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This Won't Hurt
a Bit
The
hated hypodermic may soon be replaced by a painless
microscopic needle on a silicon chip.
By: Kathleen Wong
There’s something about a hypodermic needle that makes
even grown-ups cringe. A glimpse of the shining steel shaft
with its wickedly sharp tip evokes a wave of unpleasant
sensations: the pain of steel boring through skin and
muscle; images of blood spurting red into a glass vial; and
an uncomfortable realization of the fragility of the
flesh.
It’s a cycle of thought and feeling that nearly 5 million
American diabetics experience more than once every day as
they inject themselves with insulin to maintain the right
amount of sugar in their blood. Insulin helps sugars move
out of the bloodstream and into cells, keeping the blood at
the right pH and cells well-fed. A malfunctioning pancreas
unable to secrete enough insulin causes the type of diabetes
that requires insulin shots.
Diabetics who need insulin shots usually treat themselves
after meals to help their bodies process the blood sugar
absorbed during digestion. With each injection, diabetics
give themselves more insulin than they need at the moment so
it will last until it’s time for the next injection. But
these repeated, small overdoses of insulin take a heavy toll
on the body over time. After many years, they can cause a
host of circulatory problems leading to limb amputations,
blindness, and kidney failure.
The only way to avoid small overdoses of insulin and
other drugs is, of course, to supply a continuous flow of
just the right amount of the drug. Traditionally, this has
involved hooking up an intravenous needle to a pump the size
of a shoebox—an unwieldy and impractical solution outside
the hospital. Scientists have been working for years to
develop better ways of delivering insulin and other
medications. Recent innovations include a programmable,
beeper-size pump hooked to a standard IV line, and foot-long
inhalers that deliver doses of drug into the lungs.
Now, engineers at UC Berkeley are creating a portable and
inexpensive drug delivery system capable of administering a
constant supply of insulin and other medications in a
convenient and painless manner. This tiny artificial
pancreas mixes the drug in a silicon chip the size of a
postage stamp, and injects it through a needle no larger
than a mosquito’s stinger. The needle is so small that
inserting it the necessary millimeter or two into the skin
for the day or two of drug delivery doesn’t hurt. The whole
system—including the wafer, a battery and enough insulin
for 24 to 48 hours—has virtually no moving parts and fits
inside a plastic shell no larger than a stack of eight
credit cards.
“You could just slap it on your arm and hold it there
with tape,” says Dorian Liepmann, the visionary
bioengineering professor who has been leading the research
since 1996.
Liepmann’s pressed oxford shirt and khakis look better
suited to preppy Palo Alto than the laid-back People’s
Republic of Berkeley, but they fit his ultra-organized,
got-it-under-control attitude. Texts on fluid mechanics line
his impeccable office. These books include one volume
written by his father, Hans Liepmann, a physics professor at
the California Institute of Technology. “He’s one of the
grand old men of fluid mechanics,” Liepmann says
proudly.
A desktop fountain fills Liepmann’s office, on the sixth
floor of one of UC Berkeley’s concrete bunker buildings,
with the sound of soft splashes. But rather than being
relaxing, the sight of water spinning and swirling amid a
cushion of bubbles seems to serve as a reminder of the fluid
forces Liepmann strives to divine and direct.
Before Liepmann can send his little creation into the
arms of a grateful populace, he must overcome several major
technical problems, including leaky chip valves,
shatter-prone needles and powdered drugs that won’t
dissolve. “It’s going to be really cool,” says Liepmann, “if
we can just make it work.”
Liepmann plans to achieve incredibly accurate control
over the flow of fluids with his device to deliver such
tiny, nontoxic doses of potent medications. Right now, the
device can pump out liquids at less than a billionth of a
liter per minute, or about the amount of ink needed to mark
the period at the end of this sentence.
To control such small volumes of fluids, Liepmann uses a
Lilliputian plumbing system made by standard microprocessor
manufacturing techniques.
Engineers make computer chips in much the same way Mother
Nature made the Grand Canyon—by depositing layers of
different materials and then eroding them away. But instead
of rivers cutting channels through formations of sand and
minerals, a finely tuned sequence of acid and vapor baths
eats through fine skins of the purest chemical compounds
laid atop a silvery plate of silicon.
