Nanotechnology: Huge Future for Small Innovation Medical nanotechnology promises improved diagnostics, delivery of drugs with exquisite precision, and even nanosurgery. This article, based on interviews with experts in the field, will take a look at some of the more interesting applications—some are familiar and some are still in the research stage but likely to have a major impact in the next few years. Peter Cleaveland, West Coast Editor Nanotechnology has traditionally been thought of as something from science fiction or an advance of the future. However, more applications are being developed that can offer practical uses across several industries. Medical device manufacturers have been researching nanotechnology as a solution for biocompatibility issues to antimicrobial coatings to drug delivery mechanisms. The following takes a look at a number of areas in which nanotechnology is making an impact. Antimicrobials Some of the earliest medical uses of nanotechnology have involved antimicrobial coatings—often made of nanoparticulate silver (Figure 1)—on wound dressings to prevent infection and on things like catheters to prevent the formation of biofilms. There has even been work on application of silver nanoparticle solutions directly to wounds. Figure 1: Silver nanoparticles are used as antimicrobials on medical devices and wound dressings. (Photo: Ferro Corp.) Research continues, says William F. Fischer III, research and development manager for Ferro Electronic Material Systems division of Ferro Corp. Everything hinges on surface chemistry, he explains, and some of the mechanisms by which silver destroys microorganisms are still not fully understood. “We’re trying to figure out what, if any, the surface chemistry or surface physiology or morphology has on the microbial aspects occurring naturally with silver.” Other areas of research, he continues, include “modifying the surface to fit within different chemistries and systems for both medical applications, where you’re sometimes bonding to some things such as stainless steel to some textiles.” And, he adds, there’s work on the use of silver “for coupling with medical or medicinal chemistries; it would be a carrier as well as an antimicrobial.” Orthopedics Orthopedic implants are increasingly using nanostructured coatings that allow cells to colonize their surfaces; this not only reduces problems with rejection but also improves fixation in bone. Examples include Vitoss synthetic bone graph substitute made of nanostructured beta tricalcium phosphate from Orthovita, and ultra-thin hydroxyapatite (the form of calcium phosphate found in bone) coatings from Spire Biomedical. Other orthopedic applications for nanotechnology include the use of nanotubes for elution of antibiotics and other drugs on implants, as discussed by Ketul C. Propat, M. Eltgroth, and T.A. Desai of the University of California at San Francisco in a paper entitled “Drug Eluting Nanostructured Coatings,” delivered at Nanotech 2007. Dentistry It is not uncommon to think that only orthopedic surgeons get involved with fastening things to bone, but dental surgeons do it all the time. A traditional material for dental implants is titanium, because it’s compatible with the body and, given time, “the bone in the jaw around the implant will literally grow to, and attach to the surface of the implant,” says Tait Robb, vice president, R&D, Biomet 3i. No bone cement is needed. The speed at which this osseointegration proceeds, Robb explains, depends heavily on the surface characteristics of the implant. With a simple machined surface, the usual procedure was to insert the implant, suture over it, and wait a year before attaching a crown. To speed things up, companies began to experiment with plasma spraying, first with titanium and then with hydroxyapatite. But in time, the coating could delaminate, resulting in rejection of the implant. Figure 2: Seen at 100,000x magnification, 3I’s Osseotite uses an acid etching process to cover the surface of dental implant with irregular pits 1 to 3 microns in diameter and 2 to 5 microns deep. (Photo: Biomet 3i) Figure 3: The Nanotite surface (shown at 100,000x magnification) adds a thin layer of calcium phosphate crystals between 20 and 100 nm in length and 10 to 20 nm in width over the textured surface. (Photo: Biomet 3i) 3i, says Robb, adopted a multi-step acid etching process that covers the surface of the implant with irregular pits 1 to 3 microns in diameter and 2 to 5 microns deep (Figure 2), which they named Osseotite and found could cut the waiting time to four months. The company then developed a way to add a thin layer of calcium phosphate crystals between 20 and 100 nm in length and 10 to 20 nm in width over the textured surface (Figure 3), which they brought to the market under the name Nanotite. This speeded up the process anywhere