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. Bio-compatibility, 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 polymer. 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 micro-pumps to dispense medication into the body. 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, due to complexity and size restrictions, they are unsuitable to deliver more than a few drugs or drug mixtures at a time¹.

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)¹.

General Application of MEMS:

Application of Microelectromechanical system (MEMS) technologies and micro fabrication techniques to the biomedical field has significant implications. For example, some drugs, such as hormones, may be more effective when released in a manner similar to the way it would be produced naturally. This type of dosing would be possible with MEMS devices. Implantable devices can be actuated such that the drug is released continuously, periodically, or selectively by the doctor or patient. Thus, very complex dosing patterns can be achieved. MEMS devices hold a great deal of promise in the area of transdermal drug delivery techniques as well. Transdermal drug delivery systems that are currently available are limited to passive diffusion driven devices. These techniques are useful only for small, lipophilic molecules in small doses. However, innovative MEMS devices hold promise for improving the capabilities for these drug delivery systems².

Microelectronic devices have become an integral part of our lives. They are present in our automobile, cellular phones and personal computers. To provide proper background for understanding this new field, we begin with an overview of the field of controlled release and then briefly discuss relevant work from the field of microfabrication³.

Overview of Controlled Release:³

Controlled release, as used in this, refers to materials or devices for controlling the release time of a chemical, the release rate, or both. Controlled release has proved useful in areas such as foods, cosmetics and pesticides, but it has had its largest impact in the field of drug delivery.

Figure: 1 a) Exemplary concentration c vs. Time t profile for conventional and controlled-release drug-delivery devices. b) Exemplary release rate r vs. time profiles demonstrating the difference between sustained release and pulsatile release.

The method by which a drug is delivered can have a significant effect on its therapeutic efficacy. Some drugs have an optimum range of concentrations within which the maximum therapeutic benefit is derived. Drug concentrations above or below this range can be toxic or produce no therapeutic benefit. Conventional drug-delivery systems such as tablets or injections typically result in a drug delivery profile that is initially marked by a sharp increase in concentration to a peak above the therapeutic range. Then, there is a relatively rapid decrease in concentration until the drug falls below the therapeutic range. Therefore, the time spent in the optimum concentration range may be short (Figure 1 a). Sleeping pills are a good example for illustrating the importance of drug concentration. If the drug concentration is below the therapeutic range, enhancement of sleep is not observed. If the drug concentration is above the therapeutic range, potentially fatal toxicity may be encountered. Therefore, the ideal concentration profile, in some cases, would reside in the therapeutic range and be nearly independent of time (Figure 1 a) ³.

1. Sustained Release:

The field of controlled release focused on achieving a sustained release of drug over an extended period of time (Figure 1 b) with minimal influence by outside factors such as pH. Much of this work involved polymers that released the drug at a nearly constant rate due to diffusion out of the polymer or by degradation of the polymer over time. These controlled-release systems may be of a macro- or microscopic size and exist in a number of different forms, such as oral tablets, polymer implants (rods, wafers, or pellets), and polymer microspheres. Two examples of commercially available polymeric devices for constant drug release include Gliadel (implantable polyanhydride wafers that release carmustine for the treatment of malignant brain tumors at a nearly constant rate as the polymer degrades) and Lupron Depot (injectable polymer microspheres, for treatment of endometriosis, precocious puberty, or for the nearly constant release of LHRH analogues for prostate cancer therapy).

Transdermal delivery is another method that achieves sustained release of drugs. It has proved successful for small lipophilic drug molecules such as scopolamine (motion sickness), fentanyl (pain), clonidine (hypertention), estradiol (hormone replacement), testosterone (impotence), nicotine (smoking cessation), and nitroglycerin (angina). A major advantage of transdermal delivery is that first-pass metabolism of the administrated drug by the liver is reduced. However, there is typically a lag time between the application to the skin and the establishment of a stable concentration of drug in the bloodstream, and only a limited number of drugs can penetrate the skin at rates fast enough to reach a therapeutic steady state concentration in the bloodstream without chemical enhancers or external stimuli such as ultrasound³.

