“Atomic force movies” of biological processes at nanoscale and “two-photon laser-scanning microscopy” are other imaging technologies set to revolutionize biology by giving researchers the ability to watch cells in real-time as they move about their environment, and to watch what happens inside the cell.

MRI and CT are developing apace with optical technologies. A contrast agent containing iron oxide nanoparticles has been found to improve MRI sensitivity in scans of the pelvic and para-aortic lymph nodes to predict lymph node metastases, and German and US researchers have created a portable nuclear magnetic resonance sensor that could be used to make portable MRI scanners. In CT, a breast scanner has been developed that is painless and may be able to detect tumors earlier than mammography, though it is several years from validation and approval. (An ultrasound breast scanner developed at the Karmanos Cancer Institute/Wayne State University School of Medicine shows perhaps more promise, being radiation free, much less expensive than CT or MRI, and having the potential to destroy tumors as it finds them. The Digest‘s sponsor, the Detroit Medical Center, is affiliated with Karmanos and Wayne.)

If optical, CT, MR, and ultrasound imaging aren’t enough to spell the demise of mammography, perhaps a jolt of electricity will lay it to rest. A portable device that uses electrical current to examine breasts (painlessly) for cancer is in clinical trials at some 20 centers around the world.

But wait, there’s more. Terahertz radiation (“T-rays,” which we first mentioned in 2003) may at last be about to emerge as the next frontier in imaging science, now that a way has been found to harness it.

And finally, nanomedicine may one day deliver the coup de grâce for imaging of any sort. The products mentioned in the Diapeutics section, and those of a visionary Ohio state-funded program — “smart nanoparticles” for the early detection and treatment of cancer, viral infections, and hemophilia — would eliminate the need for imaging, at least for some diseases.

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A sports medicine clinic and a handful of hospitals in the US have begun using a “Diagnostic Scope System” with a needle-like bundle of optical fibers. Inserted into a joint, the scope provides surprisingly clear pictures of tissue or bone damage with a minimum of pain and trauma. One orthopedist user described it as the “smallest, cheapest and quickest” way to examine joint problems. It can help determine answers to such questions as whether a patient needs a full or just a partial knee replacement.

The system is a by-product of technology developed for the Hubble space telescope, and has been inducted into the Space Technology Hall of Fame. The real innovation is not the fiber optics but the system’s software, which improves the image. A future version of the system could be developed for other areas of medicine such as cardiac catheterizations.

3D Microscope

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German researchers have developed a technology called SPIM (Selective Plane Illumination Microscopy) which will enable optical microscopes to reveal complex, three-dimensional processes in whole, living organisms with “unprecedented quality,” according to the European Molecular Biology Laboratory. The technology makes possible three-dimensional video of the inner workings of living organisms at a much higher level of detail than has been achieved before. A tissue sample can be rotated and viewed along different directions, without the blurring that occurs with current methods. Using the technology, live tissue specimens in suspension reveal developmental processes such as the formation of eyes and the brain in embryonic fish or other model organisms.

The presentation of SPIM at scientific conferences has generated a flood of requests for the instrument, which is being commercialized in partnership with Carl Zeiss.

Big Advance for Cell Biology

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Sandia National Laboratories’ “biocavity laser” can reveal, in real time, the inner workings of a single cell. It has been demonstrated to be able to measure changes in cells’ architecture caused by cancer, including alterations in protein density, cytoskeleton shape, and mitochondria. Researchers are now using the laser to watch the sequence of metabolic and genetic changes as stem cells differentiate into muscle, nerve, etc. cells.

The laser has already produced a detailed picture of a single cell’s mitochondria, which break down and change shape in cancer cells and so are detectable by the laser. That means it could be used by clinicians to determine on the spot whether a patient has cancer, based on an extremely small sample, though a method for removing cells from the body and delivering them directly to the laser has not yet been worked out.

Most Sensitive Cancer Test

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A new way of testing cells for cancer can both diagnose and determine the stage of cancer with as few as 50 tumor cells. Cancer cells are more elastic than normal cells. An “optical stretcher” tests the elasticity of individual cells, so can be used where traditional biopsies, which need 10,000 to 100,000 cells, would be dangerous or impossible.

The German researchers who developed the optical stretcher (a sort of optical tweezers but using unfocused rather than focused laser light) are testing it to screen for oral cancers and in the staging of breast cancer tumors.

Among other things, the technique could eliminate or reduce unnecessary mastectomies. The softer the cancer cells, the more likely they are to metastasize. The optical stretcher can determine, just by measuring cells from the primary tumor, whether or not the cancer has spread, without need to examine nearby lymph nodes for secondary tumors or order precautionary mastectomy or whole-body chemotherapy.

The device can test as many as 3,600 cells per minute, and reportedly does not cost a lot to build. It could even be suitable for dentist’s offices, to swab patients’ mouths for cancer cells. Pre-clinical trials are underway in Germany.

