Whitaker Foundation 2003 Annual Report - Advanced Materials ...

Drug patches are today’s popular delivery vehicle. They relieve ourpain, keep allergies at bay, make traveling more comfortable, preventunwanted pregnancies, and help us kick our smoking habit. Soondiabetics could have the convenience of a therapeutic patch.Currently, all of the 1 million type I diabetics in America and almosthalf of the 17 million type II diabetics need a dose of insulin two to fourtimes a day. Injections were the only option until the recent developmentof a compact insulin pump with its rigid tube piercing the skin. Eithermethod has drawbacks. Injections hurt and are bothersome to administer,and the skin opening for the pump’s tube is a welcome mat for infection.Research motivated in part by a huge market potential is seekingalternative delivery routes. Among the devices rising toward the clinicalforefront are breath inhalers shooting aerolized insulin directly into thelungs, new pills fashioned to protect insulin until reaching the intestine,and a sophisticated insulin patch, the favorite of Whitaker investigatorNadine Smith, Ph.D., at Pennsylvania State University. Smith’s patch usesultrasound to penetrate the skin, offering diabetics a noninvasive andpain-free alternative to injections.Delivering drugs through the skin with the help of ultrasound is notnew, but most devices are too heavy, too bulky, or too expensive for diabetics.Smith’s device is uniquely compact—current prototypes are about the sizeof a matchbook—and easy to use. It sticks to the skin like a bandage.To make such a small patch, Smith, an assistant professor of bioengineeringand acoustics, relied on small cymbal transducers to produce theneeded low-frequency ultrasound. Low-frequency ultrasound waves, around20 kilohertz, safely enhance drug transport through the skin 1,000 timesmore than high-frequency ultrasound, between one and three megahertz.Exactly why this occurs is unknown.Smith’s four cymbal transducers, named for their shape, measure justless than the diameter of a dime and are arranged in a two-by-two array.Think of them as four small, high-powered speakers producing imperceptiblesound waves. When placed on the skin, the ultrasound blasts open microscopicpores, or channels, in the skin with the slightest tingling sensation.These channels allow insulin contained in reservoirs in front of the transducersto pass through the skin—insulin molecules are too large to passthrough normal skin pores—then enter capillaries near the skin’s surfaceand into the blood.In experiments with rats, Smith and colleagues demonstrated that thepatch can deliver therapeutically effective doses of insulin and may be farmore efficient than anticipated. Tuning the frequency reduced the exposuretime from 60 minutes to only 20 minutes while still delivering thesame effective dose of insulin. “We are hopeful that, eventually, we maybe able to tune the system so that one to five minutes of exposure may beenough,” Smith says.More recently, Smith has demonstrated the device’s effectiveness inrabbits. In an experiment published in the Proceedings of the IEEE UltrasonicsSymposium in October, Smith stuck the patch on three different groups ofhyperglycemic rabbits. One group received the ultrasound patch loadedwith insulin; another group had the patch loaded with a saline solution. Inthe third group, insulin was loaded, but the patch was never turned on.Over a period of one hour, only the rabbits using the active ultrasoundpatch with insulin experienced a significant decrease in their blood glucoseto a safe level. The other two groups showed no decrease at all.The next experiments plan to involve sheep and possibly other largeanimals before a human prototype is attempted. Smith envisions a prototypeeither hooked to a walkman-like power supply device or suppliedwith a self-contained battery that might make the patch disposable.Another feature could pair the patch with a continuous glucose monitor,essentially creating an automatic closed-loop system.Already Smith is working toward this with another former Whitakerinvestigator, Michael Pishko, Ph.D., an associate professor in Penn State’sDepartment of Chemical Engineering. Pishko’s glucose sensor also usesultrasound to open channels in the skin, but his device instead draws outfluid from which glucose levels are then taken. Ideally, the monitor wouldtell the patch when to turn on and off to maintain salutary glucose levels.Such a system would greatly benefit elderly and young diabetics, whocould remain active without the constant watch of family or medical staff.Smith says the ultrasound patch might be modified to deliver some painrelievers, asthma drugs, hormones, or AIDS medications in addition to insulinand other drugs that cannot now be taken by mouth. “There are differentdirections we can take this,” says Smith. “We think there’s a lot of potential.”Smith received a Whitaker Foundation Biomedical Engineering ResearchGrant in 2000 for ultrasound research. Minimed sells an implantable insulin pump in theEuropean Union, but the device is still being evaluated in theUnited States for clinical use. Siegel’s smart valve, a blend ofmicroelectromechnical systems and novel polymer chemistry,may one day find its way into an implantable pump.Any implantable, automatic system of glucose monitoringand insulin delivery would have to predict the changesbrought on by meals and exercise for the unique metabolismof each patient, rather than for a standard model. Such asystem must also respond to failure, such as a blocked catheteror a dead battery.It is a tough challenge. Automating something this criticalrequires a degree of reliability that is not easy to achieve. AsHerman points out, “You have to be very sure that you’regetting real numbers. The implications of false numbers andgetting too much insulin are enormous.”Treating ComplicationsAs if the day-to-day blood-glucose balancing act weren’t toughenough, all diabetics must also be concerned with long-termcomplications. “As I get older my metabolism is slowing down,so I’m not burning as much sugar as I used to,” says Bowman.“I know I’ll start having more problems.”Many long-term complications are related to circulationreaching the smallest capillaries in the body, such as those inthe retina at the back of the eye. Retinopathy, a significantcause of blindness in diabetics, is associated with a lack ofoxygen to the retina. (See page 23.) Deficient circulation canalso contribute to cardiovascular diseases, such as atherosclerosis,stroke, and high blood pressure, as well as dental disease,kidney disease, and neuropathy.Neuropathy brings on pain or numbness in the extremitiesand hampers wound healing. It affects the longest nerves mostof all, some of which end in the foot, where diabetics oftenlose sensation. “I’ve seen patients step on a thumbtack andnot realize it,” says Brian Davis, Ph.D., a former Whitakerinvestigator and now a researcher in the Department ofBiomedical Engineering at the Cleveland Clinic in Ohio.Davis takes a holistic approach to studying diabetic footulcers. These and related problems account for 20 percent ofall diabetic admissions to hospitals. Chronic foot ulcers can leadto amputation.It’s a multifaceted problem, Davis says. Whereas mosthospitals simply look at pressure points on the foot as anindicator of risk for an ulcer, his lab takes into account friction(continued on page 23)19