2. Pulsatile Release:

The examples presented in section of sustain release are designed to release drug at a nearly constant rate. In numerous cases, however, sustained release is not the optimal method of drug delivery. Instead, delivery of pulses of drug at variable time intervals is the preferred method (Figure 1 b) and is commonly referred to as pulsatile release. This delivery method works better in certain cases because it closely mimics the way in which the human body naturally produces some compounds. Insulin is a well-known example of compound secreted by the body in a pulsatile manner. Another example of compound produced by the body in a pulsatile or periodic manner are the hormones of the anterior pituitary gland (adenohypophysis), for example gonadotropin and growth hormone, which are important in regulating reproduction and growth, respectively. Many compounds and environmental factors can stimulate or inhibit the production of these hormones. However, compound secreted by the hypothalamus, called releasing factors or hormones, play a primary role in the regulation of adenohypophysial hormones. For example, women suffering from gonadotropic releasing hormone (GnRH) deficiency may not ovulate normally, making it difficult to conceive a child. Growth hormone releasing hormone (GHRH) deficiency in children may lead to dwarfism. Pulsatile administration of GnRH and GHRH can help reduce the severity of these deficiencies. In fact, continuous administration of GnRH results in desensitization of GnRH receptors on the pituitary gland and may actually suppress the release of gonadotropins.

Much previous work on the methods of achieving pulsatile release focused on developing polymers that respond to specific stimuli: change in electric or magnetic fields, exposure to ultrasound, light, enzyme, changes in pH or temperature, or molecules present in the human body, including antigens. Transdermal delivery, typically a route for sustained delivery can be modified to produce a more pulsatile release pattern in the presence of ultrasound or voltage pulses (high voltage: electroporation, low voltage: iontophoresis). Pulsatile release systems can be externally regulated (open-loop) or self-regulated (closed-loop). A polymer implant that releases a drug when an oscillating magnetic field is applied is an example of an example of self-regulation. An example of oral and implantable polymer devices capable of delivering pulses of drug without the use of an external stimulus are those fabricated by the controlled micro-structure of the polymer matrix and release drugs at specified times as determined by the permeability of the polymer and the position of the drug in the device.

An alternative method of pulsatile release involves the use of pumps and catheters. Pumps work well for both sustained and pulsatile release and can be programmed to deliver pulses of drug solution to a patient through a catheter at different times. In fact, one of the current methods for treating GnRH deficiency in women involves wearing a pump on a belt with a subcutaneous or intravenous catheter. The pump delivers a pulse of a solution containing 5 mg of GnRH every 90 min for several weeks to months. However, some external pump and catheter system can be inconvenient and uncomfortable, can limit the patient’s mobility, can be expensive and may result in irritation or infection at the catheter site³.

MICROCHIP DEVICE DESIGN:¹

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.

Theory of Operation:³

Figure 2 shows a model embodiment of a controlled-release microchip consisting of an array of reservoirs that extend through an electrolyte-impermeable substrate. Each reservoir is sealed at one end by a thin membrane of material that serves as an anode in an electrochemical reaction and dissolves when an electric potential is applied to it in an electrolyte. There must be at least one other electrode on the device surface to serve as a cathode in the electrochemical reaction. The cathode can be made of any conductive material but is usually made up of the same material as the anodes to simplify fabrication procedures. In addition, any number of cathodes can be included on a microchip, and they can be of any shape or size to suit the electrode design desired for a particular application. The reservoirs are filled through the open end with the chemical to be released. The open ends of the reservoirs are then sealed with a waterproof material.

Figure: 2 Reservoir Chip Schematic ⁴

The device is submerged in an electrolyte containing ions that form a soluble complex with the anode material in its ionic form. An electric potential is applied to an anode membrane when release from its corresponding reservoir is desired. This causes oxidation of the anode material and formation of soluble complex with the electrolyte ions. The complex then dissolves in electrolyte, and the membrane disappears. Figure 3 shows the principle of operation schematically. The chemical in the newly opened reservoir is now exposed to the surrounding electrolyte and is free to dissolve in the electrolyte and diffuse out of the reservoir.