This process allows Liepmann to etch mazes of valves,
mixers, channels and circuits onto silicon chips in any size
or design he chooses. One experimental chip, made by one of
Liepmann’s graduate students, spans only one centimeter on a
side but contains five mixers, 72 valves and 35 pumps. The
system’s small size makes for tough testing conditions; to
watch his devices work, Liepmann must maneuver them under a
microscope and display the action on a television
screen.
A push of the on button starts the show. A highly
efficient version of a watch battery powers up, opening a
valve that is damming a reservoir of liquid insulin. The
insulin is so concentrated that an entire one- or two-day
dose can fit inside a pressurized pouch onboard the card.
Designed by Becton Dickinson, the medical supply company
helping to fund Liepmann’s research, the pouch squeezes the
liquid insulin at a constant pressure into a channel on the
silicon chip. Past the first valve, the insulin enters a
mixer and is diluted with water. The diluted drug then flows
out of the chip and into the needle, where it trickles into
the patient’s skin.
The valve is a key component of the chip. Called a gate
valve, it operates like the slide bolt on a door. The gate
consists of a silicon block with a mass of only one
millionth of a gram, which dams a channel no wider than a
strand of human hair. When the battery is turned on, current
travels down platinum wires embedded into the silicon strata
of the chip. Like the coils in an electric blanket, the
wires line the floor of water-filled valve chambers
containing a cross-shaped block of silicon. The coils boil
water trapped inside the valve chamber. Bubbles from the
boiling water push on the cross’ arms and force it away from
the main channel. This holds the valve open. More bubbles
generated on the other side of the cross’s arms closes this
gate valve.
To prevent the drug from flowing backward, one-way or
check valves dot the channels between gate valves. The check
valves consist of several silicon posts standing like
sentries across the channel just behind a coil of platinum
wires embedded into the passageway floor. Current flowing
through the wires boils the flowing liquid (plain water or
liquid drug) to create bubbles large enough to block the
channel. Fluid flowing backward pushes the check valve
bubble into the posts, where it must stop. Forward-flowing
bubbles, facing no obstructions, travel far enough from the
heating coil for the surrounding liquid to cool. The gas
bubble recondenses into liquid at the lower
temperatures.
Because both types of valves operate with thermal, or
boiling bubbles, they pose several major problems Liepmann
has yet to solve. The high temperature required to boil the
liquid degrades heat-sensitive drugs. In addition, says
Liepmann, the need to keep the valve fluids heated drains
too much power from the batteries. “The heat’s being sucked
away by the silicon all the time, and so you constantly have
to put energy in to keep the valve closed,” he says. “That’s
not a good situation.”
Nor has Leipmann been able to waterproof the gate valves
holding back uncontrolled floods of drug and water. At
boiling temperatures, the liquid on one side of a valve
bubble tends to evaporate, travel through the bubble as a
gas, and condense on the other side of the valve. The result
is a net flow of liquid across the so-called seal. Valve
leaks alter the amount of drug delivered to the patient,
which may cause medical problems. The resourceful Liepmann
says he’s now investigating the phenomenon as another method
to control liquid flows through small spaces. And Burton
Sage Jr. of Becton Dickinson believes that coating the gate
valve surfaces with water-repellent materials could seal
them.
To avoid the bubble troubles surrounding the thermal gate
and check valves, Liepmann may substitute valves that make
bubbles by splitting water molecules into hydrogen and
oxygen gas with an electric current. He can form these
electrolysis bubbles easily; it’s getting rid of them that’s
the problem. “They usually don’t explode,” Liepmann says,
“they implode. Very violently.” The bursts of energy would
carve pits in the smooth walls of the channels and damage
the seals on the valves. Liepmann thinks coating the bottom
surface of the valves with a chemical catalyst could weaken
the force of the implosion.
Mixing concentrated drugs with a dilution liquid before
delivering them into the body is also proving problematic.
Water and other liquids that seem thin and slippery when
poured into a drinking glass act thick and viscous in tiny
environments. The minute size of the channels and reservoirs
makes liquids much more difficult to transport.
The culprit is surface tension, a peculiar force that
makes fluids sticky. Surface tension lets water poured to
the top of a cup rise above the lip and stick there a moment
before running over. Surface tension keeps the water
molecules in a raindrop together. But surface tension also
makes liquids thick and difficult to mix in microscopic
quarters. When the overall volume of liquid is small
compared to the amount of liquid contacting the surfaces
around it, as in Liepmann’s channels, the force of surface
tension dominates the fluid’s behavior.
