7 - Integrated Microsystems for Controlled Drug Delivery[1]

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Integrated microsystems for controlled drug delivery

S. Zafar Razzackia,1, Prasanna K. Thwara,1, Ming Yanga,1,Victor M. Ugazb,1, Mark A. Burnsa,c,*

aDepartment of Chemical Engineering, University of Michigan, 2300 Hayward, 3074 HH Dow Building, Ann Arbor, MI 48109-2136, USAbDepartment of Chemical Engineering, Texas A&M University, USA

cDepartment of Biomedical Engineering, University of Michigan, 2300 Hayward, 3074 HH Dow Building, Ann Arbor, MI 48109-2136, USA

Received 26 January 2003; accepted 20 August 2003

Abstract

Efficient drug delivery and administration are needed to realize the full potential of molecular therapeutics. Integrated

microsystems that incorporate extremely fast sensory and actuation capabilities can fulfill this need for efficient drug delivery

tools. Photolithographic technologies borrowed from the semiconductor industry enable mass production of such microsystems.

Rapid prototyping allows for the quick development of customized devices that would accommodate for diverse therapeutic

requirements. This paper reviews the capabilities of existing microfabrication and their applications in controlled drug delivery

microsystems. The next generation of drug delivery systemsfully integrated and self-regulatingwould not only improve

drug administration, but also revolutionize the health-care industry.

D 2003 Elsevier B.V. All rights reserved.

Keywords: Controlled drug delivery; Integrated microsystems; Microfabrication; Microfluidic; Sensing; Actuation

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

2. Challenges in drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

3. Photolithography and microfabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

3.1. Silicon processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

3.2. Soft lithography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

4. Microfabricated drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

4.1. Biocapsules and microparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

4.2. Microneedles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

4.3. Implantable microsystems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

5. Smart integrated microsystems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

0169-409X/$ - see front matterD 2003 Elsevier B.V. All rights reserved.doi:10.1016/j.addr.2003.08.012

* Corresponding author. Department of Chemical Engineering, University of Michigan, 2300 Hayward, 3074 HH Dow Building, Ann

Arbor, MI 48109-2136, USA. Tel.: +1-734-763-3078; fax: +1-734-763-459.

E-mail address: [email protected] (M.A. Burns).1 These authors contributed equally to this work.

www.elsevier.com/locate/addr

Advanced Drug Delivery Reviews 56 (2004) 185198


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6. Commercial applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

7. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

1. Introduction

Microfabricated systems have revolutionized biol-

ogy and medicine with numerous enabling technolo-

gies. The plethora of biomedical microelectromechan-

ical systems (bioMEMS) emerging today range from

fascinating molecular motors that swim inside a cell

utilizing the intracellular energy-rich ATP molecules

[1] to sophisticated point-of-care diagnostic devices

capable of foretelling ones predisposition to diseases

by reading the information encoded in a small segment

of DNA [2]; from devices that manipulate single

molecules to systems that can analyze the entire

cytosolic contents of a single cell; from extremely

sensitive sensors that can track down even attomolar

traces of a biochemical substance [3] to highly inte-

grated microfluidic devices that can perform multiple

serial processing on nanoliter volume samples in an

automated fashion [4]. With the advent of sub-micron

lithography techniques in the microelectronics indus-

try, these bioMEMS devices will improve in their

versatility, efficiency and user-friendliness. One ofthe areas where bioMEMS devices are poised to offer

a host of benefits is therapeutics. In this paper, we

review the current generation of bioMEMS devices

used in drug delivery applications and offer some

directions toward which future research might be

steered.

2. Challenges in drug delivery

Modern therapeutic techniques are based onrational design and highly targeted delivery of spe-

cific drug compounds. While this has been proven to

be far more superior and effective than the traditional

therapeutic methods employing non-specific drug

cocktails, a more meticulous effort is required in

drug design, toxicological testing and selection of

appropriate delivery vehicles. Advances in micro-

fabrication and bioinformatics have helped to greatly

accelerate the drug discovery process in recent years

by streamlining the process of identifying molecular

targets and their agonists/antagonists. Analysis of

genomic and mRNA data for over or under expressed

genes can provide clues that would help to identify

the biological molecules associated with a particular

disease. Combinatorial approaches coupled with high

throughput screening tools like peptide and protein

microarrays have led to a huge surge of data to aid in

target identification. Once a molecular target is iden-

tified, conventional structural proteomics tools in-

cluding capillary electrophoresis, mass spectrometer

and NMR can be used to elucidate the complex

secondary and tertiary structures associated with the

target proteins. This structural information of the

targets can then be used to browse through the

database of known drug molecules or could be

coupled with synthetic biochemistry methods to iden-

tify potential therapeutic compounds. These steps,

though not time-consuming in modern lab settings

require huge capital investments, infrastructure and

highly trained personnel.

