Giving Heart Disease the Cold Shoulder

Originally Published MDDI September 2001

R&D DIGEST

THIS MONTH: Cooling the Body from the Inside Out |Microstamping Used to Create Neuronal Networks | Basic Cancer Research Aided by Specialized PET System | Ongoing Clinical Trials Test Artificial Retina

Cardiologists at Rush-Presbyterian-St. Luke's Medical Center (Chicago) are assessing the safety and effectiveness of a therapeutic technique for cooling the body of heart attack patients in hopes of reducing the amount of tissue damage incurred during the episode. The method involves use of an intravascular device designed to cool the core body temperature from 98° to 89°F. The device, the SetPoint Endovascular Temperature Management System from Radiant Medical (Redwood City, CA), is used to cool the body "from inside out," allowing the skin to remain warm while the heart and other internal organs are cooled. According to the researchers, this approach "fools the body" and is effective at preventing patient discomfort. Some patients have even noted that they feel "too warm" during this therapy.

According to Gary Schaer, MD, director of the Rush cardiac catheterization lab, "Tests on animals have shown that circulating a cool saline solution within a long balloon catheter placed in the inferior vena cava can reduce body temperature and diminish the amount of heart tissue damage by as much as 90%." He adds that preventing damage during the early stages of a heart attack generally gives patients a better chance at future recovery.

Patients receive a mild sedative and a blanket to keep warm during the procedure. The system includes a single-use balloon catheter that is inserted in the femoral artery near the groin. Cool saline is then circulated throughout the catheter to reach and maintain a body temperature of 89°F. The Rush-Presbyterian researchers believe that maintaining this temperature is necessary to prevent further tissue damage after a heart attack. According to a co-investigator, approximately 30 minutes is needed for the patient's body temperature to reach the target level. He adds that the saline solution never comes in contact with the patient's own blood or fluids. The patient's body temperature is kept at 89°F for approximately three hours following the 90-minute cooling procedure, before being warmed up gradually with the SetPoint device.

Lithographic Technique Creates Neuronal Networks

Researchers speculate that the ability to manipulate the attachment and growth patterns of individual nerve cells could provide the basis for advances in medical technology. Among the potential applications are biosensors, drug screening, implants, and prosthetics.

According to Bruce Wheeler, professor of electrical and computer engineering at the University of Illinois at Urbana-Champaign and a researcher at the Beckman Institute for Advanced Science and Technology, "Controlling tissue response is particularly important for implants, which tend to work for a while, then lose electrical sensitivity." Wheeler explains that, "If we can better understand and control the interface between electronic components and nerve cells, we could build more sophisticated and longer-lasting implants."

The researcher explains that his team uses a lithographic technique called microstamping, or microcontact printing, to produce patterned surfaces on glass substrates that integrate biocompatible materials and live nerve cells. The method can be used to precisely reproduce a master pattern with biologically relevant materials.

According to Wheeler, "The microstamp works the same as a conventional rubber stamp except that the ink is polylysine and the patterns produced are measured in micrometers, or the same size as the cells themselves." He adds, "We are able to get nerve cells to attach and grow long processes out along the patterns of microprinted polylysine; our efforts are focused on creating networks of neurons that are active electrically so that we can investigate how the neurons communicate with each other."

The main advantage of the technique is that it is inexpensive, according to Wheeler. "Once you've made a master mold you can create dozens of stamps—even more—without the need for expensive equipment." Transferring the pattern also requires no expensive equipment, Wheeler explains, "[but] if you have to align multiple patterns, then some good optical equipment is needed."

The technique is additive, as opposed to subtractive laser and photoresist-based techniques, the researcher explains. "It differs from previous methods of microcontact printing in its use of much higher relief stamps (10-20 mm) and surface linker chemistry in order to overcome surface tension that causes spreading of aqueous solutions at micrometer scales," Wheeler says. "Unlike previous photoresist, laser, and stamping approaches, this technique is extensible for sequential deposition of several biomolecules on the same substrate in order to create intricate patterns of biomolecules relevant to neural development as well as biotechnology applications."

Microlithographic techniques also can be used to fabricate planar microelectrode arrays. Confining the neurons to narrow tracks that intersect electrodes creates a technological basis for robust, designable neural networks useful for studying basic neuroscience or for constructing elaborate neural biosensors.

Wheeler says one area of particular interest is development of neural prostheses. "The most successful," he explains, "is the cochlear implant where an array of electrodes is placed in the cochlea and used to stimulate the auditory nerve to restore a sense of hearing for certain deaf patients. This works great, but, by microelectronic standards, the electrodes are large (e.g., 1 mm in diameter) and lots of nerve fibers are activated for each electrical pulse."