Imagine pouring cream into a cup of coffee. The thin
liquids splash and swirl together, creating clouds and
eddies like water in a whirlpool. This turbulence, a
hallmark of liquids under little surface tension, makes
mixing fast and effortless. Now imagine pouring honey into a
cup of molasses. The two liquids are so thick that the
turbulence of splashing can’t help them mix; the honey
merely oozes atop the molasses in a uniform glob.
Liepmann and his graduate students have devised a clever
way to mix fluids without the help of turbulence using a
mechanism that operates much like a jerry-rigged Jacuzzi.
The mixer consists of an oval chamber with pipes on each
long side that resemble the handles of an urn. Fluids enter
for mixing through a valve at one of the narrow ends of the
oval, and leave for delivery into the body through another
valve at the opposite end. Powered by nearby bubble pumps,
the urn handle pipes take turns sucking up fluid from one
corner of the oval and squirting it into another like
microscopic hot tub jets to circulate the fluid. The
researchers discovered that irregular siphoning and
squirting cycles thoroughly mix the most viscous fluids in
less than five seconds.
Even though Liepmann’s drug delivery device still
presents many technical problems, other scientists think it
holds great potential as a drug delivery system. “The
technology is very good for drug preparation, when you need
to mix together components in exact quantities,” says Mauro
Ferrari, a microfluidics engineering professor at Ohio State
University in Columbus. “For example, if you’re mixing
together blue and yellow dyes, you can be very careful about
how much blue and yellow you mix to come out with exactly
the right shade of green.”
However, some researchers have reservations about whether
Liepmann can overcome problems posed by his tiny
silicon-ceramic needles. Tejal Desai, a professor of
bioengineering at the University of Illinois at Chicago,
says the silicon could irritate the immune system. Desai
says the body would grow a net of fibrous scar tissue around
the needle, which would make it difficult for the drug to
enter the bloodstream. But there are ways to overcome this
problem, says Desai. “You can use silicon as a scaffold, but
then make it more biofriendly by camouflaging it with
biocompatible materials.” She says coating the needle with a
gel called polyethylene glycol would reduce the likelihood
of scarring and tissue damage.
The fact that the microneedles are much sharper than
standard hypodermics, says Liepmann, will further limit the
amount of scarring they cause.
According to Liepmann, the real health risk stems from
his needles’ inability to bend. Instead of flexing like
standard steel hypodermics, Liepmann’s glasslike needles
tend to shatter if bent, leaving microscopic splinters in
the skin. The body would probably immobilize the particles
in capsules of scar tissue. The specter of microscopic
slivers of silicon lingering within the skin of millions of
diabetics could very well cause the Food and Drug
Administration to reject the device.
Liepmann is already working to stabilize the needle
shafts by molding them with internal support posts. He’s
also investigating the feasibility of putting polymers on
the outside to hold the pieces together if the needle
breaks.
Liepmann remains confident that he’ll find practical
solutions to these problems within the next two years. He
eventually plans to endow the device with a microprocessor
to control the valves and flow rates. Adding a computer
onboard would be easy, since microprocessors are made using
the same type of etching process Liepmann employs to
manufacture his drug delivery chips. With a smart drug
delivery device, he says, “you might have a little garage
door opener so that if you’re a diabetic and you’re eating a
sundae, you just hit a button and get a boost of
insulin.”
As exciting as this sounds, Liepmann has even loftier
goals for future models. “The Holy Grail of this whole thing
is to also have a glucose sensor elsewhere in the body,” he
says. The sensor would take continuous readings for glucose
levels in the blood, and determine whether more or less
insulin was needed to keep concentrations within the safe
range. Using the body as an electrical conductor, the sensor
would transmit an electrical signal to the pump and adjust
its flow rate. “It’s not curing diabetes,” says Liepmann,
“but we can control the system enough that we can have an
external pancreas.” He and Becton Dickinson plan to make the
drug delivery system inexpensive enough to discard after a
single use.
Liepmann doesn’t plan to stop at revolutionizing insulin
delivery. He’s already examining ways his system can improve
the delivery of all kinds of drugs, especially those that
are stable only in freeze-dried form. Such drugs spoil fast
once they’re reconstituted into a liquid. Liepmann wants to
make the device capable of reconstituting the drug after the
battery is turned on, allowing the drug to stay freeze-dried
until needed and prolonging the shelf life of the drug.