These drug discovery efforts are generally focused

on identifying a specific drugtarget pair and rarelyinclude the toxicological information in the search

process. In most cases, a sufficient amount of toxico-

logical data has not yet been collected for newly

synthesized drug compounds, making it difficult to

select an appropriate delivery vehicle. For example,

cytotoxic drugs like gemcitabine, rubitecan, daunoru-

bicin, and doxorubucin, currently used to treat diseases

like cancer and HIV are very efficient in destroying the

invading virus and cancerous cells, but also have been

found to induce apoptosis in adjacent normal cells.

Even drugs with lower levels of cytotoxicity oftenmust still operate within a narrow therapeutic window

in order to maintain bioavailability between a mini-

mum threshold functional concentration and the criti-

cal toxic concentration above which irreversible

damage to functional organs could occur(Fig. 1). At

the molecular level, drug molecules often possess non-

specific affinity towards receptors on the cell surface

other than the targeted proteins, which can lead to

undesirable side effects as in the case of tranquilizers

and histamine blockers. Moreover, the optimal con-

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centration necessary to induce a desired therapeuticresponse to a particular drug may vary between the

individuals making the issue even more problematic.

Stability and bioavailability are also important

considerations in the design of drug delivery systems,

especially for protein drugs. Such drugs suffer from a

number of limitations including degradation by pro-

teolytic enzymes, immune response and lack of flex-

ibility for structural modifications (e.g., to tune

absorption properties).

Recently, there has been a great interest in gene/

DNA therapy for treating several hereditary disorders.However, like proteins, naked DNA is extremely

unstable and consequently must be quickly integrated

into the host genome in order to be effective. Viral

vectors have proven to be one of the most successful

methods of delivering DNA to host cells, although

many safety concerns still need to be addressed.

Various modes of administration including oral,

intravenous, transdermal and pulmonary pathways

can be used to ensure sufficient bioavailability. How-

ever, many drugs also require a more controlled and

sustained release profile. A common example for this

scenario is the insulin supplement given as intrave-

nous injections to patients suffering from Type I

diabetes. Ideally, the administered insulin supplementshould closely mimic the insulin release profile of the

pancreatic islets. Multi-dose schemes and constant

infusion pumps have been employed to achieve this

goal, but have had only limited success in attaining a

highly controlled level release. Another application

requiring a non-linear drug release profile is tissue

regeneration in victims of acute organ failure or partial

organ loss, where growth factors must be precisely

administered in order to promote growth and prolif-

eration of the native tissue and, if necessary, facilitate

differentiation of the cells into the appropriate cell

type in a time-dependent fashion.

All these constraints necessitate drug delivery

methods with high specificity that ensure proper

bioavailability of functional drugs at the target site

with the desired rate and dosage of release. Recent

technological advances are beginning to enable the

development of devices that are powerful enough to

deliver extremely potent drugs in a precisely con-

trolled manner, intelligent enough to respond to the

behavior of the surrounding physiological environ-

ment, and compact enough to fit inside a blood vessel.

Such devices involve complex micron-scale networksof fluidic and electronic components capable of oper-

ating in an integrated manner. This new generation of

novel drug delivery devices owes much of its devel-

opment to advances in microfabrication and micro-

machining technology for the construction of micro-

fluidic systems.

