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Most — if not all — technologies tend to get smaller. Smaller means easier to use, more usable in a greater variety of places and circumstances, and probably (though not always) easier to make.

Smaller also (usually) means safer, since fewer parts. But really small could offer a variety of problems, and it may be an issue of real concern especially with last month's report that "nano-tubes" may act much like asbestos fibers, so that, if flying loose in the environment, they present the very same health problems as asbestos fibers. (But perhaps the knowledge of this particular danger will offer protection against their being allowed loose.)

Other concerns will follow, yet to be revealed, given the early-stage development of this technology, and the FDA has assured us that it is on top of the regulatory problems it must consider in approving nanotech products, or products using nanotechnology.

Still to be known, however, are the ultimate rewards and ultimate value of this technology subjects currently being debated by pundits and nanotech's proponents and critics.

But the researchers involved don't appear to be fazed by the risks and the various prognostications as to its value. The scientists at technology companies, research institutes and academic centers are pushing ahead, developing new discoveries and applicable advances on a daily basis, a great many of them targeting the healthcare research and clinical arenas.

What follows is an overview of some of the more interesting developments and research pathways to new products.

Nano-tube sensor

Speaking of those potentially dangerous nano-tubes, a group of researchers is using this type of nanotech to measure minute amounts of insulin the success of this effort offering a major step toward developing the ability to assess the health of the body's insulin-producing cells in real time and to free those with Type I diabetes from insulin injections would be a major step forward in the diabetic arena.

This system has been developed by a research team of Vanderbilt University (Nashville, Tennessee), headed by associate professor of chemistry David Cliffel. The system works by transplanting insulin-producing cells into the livers of diabetics to replace the cells that the disease has disabled or destroyed, using a new electrode for a device called a microphysiometer.

The new electrode is built from multi-walled carbon nano-tubes, which are like several flat sheets of carbon atoms stacked and rolled into very small tubes. The nano-tubes are electrically conductive and the concentration of insulin in the chamber can be directly related to the current at the electrode. The nano-tubes operate reliably at pH levels characteristic of living cells.

The microphysiometer assesses the condition of living cells by placing them in liquid nutrient, confining them in a very small chamber and then measuring variations in their metabolism. The volume of the chamber is only three microliters about 1/20th the size of an ordinary raindrop allowing the electrode to detect the minute amounts of insulin released by special pancreatic cells called Islets of Langerhans.

Current detection methods measure insulin production at intervals by periodically collecting small samples and measuring their insulin levels. The new sensor detects insulin levels continuously by measuring the transfer of electrons produced when insulin molecules oxidize in the presence of glucose. When the cells produce more insulin molecules, the current in the sensor increases and vice versa allowing the researchers to monitor insulin concentrations in real time.

Internal beacons via nano-strategy

Physicians' quest to see what is happening inside the body has been hampered by limits on detecting tiny components of internal structures and events.

To solve this problem, researchers at the Stanford University School of Medicine (Stanford, California) have developed an imaging system that can illuminate tumors in living subjects, getting pictures with a precision of nearly one-trillionth of a meter.

Called Raman spectroscopy, this technique expands the available toolbox for the field of molecular imaging, said team leader Sanjiv Sam Gambhir, MD, PhD, professor of radiology and senior author of a study describing the method published in the Proceedings of the National Academy of Sciences.

Gambhir used Raman spectroscopy for this deep imaging method, using tiny nano-particles injected into the body to serve as beacons. Then, by beaming a laser from outside the body, these specialized particles emit signals that are measured and converted into a visible indicator of their location.

"This is an entirely new way of imaging living subjects, not based on anything previously used," said Gambhir, who directs the Molecular Imaging Program at the school of medicine. He said signals from Raman spectroscopy are stronger and longer-lived than other available methods and the particles used this way can transmit information about multiple types of molecular targets simultaneously. "Usually we can measure one or two things at a time," he said. "With this, we can now likely see 10, 20, 30 things at once."

To develop Raman spectroscopy as a clinical tool, the researchers used two types of engineered Raman nano-particles: gold nano-particles and single-wall carbon nano-tubes.

