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Microchip: A Ubiquitous technique for Drug Delivery.

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 Asian Journal of Biomaterial Research 2016; 2(1):22-28 22

Review Article

Microchip:AUbiquitous technique for Drug Delivery

1 2 1
Ashish Garg *, Prakash Pandey , Vaibhav Patel
1
Department of pharmaceutics, Guru Ramdas Khalsa Institute of Science and Technology (Pharmacy),
Kukrikheda, Barela, Jabalpur, M.P. India 483001.
2
Department of pharmaceutics, Rani Durgavati Vishwavidyalaya, Jabalpur, M.P. India 482001.

Received: 19 January 2016 Revised: 27 February 2016 Accepted: 1 March 2016

Abstract
Objective: In the past few years a number of experiments has been performed to enhance the productivity of drug
delivery and to nd a fervent system for drug delivery inside the body. Even though the controlled release system is
distinctly being the most inuential drug delivery method, there still has been an increased interest in miniature drug
delivery systems for delivery of hormones, anticancer agents and vaccines. Conclusion: A summary of various drug
deliveries through microchip it will be a terric advantage to discover a drug delivery device that is competent of
controlled or continuous release of a large variety of drug and other therapeutics that can be securely implanted inside
the body. It is concluded that by microchip technology, revolutionary innovation that have found wide spectrum of uses
in the elds ranging from medicine, communications, diagnostics and electronics.
Keywords: Drug delivery, controlled release, hormones, anticancer

Introduction years at a time, it should hold a large variety drugs or other

The micro electromechanical system (MEMS) based
Implantable drug delivery system obeys this principle. This
therapy have need of repeated low dosage infusions over many
days or months and the comfort of the patient can be really
involved by the use of a miniature system. Reduced side effects,
effective drug delivery, easiness of use, lower cost and patient
comfort assume contributes it the topmost priority. The dosage,
infusion rate and drug combination is diverse depending on the
type of the clinical condition, patient response to treatment.
Rapid expansion in medical field requires prompt changes in
drug delivery mechanism. Biocompatibilities, material
consistency, method of drug release are only a few of the
countless important factors that are needed to be considered in
originating a productive drug delivery system of this type. Thus
it is necessary to design a drug delivery device that has the same
features such as simple to use and manufacture, multi-welled so
that drugs and other molecules can be released for weeks or
*Address for Corresponding Author:
Ashish Garg
Drug Delivery and Nanotechnology Laboratory
Department of Pharmaceutics
Guru Ramdas Khalsa Institute Science and Technology (Pharmacy)
Barela, Jabalpur (MP) India
M: +919993624362; Email: ashish.garg071010@gmail.com
molecules of varying dosages and also should be competent
to deliver these substances in a controlled and reliable
manner and lastly it should be biocompatible and small
enough to be implantable in the human body (Ramille and
Capito, 2000).
Microchip offers both the rate and the time release
of molecule. The device comprises substrate incorporated
multiple reservoirs which are capped with conductive
membrane (gold) and wired with integrated circuit
controlled by microprocessor. Reservoirs are fixed into
substrate by employing either chemical etching or ion beam
etching techniques. Hundreds to thousands reservoirs can be
fabricated on a single microchip using microfabrication.
The molecules to be released are encased into reservoir by
injection. The reservoir can enclose multiple drugs or other
molecule in different dosages. The filled reservoirs can be
capped with substances that take down or allow the
molecule to diffuse out of reservoir over time or materials
that oxidize and dissolve upon application of electric
current. Drug release from the active device can be
regulated by a preprogrammed microprocessor. This system
consists of a polymeric device that has been designed to
offer drug release via diffusion of the drug out of the
polymer or disintegration of the polymer over a period of