3. Photolithography and microfabrication

Microfluidic devices are generally produced usingmicromachining techniques adapted from standard

semiconductor processing technology. These techni-

ques rely on photolithography as the principle means

of transferring finely detailed features to the surface of

the desired substrate. The photolithographic process

involves applying a photosensitive coating to the

substrate surface, exposing the coated substrate to light

through a mask containing an image of the pattern to

be transferred, and immersing the substrate in a devel-

oper solution, which selectively removes photoresist

Fig. 1. The therapeutic window for a particular drug is defined by

the upper toxic limit and the lower threshold limit[5]. The position

and the width of this window can vary between patients for different

drugs and pose challenges on controlled delivery. The figure depicts

the four cases of the therapeutic window. (A) The concentration

profile of the drug is optimal when the fluctuations of the drug

concentration associated with a dosage scheme are contained within

the therapeutic window. (B) The therapeutic window can be shifted

upwards due to high resistance in the body of patient or antagonistic

interactions with another drug. (C) The therapeutic window can also

be shifted downwards due to hypersensitivity of the patient or

synergistic interactions with another drug. (D) It can also be narrow

for a same drug in a child as compared to that of an adult. The drug

delivery and dosage schemes have to be adjusted for these sub-

optimal situations.

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depending on whether or not it has been exposed to

light. This process yields a high-fidelity replica of the

mask image on the substrate surface (Fig. 2). Once a

pattern has been transferred to the substrate, subse-quent micromachining processes are performed to

either selectively deposit or remove material in the

patterned regions.

While many of these processes are borrowed

directly from existing semiconductor fabrication tech-

nology, microfluidic systems present a number of

unique fabrication challenges of their own. For ex-

ample, the size scale of structures to be machined is

on the order of tens of microns, whereas those in

semiconductors are typically micron scale or smaller.

Deposition of the thick material layers necessary to

construct these larger structures introduces difficulties

in maintaining surface uniformity across the device

and/or wafer, while removal of large amounts ofmaterial requires the use of etching processes that

allow adequate control to be exerted over such

characteristics as surface roughness and channel side-

wall profiles. Microfabricated devices also require

fluidic circuitry (pumps, valves, etc.) to precisely

meter and control the motion of liquids within a

microchannel network, as well as an effective inter-

face with the external environment[6]. Successive

micromachining process can also be applied to pro-

duce devices incorporating complex multilayered

Fig. 2. Illustration of some typical micromachining processes. (A) Photolithography is first used to transfer a pattern to the surface of a substrate

coated with photosensitive resist. Next, the development process selectively removes photoresist depending on whether or not it has been

exposed to light. Subsequent micromachining steps consist of either depositing or removing material in the patterned areas, after which the

remaining photoresist is stripped away. (B) Polymer-based devices are generally produced using a casting or soft lithography process, in which

a master incorporating the negative image of the desired structures is first produced using the micromachining techniques outlined in (A). This

master then serves as a mold or stamp that is subsequently used (and re-used) to produce molded replicas of the initial design.

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structures. While the field of microfabrication for

microfluidic applications is relatively new, a sufficient

body of literature has been accumulated to stimulate

the publication of several recent reviews and texts[712].

3.1. Silicon processing

Novel fabrication technologies continue to evolve

at a rapid pace, and a comprehensive review of every

existing application is beyond the scope of this paper.

Instead, we focus on two predominant approaches

currently employed, in one form or another, in the

production of the majority of microfluidic devices.

The first approach closely mirrors semiconductor

fabrication by making use of conventional silicon

and glass substrates. In these devices, fluidic channels

are fashioned by etching directly into the substrate

either by immersion in a chemical solution (wet

etching) or by exposure to a chemically reactive

plasma (dry etching). Here, the mask layer serves a

dual purpose of defining the pattern to be etched and

protecting the substrate from degradation in areas that

are not to be etched. Dry etching processes are

generally capable of producing deeper features with

greater sidewall uniformity, however specialized

equipment is required. Hybrid glass/glass and sili-con/glass devices, in which etched glass fluidic chan-

nels are bonded to a flat glass or silicon substrate,

have been widely used in a variety of microfluidic

applications [1315]. Because arrays of electronic

components (electrodes, heaters, temperature sensors,

photodetectors, etc.) can be easily patterned on a

silicon surface, glass/silicon devices are especially

attractive in applications requiring integrated fluidic

and electronic circuitry [4,1618].

3.2. Soft lithography

A second fabrication approach involves the use of

molding or stamping techniques to construct fluidic

channels in polymer substrates. The wide appeal of

polymer-based devices is largely a consequence of the

ease with which fluidic components can be con-

structed with minimal use of specialized equipment.

