Breaking Down Barriers

Each year approximately 10 million people worldwide suffer a stroke and almost 2 million of them die. For the people who survive, there is a long road to recovery and a high likelihood of permanent disability. Between 50% and 70% of survivors will return to an independent lifestyle. But 15% to 30% may be permanently disabled, and as many as 20% will require long-term care in a hospital or nursing home.

A stroke consists of a sudden loss of blood flow to part of the brain. In 85% of cases this is the result of an artery being blocked, usually by a blood clot. The remaining 15% of patients have arteries that rupture, spilling blood into the brain. When blood stops delivering oxygen and nutrients such as glucose, brain cells begin to die. As the cells start losing energy, they stop functioning in their normal way. Thus, the primary symptoms are sudden onsets of neurological dysfunction, such as numbness, weakness, loss of vision, difficulty speaking or understanding speech, dizziness, or loss of coordination. If blood flow is restored within three to six hours after the onset of the stroke, many brain cells can be saved, and the damage can be limited. If the blood flow is not restored, the damage will be permanent and any recovery will be slow and difficult.

One of the most promising lines of research is in developing tools to more effectively remove blood clots from brain arteries. For many years, cardiologists and interventional radiologists have been placing catheters into the heart and other organs for diagnosis and treatment. Thanks to advances in catheter technology over the last decade, a new field of medicine called interventional neuroradiology has opened. These physicians are trying to treat the stroke-causing blood clot at the actual site of obstruction: in the artery inside the brain.

A number of clinical trials are underway to investigate techniques for removing blood clots. Some physicians are delivering TPA, the same clot-busting drug approved for intravenous use, directly to the clot. Others are using mechanical techniques to avoid clot-dissolving drugs entirely, for example, using high-pressure fluid jets to disrupt clots, or snares to capture and remove them. Other researchers are attempting to directly ablate clot material. The method we're pursuing is photoacoustic emulsification, in which laser light delivered through fiber optics generates high-frequency acoustic energy.

In 1996 researchers at Lawrence Livermore National Laboratory (LLNL; Livermore, CA) postulated that clot material might be reduced to very small particles, or emulsified, by acoustic energy in the form of pressure and shock waves.^1,2 Lasers and fiber optics excel at the efficient transmission of very intense energy, so investigators theorized that a beam delivered properly might effectively generate such acoustic energy.

Localized heating by a laser beam generates a vapor bubble that drives lower- pressure, long-duration pressure waves. Meanwhile, depositing energy into a fluid more quickly than the fluid can expand toward equilibrium generates shock waves. This fluid expansion proceeds at the speed of sound in the medium. Thus if the energy is deposited in the target volume in a time shorter than the acoustic transit time across the shortest heated dimension, a shock wave will be produced. The combination of the lower-pressure, long-duration pressure wave and the short-duration, high-pressure shock wave produces an emulsifying acoustic field. Lab tests on clot materials showed that this indeed could be an effective method, so Endovasix and LLNL researchers worked to find the best parameters.

The demands of producing low-pressure waves efficiently while generating a minimum of waste heat requires the deposition of very high volumetric energy concentrations in the working fluid (either blood or an introduced fluid dye). This is because it is necessary to convert the working fluid at a body temperature of 37°C to a vapor at 100°C before producing any useful acoustic energy. For optimal low-pressure wave generation, the penetration depth of the laser beam should be short and fiber diameters very small. For practical purposes, this optimization is limited by the mechanical robustness of the fiber tips, however.

Unlike the case of pressure waves, shock-wave production need not be accompanied by a vapor phase transition. The generation of shock waves is optimized by the opposite parameters that optimize the lower-pressure wave generation. To optimize the shock wave, we need to use larger fiber diameters, larger penetration depths, and shorter pulse durations. Compared with the energy in vapor-bubble-generated pressure waves, the actual energy in the shock wave is very small, yet it is very important to the emulsification process.

