimensions, respectively. In this lens-free tomography modality, the sample is placed directly on a digital sensor array with, e.g., ≤ 4 mm distance to its active area. A partially coherent light source placed approximately 70 mm away from the sensor is employed to record lens-free in-line holograms of the sample from different viewing angles. At each illumination angle, multiple subpixel shifted holograms are also recorded, which are digitally processed using a pixel superresolution technique to create a single high-resolution hologram of each angular projection of the object. These superresolved holograms are digitally reconstructed for an angular range of ± 50°, which are then back-projected to compute tomograms of the sample. In order to minimize the artifacts due to limited angular range of tilted illumination, a dual-axis tomography scheme is adopted, where the light source is rotated along two orthogonal axes. Tomographic imaging performance is quantified using microbeads of different dimensions, as well as by imaging wild-type Caenorhabditis elegans. Probing a large volume with a decent 3D spatial resolution, this lens-free optical tomography platform on a chip could provide a powerful tool for high-throughput imaging applications in, e.g., cell and developmental biology.

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