The U.S. military, which is funding part of the project,
is taking a particular interest in this feature for treating
soldiers in the battlefield. “The military wants to be able
to put these in big cargo planes, fly them out and let them
cook in the desert in Quonset huts for awhile, or let them
get really humid and hot in a jungle environment, or freeze
them in the Arctic,” says Liepmann.
Liepmann hasn’t yet worked out how to completely
reconstitute a powdered drug with a dilution liquid. Mixing
exact quantities of drug is critical—the wrong dose could
poison or kill someone. At first, Liepmann’s team tried to
make more than one batch of medication from a single large
cake of dried drug. Each time the device needed more
medication, team members reasoned, it could just flow more
dilution liquid over the powder. “The first time, it works
great,” says Liepmann. “But by the second time, it’s turned
into cement.” He compares the effect to what happens when
water runs over a pile of sugar crystals. The first few
drops dissolve and carry away the surface grains of sugar
nicely. But any residual moisture molecules will work their
way into the pile of granules and bond the remaining
crystals into a solid mass that is much more difficult to
dissolve.
To deliver continuous doses of drugs that, once
reconstituted, degrade within a few hours, Liepmann now
plans to make cards with several chambers. Each chamber
would hold one cake of dried drug. A microprocessor would
tell the device when to dissolve the contents of each
chamber as it is needed over time.
Abe Lee, who monitors Liepmann’s research for the
military at the Defense Advanced Research Projects Agency in
Arlington, says the technology will save medics time and
expand their treatment options on the battlefield by
allowing them to set up an intravenous drip in an active
patient. He also says Liepmann’s device might someday
provide fighting soldiers with lifesaving antidotes to
chemical or biological weapons.
Adding narcotics to a card with an electronic controller
could also help wounded soldiers and people with chronic
pain keep their discomfort at more tolerable levels. “You
can just push a button and it delivers the drug for
patient-controlled pain relief,” says Becton Dickinson’s
Burton Sage. And although the drug delivery device sounds
like an easy way to get addicted to painkillers, it probably
isn’t. Several studies have shown that patient-controlled
pain relief not only reduces the amount of narcotic patients
use, but it also helps them handle periodic pain surges
without having to call for a doctor.
Sage says Becton Dickinson first plans to replace the
despised hypodermic needle with the new microscopic version.
He envisions coupling a standard syringe barrel to a
centimeter-square pad of microneedles. The needle array
would look and feel like sandpaper against the skin. This
hybrid device would be able to inject liquid medications
just as efficiently as a standard hypodermic, but without
the pain.
Eventually, Sage says, the company plans to manufacture
Liepmann’s entire drug delivery system. Although the
University of California owns all the patents on the
technology, the military and Becton Dickinson retain the
right to manufacture the devices because they are funding
the research. “The government can always march in,” Sage
says, “but it’s not likely.” He says he’s confident the
military won’t compete for the manufacturing rights because
the government usually leaves mass production to private
industry.
The device could also allow people to use other drugs
previously dismissed as too toxic to take by mouth. The
stomach absorbs most oral medications and sends the drugs
directly to the liver. But some drugs, including several
medications for Alzheimer’s disease, are extremely toxic to
the liver if taken in pill form or added to the bloodstream
in one large injection. Because Liepmann’s system delivers
such small doses of drugs directly into the tissues, it
might make many medications available that were shelved
before.
Liepmann also envisions using the system to inject more
than one type of drug at once. He can already manufacture
the needles to contain more than one channel. Several
autonomous drug delivery systems can fit on a single silicon
chip because the pump systems are so small. “You can just
use one needle and add the smarts to it with the
electronics,” Liepmann says, “so you could have several
different drugs, and then have the electronics control the
delivery rate.”
The ability to inject multiple drugs with one system
could drastically simplify the medication regimens of very
sick people and also improve their health. “My wife, who is
a geriatric psychiatrist, is very excited about this because
her patients are often on several drugs,” Liepmann says.
“It’s hard even for me to keep track of taking medications
when I have to. When you’re talking about older people, and
medications like cardiac medicine that are life-threatening,
you can’t mess around.”
And if Liepmann has his way, people will no longer need
to fuss with complicated drug regimens, the sick will be
healed by wearing custom drug delivery cards, and only the
very, very old will remember the visceral revulsion evoked
by the sight of a hypodermic needle.
-
- BIO
-
- WRITER
Kathleen Wong
- B.A., biology and
literature (double major), University of California, Santa Cruz.
Internship:
U.S. News and World Report, Washington, D.C..
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Text ©
1999 Kathleen Wong
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