Much research has been ongoing in the quest to find an ideal system for drug delivery within the human body. Drug delivery is a very important aspect of medical treatment.
Microchip for Drug Delivery
Introduction
Much research has been ongoing in the quest to find an ideal system for drug delivery within the human body. Drug delivery is a very important aspect of medical treatment. The effectiveness of many drugs is directly related to the way in which they are administered. Unfortunately, this can make it very difficult to select the proper drug delivery system. Some therapies require that the drug be repeatedly administered to the patient over a long period of time, or in specific amounts at a time in order to maximize drug effectiveness. In many cases, patients often forget, are unwilling, or are unable to take their medication. Furthermore,some drugs are too potent for systemic drug delivery and may cause more harm than good. Therefore, it is of a great advantage to find a drug delivery device that is
capable of controlled, pulsatile or continuous release of a wide variety of drugs and other therapeutics that can be safely implanted inside the body. Biocompatability,material reliability, method of drug release, and processibility, are only a few of the many significant factors that need to be considered in creating a successful and effective drug delivery system of this type.
Some drug delivery systems already exist that attempt to control the release
rate of drugs. One such system includes polymeric devices that have been designed
to provide drug release over a period of time via diffusion of the drug out of the
polymer and/or degradation of the polymer7. This system, however, is too simple to
have the ability to precisely control the amount or rate of drug released. In some
cases, the polymer degrades too fast because of unexpected environmental
conditions within the body (i.e. in the presence of enzymes that increase the
degradation rates of biodegradable polymers). Other devices are ones that are
electromechanically driven and include features such as inlet and outlet valves
and/or micropumps to dispense medication into the body8. These devices include
miniature power-driven mechanical parts that are required to either retract,
dispense, or pump in order to deliver drugs in the body. These devices, however, are
complicated and are subject to breakdown (i.e. fatigue or fracture). Furthermore,
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due to complexity and size restrictions, they are unsuitable to deliver more than a
few drugs or drug mixtures at a time.
It is therefore necessary to design a drug delivery device that has the
following characteristics: 1.) one that is simple to use and manufacture, 2.) one
that is multi-welled so that drugs and other molecules can be delivered for weeks or
years at a time, 3.) one that can hold many different drugs or other molecules of
varying dosages and can release these substances in a controlled dependable
manner, and 4.) one that is biocompatible and small enough to be implantable in
the human body (i.e. a microchip). The microchip that will be described in this
manuscript is based on the invention by Langer et al. at the Massachusetts
Institute of Technology.
Microchip Device Design
The microchip delivery system consists of a substrate containing multiple
reservoirs capable of holding chemicals in the solid, liquid, or gel form. Each
reservoir is capped (i.e. with a conductive membrane) and wired with the final
circuitry controlled by a microprocessor. This central processor should be able to
actively control electrically the exact time of release and the amounts of drugs
dispersed by controlling the dissolution of the gold membrane. The system should
be reasonable to manufacture by standard microfabrication techniques and still be
cost-effective.
The Design Approach—An Overview
The Substrate
According to system design, the reservoirs will be patterned into the
substrate. This can easily be done by standard etching techniques of
microfabrication. Any material that can serve as a support, is suitable for etching,
and is impermeable to the molecules to be delivered and to the surrounding fluids
may be used as a substrate. For this in vivo application, biocompatibility should be
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considered. Non-biocompatible materials, however, can also be enclosed within
biocompatible materials like poly (ethlene gylcol). One example of a strong, nondegradable,
easily etched substrate that is impermeable to the delivered chemicals
and non-degradable to the surrounding environment within the body is silicon. It
should be noted that for some applications a material degradable over time might
be preferred. For example, brain implants make the removal of a device difficult or
too endangering to the patient and therefore this device would not be applicable.
Release System
The design of a release system depends on the treatment required by the patient
whether it is a continuous or pulsed release. Drug delivery can be achieved by a
passive or active release system. In the passive system, the drugs diffuse through a
membrane or enter the body by the degradation of the substrate. Active systems
are triggered by a microprocessor and are preferred due to a more predictable
release profile. The exact time release and amounts of drugs can then be controlled.
