Fall 2007
In this Issue:
Focus On Biomaterials
Treating Chronic Disease with Ultrasound
Penn State is attacking diabetes on a number of fronts – in the doctor’s office, the lab, in what are called lifestyle or behavioral modifications, and, not least, through engineering and technological approaches.
Today, diabetes cannot be cured, but it can be controlled. For many diabetics this means careful monitoring of their blood glucose level with painful finger pricks to test for blood sugar and needle injections of insulin as often as four times a day. This combination of finger pricks and injections makes maintenance of their disease a major compliance issue for diabetics.
One answer is being researched in the Therapeutic Ultrasound Applications Laboratory of Nadine Barrie Smith. Using ultrasound technology developed at Penn State for use in underwater naval detection, Smith has developed a device that she believes is capable of delivering therapeutically effective doses of insulin, and other medications, through the skin barrier without needles.
The skin is a formidable barrier to the relatively large molecules in most therapeutic drugs. The outermost layer of skin, called the stratum corneum, made up of many layers of dead cells, is the primary barrier. Low frequency ultrasound creates microbubbles in the skin that disrupt the lipid bilayer of the cell walls, allowing water channels to form that can carry the drug through the stratum corneum.
The process is not fully understood, but it is believed to be the result of a phenomenon called cavitation. During World War I, the British navy approached the physicist Lord Rayleigh to find out what was causing damage to their ship propellers. He determined that the high speed of the blades created turbulence with pressure variants that caused bubbles to form on the propeller. When the bubbles collapsed, the pressure wave created temperatures inside the bubbles equal to the surface temperature of a bright star, about 15,000 degrees K. Fortunately, cavitation in low frequency ultrasound is on such a small scale that only the immediate cell is affected.
“The major drawback in exploiting ultrasound for transdermal drug delivery so far has been the size and lack of mobility of the commercial ultrasound devices,” Smith explains. As it happens, Penn State has a history of ultrasound technology development which continues to the present. Smith uses an array of light, compact ultrasound transducers called cymbals, invented by Penn State materials scientist Robert Newnham in the 1990s. Cymbal transducers have a titanium cap with a shallow cavity underneath in contact with a piezoelectric layer of lead zirconate-titanate ceramic. An electrical charge causes the ceramic to deform, which in turn causes the end caps to oscillate at an adjustable resonance frequency. Amplification factors can be as high as 40 times that of the ceramic itself. These powerful ultrasound transducers are small; an array of 9 transducers measures only about 2 ¼ inches on a side and weighs less than an ounce.
A thin reservoir holding insulin is located between the transducer array and the skin. An electric current activates the cymbals producing the ultrasound wave that drives the drug through the skin without pain or puncture. The process takes about five minutes.
“The device has been tested on human skin in vitro and on smaller animals, such as rabbits,” Smith says. “We recently concluded tests on pigs from the Penn State Swine Center that weighed 110 to 140 pounds, fairly comparable to humans.” The results demonstrated that the ultrasound array could safely reduce diabetic glucose levels to a normal range, at least in pigs. The device will need further testing to determine if it is safe and effective for humans.
“The skin stays permeable to drug delivery for some time after the ultrasound is removed. In the future a diabetic might be able to just wear a patch against the skin that delivered the drug, like a nicotine patch. As far as I can see, this will work for any kind of drug delivery.”
The Diabetic Eye
One of the complications of high blood sugar levels is damage to the blood vessels that feed the retina, the light sensitive membrane at the back of the eye. Weakened or blocked blood vessels can leak into the inner part of the eye causing blurred vision and dark spots that float in the field of vision. The disease, called diabetic retinopathy, is the leading cause of blindness among working age adults in the U.S. and around the world.
Prof. Smith is one of a group of faculty working with the Penn State Institute of Diabetes and Obesity to develop ultrasound to study changes in the progression of the disease in the retina. With colleagues Susan Trolier- McKinstry, Tom Jackson, Wen-wu Cao, and their clinical partner at the Hershey Medical Center Thomas Gardner, Smith is developing high frequency, high resolution ultrasound arrays that can be focused at any spot within the eye where the disease is manifesting.
According to Trolier-McKinstry, “We hope to give clinicians a new imaging modality that is less expensive and cumbersome than MRI. Ultrasound is popular because it is cheap and can be used in doctors’ offices. We hope to do something comparable.”
Ultrasound for Interventional Medicine
At higher frequencies, ultrasound can heat and destroy tissues. In this process, called ablation, the pressure wave of the ultrasound literally cooks the targeted area by cavitation. Smith builds intracavitory ultrasound arrays, based on the Penn State cymbal technology, that are small enough to go inside the body to get closer to their target. The devices have seen extensive use in hospital settings in conjunction with magnetic resonance imaging, which is used to guide the ultrasound beam and to give precise information about location and tissue heating. The primary use to date has been to relieve the pressure caused by benign prostatic hyperplasia, enlarged prostate, which otherwise requires surgery.
With the medical technology company Medtronic, Smith is developing a device that can be lowered through the throat into the esophagus to ablate heart tissue, burning a hole in the heart muscle to stop the electrical malfunction of atrial fibrillation, a condition that affects over two million Americans annually and can lead to stroke and death. Ultrasound ablation can also cook tumors, such as in breast cancer, and has been used in high intensity focused ultrasound (HIFU) to open the blood-brain barrier for drug delivery.
Smith teaches the bioengineering senior design project, a course in which students take on real world bioengineering projects and find solutions within a very short timeline. Smith is comfortable with the fast pace. “I like working on something that will make a difference right now,” Smith says, “not in 10 or 20 years.” For all those who hate poking themselves with needles, a portable insulin patch can’t come any too soon.
Nadine Barrie Smith is associate professor of bioengineering in the College of Engineering. Validate to view address - Send Email via form