When adapted for human use, they say, the technique has the potential to be useful during surgery, for example, in the removal of cancerous tissue. The extreme sensitivity of the image could enable detection of even the most minute malignant tissues, and a clinical trial is planned to test the gold nano-particles for use in conjunction with a colonoscopy for detection of the earliest stage of colorectal cancer.

Gambhir compared the Raman spectroscopy work to the development of positron emission tomography (PET), an increasingly routine technique using radioactive molecules to generate 3-D images of body biochemistry. "Nobody understood the impact of PET," when first discovered 20 or so years ago, he said. "Ten or 15 years from now, people should appreciate the impact of this."

Perflurocarbon-based nano-particles

Perfluorocarbons, a class of inert, oily polymers, have a proven track record in a variety of clinical uses, including contrast-enhanced ultrasound imaging and eye surgery, to correct a detached retina.

Researchers at the Siteman Center of Cancer Nanotechnology Excellence (St. Louis), led by collaborators at the Washington University School of Medicine, Samuel Wickline, MD, and Gregory Lanza, MD, are well on the way to developing a new use for perfluorocarbons as the building blocks for nano-particles capable of delivering imaging agents and drugs to tumors.

In one of their newest papers, published in The FASEB Journal, the Siteman team reports on its work using targeted perfluorocarbon nano-particles to deliver both a potent fungal toxin known as fumagillin, and an MRI contrast agent to the rapidly growing blood vessels that permeate a tumor.

Fumagillin has shown promise in human clinical trials as an anticancer agent for a wide variety of cancers, but therapeutic doses of the drug produce sudden, severe side effects. To overcome this limitation, the investigators encapsulated fumagillin in perfluorocarbon nano-particles targeted to b3 integrin, a molecule found on the surface of newly developed blood vessels in tumors. The researchers found that this formulation was active in both stopping angiogenesis in tumors and reducing tumor size at fumagillin doses more than a 1,000-fold lower than those used in earlier animal studies, and some 60-fold lower than the doses used in human clinical trials.

At this markedly lower dose, nano-particle-delivered fumagillin not only was equally effective as the much higher dose of unencapsulated fumagillin but also produced measurable side effects in the animals receiving the nano-particle formulation.

Nanofibers heal spinal cords

An engineered material that can be injected into damaged spinal cords could help prevent scars and encourage damaged nerve fibers to grow. The liquid material, developed by Northwestern University (Evanston, Illinois) materials science professor Samuel Stupp, contains molecules that self-assemble into nano-fibers, which act as a scaffold on which nerve fibers grow.

Stupp and his colleagues described in a recent paper in the Journal of Neuroscience that treatment with the material restores function to the hind legs of paralyzed mice.

Research had done something like this previously, but those experiments involved surgically implanting various types of material, but these nano-fibers can be implanted simply by injection. The nano-fibers then break down into nutrients in three to eight weeks, according to Stupp.

The finding is exciting because of the thousands of people who have injuries to the spinal cord, for which there is no cure. When the spinal cord is damaged, nerve stem cells form a scar at the point of the injury, blocking nerve fibers and keeping them from growing, says John Kessler, professor of stem cell biology at Northwestern's Feinberg School of Medicine (Chicago), who collaborated on the work with Stupp.

"It is like cutting a telephone cable," Kessler says of this type of injury, and adding: "We're thinking of regrowing the nerve fibers and rewiring the cut."

Other researchers have attempted a variety of approaches to regenerate nerve fibers. The new strategy has the advantage of utilizing a liquid injected directly into the spinal cord, with the liquid's negatively charged molecules clumping together in contact with positively charged particles, such as calcium and sodium ions, in the body.

The molecules then self-assemble into hollow, cylindrical nano-fibers, which form a scaffold that can trap cells. On the surface of the nano-fibers are biological molecules that inhibit scars and encourage the growth of nerve fibers.

To develop this technique for human therapeutics, Stupp has co-founded Nanotope (Stokie, Illinois), which is working to make a material that meets FDA standards to test in clinical trials. Basic tests of the material in human cell cultures have, the company reports, have shown no toxicities.