A key consideration is identifying polymer materials

with properties suitable for biochemical applications

such as biocompatibility, electric neutrality, and opti-

cal transparency at desired wavelengths (see, for

example, Ref. [19] for a recent review). While a

number of materials have been successfully used to

construct microfluidic devices, the silicone elastomerpoly(dimethyl siloxane) (PDMS) has emerged as one

of the most widely used [20,21].

Fabrication of polymer-based devices typically

begins with the construction of a master that con-

tains a negative image of the desired structures and

will ultimately serve as a template for the production

of the final microfluidic devices. Masters are usually

constructed from silicon or thick photoresist, and are

produced using conventional silicon-based processing

techniques. Once the master has been constructed, it

can then be used to produce devices by employing

either a casting process (often referred to as soft

lithography) whereby a mixture of silicone resin and

crosslinker is poured over the master and allowed to

cure, or a stamping process (hot embossing) whereby

the master is pressed into a film of polymer that has

been softened by heating to just below its melting

point. Aside from fabrication of the master, this

process does not need to be carried out in a clean-

room environment. Polymer devices have the advan-

tage of being simple and relatively inexpensive to

construct since a single master can be used repeat-

edly to produce many devices. Additionally, theinherent mechanical flexibility of PDMS structures

can be harnessed to construct pumps and valves that

operate by inducing deformations in the substrate

itself[21].

Despite their reduced cost, polymer-based devices

offer only a limited ability to embed electronic

circuitry. Consequently, silicon-based devices remain

an attractive and viable alternative because of the

ability to integrate electronic components directly

within a microfluidic system. For example, this

approach has been used to construct a device capableof performing DNA amplification followed by anal-

ysis of the reaction products by gel electrophoresis

using embedded photodetection circuitry to image

the migrating bands [16]. Furthermore, much of the

added cost and complexity associated with silicon-

based devices can be offset by the economics of

scale associated with miniaturization. Using photo-

lithographic techniques, fabrication costs remain es-

sentially constant regardless of the number of

devices produced on a single wafer. Consequently,

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in a fashion completely analogous to developments

in the semiconductor industry, sufficient miniaturiza-

tion could ultimately yield biological analysis devi-

ces small enough to be portable, yet inexpensiveenough to be disposable [22].

4. Microfabricated drug delivery systems

Currently, numerous sophisticated and potent new

drugs are being developed. However, conventional

drug delivery methods have limitations in effectively

delivering these drugs into the human body. For

example, oral delivery of new protein-based or

DNA-based drugs is generally not feasible because

of the degradation of the drugs in the gastrointestinal

tract and first-pass elimination in the liver. The usual

alternative of oral delivery, intravenous or intramus-

cular injection, can deliver these drugs in large

quantities, but pain and tissue trauma to the patients

often result from the use of needles. Moreover,

conventional injection is unable to provide sustained

release, which greatly reduces the effectiveness of the

drugs.

Many approaches have been proposed for effec-

tively delivering drugs into the human body. These

new drug delivery methods can be categorized intothree major groups: (a) biocapsules and microparticles

for controlled and/or site-specific drug release; (b)

Microneedles for transdermal and intravenous deliv-

ery; and (c) implantable microsystems. Microelectri-

cal mechanical systems (MEMS), especially Bio-

MEMS, have found numerous applications in all

three areas.

4.1. Biocapsules and microparticles

Biocapsules and microparticles have been inten-sively investigated as a new drug delivery method. By

encapsulating drugs in a biodegradable microsphere

or microparticle, a sustained or controlled drug release

profile can be achieved. Site-specific delivery can be

achieved by binding ligands to the surface of micro-

particles in order to target specific sites. So far, much

of the research conducted in this area has been

focused on seeking biodegradable and biocompatible

polymer materials to make the microspheres or micro-

particles [2325]. Microfabrication technology has

recently been used in fabricating nanoporous mem-

branes for drug encapsulation, and microparticles for

site-specific oral delivery.