The chip can be placed strategically as well for drugs that are too potent for a
continuous release. The device being described will be employing an active system.
Reservoir Caps
In the active timed-release devices, the reservoir caps consist of thin films of
conductive material patterned in the shape of anodes surrounded by cathodes. Any
conductive material that can oxidize and dissolve in solution upon application of an
electric potential can be used for the fabrication of the anodes and cathodes. The
anode is defined as the electrode where oxidation occurs. The portion of the anode
directly above the reservoir oxidizes and dissolves into solution upon the application
of a potential between the cathode and anode. This exposes the release system to
the surrounding fluids and results in the release of the molecules or drugs. Gold is
chosen as the model membrane material because it is easily deposited and
patterned, has a low reactivity with other substances and resists spontaneous
corrosion in many solutions over the entire pH range2. However, the presence of a
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small amount of chloride ion creates an electric potential region which favors the
formation of soluble gold chloride complexes5. Holding the anode potential in this
corrosion region enables reproducible gold dissolution. Potentials below this region
are too low to cause appreciable corrosion, whereas potentials above this region
result in gas evolution and formation of a passivating gold oxide layer that causes
corrosion to slow or stop2. Gold has also been shown to be a biocompatible material.
Control Circuitry and Power Source
The control circuitry consists of a timer, demultiplexer, microprocessor or an input
source. The microprocessor will control the desired reservoir to be activated so that
a variety of drugs may be contained in each specific reservoir. The input source can
either be a memory source, remote control device or a biosensor. A thin-film microbattery
can be used as a power source. All of these can be patterned directly onto
the device.
Reservoir filling
Three-dimensional printing is capable of fabricating complex structures by ink-jet
printing liquid binder onto loose, fine powder6. The printing pattern can be
obtained from a computer-aided-design model (CAD). Inkjet printing in
combination with a computer-controlled alignment apparatus is capable of
depositing as little as 0.2 nl of a liquid or gel solution of known concentration into
each reservoir2. The volume of the reservoirs can be controlled by specifying the
appropriate printhead to deposit a pre-determined amount of binder. The drug is
pushed out of the nozzle as the vapor bubble within the nozzle expands upon
heating. The relationship between the amount expanded by the vapor bubble to the
heat added follows the ideal gas law relationship (Fig. 1).
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Schematic of Reservoir Filling: Inkjet Method10
PV = nRT
Substrate
Vapor
Bubble Heater
Drug
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Schematic Representation of Microchip Design1 (Figure 2)
Microfabrication
Fabrication of these microchips begins by depositing ~0.12 m of low stress,
silicon-rich nitride on both sides of prime grade, (100) silicon wafers using a vertical
tube reactor2. The silicon nitride layer on one side of the wafer is patterned by
photolithography and electron cyclotron resonance (ECR) enhanced reactive ion
etching (RIE) to give a square device containing square reservoirs. The silicon
nitride serves as an etch mask for potassium hydroxide solution at 85C, which
anisotropically etches square pyramidal reservoirs into the silicon along the (111)
crystal planes until the silicon nitride film on the opposite side of the wafer is
reached. The newly fabricated silicon nitride membranes completely cover the
square openings of the reservoir. Gold electrodes (0.3-0.5 m thick) are deposited
Device Dimensions:
17mm x 17mm x 315m
Reservoirs
400 total
.05 mm spacing (bottom side)
25 nl volume
Square pyramid side wall
slope:
54
Fill opening:
500m x 500m
Release end:
30m x 30m
Gold caps:
50m x 50m x .3m
Figure 1
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and patterned over the silicon nitride membranes by electron beam evaporation and
lift-off. Some portions of the electrodes must be protected from unwanted corrosion
by an adherent, non-porous coating that isolates the electrode materials from the
surrounding electrolyte. Silicon dioxide is used as a model protective coating
because its physical properties can be tailored to a particular application by
selecting the appropriate processing conditions2. A layer of plasma enhanced
chemical vapor deposition silicon dioxide is deposited over the entire electrodecontaining
surface. The silicon dioxide located over portions of the anode, cathode,
and bonding pads are etched with ECR-enhanced RIE to expose the underlying gold
film. This technique is also used to remove the thin silicon nitride and chromium
membranes located in the reservoir underneath the gold anode. The reservoirs are
then filled with the molecules or drugs to be delivered by the aforementioned
reservoir filling methods and subsequently sealed.