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 Asian Journal of Biomaterial Research 2016; 2(1):22-28
time (Jones, 1996). In some cases, the degradation of polymers
takes place too fast due to unexpected environmental conditions
within the body (i.e. in the presence of enzymes that raise the
degradation rates of biodegradable polymers) and the other
devices which liberate the medication into the body
electromechanically and include features such as inlet and outlet
valves and/or micropumps. These devices include minute
power-driven mechanical parts that are necessary to retract,
dispense or pump in order to release drugs in the body (Ratner
and Hoffman, 1966).
Controlled Drug Delivery System
Controlled release relates to devices or materials for regulating
the release time of a chemical and the release rate or both. The
manner by which a drug is released can have a considerable
effect on its therapeutic efficiency (Bakken and Heruth, 1991).
Some drugs have an optimal range of concentration within
which the highest therapeutic results are obtained. Drug
concentration above or below this range can produce toxic or
either no therapeutic effect. It means that drug delivery fails to
confirm that the drug reaches only targeted tissue. Thus, the
controlled drug delivery can be applied to fulfill these
objectives.
1. Release the drug promptly to the tissue and then
distribute it into the other body parts.
2. The controlled drug delivery system reduces the cost of
the treatment and regulates the release of the drug in
body.
3. The controlled drug delivery system provides offers
localized concentrations making the treatment more
valuable. The controlled release system is also used in
foods, cosmetics and pesticides but it had the greatest
impact in the drug delivery of drug (Langer, 1998).
Sustain release drug delivery system
Usually the purpose of sustain release dosage form is to retain
the therapeutic levels of the drug in blood or tissue for a longer
period of time. This is generally done by achieving zero order
release from the dosage form. Zero-order release is independent
of the amount of drug in delivery system (constant release rate).
The sustain release system normally do not attain this type of
release illustrated in figure 1, and try to mimic zero-order release
by providing the drug in a slow first order fashion/ rate (i.e.
concentration dependent).
Pulsatile Release System
Pulsatile release is basically related to the cardiac rhythms of the
body. The key features of pulsatile release is that the drug release
occurs on the basis of previously determined time interval, the
artificial or natural stimuli etc. Pulsatile drug delivery is
different from sustain release system of drug. This Pulsatile
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release system is fabricated for chronopharmacotherapy
(Youan, 2004), which is based on circadian rhythm. In
number of cases, the sustained release is not the optimal
method of drug delivery but instead pulsatile release system
is the favored method for the delivery of pulse of drug at
different time of interval (Figure 2). This type of drug
delivery method works superiorly in several cases in human
body because it mimics the way in which the human body
biologically produces some compounds. The numbers of
compounds produced by the body in a pulsatile or periodic
manner are the hormones of the anterior pituitary gland
(adenohypophysis), for example gonadotrop, which is a
growth hormone and regulates the reproduction and growth
respectively. Insulin is a well-known example of a
compound secreted by the body in a pulsatile manner
(Metthews et al., 1983).
Figure 1. Drug level v/s time profile showing between zero-order
release, slow first order release and release from a conventional
tablet or capsule
Figure 2. Drug Release Profile
Implantable controlled drug delivery
The implantable controlled drug delivery system are also
resourceful to release the medications in proper amount to
those parts of the body which are immunologically
insulated and conventional modes of drug delivery cannot
reach them e.g. the cornea. Implanted drug delivery
systems are now extensively being utilized to understand
the therapeutic potential of peptides. Every microchip
comprises an array of discrete reservoirs from which dose
delivery can be controlled by the telemetry. An Implantable
microchip-based drug delivery comprises an integrated
circuitry system and associated software that control the
drug in one or more reservoirs. The Implantable microchip
components may include mechanical elements, sensors,
actuators and other electronics. Microchip-containing
 Asian Journal of Biomaterial Research 2016; 2(1):22-28
subdermal implants can be used for information storage like
implants include personal identification, medical history,
medications, allergies and contact information. MEMS based
drug delivery devices could less the limits and on several levels
offers great dosing flexibility (Kim and Lee, 2006).
Controlled release microchips
Microchip device controls both the rate and time of release of
numerous chemical constituents. The controlled release
microchips were originated by Santini and colleagues, to solve
the problems of drugs delivery. Several disorders require the
drugs to be released at controlled rate and time, to overcome these
obstacles a silicon microchip has been developed. The microchip
drug delivery device have many qualities like eradicating a
number of pharmacological hindrance which are faced today;
having a small size, imparting a highly controlled release of
drugs and the capability to execute multiple functions
concurrently (Santini et al., 1999).
AGestalt of Microchip Device
The microchip delivery system (Figure 3) incorporates substrate
comprising multiple reservoirs which are capable of holding
chemicals in the solid, liquid or in gel forms. Each reservoir is
covered (i.e. with a conductive membrane) and wired with an
integrated circuit controlled by a microprocessor.
Table 1. Different components of Microchip device
Device Dimensions 17mm x 17mm x 315μm
Reservoirs 400 total ;
0.05 mm spacing (bottom side);
25 ml volume
Square pyramid side wall slope 54º
Fill opening 500μm x 500μm
Release end 30μm x 30μm
Gold caps 50μm x 50μm x .3μm
Figure 3. Microchip Device
This central processor unit is proficient to electrically control the
time of release and also the amounts of drugs discharged by