The Design Approach – An overview¹

Device Dimensions⁴: 17µm x 17µm x 315µm

Reservoirs: 400 total

0.05 µm spacing (bottom side)

25 nl volume

Figure: 3 Diagram of the Reduction-Oxidation Reaction

Square pyramid side wall slope: 54°

Fill opening: 500µm x 500µm

Release end: 30µm x 30µm

Gold Caps: 50 µm x 50 µm x 0.3 µm

1. 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 considered. Non-biocompatible materials, however, can also be enclosed within biocompatible materials like poly (ethylene glycol). One example of a strong, non-degradable, 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 applicable¹.

2. 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 system¹.

3. 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 range⁵. However, the presence of a small amount of chloride ion creates an electric potential region which favors the formation of soluble gold chloride complexes⁶. 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 stop. Gold has also been shown to be a biocompatible material.

Simpler versions of this device utilize passive delivery techniques (Figure 4). One such device is designed so that the reservoir membrane is somewhat porous and allows a slow diffusion of the drug out of the reservoir. In this technique, biocompatibility issues are limited to using materials safe for the body and prevent biofouling. Another passive technique involves the use of membranes that slowly deteriorate. The thickness of the membrane determines the time until the drug in the reservoir is released. In addition to the concerns associated with the permeable membrane technique, there are concerns about the biocompatibility and biofouling of the products of the deterioration reaction. These techniques offer some control over the dosing, but leave a great deal to be desired.

Figure: 4 MicroCHIPS Reservoir Technology

On the other hand, active delivery techniques allow for much greater control over the dosing of the drug. An active delivery device requires actuation of the device before the reservoir is opened and the drug delivered. This actuation can be provided in a wide variety of different ways. Electrically actuated membranes have great potential and are focused on in the next section of this paper. As mentioned before, the advantage of active delivery is the great deal of control it provides over the dosing of the drug. Control elements can be incorporated into the device. For example, incorporating integrated circuitry into the device along with chip sets could allow for highly controlled timed release of the drug, patient or doctor controlled release of the drug (using wireless technology), or even self-administering devices that detect when further dosing of the drug is required. Although active techniques offer greater control than passive techniques, even more biocompatibility issues arise. For instance, chips require power, which means an electrical current will need to run through the device. These current carrying parts will need to be sufficiently insulated from the surrounding environment. Usually, this can be accomplished by using an appropriate surface coating².

Similar to the self-administering device mentioned above is the so-called .smart pill. This matchstick sized device can be implanted into the body of a patient (see Figure 5). Equipped with an external sensor, the smart pill detects the conditions in its surrounding environment. This information is passed on to a chip where the information is processed. The chip then determines the course of action to take. A signal is sent to the included battery pack, which actuates a membrane. The membrane contracts and just the right amount of the drug is released².

Figure: 5 The Smart Pill

4. 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 micro-battery can be used as a power source. All of these can be patterned directly onto the device¹.

Figure 6: Reservoir Filling: Inkjet Method ⁸

5. Reservoir filling:

Three-dimensional printing is capable of fabricating complex structures by ink-jet printing liquid binder onto loose, fine powder⁷. 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 reservoir⁵. The volume of the reservoirs can be controlled by specifying the appropriate print-head 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 amounts expanded by the vapor bubble to the heat added follows the ideal gas law relationship (Fig. 6).

Mathematical Foundation:¹

1. 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 reservoirs 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.

Reservoir volume storage capacity = 25 nl /per reservoir * 400 reservoirs =0.01 ml

2. 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 complexes⁶. Holding the anode potential in this corrosion region enables reproducible gold dissolution. The gold chloride complex is formed by the following reaction:

3. IC circuitry:

3.1 General circuit design:⁴

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 (Figure 7).

Figure: 7 IC circuitry diagram

3.2 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 Laboratory. These batteries are typically less than 15 microns thick and occupy one-centimeter square of area. The capacity of this type of battery is 2mWh⁹.

A schematic cross section of the battery is shown below (Fig. 8). 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: 8 A schematic cross section of the battery

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.

3.3 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 year¹.