Nano-magnetics

Nanotechnologies also are being linked to magnetics. As one example, NanoBioMagnetics (NBMI; Edmond, Oklahoma) has received a U.S. patent based on the use of magnetically responsive nano-particles implanted in the middle ear to drive tissue vibrations that can amplify sound. It says this technology was the first demonstration of the nano-mechanical movement of tissue, in principle operating much like a typical electromagnetic hearing aid.

Development and validation was done from 2002 to 2004, and the company has said it plans to move the strategy to commercialization through partnerships. Its focus is to reduce the size of hearing device systems and making them totally implantable, thus producing improved economics and patient compliance.

Charles Seeney, CEO and founder of NBMI, and co-inventor on the patent, said, "Miniaturization of hearing devices through ever smaller electronic components is part of an emerging trend, based on applying nanotechnology to human healthcare needs."

In another use of magnetics, microscopic magnets may enable the "arming" of human cells to target tumors, a strategy being developed by a group of researchers being funded by the Biotechnology and Biological Sciences Research Council (Wiltshire, UK). The group's research, published in Gene Therapy shows that inserting these nano-magnets into cells, results in many more cells successfully reaching and invading a malignant tumor.

Using human cells as delivery vehicles for anti-cancer gene therapy has long been an attractive approach, but these cells usually reach tumors in insufficient numbers to effectively attack them. Now, UK researchers Claire Lewis, at the University of Sheffield, Jon Dobson at the University of Keele, and Helen Byrne and Giles Richardson, at the University of Nottingham, are attempting to overcome this problem by inserting nano-magnets into monocytes a type of white blood cell used to carry gene therapy and injecting the cells into the bloodstream. The researchers than placed a small magnet over the tumor and found that the magnetic field attracted more moncytes to the tumor cite.

Dobson said, "Though the concept of magnetic targeting for drug and gene delivery has been around for decades, major technical hurdles have prevented its translation into a clinical therapy. By harnessing and enhancing the monocytes' innate targeting abilities, this technique offers great potential to overcome some of these barriers and bring the technology closer to the clinic."

Iron nano-particles and nano-rods

Iron nano-particles designed to collect in lymph nodes containing metastatic cancer cells have proven that they can help physicians detect the metastatic spread of prostate cancer.

A team of investigators at Harvard Medical School (Boston) has developed pilot-phase data showing that these nano-particles can detect lymph node metastases in a highly specific manner in patients with renal cell carcinoma, which accounts for some 20% of kidney cancers.

Reporting its work in Oncology, researchers headed by Alexander Guimaraes, MD, PhD, Mukesh Harisinghani, MD, and Ralph Weissleder, MD Weissleder the principal investigator at the Massachusetts Institute of Technology-Harvard Center for Cancer Nanotechnology Excellence (one of eight centers supported by the National Cancer Institute), showed that dextran-coated iron oxide administered to nine patients with kidney tumors could identify and distinguish lymph node metastases from benign lesions using MRI.

The researchers conclude that these studies warrant a larger trial to determine if iron oxide nano-particles can serve as a non-invasive diagnostic for metastatic disease.

Quantum dots have shown promise as ultra bright contrast agents for use in a variety of cancer imaging studies. Now, a team of investigators at the Multifunctional Nanoparticles in Diagnosis and Therapy of Pancreatic Cancer Platform Partnership, headed by Paras Prasad, PhD, of the State University of New York (Buffalo), has shown that quantum rods may perform even better than their spherical cousins.

Reporting their work in Advanced Materials, the investigators created quantum rods of two different sizes: One quantum rod emitted orange light; the other emitted red light. The investigators then attached the red quantum rod to a monoclonal antibody that recognizes a protein known as mesothelin and the orange quantum rod to a monoclonal antibody that binds to a protein known as Claudin-4. These two proteins are over-expressed by both primary and metastatic human pancreatic cancer cells.

After adding both of the conjugated quantum rods to pancreatic cells growing in culture, the investigators were able to spot both optical labels using standard fluorescence microscopy.