Medical Device & Diagnostic Industry
HREF="/mddi/by_issue.html">MDDI Article Index
An MD&DI August 1998 Column
Research is heating up in the area of RF, microwave, and high-frequency ultrasound for use in therapeutic devices.
For decades, scientists have been using electromagnetic and sonic energy to serve medicine. But, aside from electrosurgery, their efforts have focused on diagnostic imaging of internal body structuresparticularly in the case of x-ray, MRI, and ultrasound systems. Lately, however, researchers have begun to see acoustic and electromagnetic waves in a whole new light, turning their attention to therapeuticrather than diagnosticapplications.
Current research is exploiting the ability of radio-frequency (RF), micro-, and ultrasonic waves to generate heat, essentially by exciting molecules. This heat is used predominantly to ablate cells. Of the three technologies, RF was the first to be used in a marketable device. Microwave devices are entering the commercialization stage, and ultrasound devices could be soon. All three technologies have distinct strengths and weaknesses that will define their use and determine their market niches.
Figure 1. Somnus Medical Technology's (Sunnyvale, CA) Somnoplasty system includes an automated RF generator with temperature monitoring and a suite of disposable surgical handpieces that deliver controlled thermal energy into the targeted area to reduce tissue volume and stiffen soft tissue.
"For the most part, the destruction mechanisms are the same, but there are certain advantages to certain techniques," explains Mark Buchanan, vice president of Advanced Surgical Systems, a manufacturer of ultrasound amplifiers in Cambridge, MA. Microwaves don't penetrate very deeply, he says, but they can propagate through almost any tissue type. Ultrasound can penetrate quite deep into the body but can't pass through bone or gas; it can also focus on small points, whereas microwaves cannot be focused. RF waves are applied through electrodes that must contact the target tissue directly.
The underlying principles are pretty straightforward, according to Kevin Larkin, vice president of operations and marketing at Fidus Medical Technology (Fremont, CA). In RF ablation, for example, "You take a catheter with a metal tip, put it adjacent to the tissue you want to ablate, run the current through it, and because of high current density, it essentially burns a crater in that area," he says. Microwave ablation involves transmitting energy from a generator through a catheter tipped with a microwave antenna. "That transducer or antenna can be of varying lengths," he explains, "and if you think of it as a coil of wire that looks very much like a spring out of a ball-point pen, you can image being able to size it from half an inch long to a couple of inches long. Once energized, that antenna releases microwave energy in a radial fashion. If you've positioned the antenna next to tissue that you know you want to have ablated, a field is created, and just like it does in the kitchen, the microwave energy excites [mostly] water molecules, and in motion, they generate heat."
Fidus is one of several companies pursuing microwave technology for treating cardiac arrhythmias, an area where RF has already made progress. In 1995, for example, Cardiac Pathways Corp. (Sunnyvale, CA) received an IDE from FDA to begin clinical trials on its cooled RF ablation system for treating ventricular tachycardia, a condition that often arises in heart-attack survivors. In a nutshell, the scar tissue formed by a heart attack can form a return pathway or circuit for the electrical impulses that stimulate heart function, causing it to beat much faster. The objective is to kill these cells and restore appropriate electrical activity to the heart. The name of the Cardiac Pathways devicethe Chilli cooled ablation catheterpoints out a shortcoming in the first generation of RF ablation devices. Excessive heating of the tissue and the ablation electrode limited the amount of energy that could be safely delivered and therefore restricted lesion size. The Chilli uses a closed-loop fluid circulation system to cool the catheter tip and can therefore prevent coagulation and create wider and deeper lesions by transferring higher energy levels.
Of course, creating long and deep lesions is what microwaves do best. "One of the perceived values is that you can make long or linear or continuous lesions," Larkin says. "For curing, as an example, atrial flutter (or, presumably, atrial fibrillation), what is known already is that it's absolutely a requirement to make a lesion that has some length," he explains. "In atrial flutter, the mechanism is very well understood, and the approach is very well defined: you ablate what's called the isthmus, which is easily located during EP mapping, and in an adult, that can be about one and a half to two and a half centimeters long. So you can see that what you want to do is make an ablation potentially as long as the isthmus. That matches up nicely with microwave energy's ability."