Nanoporous membranes are produced using micro-fabrication technology, such as photolithography, thin

film depositions and selective etching, to create mem-

branes composed of silicon with highly uniform

nanometer-sized pores. Microfabricated membranes

provide several advantages over polymer materials:

smaller pore size (10100 nm range), high uniformity

and thinner membrane thickness. Moreover, because

microfabricated membranes are made from silicon,

they are biologically, chemically and mechanically

stable. Desai [26] reported microfabricated biocap-

sules with nanoporous membranes for effective immu-

noisolation of transplanted islet cells for treatment of

diabetes (Fig. 3). Surface and bulk micromachining

technologies are integrated in the biocapsule fabrica-

tion process, resulting in a diffusion membrane with

uniform pore size distribution as well as mechanical

and chemical stability, surrounded by an anisotropi-

cally etched silicon wafer that serves as the encapsu-

lation cavity. Insulinoma cells (4500 cells/biocapsule)

were enclosed within these microfabricated biocap-

sules and released through the semipermeable nano-

porous membranes. This research demonstrates the

feasibility of using microfabricated biocapsules as analternative to conventional polymeric based biocap-

sules for possible use as in vivo insulin secreting

bioreactor[27].

Microfabrication technology has also been used to

create microparticles for site-specific delivery [26].

Unlike conventional particulate drug delivery sys-

tems such as polymer microspheres and liposomes,

microfabricated microparticles are thin, disc-shaped

structures. These particles can be designed with a

thickness of 150 Am and diameters of 1 to 100s of

microns. Particles can be asymmetrically designedwith single or multiple drug reservoirs, and ligands

bound to one side can target specific sites. Micro-

fabricated particles can combine enteric coating,

bioadhesive agents, permeation enhancers and en-

zyme inhibitors into a single drug delivery platform.

The size and shape of the particles can be easily

controlled to obtain the optimal delivery profile.

These devices are especially effective for oral deliv-

ery of peptide and protein-based drugs through the

intestines.

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4.2. Microneedles

Transdermal (across skin) delivery of drugs over

extended periods of time is a convenient, controlled

way to administer medication. Compared to conven-

tional oral delivery and injection, transdermal drug

delivery overcomes the limitation of gastrointestinaldrug degradation and eliminates the pain and incon-

venience of intravenous and intramuscular injection.

However, the efficiency of transdermal drug delivery

is greatly limited by the low permeability of the

human skin particularly the outer 1020 Am of skin

(stratum corneum layer). A variety of approaches have

been taken to increase the rate of transport across the

skin using, for instance, chemical enhancers, ionto-

phoresis, electroporation, or ultrasound [28].

A novel approach to transdermal drug delivery

uses microfabricated microneedle arrays that are long

and robust enough to penetrate the stratum corneum

but short enough not to stimulate nerves in deeper

tissues [29]. Arrays of bulk micromachined solidsilicon microneedles were fabricated by a single-mask

reactive ion etching process and shown to increase

skin permeability for a variety of different molecules

by orders of magnitude [28,30] (Fig. 4). Arrays of

hollow silicon microneedles were also fabricated by

using deep reactive ion etching to form the needle

lumen, followed by a reactive ion etching process to

Fig. 4. Microfabricated solid silicon microneedle arrays. Left: A section of a 20 20 array of microneedles. Right: Microneedle tips inserted

across epidermis (n 1998 IEEE) [28].

Fig. 3. A microfabricated biocapsule for in vivo insulin secretion (reprinted with permission [26]).

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form the tapered wall of the microneedles. These

hollow microneedles can increase the skin permeabil-

ity even further than the solid microneedles [29].

Microneedles can also be integrated with micro-sensors or microactuators to form sophisticated drug

delivery systems. Zahn et al. [31] recently reported a

portable drug delivery device with integrated micro-

needles and an on-chip MEMS positive displacement

micropump for continuous drug delivery applications.

Microneedles are fabricated using a polysilicon micro-

molding method. The generation and collapse of ther-

mally generated bubbles with flow rectified by direc-

tional check valves are used to achieve net pumping.

Water flow rates of approximately 1.0 nl/s were

obtained and continuous pumping for more than 6

h was achieved.

Another example is a multichannel silicon probe

[32] to deliver very small and precise amounts of bio-

active compounds into highly localized areas of neural

tissue while simultaneously recording electrical signals

from neurons and electrically stimulating neurons in

vivo (Fig. 5). The multichannel neural probes are bulk

silicon micromachined, using a series of oxidation,

boron diffusion, and wet-etching steps. Integrated com-

plementary metaloxidesemiconductor (CMOS) cir-

cuitry and electrodes are also fabricated on the probe

for neuron stimulation and recording. A more sophis-ticated drug delivery device containing integrated

microchannels, fluidic cables, dielectric shutters over

the injecting orifices, and in-line flowmeters to verify

the intended dose, along with the electrical recording

and stimulating circuitry, can achieve chronic in vivo

drug delivery to the neural cells [33].