between three and ten times. It may soon be possible, says Robb, to complete an implant procedure in a day. Soft Tissue Repair Samuel Stupp at Northwestern University has reported promising results from nanofiber-based self-assembling tissue scaffolding that seems to aid the repair of damaged spinal cord neurons, enabling paralyzed mice to walk again. Stupp has also worked with nanostructures made from designed peptide amphiphile molecules that self-assemble in the presence of heparin and, combined with nanogram amounts of angiogenic growth factors; display heparin chains and greatly stimulate angiogenesis to aid wound healing. Other Coating Applications While most nanoparticulate coatings are designed to fight infection or enhance biocompatibility, one company has a nanoparticulate medical lubricant. In September 2006, ApNano Materials Inc. announced an anti-friction medical coatings line based on its NanoLub solid lubricant made of nanoparticles of tungsten disulfide in inorganic Fullerene-like nanostructures. Intended applications include guide-wires in catheters, orthodontic wires and braces for teeth straightening, and coatings for artificial joints and hips. Imaging and Heating The idea of nanotech-based imaging is straightforward: tag nanoparticles that fluoresce or show up well on x-ray or MRI with appropriate antibodies and let them find the cells in question. Mostafa El-Sayed, PhD, director of the Laser Dynamics Laboratory and chemistry professor at Georgia Tech, and his son Ivan El-Sayed, MD, assistant professor of otolaryngology at UCSF Medical Center, have been experimenting with gold nanoparticles tagged with an antibody for the EFGR protein commonly found on the surfaces of cancer cells. The particles attached themselves to the cancer cells and lit up under dark-field microscopy. In later work they discovered that the tagged cells absorbed laser light much more than did normal cells, and could thus be killed by heating them with the laser. Other researchers have proposed the use of very short high-power laser pulses to cause gold nanoparticles to explode (so-called nanobombs), destroying the cells to which they are attached in the process. One drawback to this technique is that it works well only on cancers close enough to the surface for laser treatment, like oral cancer, but there may be a way around that. Researchers Alexander Wei, Ji-Xin Cheng, and others at Purdue University have been studying the use of gold nanorods that respond to near infrared (NIR) light (which penetrates the skin fairly well) by fluorescing brightly—tens of times as brightly as such conventional materials as rhodamine—and can be fabricated to be absorbed into cells or accumulate on their surfaces. When the intensity of the NIR is increased, the nanorods heat up, damaging or killing the cells. Other researchers at the Korea Electronics Technology Institute have been experimenting with gold nanoshells that can be tuned to specific NIR wavelengths. Figure 4: Iron oxide-cored nanoprobes coated with polymers and sugars to hide them from the immune system plus monoclonal antibodies bind to tumor cells. An alternating magnetic field then heats them to kill the tumor cells. (Photo: University of California, Davis) Gold is not the only material that can be used in this way. Researchers at UC Davis, led by Drs. Sally and Gerald DeNardo, are investigating the use of iron oxide-cored nanoprobes (Figure 4). The particles are coated with polymers and sugars that hide them from the immune system and equipped with monoclonal antibodies that cause them to bind to tumor cells. Once the particles are attached, an alternating magnetic field heats them, killing the tumor cells. The nanoprobes later degrade and are eliminated from the body. In 2005, a research team at the University of Paris headed by Patrick Couvreur, Ph.D. showed similar results in vitro using folic acid-tagged particles, and researchers at Virginia Commonwealth University led by Everett E. Carpenter, Ph.D. have experimented with nanoparticles made of magnetic ferrites that would, perhaps, combine both detection and treatment into a single process. The idea would be for the nanoparticles to act as an MRI contrast agent, then be heated by increasing the power to the MRI coils. Nanotech-Based Diagnostic Sensors One company using nanotechnology for in vitro diagnostics is BioForce Nanosciences, which has developed a way to do multiple tests on vanishingly small samples. Called the Nano eNabler molecular printer, it’s a benchtop device that places tiny droplets of liquid (Figure 5) onto surfaces with nanometer spatial precision. This can be used to create ultraminiaturized chips, sensors, and biomedical devices. With droplet sizes measured in femtoliters or attoliters, it doesn’t take much sample size. “We’ve done a cancer biomarker test on four cells . . . by conventional fluorescence, and got a reliable result,” says Eric Henderson, Ph.D., CEO, chief science officer, and founder of BioForce Nanosciences. While most tests use fluorescence, he says, “we can [also] read things out by AFM [atomic force microscopy], . . . and potentially other methods like mass spec and surface plasma resonance.” Figure 5: The Nano eNabler system’s SPT consumable print cartridge includes one or more reservoirs for the researcher’s sample(s). (Photo: BioForce Nanosciences Inc.)   