Larkin also points out two more fundamental aspects of the microwave technique. First, because the energy is radiated from an antenna, direct tissue contact is not necessary. "Given that the interior surface of the heart has a lot of irregularities, a microwave approach is a more forgiving approach," he says. Also, with no electrode, there's nothing on the catheter to get hot, so the potential for building up coagulum is basically nonexistent.
Figure 2. The Prostatron uses transurethral microwave therapy to treat benign prostatic hyperplasia. A microwave antenna encased in a urethral catheter is positioned at the bladder neck during treatment (EDAP Technomed, Inc., Burlington, MA).
Fidus is concentrating on atrial arrhythmia, but NASA's Johnson Space Center has developed a microwave device that would compete with the RF device from Cardiac Pathways for treating ventricular tachycardia. "We've been working on a catheter that would be inserted probably through a person's thigh up into the heart and use microwave energy to cook the diseased cells," explains Dickey Arndt, PhD, the primary inventor. "What we wanted to do is increase the temperature anywhere from 10° to 20° above ambient, while at the same time minimizing any heating of the blood or surface tissue of the heart," he explains. "The problem is, we wanted to get a fairly high temperature rise one to two centimeters down inside the heart, and it's difficult to get the heat down that far without cooking everything between the antenna and the target area."
Arndt and his team modeled the thermal and electrical conductivity of the heart and established reasonable frequencies for the microwave radiation, but even then, their work was far from over. "One thing is to come up with a good frequency," he says. "Another is to optimally design the antenna on the end of a catheter so it will effectively transfer energy through the surface of the heart and into the heart tissue. That's basically a matter of impedance matchingwe've come up with some schemes for that." Arndt's team has conducted tests with a phantom and beef hearts using fiber-optic thermocouples to measure temperature rise. "The bottom line is, we can get good heat penetration. We can get a temperature rise of 20° at a depth of 15 to 20 millimeters in less than five minutes," he says. "Also, we've monitored the temperature rise of the blood around the antenna, and it's less than 2°." NASA is currently looking for partners to help commercialize the technology.
Microwaves may be better suited for certain procedures, but RF technology is definitely versatile and remains the best choice for many applications. For example, Somnus Medical Technologies (Sunnyvale, CA) has introduced an RF device for treating snoring and upper airway blockages (Figure 1). The device uses RF energy to create submucosal lesions in the soft palate, which are naturally absorbed into the body, resulting in a reduction in tissue volume. The procedure, called Somnoplasty, reportedly takes less than 30 minutes, with the actual RF ablation lasting less than 5 minutes on average. The company is currently conducting clinical evaluations in the United States and Europe to expand claims to include the reduction or elimination of other obstructions of the upper airway.
Oratec Interventions (Menlo Park, CA) has developed another novel use for RF energy. Rather than ablate tissue, Oratec's device shrinks it. Specifically, the device is designed for orthopedic procedures in which ligaments and tendons need shoring up. "We're denaturing the tissue, manipulating the collagen molecule," explains Hugh Sharkey, Oratec's executive vice president and CTO. "We're not looking to remove the tissue, but to manipulate the collagenous molecules in such a way that we can affect a clinical outcome." The process, known as electrothermal arthroscopy, has been successful in treating various joint instabilities. The conventional treatment for a shoulder instability, for example, would entail pulling the ligamentous shoulder capsule up, folding it over on itself, and sewing it downa technique known as plication. The RF process simply shrinks the capsule, leaving a scaffold or template for new type-1 collagen to move into. "We don't want these tissues to go away," Sharkey points out. "We want them to become more resilient. So we're working with temperatures on the order of 50° to 75°C. Typically, ablation devices are operating at much higher temperatures."
Figure 3. Transurethral needle ablation, an alternate treatment option for benign prostatic hyperplasia, uses RF waves delivered through the ProVu device shown here (VidaMed, Inc., Fremont, CA).
Temperature control is obviously important in a procedure like this, and Oratec's system monitors not only the temperature of the tip electrodes, but impedance as well. "It's important to note that tissue heats up in response to the current flowing through it," he says, "and it's that step up in resistance where heating occurs." In other words, he says, the wire doesn't heat up because it's a good conductor and the electrode doesn't heat up because it's a good conductor, but the tissue heats up because it's a poor conductor. Sharkey doesn't believe microwaves would do as good a job. "Everybody has put a potato in the microwave and hit hot spots and cold spots. Microwaves oscillate much smaller ions, so it's easy to get cell-by-cell differences in impedance that cause hot and cold spots," he says.