According to the researcher, "Attempts at making much smaller electrodes (e.g., 10 mm in diameter) to stimulate individual neurons have been limited by the tissue reactions (essentially the build up of scar tissue; this happens in cochlear implants, too, but the larger electrical currents spread far enough to stimulate lots of neurons)." Wheeler concludes, "In order for the next generation of neural implants to work (perhaps restoring a crude sense of vision by stimulating the visual cortex), we have to learn how to control the electrode/neuron interface—clever surface chemistry is promising and micropatterning may contribute."

New PET Machine Will Open Door To Cancer Research

Basic cancer research is generally limited to studies of small-animal models—primarily rodents. The resolution of conventional imaging systems intended for larger subjects, however, makes such devices unsuitable for these research applications. A new type of positron emission tomography (PET) scanner, called the MicroPET, is expected to enable increased use of the imaging modality in basic cancer research, as well as to expand research on drug and alcohol addiction. The device is intended only for animal use.

The MicroPET is about one-fifth the size of a human PET scanner and is being used in studies being conducted at Wake Forest University Baptist Medical Center. It is the second scanner of its kind in the United States, according to Wake Forest.

"The MicroPET is opening up a whole new line of research that we were not capable of doing before the scanner arrived," says Robert H. Mach, PhD, professor and vice chairman for research of the Division of Radiologic Sciences (Radiology) and professor of physiology and pharmacology. He adds, "The main advantage of the MicroPET over clinical PET scanners is the spatial resolution." The spatial resolution of clinical PET scanners ranges from 5 to 8 mm, depending on the model. In contrast, the resolution of the new system ranges from 1.8 to 2.3 mm.

Says Mach, "This higher resolution means that we will be able to image small brain structures in our nonhuman primate models that cannot be visualized with a clinical PET scanner." Researchers will also be able to use the system with rodent models of disease. Mach explains that molecular imaging capabilities "are important for certain types of research applications, such as tumor-bearing rats and mice."

Wake Forest investigators have used PET scanners for several years to study addiction and behavioral disorders associated with chronic disease in monkeys. Mach indicates, however, that ongoing studies using the existing PET scanner will not be switched to the new scanner. These are longitudinal studies following the same animals over a period of several years and comparing data on the same portion of their brains over that time. According to Mach, the engineering jump between the two systems is so large that switching machines could threaten the studies because the scientists would no longer be certain they were comparing the same things.

Mach adds, "The key thing in cancer research is early diagnosis and understanding the molecular properties of tumors so you can design an appropriate treatment strategy. We hope to use this scanner as a means of initiating a program on the molecular imaging of cancer."

In the meantime, Mach and others are working to get the MicroPET validated and in operation for primate studies. The researcher also believes that additional applications for the system will also be explored. Says Mach, "I believe our program, with its rich history of animal imaging, postures us quite nicely to be competitive for grants supporting imaging research using animal models of disease."

Clinical Trials in Progress for Artificial Retina

Research is continuing on implantable artificial retinas developed by brothers Alan Chow, MD, and electrical engineer Vincent Chow (see the July 1999 issue of Medical Device & Diagnostic Industry). In July, as part of an FDA-approved study, the Illinois researchers implanted artificial silicon retinas (ASRs) into the eyes of three individuals blinded by retinal disease.

The clinical study of the device was initiated about a year ago when the chips were implanted in three other people, who had suffered vision loss as a result of retinitis pigmentosa. The ongoing trial is described as "a first-of-its-kind safety, feasibility, and efficacy study to restore visual function."

The chips are 2 mm in diameter, about the width of the head of a pin, and a thousandth of an inch thick, thinner than a sheet of paper. Each ASR contains approximately 3500 microphotodiodes, each with its own electrode. The electrodes are intended to stimulate the remaining retinal cells from underneath the retina in a pattern resembling the light images focused on the chip. According to the researchers, the chips are completely self-contained and require no batteries or external power sources—they receive their power solely from light entering the eye.

Says Alan Chow, who led the team of four eye surgeons in the recent operations, "We've had more than a year to follow the original three patients and have important information relating to how these chips function. Implanting three additional patients will give us a larger statistical base to evaluate and understand these results."

Each procedure required approximately two hours to perform. The patients were all discharged from the hospital one day after the surgery and are recovering at home. Chow explains that, "Although it is too early to report the complete safety and efficacy results of the study, we hope to do so within several months as a part of a scientific presentation after FDA has had an opportunity to review the data."

The brothers are cofounders of Optobionics Corp. (Wheaton, IL), which is developing the ASR technology. The chip is designed to treat both retinitis pigmentosa and macular degeneration. Both conditions are caused by a loss of the light-sensing photoreceptor cells of the retina.

The researchers believe that by converting light into minute electrochemical signals, the microphotodiodes on the chip mimic the function of the photoreceptors to stimulate the remaining viable cells of the retina. The chip is designed to treat the group of conditions called outer retinal disease. They note, however, that the device cannot treat retinal conditions where the nerve fibers leading to the optic nerve have been damaged. They suggest, for example, that it would be ineffective for treating glaucoma or conditions affecting the seeing part of the brain, such as in strokes.

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