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Schematic Representation of Microfabrication Process (Figure 3)
1.) Deposit layer of insulating material,
silicon nitride (0.12 mm), onto the
substrate by PECVD
2.) Pattern by photolithography and square
reservoirs are etched by ECR-enhanced RIE
3.) With potassium hydroxide solution at
85°C, anisotropically etch square pyramidal
reservoirs into the silicon along the (111)
crystal
4.) Invert and deposit gold electrodes (0.3-
0.5 mm thick). Pattern by E-beam
evaporation and liftoff.
5.) Deposit electrode protective coating,
silicon dioxide, by PECVD. Silicon dioxide
over anode, cathode and bonding pads are
etched with ECR-enhanced RIE to expose
gold film.
6.) Remove SiN layer in the inside of
reservoir by RIE to expose gold
membrane.
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7.) Fill reservoirs by inkjet printing
through opening (500 mm x 500 mm)
8.) Bottom of reservoirs capped with a
silicon nitride coating
9.) Device can now be patterned with IC
control circuitry and thin-film battery.
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MATHEMATICAL FOUNDATION
Reservoirs
Premature release of drug
Special precaution must be taken to avoid the premature rupturing of the gold
reservoir cap. The culprit would be the filled reservoir of gel or liquid. Any volume
of air that is trapped in the reservoir, could expand with an external rise in
pressure or temperature governed by the gas law. The gas law is as follows:
PV=nRT
where P = pressure, V = Volume, n = number of moles, R = Gas constant, T =
Temperature
The expanded volume of air, if large enough, could place enough pressure to
break the membrane. However, the gold membrane can withstand pressures up to
3 lb per square inch. In order to avoid this, the ink-jet filling of the reservoirs will
take place inside a vacuum to completely avoid the formation of any air bubbles.
The inkjet technology as well can deposit as little as 0.2 nl of liquid.
Release-anodic corrosion of gold
The dissolution of gold to release the desired drug occurs by a chemical red-ox
reaction. This is governed by the electrochemical potential of gold. The presence of
a small amount of chloride ion (a natural electrolyte in the body) creates an electric
potential region which favors the formation of soluble gold chloride complexes5.
Holding the anode potential in this corrosion region enables reproducible gold
dissolution. The gold chloride complex is formed by the following reaction:
Au à Au+ + e-
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Cl- + e à Cl
Au + Cl à AuCl
The active potentiostatic polarization curves for various metals are shown in
the graph below (Figure 4).
Figure 4
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Example Calculations: At -1.04 V w.r.t. SCE, the current density for gold in the
active region is ~102 A/cm2. Based on the dimensions of the gold cap (30 m x 30
m), this would require a current of 9e-4 mA. The power corresponding to this
current is (P=VI) 9.36e-4 mW. If voltage is applied for 30 seconds, this corresponds
to 7.8e-6 mW-h—far below the battery capacity of 2mW-h. Even if all 400 of the
reservoirs were released at once this would require (400*7.8e-6 =) 0.00312 mW-h,
still below the capacity of the battery. However, the battery must also power the
microprocessor, timer and send voltage through the demultiplexing circuitry. This
is summarized in a later table.
Reservoir volume storage capacity : 25 nl/per reservoir * 400 reservoirs = .01 ml
IC Circuitry
General circuit design1
A biosensor will be used as the “trigger” or input source to the microprocessor.
The microprocessor will have a programmed map of the drugs available in the
reservoirs. These reservoirs will be interconnected in a multiplexing circuitry and
will be activated by the microprocessor. A lithium thin film battery will be used as
the power source.