We achieved efficient local emulsification of clot materials by optimizing energy, pulse width, fiber diameter, and repetition rate. For example, with 100 µm fibers, efficient emulsifications may be produced with 200 µJ, 20-ns pulse widths, and 5 kHz repetition rate using a doubled neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. More than 99% of the clot fragments produced were less than 10 µm in diameter, small enough to easily pass through the arterial system. In addition, we believe that the body's natural ability to dissolve clot materials is dramatically enhanced by increasing their surface area; clot emulsification would enhance this process.

The technique does face challenges in a clinical setting. The blood vessels in the human brain are extremely tortuous and curvy, so the effective range of the acoustic emulsification phenomena is limited. Extending that effective distance by simply increasing the laser energy produces acoustic energy close to the tip that could damage vessel walls. Thus we had to develop a methodology for targeting clots.

Research into the fluid motions produced by the expanding and collapsing vapor bubble indicated that this phenomenon might be harnessed to provide energetic fluid flows.³ A very simple example is a bubble expanding and collapsing in the orifice of a cylindrical structure. The bubble, in essence, is an engine to drive a pump. In this case net fluid flow is into the "bubble end" of the tube.

An excitation device operating in pulsed mode can produce a fluid pulse at low repetition rates or a pulsating but continuous flow at high repetition rates. The resultant fluid flow can then drive a variety of physical phenomena. Many mechanisms have been demonstrated, from multistage micro-pumps to micro-propulsion systems that produce translation, rotation, and so on. The pump performance may be tailored to application--small-diameter pump tubes exhibit low-velocity pumping but can produce higher head pressures, while larger pump tubes can exhibit larger pump velocities.

Figure 1. In a clot-emulsification device, acoustic generating fibers are resident in each window. The pump stage is in the distal-most section and pumps fluid into the windows and out the tip.

For the purposes of this stroke treatment device, the pumping mechanism has been used to suck the clot material to the vicinity of the acoustic field where it can then be effectively emulsified (see figure 1, above). In such a case, we multiplex optical power between the fibers used for the pumping function (pulsing the bubble) and those used for the acoustic function (generating pressure and shock waves). The device includes windows in which a fiber tip triggers the acoustic emulsification of adjacent materials. The cylindrical pump tube is situated within the endmost section of the device such that it will suck the fluid into the windows, pulling clot material with it. This fluid pumping dramatically enhances the effectiveness of clot reduction. Typical blockages in the brain's blood vessels are 1 to 2 cm in length, and these can be removed in two to four minutes (see figure 2, below).

Figure 2. An angiogram shows an obstructed artery in the left hemisphere of a patient's brain (left). Flow is restored after clot emulsification (right).

The selection of the laser source to provide energy to pump and emulsify involves the tradeoff of system reliability and simplicity, as well as optimization of the phenomena. To optimize energy deposition in blood, the optimal wavelength would appear to be approximately 410 nm. Lasers operating at 410 nm are not readily available, though there are several ways to go about producing this wavelength. The approaches, however, may raise issues of reliability in the laser system. A frequency doubled Nd:YAG laser operating at 532 nm can be effective due to the double absorption peak in blood at about 530 nm. There is also a substantial difference in the absorption of the blood and of the vessel wall at this wavelength, with that of the wall being reasonably small. In fact, direct illumination of the wall will generally not produce damage at these wavelengths and parameters.

Currently our device is for investigational use only; clinical trials are underway.

Lasers have been used in medical applications in a variety of ways over the years, not all of which have been effective. In this application, a laser and fiber optics are merely a way to transport energy to a site of treatment. This transport of energy is not possible with other technologies. The use of that energy, for emulsification and fluid pumping, is novel and may prove to be an effective way to remove stroke-causing arterial obstructions. Other applications for these technologies are being investigated. oe

1. Celliers et al., US Patent 6,022,309, USPTO, February 2000.

2. Glinsky et al., Physics of Fluids, vol. 13, no.1, pp.20-31, January 2001.

3. Esch et al., US Patent 6,139,543, USPTO, October 2000.