Still, there are a few areas where RF and microwave are going head to head with no clear winner. In the urological market, for example, both RF and microwave devices are being used to treat benign prostatic hyperplasia (BPH). According to the Health Care Financing Administration, the condition, commonly referred to as enlarged prostate, is detectable in about 50% of all men over the age of 60 and 90% of men age 85. Roughly half of these cases will require therapeutic intervention. Transurethral resection of the prostate (TURP) is the most common surgical treatment, but it carries a high risk of complications. Less-invasive therapies have been sought for some time, beginning with laser-based devices and balloon dilation, but the simplicity and effectiveness of transurethral microwave therapy (TUMT) and transurethral needle ablation (TUNA) could easily eclipse these earlier treatments.
EDAP Technomed, Inc. (Burlington, MA), was among the first to enter this market with its Prostatron system, one of the few medical devices currently approved by FDA for treating both symptoms and obstructions caused by BPH (Figure 2). The microwave-based Prostatron competes directly with the Targis system, a microwave device developed by Urologix, Inc. (Minneapolis). According to Michael Krachon, technical manager for EDAP Technomed, Prostatron TUMT works by inserting a microwave antenna encased in a urethral catheter into position at the bladder neck. A set of channels running through the catheter carries cooling water to preserve the urethra. The device then delivers up to 70 W of microwave energy to the prostate, heating the gland to 45°60°C. This heating is maintained for the duration of the treatment, which takes about an hour from start to finish. A fiber-optic thermosensor continuously monitors the treatment temperature.
TUMT can expect stiff competition from TUNA, the RF approach developed by VidaMed, Inc. (Fremont, CA). The company's ProVu uses a disposable cartridge with a reusable handle to deploy two electrode needles through the urethra and into the prostrate (Figure 3). The needles are shielded to prevent damage to the urethra, and a scope is used to ensure proper placement. The ProVu can reportedly achieve an interstitial temperature of 100°C while keeping urethral temperature below 42°C. Both TUMT and TUNA can be performed in the urologist's office in less than an hour and require only minimal anesthesia.
These treatments are still relatively new, and further improvements can be expected. It's unclear, however, whether either technique will come to dominate the other. In the end, it might come down to economics. VidaMed claims that the TUNA procedure will prove more cost-effective than other thermal therapies and has been actively pushing for Medicare reimbursement at the state level. Also, long-term effects have not yet been documented.
EDAP's Prostatron is currently being reimbursed by Medicare in 49 states and by more than 300 private-pay insurance companies. EDAP is hoping to extend the technology to related areas. "Other applications we are looking at," says Krachon, "would be other aspects of prostate disease and, eventually or potentially, other abdominal organ diseases."
RF energy may hold as much potential for treating women's health problems as it does for treating men's. BEI Medical Systems (Teterboro, NJ) has begun distributing its BiSafe system for an outpatient procedure known as large-loop excision of the transformation zone (LLETZ). The system comprises an RF generator and disposable electrodes designed to remove abnormal cervical tissue and coagulate bleeding vessels. Devices of this type have been available for several years, but BEI's is reportedly the first to use bipolaras opposed to unipolarenergy. According to the company, bipolar energy reduces thermal artifact, allowing for improved diagnosis of removed tissue samples. The company expects to introduce another bipolar device for removing benign uterine fibroids by the end of this year and is conducting clinical trials of its HydroThermAblator, an RF device for treating excessive uterine bleeding.
While RF and microwave devices carve out their market niches, they may soon feel the heat from a technology that could potentially combine the best traits of bothhigh-density ultrasound. While not new, it has taken nearly two decades to reach its current level of practical application. Although ultrasonic waves require a liquid or gel-like medium for propagation, they could be administered without direct tissue contact. In addition, the focal pointwhere heating occurscan be made quite small. So, in effect, ultrasonic generators could be positioned outside the body to ablate a targeted section of tissue within.
"The physics of ultrasound interaction are quite different from microwave," explains Charles Cain, PhD, chair of the biomedical engineering department at the University of Michigan. "The wavelengths are different, the methods of propagation are different." The idea of focusing ultrasound inside the body to effect some change is not necessarily new, he says, but up until now, there have been no reliable ways of monitoring and controlling the process. "For ultrasound, probably the largest problem is feedback and control," he explains. "In other words, since ultrasound systems are very effective at focusing energy at very small volumes, you have to know exactly what you're doing. It's easy with microwave, but with ultrasound, you need to be able to visualize a target volume and verify that you're focusing your energy there and verify that you've done something. If you're doing that noninvasively, you see that's not a trivial thing to do."