Nano-video-microscopy

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Taking a single picture at nanoscale using an atomic force microscope takes about ten seconds. MIT researchers have found a way to capture nanoscale images a million times faster, which could lead to “atomic force movies” capturing (for example) the motions of the microfluidic pumps used in the purification and analysis of DNA and proteins or provide moving images of biological processes.

At a slightly larger level, biologists already have a tool to make movies of cells moving about inside living tissue. Called two-photon laser-scanning microscopy, it is claimed to revolutionize biology by giving researchers the ability to watch cells in real-time as they move about their environment and discover how cells signal to each other and migrate within tissues such as nerves and lymph nodes. UC Berkeley researchers have already used the technique to watch thymus cells moving at about an inch per hour and turning into either helper or killer T cells. Two-photon imaging may next be used to study the movement of signaling molecules within the cells.

MRI Advances

Source: The Advisory Board, 2005. “Nanoparticle-enhanced MRI improves sensitivity in lymph node metastasis detection.” Technology Watch (subscription service), April 24.

Source: The Advisory Board, 2005. “Researchers developing portable magnetic resonance device.” Technology Watch (subscription service), April 11. (Citing the Xinhua News Agency.)

Injecting patients who have endometrial or cervical cancer with a lymph node-specific contrast agent made of ultra-small particles of iron oxide (USPIO) has been found to improve MRI sensitivity in scans of pelvic and para-aortic lymph nodes to predict metastases, without decreasing specificity. The researchers conclude that USPIO-MRI can improve surgical and nonsurgical treatment for patients with cervical and endometrial cancer by allowing surgeons to preoperatively identify malignant nodes, avoiding

surgical lymph node sampling when USPIO-MRI results are negative, and improving the definition of the radiotherapy fields.The Advisory Board also reports that German and US researchers have created a portable Nuclear Magnetic Resonance (NMR) sensor, which could be used to make portable MRI scanners.

CT for Breast Cancer

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UC Davis researchers are testing a breast CT machine that is painless and may be able to detect tumors earlier than mammography. Several years of clinical trials are anticipated before its effectiveness can be proven, according to the Sacramento Bee. The patient lies face-down on a padded table with a circular opening for the breast, which is scanned by a CT machine under the table. The patient must hold her breath for 17 seconds while the images are taken. The first trial will enroll about 190 UC Davis patients to confirm that the CT can detect breast tumors as well as mammography does. A larger trial would then determine whether it detects tumors at an earlier stage of development. An earlier safety trial confirmed that it will reliably deliver no more radiation to the breast than a typical two-view mammogram. Images taken on early study recruits are much clearer than mammography images.

The new machine is small enough to be used in an individual practitioner’s office.

Impedance Scanning

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Clinical trials of a painless, portable device that uses electrical current rather than X-ray to examine breasts for cancer is underway at some 20 centers around the world. “Impedance scanning,” as the underlying technology is known, is based on evidence that electrical current passes through cancerous tissue more easily than normal tissue. The takes about 10 minutes, does not require breast compression, can detect “very small” tumors, produces a report rather than an image, and is accurate enough for widespread use, according to its developers.

The device sends a small current through electrodes placed over each breast, and immediately calculates and presents negative or positive results. Electrocardiograms, which have been used for years to assess heart muscle, also are based on the theory that normal and diseased tissue conduct electricity differently. The technique may have the potential to replace mammography and be better able to assess the denser breasts of younger women, thus detecting cancers in younger women.

Imaging’s Next Frontier: T-rays

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Terahertz radiation is considered by some to be the next frontier in imaging science. “T-rays” can penetrate tissue without causing radiation damage and distinguish among tissues with varying water content, such as fat and muscle. But T-rays have been difficult to harness, because computer chips still only operate at a few gigahertz and cannot process terahertz oscillations. Japanese and US researchers have proposed a way to harness terahertz rays for body imaging using a sort of “tuner” to filter and select the optimum T-ray frequencies for coherent images.

And the computer chips are not far behind: scientists at the University of Illinois have created a “pseudomorphic heterojunction” transistor that exceeds 600 gigahertz and could soon reach into the terahertz range.

Targeted Nanoparticles for Diapeutics

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The Case Western Reserve University School of Medicine has won a US$4 million Ohio state grant to make “smart nanoparticles” for the early detection and treatment of cancer, viral infections, and hemophilia. The nanoparticles will be designed to:

• Light up on imaging only at sites of disease,
• Deliver photoactivated molecules to cancerous lesions so as to kill the tumors, not the healthy tissue around them,
• Deliver payloads of corrective genes to treat genetic disorders, and payloads of inhibitory nucleic acids to suppress viral infections or cancers, and
• Deliver effective drugs that are otherwise too toxic or too insoluble to be used in humans.

This is just a small part of an ambitious and laudable 10-year, US$1.1 billion initiative called the Ohio Third Frontier Project, designed to expand Ohio’s high-tech research capabilities and promote start-up companies to create high-paying jobs for generations to come.