4.3. Implantable microsystems

Implantable devices are preferred for therapies that

require many injections daily or weekly. They can be

either implanted into the human body or placed under

the skin, consequently reducing the risk of infection by

eliminating the need for frequent injections. Most

implantable microsystems do not cause pain or tissue

trauma due to their small size and are often virtually

invisible [34]. In addition to a reduction in the number

of injections, implantable drug delivery systems have

the advantage that the dose level can be precisely

regulated according to the therapy and the particular

patients requirements due to the interactive and con-

trollable nature of these devices. MEMS systems

combine small size, low power requirements, and the

potential to precisely meter fluid samples, all of which

facilitate implantation [35]. For these reasons, MEMS-

based microsystems are attractive candidates as im-

plantable drug delivery systems.

One method for achieving complex drug release

patterns involves using microfabrication technology to

develop active implantable microfluidic devices that

incorporate micropumps, valves and flow channels todeliver liquid solutions. One of the key components in

those devices is the miniature fluid-dispensing system

or micropump. Various pumping methods are avail-

able, including electroosmotic pumping for ionic flu-

Fig. 5. Micromachined neural tissue drug delivery probe. Left: Sketch of a probe having three delivery channels along with recording and

stimulating electrodes. Right: SEM view of a probe with three delivery channels (n 1997 IEEE) [32].

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ids, positive displacement pumps that use piezoelectric

components, and pneumatic, bubble, or surface-ten-

sion pumps that rely on moving gasliquid interfaces

to displace fluids [36].

One example of such a micropump is a silicon

piezoelectric pump for delivering low flow rates of

liquid drugs with high precision [37] (Fig. 6). The

pump was developed for insulin infusion in diabetic

patients and is based on silicon bulk micromachining,

silicon pyrex anodic bonding and piezoelectric actu-

ation. The flow rate is linear with actuation frequency

and virtually insensitive to inlet and outlet pressure,

actuation voltage, temperature, viscosity and aging.

More recently, the same group reported an improved

micropump design with higher pumping linearity and

accuracy [38]. A micromachined pressure compensat-

ing flow regulator was also developed to provide a

constant liquid flow rate within a pressure range of

100600 mbar and can possibly be used to replace the

flow restrictor in an elastomeric infusion system [39].

Implantable drug delivery devices other than active

microfluidic devices have also been investigated. A

solid-state silicon microchip for controlled release of

single or multiple chemical substances on demand

was developed [40] (Fig. 7). The release mechanism is

based on the electrochemical dissolution of thin anode

gold membranes covering microreservoirs filled with

chemicals in solid, liquid or gel form. A sequential

microfabrication process including photolithography,

chemical vapor deposition (CVD), electron beam

evaporation and reactive ion etching (RIE) has been

used to create 34 microreservoirs on the chip, each

covered by a thin gold membrane functioning as the

anodes. The gold membrane can be dissolved when a

Fig. 7. A solid-state silicon microchip for controlled release [40]. (Reprinted by permission from Nature 397, 335338 (1999) Macmillan

Magazines Ltd.)

Fig. 6. Micromachined silicon piezoelectric micropump. Left: photograph of the micropump chip. Right: SEM view of the pumping membrane

(n 1999 IEEE) [37].

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desired voltage is applied, and the drug inside diffuses

out into the surrounding fluid. Each reservoir can be

addressed individually, creating a possibility for

achieving many complex release patterns.

5. Smart integrated microsystems

In order to activate the delivery of drug compounds

or solutions from the various devices previously

described, a signal must be received by the system

to trigger its function. In most conventional devices,

this signal is manually initiated. However, devices that

function without human intervention can be devel-

oped by integrating chemical sensors into these devi-

ces. This feature is necessary in order to make drug

delivery devices truly robust; the systems could be

capable of monitoring a patients physiological con-

dition and smart enough to deliver the necessary

combination of drugs to treat the condition at any

given time. This means that the drug delivery system

should be able to: (a) monitor the physiological

conditions inside the patient body and convert it to

electronic signals by means of physical and chemical

transducers; (b) receive the electronic signals, analyze

them, and make proper control regulations by means

of microcontrollers; and (c) release the appropriateamount of drugs by means of microactuators. Thus,

future drug delivery systems might contain not only

the microactuator components such as micropumps,

microvalves and flow regulators, but also physical and

chemical microsensors, and control electronics. Elec-

trical interconnects, wires, and packaging components

are also needed to obtain a fully functional, automat-

ed, self-regulating microsystem. All of these compo-

nents must be integrated into a miniaturized device so

that reliability is increased and cost is reduced. From

this point of view, functional integration could be oneof the most important requirements for future drug

delivery systems.