BioForce is also working on something called the Virichip, which can detect viruses by their proteins, rather than by DNA. “You can detect multiple viruses simultaneously,” says Henderson, “and once you’ve done the detection, the chip can be subjected then to DNA testing, to immunotesting, to cell culture testing, because the viruses are still on the chip and are still alive or viable.” Drug Delivery Hand-in-hand with the use of nanoparticles to detect diseased cells comes their use to deliver therapeutic agents to the surface or even within cells. This topic is receiving a great deal of attention and 69 papers delivered at NSTI’s Nanotech 2007 event were devoted to it. A group at the University of North Carolina at Chapel Hill is developing a way to create nanoparticles of specific shapes by a very direct approach: molding them (Figure 6). The process, called Particle Replication in Nonwetting Templates (PRINT), is in some ways akin to embossing, says Joe DeSimone, PhD, the William R. Kenan, Jr. Distinguished Professor of Chemistry and Chemical Engineering, University of North Carolina at Chapel Hill and professor of chemical engineering at North Carolina State University, but unlike liquid embossing it leaves no flash, or layer of waste material, between the individually molded particles. Figure 6: Particle Replication in Nonwetting Templates (PRINT) creates nanoparticles by molding them. (Source: Joseph DeSimone, University of North Carolina at Chapel Hill) Particles can be made of a number of different polymers that can be tuned to degrade or dissolve at controlled rates or at selected pH values to deliver their cargo once they reach their target. “Cargoes,” says DeSimone, “range from small molecule therapeutics to [things] like paclitaxol and taxotere, to biological cargoes, including proteins.” To deliver the particles where needed, he says, “we decorate the surface of the particles with ligands that either allow [them] to be long circulating particles or targeted particles such as a targeting peptide or an antibody or an antibody fragment or an aptamer.” To commercialize the technology, DeSimone and his team have formed a company called Liquidia Technologies. The PRINT process can turn out significant quantities of particles, he says. “The company right now has a pilot line that allow manufacturing of particles in a continuous manner,” he says, “making right now hundreds of milligrams in a few hours, and has new equipment coming online that will get into the 50 gram per day range.” Nanosurgery Nanorobots are still mostly the subject of science fiction, yet several researchers are working on moving them into the real world. In the fall of 2006, Monash University in Australia received a multimillion dollar grant to pursue development of medical nanorobots. A nanorobot would carry its own power supply and micromotor that would drive “a special flagellar propeller that allows it to swim within the human body and perform tasks by remote control, mimicking the swimming behavior of E. coli bacteria,” said Dr. James Friend, lead investigator on the micro-robot project. Besides the propulsion system, a nanorobot would include a sensor to enable it to find target cells, a power source, an actuator for performing a task, and in some cases, a communications capability to enable it to transmit its findings and receive commands from outside the body. In a paper entitled “Medical Nanorobot Architecture Based on Nanobioelectronics” published in Recent Patents on Nanotechnology (2007, 1, 1-10), Adriano Cavalcanti of the CAN Center for Automation in Nanobiotech in Sao Paulo, Brazil suggests that a system using low-frequency inductive power transfer might be a good approach. The present medical applications of nanotechnology barely scratch the surface of what’s possible, and it’s an area that medical device manufacturers should monitor closely. ONLINE For additional information on the technologies and products discussed in this article, visit the following websites: www.ferro.com www.orthovitaportal.com www.spirebiomedical.com www.biomet3i.com www.apnano.com www.bioforcenano.com www.liquidia.com Medical Design Technology, Advantage Business Media, Ste. 600, Box 912, 100 Enterprise Drive, Rockaway, NJ Email for more information Company's other products Email to a colleague See more Product R&D