Some researchers are logically trying to combine ultrasonic imaging with ultrasonic therapy, as the two processes would take place at different wavelengths. But others expect the big break to come from MRI. Indeed, many of the big MRI firms such as GE, Siemens, and Phillips are reportedly pursuing the technology.
At the Mayo Clinic (Rochester, MN), Joel Felmlee, MD, is helping to work out the bugs in GE's ultrasonic ablation system. "My work so far has been to take a set of equipment developed by GE Medical Systems and do the testing that would be appropriate for a clinical trial," he says. His primary focus currently is on the accuracy of the spot position. "I ask the question, 'Is the spot where you think it is?'" he explains. The spot in question is a cylinder about 12 mm in diameter by 46 mm in length. "We call it a grain of rice," he says. The GE system strives to put these grains side by side to fill a volume and ablate it. Temperature changes affect the MR image, allowing the clinician to monitor the procedure. "I don't think this is so new in terms of the ultrasound ablation," he says, "but the novelty is you can get it to work within an MR scanner."
Felmlee and his colleagues have been conducting experiments to assess the accuracy of the machine, which is primarily intended for shallow lesions or skin lesions. Some important questions remain to be answered. "We've looked at the accuracy of the positioning system and we're using thermal imaging to understand the focal spotis it the size that we think it is? We have some lenses that are used to increase the size of the focal spotis that increase what we expect? Then we'll look at surface effectsas you bring your focal spot closer, can you spare the skin?" Near-field heating needs to be understood better, he says. Though the machine may be focusing at depth, energy is still being directed at the surface. "We need to see what exactly is happening at the surface," he says. "That's the next thing I'd like to understand."
Reliability also needs proving. As Felmlee puts it, "If you're going to put someone on the table, and the therapy is going to take three or four hours, you can't have a breakdown midway through. That's an obstacle for us presently, and during the next six months, we'll see if we can't get past it." Another hurdle will be establishing patient benefit. "There's risk associated with everything we do in medicine, and if this would allow the same or better results with less risk, that's a win. If it would get the same results with the same risk, that wouldn't be worthwhile," he says.
Of course, an MRI-guided system will be expensive. That's one of the reasons Cain and his colleagues at Michigan are pursuing ultrasonic guidance. The key, he says, is to use a phased-array systemnot unlike a modern phased-array radar system. A phased array comprises multiple elements with amplifiers behind each one to reinforce radiation patterns in one direction and suppress them in others. In contrast to a fixed-focus system, a phased array allows beam steering and phase control. "I think most people are coming around to our way of thinking that these are probably the best way to do this," Cain says. "For example, in cardiac ablationputting lesions on a beating heart. There, you may have to focus around the ribs, and phased-array systems very nicely allow you to do that. You can actually form a beam on a moving target and in real-time follow that target."
Phased arrays might make the small focal point easier to work with. "If you can think of an ultrasound system as nominally focusing on a spot about a wavelength in diameter, and that wavelength is a couple of millimeters, and if you're trying to ablate a tumor that's a centimeter in diameter, you see the problem is not that you can't get the energy into a small enough volumeit's the opposite: how do you spread it out? A phased-array system allows you to do that."
On the other hand, that small focal spot opens up additional opportunities for intricate surgeries that would be difficult through conventional means. Felmlee in particular expects to see applications in and around the eye. Cain has been investigating yet another applicationactivation of cancer-fighting drugs. In this instance, the technology would function similarly to photodynamic therapy but would benefit from ultrasound's ability to focus at depth. So far, he says, the effects aren't profound. "But they're interesting enough that a lot of people have started looking at it."
In general, all three technologies should become more prevalent in coming years. The idea of removing internal tissue without actually cutting into it is obviously attractive, and new applications ranging from liver-tumor removal to spinal-tissue repair are reportedly in the works. Scientists at Thomas Jefferson University (Philadelphia), for example, have patented an angioplasty catheter that uses microwave radiation to soften arterial plaque prior to balloon inflation. So it seems that even procedures that can't be converted to a strictly radiative approach will still be affected by the technology. "I think it's going slowly right now," says Advanced Surgical's Buchanan, adding, "but it's starting to pick up momentum."