Although no fully integrated, fully functional drug

delivery device has yet been reported, the technology

required to build such a system exists. Similar tech-

nologies are being studied for a number of other

bioMEMS applications. For example, a microfluidic

system has been developed for rapid delivery of small

sample volumes to biosensors, which can assay sam-

ples taken from a bulk flow [41]. Other microfluidic

immunoassay devices have also been developed with

the ability to self-calibrate [42]. Fluidic networks have

been developed with integrated semiconductor detec-

tors/emitters for fluorescent spectroscopy on smallvolumes of solution [43]. Cell lysis, multiplexed

PCR amplification and electrophoretic analysis have

been performed sequentially on an integrated mono-

lithic device [44]. A microfabricated electrophoretic

bioprocessor has been developed for integrated DNA

sample desalting, template removal, pre-concentra-

tion, and capillary electrophoresis (CE) analysis [45].

In addition to these simpler attempts at integration,

more components are being combined into highly

integrated microfluidics-based DNA analysis Micro-

systems [4]. These microfluidic systems have found

many potential medical applications in clinical diag-

nostics, immunoassays, DNA and protein separation

and analysis, cell culture and handling, and drug

delivery. These diverse applications reflect the many

advantages of processing fluid systems in small dimen-

sions: precise volumes of fluid can be moved rapidly

and efficiently; chemical analysis is especially accu-

rate, owing to the combination of small sample vol-

umes and sensitive detection methods; and diagnostic

and delivery methods can often be integrated in a single

device. The last feature is particularly important for

constructing a fully integrated drug delivery system.An example of such an integrated chemical anal-

ysis system is shown in Fig. 8. These types of

microfabricated devices are often referred to as

Lab-on-a-Chip devices since they presumably con-

tain most of the major components of a chemical or

biochemical lab on a single substrate. The device

shown has regions to accurately meter and mix nano-

liter-sized samples, thermally cycle the chemical reac-

tants, and separate and detect the products of that

reaction [4]. All of those components fit together onto

a device measuring approximately 1 cm

2

in total area,and the devices are fabricated using conventional

photolithography and micromachining techniques.

The device can be interfaced and controlled by a

personal computer, suggesting that standalone opera-

tion is feasible. Also, since only low voltages are used

on the chip, batteries should be sufficient to power the

chip, a necessity for portable, handheld operation.

The Lab-on-a-Chip device described above is

particularly important and relevant to drug delivery

systems because it is a fully functional example of a

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system with active sensing on-chip. As discussed

earlier, chemical sensing is vital to the development

of a complex drug delivery system capable of self-

regulated, responsive operation. The chip uses temper-

ature sensors for closed-loop control of thermal reac-

tions such as DNA amplification polymerase chain

reaction (PCR), which requires temperature cycling

between denaturation, primer annealing, and extension

temperatures. Optical fluorescence detectors are alsoincluded on the device for the sensing of size-fraction-

ated reaction products. Diodes are implanted on the

silicon substrate and covered with an interference

filter. When coupled with an excitation source, they

are capable of detecting migrating bands of DNA

during on-chip electrophoretic separation. These are

just two examples of the types of sensing which can be

performed on a microfabricated device. Further inves-

tigation has been published on other chemical sensors

such as on-chip electrochemical detection [46]. These,

and perhaps other more sophisticated methods ofchemical sensing, can be integrated into the drug

delivery systems of the future.

In addition to the importance of sensing applica-

tions, microfluidics will help to advance the function-

ality of drug delivery devices. By taking advantage of

the ability to store fluids in reservoirs on chip until

mixing is desired, it is possible to achieve complicated

drug release profiles, delivery schemes and chemis-

tries. Delivery of multiple solutions without mixing is

also possible using laminar flow systems [47]. The

components used in typical Lab-on-a-Chip and

other similar microfluidic devices can be combined

to design other complex integrated fluidics systems for

applications such as drug delivery, all within an ultra-

compact device that can be produced at low unit cost.

