Right now, this convergence of structural and functional interrogation is very much a defining theme within the medical-imaging community. Already the R&D community is talking up early-stage work on what could be the next big thing in dual-modality imaging: combined PET/MRI systems. "The ability to correlate multiple physiological, metabolic or molecular signals though PET and MRI, accurately co-registered with the high-resolution anatomical localization provided by MRI, offers some tremendous opportunities," noted Simon Cherry of University of California Davis in a recent Talking Point article on medicalphysicsweb (see Seeing double: joined-up thinking on PET/MRI).

Beyond the fusion of established clinical-imaging modalities, however, lies an equally, if not more enticing, prospect: the immense potential of optical radiation in cancer diagnosis and screening. In the laboratory, optics-related research is proceeding apace on many fronts. Scientists are exploiting optical techniques in conjunction with CT to evaluate parameters such as morphology, vasculature, blood flow and oxygenation in suspect tissue. Others are pairing optical tomography or spectroscopy with MRI in order to differentiate benign from malignant lumps in the breast (see Special report: optical breast imaging). Meanwhile, significant efforts are under way on the use of optical imaging in drug development - evaluating the efficacy or otherwise of molecularly targeted therapies for cancer - and to gain a better understanding of the disease states that exist post-therapy.

Cancer-specific fluorescence
Technology push is one thing that's not lacking in biomedical optics. Fluorescence imaging, because of its exquisite sensitivity, is one technique that's attracting plenty of interest as a potential alternative to conventional molecular-imaging approaches. With this in mind, US researchers last month unveiled an imaging agent that selectively binds to certain cancer cells and fluoresces only when processed by these cells.

This cancer-specific fluorescence allowed the investigators to successfully visualize very small tumours in the peritoneum (the tissue that lines the wall of the abdomen) in mice with ovarian cancer. They claim that the sensitivity of their approach (92%) holds out the promise of one day being able to optically enhance surgical or endoscopic procedures, allowing for more complete surgical removal of metastatic disease.

The team, led by Hisataka Kobayashi at the US National Cancer Institute (NCI) Center for Cancer Research, part of the National Institutes of Health, created a protein molecule (called avidin) which binds to another protein commonly found on the surface of cancer cells that can metastasize to the peritoneum. During the study, Kobayashi and colleagues joined their compound to three molecules of a fluorescent marker called rhodamine X.

In this new compound, which they called Av-3ROX, the rhodamine X molecules are unable to fluoresce. However, when Av-3ROX is taken up by cancer cells after binding to them, it is broken down in sac-like compartments (called lysosomes) inside the cells. When enzymes in the lysosomes break the compound into smaller pieces, the rhodamine X is released and is able to fluoresce.

"Conventional imaging methods such as nuclear isotopes, MRI or CT use contrast agents that make a signal whether they are bound or unbound to a cancer cell," noted Kobayashi. "Our method will make a signal only from cancer cells. It's cancer-specific imaging."

Malign or benign?
A different take emerged at the American Chemical Society's annual meeting in Chicago, IL, in March. Here a team from Harvard Medical School (Cambridge, MA) reported on animal studies of an imaging agent that could one day be used in an optical adjunct to mammography, helping to distinguish malignant tumours from non-cancerous masses when screening for breast cancer.

The contrast agent - which relies on optical radiation rather than X-rays - selectively targets and highlights malignant micro-calcifications in the breast, ignoring similar micro-calcifications found in benign breast conditions. Though scientists can't explain exactly why these calcifications occur, studies show that the calcifications in malignant breast tumours contain a higher proportion of a particular calcium salt called hydroxyapatite. In benign tumours, the predominant calcium salt is calcium oxalate.

The contrast agent is designed using a combination of bisphosphonate, a type of drug used to strengthen bone, with a near-infrared fluorophore. When used with optical tomography, it is possible to reconstruct a 3D image of deep-lying tissues, highlighting any areas where malignant tumours appear.

"Because this agent is highly selective in targeting the product of malignant tumours, this approach may prove most useful for monitoring women who have dense breast tissue, or those who are at a higher-than-average risk for developing a malignant breast tumour," noted team leader John Frangioni, associate professor of medicine and radiology at Harvard Medical School.

Future studies will focus on translating the new compound to the clinic for human testing, though it's likely to be years rather than months before the compound is ready for human trials.

Go with the flow
Next month, yet another variation on the biomedical optics theme will feature at the Conference on Lasers and Electro-Optics (CLEO) in Baltimore, MD. Here, scientists from Duke University (Durham, NC) will describe a developmental laser-based technique that generates 3D images of blood vessels by taking advantage of the natural multiple-photon-absorbing properties of haemoglobin. The big plus: there's no need for contrast agents or fluorescent markers.

The scientists claim that their approach, which has been demonstrated in vitro, can provide images of blood vessels in relatively deep tissue (up to 1 mm below the skin's surface) with micron-scale resolution. In a clinical setting, that sort of functionality will likely prove useful in tracking the angiogenesis (growth of new blood vessels from existing ones) associated with melanoma, the deadliest form of skin cancer.

So how does the Duke technique work? Basically, two lasers at different wavelengths send ultrashort pulses (lasting only a femtosecond, 1x10-15 s) onto a blood vessel. The haemoglobin absorbs light from both of these lasers at the same time - a process known as two-photon absorption - and then gives off signals that can be detected to build up an image.

One "pump" laser excites haemoglobin molecules to a higher energy state; the other "probe" laser monitors the haemoglobin after the excitation. Sometimes the pump laser is off and there is no two-photon absorption. By subtracting the signal from the "off" state from the "on" state, the researchers remove unwanted scattered light from the data and can get high-quality signals from haemoglobin molecules.

To map out the haemoglobin distribution, laser beams scan across the sample, a process that reveals the outlines and contours of blood vessels. Taking images at different depths and stacking these images layer by layer subsequently yields a 3D reconstruction of the blood vessels.

All of which is extremely encouraging. It's worth noting, however, that analysis by medical device maker Johnson & Johnson reveals some 87% of innovations in the medical market originate from the clinicians working in hospitals - presumably because they have a better understanding of the problems encountered in diagnosis and treatment.

Clearly, then, if next-generation optical imaging modalities are to make the transition out of the lab and into the market-place, they must address an identifiable medical need and offer substantive differentiation versus established technologies, whether on price, performance or both. None of that is going to be easy, but getting the clinicians in the development loop sooner rather than later can only help.