BIOSENSOR
MICROPROCESSOR DEMULTIPLEXER
MINIATURIZED
MULTI-WELLED
DRUG DELIVERY
DEVICE
TIMER POWER
SOURCE
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Capabilities of battery and power requirements
The power source requirements are small size, sufficient power capacity, device
integration capability, and last a sufficient time before recharging. Our device will
incorporate a rechargeable thin film solid-state battery developed by Oak Ridge
National Laboratory3. These batteries are typically less than 15 microns thick and
occupy one-centimeter square of area3. The capacity of this type of battery is 2mWh.
A schematic cross section of the battery is shown below (Fig. 5). It consists of a
LiCoO2 cathode and a lithium metal anode. The electrolyte between the anode and
cathode is lithium phosphorus oxynitride. Platinum is used as the current collector.
Figure 5
The function of a thin film battery is not much different from a common
Eveready or Duracell battery. Ion flow is through the electrolyte and electron flow
is through the external circuit. They are both driven by a red-ox reaction between
the anode and the cathode materials. The following figure illustrates this concept :
Figure 6
substrate
cathode
protective
electrolyte
anode
current
15 mm
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In addition to the power needed to induce the red-ox gold and chloride
reaction, the power of the control circuitry needs to be accounted for. The
approximations of these requirements are shown in the following table.
Calculations were based on the following equations:
P=IV V=IR
where P = power, I = current, V = voltage, and R = resistance
The power required is still below the battery capacity of 2mW-h. Therefore,
all of the reservoirs can be released using the one lithium battery.
Delivery Schedule
The drug delivery schedule is heavily dependent on patient need. However,
the 400 reservoirs add flexibility to patient treatment. The multiple reservoirs can
hold multiple drugs and can release them in varying amounts. For example, with
the battery capabilities, the patient can be administered 25 nl (one reservoir) per
day. At this rate, the drugs can be delivered everyday for over a year!
Load
Power Consumption
Operating Time (s)
Watt Hours
Microprocessor
-Gold Dissolution
-Demultiplexer
.51 mW
30
.0043 mW-h
Timer
.05 mW
30
.0004 mW-h
Power Required x 1 reservoir:
.0047 mW-h
Power Required x 400 reservoirs:
1.88 mW-h
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Conclusions
In conclusion, the designed microchip for drug delivery allows for storage and
dependable controlled release of multiple drugs. This device is less complex and
much more dependable than the aforementioned devices that attempt to control
drug release rate (i.e. electro-mechanical or polymer systems). The microchip can be
created by general microfabrication techniques and can also be self-contained,
which eliminates the need for patient or doctor intervention. The proposed device
described (assuming one dose per day) can last over a year; however, the delivery
abilities do depend on patient need.
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References
1. A Controlled Release Microchip. MIT News January 20, 1999.
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Nature 397, 335-338 (1999).
3. Bates, J. B. & Dudney, N. J. “Thin Film Rechargeable Lithium Batteries for
Implantable Devices.” ASAIO Journal 43, M644-M647 (1997).
4. Merchant, B. “Gold, the noble metal and the paradoxes of its toxicology.”
Biologicals 26, 49-59 (1998).
5. Frankenthal, R.P. & Siconolfi, D. J. “The Anodic Corrosion of Gold in
Concentrated Chloride Solutions. Journal of Electrochemical Society 129,
1192-1196 (1982).
6. Wu, B. J. and Cima, M. J. “Effects of Solvent-Particle Interaction Kinetics on
Microstructure Formation during Three-Dimensional Printing.” Polymer
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Saddle River, NJ, 1996, p.185.
8. Biomaterials Science: An introduction to Materials in Medicine. Ed. Ratner
and Hoffman. Academic Press: 1966. pgs. 347-355.
9. Madou, Marc. Fundamentals of Microfabrication. 1997, CRC Press.
10. Kovacs, Gregory. Micromachined Transducers. 1998, WCB McGraw-Hill.