MICROFABRICATION PROCESS:

The following steps are required for this microfabrication process^1,5:-

· Fabrication of these microchips begins by depositing ~0.12 mm of low stress, silicon-rich nitride on both sides of prime grade, (100) silicon wafers using a vertical tube reactor.

· 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 85°C, which anisotropically etches square pyramidal reservoirs into the silicon along the 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 µm thick) are deposited 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 conditions.

· A layer of plasma enhanced chemical vapor deposition silicon dioxide is deposited over the entire electrode containing 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.

· All the above process of microfabrication is described in schematic representation in Figure 9.

MICROCHIPS, Inc. PRODUCT DETAIL:¹⁶

Pioneering Applications in Biochemical Sensing: Diabetes:

For the five million Americans with insulin-requiring diabetes (40 million worldwide), closely managing glucose levels is critical to avoiding the acute dangers of low blood sugar and the long term complications of prolonged hyperglycemia. MicroCHIPS first product in development is a continuous sensing platform designed to transform how people with diabetes manage the condition.

MicroCHIPS continuous glucose monitor will be a discreet, long-term implanted monitor designed to wirelessly deliver continuous, convenient, reliable and accurate glucose measurements. Sophisticated alerts and alarms will be designed to provide additional peace of mind and security, if glucose levels fluctuate beyond pre-set boundaries, alerts can warn the user, or his/her caregivers, of the condition. This product under development will be the first in a series of intelligent medical devices on the path towards closed-loop monitoring and therapy systems that will deliver confidence and freedom to people with diabetes.

Figure: 9 Schematic Representation of Microfabrication Process¹⁰

Driving Intelligent Drug Delivery: Osteoporosis:

MicroCHIPS drug delivery devices are being designed to deliver more effective drugs, allow fewer patient interventions, and assure compliance, all of which are essential in conditions ranging from cancer to infertility to osteoporosis. Our drug delivery platform offers the ability to store, protect, and precisely control the delivery of highly concentrated proteins and peptides. They used novel formulation techniques to create long-term drug stability and proprietary technology to protect our drug reservoirs. MicroCHIPS current drug delivery efforts are focused on the development and testing of a delivery device for PTH (1-34) for the treatment of osteoporosis. For the 200 million people world wide with osteoporosis, poor compliance with daily injections of anabolic agents limits their effectiveness. MicroCHIPS delivery device under development has the potential to overcome the compliance limitations associated with injectable drug delivery.

CONCLUSION:

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.

REFERENCES:

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4. A Controlled Release Microchip. MIT News January 20, 1999 from the world wide web: http://web.mit.edu/ newsoffice/nr/1999/microchipcom.html

5. Santini JT, Cima MJ, Langer R. A controlled release microchip. Nature 1999, 397, 335-338.

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8. Kovacs, Gregory. Micromachined Transducers. WCB McGraw-Hill. 1998; 77-119.

9. Bates JB, Dudney NJ. Thin Film Rechargeable Lithium Batteries for Implantable Devices. ASAIO Journal. 1997; 43:M644-M647.

10. Voskerician, Gabriela, et al. Biocompatibility and Biofouling of MEMS Drug Delivery Devices. Biomaterials 2003; 24:1959-1967.

11. Maloney JM. An Implantable Microfabricated Drug Delivery System. ASME International Mechanical Engineering Congress. 15 November 2003,1-2.

12. Maloney JM, Uhland SA, Polito BF, Santini JT. Electrothermally activated microchips for implantable drug delivery and biosensing. Journal of Controlled Release, 2005; 109:244-255.

13. Dragoljic J, Harrison DJ. Monitoring of Subcellular Functions on Microchip.7^th Int. conference on Miniaturized Chemical and Biochemical Analysis Systems. 5 October 2003,1167-1170.

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15. Charles Smith. Human Microchip Implantation. Journal of Technology Management & Innovation, 2008; Vol-3, Issue-3;151-160.

16. MicroCHIPS, Inc. product detail from the world wide web: http://www.mchips.com/products.html

Received on 08.12.2009 Modified on 01.02.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 361-367