6. Commercial applications

The drug delivery devices of the future are taking

some important cues from integrated microfluidic

devices. This challenge of integrating active sensing

components into a compact, low-power microfluidic

drug delivery system is one that has appealed to

biotechnology companies looking to develop self-

regulating microsystems as the complete therapeutic

solution to chronic illnesses such as diabetes or HIV.

The Ohio-based company ChipRx is developing an

integrated, self-regulating responsive therapeutic de-

vice (Fig. 9). ChipRx describes its target device ashaving biosensors, electronic feedback and drug/

countermeasure release fully integrated. The match-

stick-sized device is designed to sense the physiolog-

ical levels of metabolites, such as glucose. When a

change is detected, a signal is sent from the sensor to

the batteries, which emit an electrical charge. The

electrical charge then triggers the opening of a re-

sponsive material, allowing the release of the desired

therapeutic agent (e.g., insulin) from a reservoir.

When glucose levels return to normal, the sensor

Fig. 8. A schematic of an integrated microfluidic device for DNA analysis (reprinted with permission [4]).

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stops the release of electrical charge from the battery,

closing the reservoir and preventing the release of

more insulin [48]. This type of continuously respon-

sive, integrated delivery system will truly revolution-

ize individualized patient care.

The micro-well device described earlier is being

developed by MicroCHIPS, for use as external and

implantable systems for the delivery of proteins,

hormones, pain medications and other pharmaceutical

compounds [49] (Fig. 10). One great advantage of the

MicroCHIPS multi-well approach is the ability to

store and release multiple drugs or chemicals from a

single device. With increased integration, these devi-

ces show promise of being developed into an intelli-

gent device. By coupling the release mechanism

(described in an earlier section) of each well to

sensors, complex chemical release patterns can be

achieved as needed.

TheraFuse of San Diego is combining microneedle

technology with microfluidics to produce a next

generation minimally invasive wearable drug infusion

system. At approximately the same dimensions as a

silver dollar coin, this wearable system will consist ofa disposable polymer component containing the ther-

apeutic compound and microneedles held to the skin

by an adhesive. A reusable unit containing micro-

fabricated logic, metering and communication circuits

can then be interfaced with the disposable component

to form a completely integrated delivery system.

Whereas most fluidics devices rely on pumps for fluid

delivery, the TheraFuse device incorporates a pressur-

ized reservoir used to move the solution through a

closed fluidic network, until injection occurs across

the layers of the skin. In addition, a metering system isintegrated into the fluidics component to insure accu-

rate delivery. Like the Lab-on-a-Chip devices,

TheraFuse is also attempting to design highly inte-

grated microfluidic systems for drug delivery.

7. Conclusions

The average American probably visits a local drug

store or pharmacy once a week to refill an old

Fig. 9. A schematic of ChipRxs self-regulating responsive therapeutic system (reprinted with permission [48]).

Fig. 10. Above, left: On the chip, medicine is stored beneath 50-Am

squares of gold membrane (top). Applying a small electric charge

dissolves the gold cap, releasing the drug (bottom). Above, right:

One prototype chip holds 100 drug-containing reservoirs (top). The

circuitry on the reverse side (bottom) directs electric current to each

reservoir[40,49]. (Photographs: left (2) Reprinted by permission

from Nature 397, 335 338 (1999) Macmillan Magazines Ltd.; right

(2) Courtesy of MicroCHIPS, Inc./Carita Stubbe.)

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prescription or to pick up new medications. People

have become used to taking a pill with their meals or

administering an insulin injection every morning.

Microfluidic drug delivery systems may provide alter-natives to these modes of administration. Just as Lab-

on-a-Chip technologies are scaling down entire lab-

oratories to a single device with the capability of

performing complex biochemical assays, it is now

foreseeable that a compact, microfabricated device

might soon be able to perform the same function as a

doctor and pharmacist. An integrated, smart device

that is able to respond continuously to physiological

changes and deliver precise amounts of therapeutic

compounds will make a considerable impact on the

way people live their lives. In the near future, the

average American may not have to worry about filling

any prescriptions at the pharmacy. The Pharmacy-on-

a-Chip will be delivering drugs where they are

needed, when they are needed.

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