regulating the dissolution of the covering membrane. The
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microchip drug delivery system should be fabricated by
standard microfabrication technology which is a cost-
effective technique. Each microchip measuring 15× 15×1
mm³ consist of 100 individually addressable 300-ml
reservoirs. The microchip is scheduled specifically such
that reservoirs open up remotely when activation of electro
thermal process is done to liberate the drug in a controlled
rate in specific site of action (Langer, 2001).
Substrate
By virtue of the microchip drug delivery system design, the
reservoirs are patterned into the substrate. This can be done
by the conventional etching techniques of microfabrication
process. Any material that can be employed for support or
provide support, is appropriate for etching and the material
which is impervious to the molecules to be released and to
the surrounding fluids are utilized as a substrate (Ramille
and Capito, 2000). For this type of in-vivo application, the
biocompatibility of material should be taken into
consideration. The example of a strong, easily etched
substrate that is impervious to the delivered chemicals and
non-degradable to the surrounding environment within the
body is silicon. In some applications materials which are
degradable over time might be preferred. For example,
brain implants- the removal of a device is very problematic
and dangerous to the patient and thus this device cannot be
utilized for the treatment of such diseases like brain tumors
(Ramille and Capito, 2000).
Release System
Usually the design of a release system relies upon the
medications which are required by the patient whether it is a
continuous or pulsed release. The release system is chosen
on the basis of the period over which release is desired,
commonly in the range of at least three to twelve months for
in vivo applications. Contrariwise for in vitro applications
the desirable release times are as short as a few seconds.
Drug delivery can be achieved by a passive or active release
system. In the passive release system, the drugs enter in the
body through diffusion of a membrane or by the
decomposition of the substrate and in active systems are
activated by a microprocessor. The molecule which are
released or may be encased into the reservoirs in their pure
form either in liquid solution or gel may be encapsulated
within the release system which release incorporated
molecules by diffusion or disintegration of the matrix. The
selection of the release system is dependent upon the
predicted rate of release of the molecules. Non-degradable
and degradable, both release systems may be employed for
delivery of molecules. Release system can be natural or
 Asian Journal of Biomaterial Research 2016; 2(1):22-28 25
synthetic, but synthetic release systems are mostly chosen and bonding pads are engraved with ECR-enhanced RIE to
because of their better release profiles (Ramille and Capito, expose the underlying gold film. The thin silicon nitride and
2000). chromium membranes which are situated in the reservoir
Reservoir Caps below the gold anode can be removed using this technique.
In active release system or devices, the reservoir caps consist of Then the reservoirs are packed with the molecules or drugs
thin films of conductive material that act as anodes and are which are to be delivered by the aforesaid reservoir filling
surrounded by cathodes. Any conductive material that can methods and then afterwards sealed (Staples et al., 2006).
dissolve and oxidize in solution when electric potential is applied
can be utilized for the fabrication of the anodes and cathodes. The
segment of the anode just above the reservoir oxidizes and
dissolves into solution when the electric potential is applied
between the cathode and anode. This phenomenon opens up the
release of the molecules or drug into the surrounding fluids.
Reservoir filling
The three-dimensional printing is proficient for the fabrication of
complex structures by ink-jet printing liquid binder onto loose
fine powder. The printing pattern can be acquired by computer-
aided-design model (CAD). By identifying the appropriate print
head to deposit a pre-determined amount of binder, the volume of
the reservoirs can be managed. The drug is cleared out of from the
nozzle, as the vapor bubble within the nozzle expands upon
heating. The correlation between the amounts expanded by the
vapor bubble to the heat added obeys the ideal gas law
relationship (Ramille and Capito, 2000).
Microfabrication
Fabrication of these microchips (Figure 4) initiates by the
deposition of ~0.12 mm of silicon- nitride on both sides of prime
grade, (100) silicon wafers utilizing a vertical tube reactor Figure 4. Microchip– Fabrication Process
(Santini et al., 1999). The deposition of the silicon nitride layer Working process of Microchip
on one side of the wafer is designed by employing The microchip drug delivery device consists of numerous
photolithography and electron cyclotron resonance (ECR) which reservoirs, each reservoirs layered by a thin membrane of a
enhances reactive ion etching (RIE) to offer a square device material that behaves as an anode (i.e. gold) in an
consisting of square reservoirs. The silicon nitride layer act electrochemical reaction. The electrodes which are
toward as an etch mask for potassium hydroxide solution at 85ºC, positioned on the surface of the microchip perform as
which anisotropically etches square pyramidal reservoirs into the cathodes for electrochemical reaction. Generally the
silicon along the crystal planes until the silicon nitride film on the cathode is made by the same material as the anodes to
opposite side of the wafer is obtained. The square apertures of the simplify the fabrication process. All the reservoirs are filled
reservoir can be entirely covered by the newly fabricated silicon with a compound or drugs which are to be released. A water-
nitride membranes. By electron beam evaporation and lift-off the resistant ingredient is used to seal the open ends of the
gold electrodes (0.3-0.5 mm thick) are deposited and patterned reservoirs. Whenever release of the compound from a
over the silicon nitride membranes. The portions of the specific reservoir is desired, an electrical voltage
electrodes are protected from undesired corrosion by adherent (approximately 1 volt) is applied between the anode
and the non-porous coating isolates the electrode materials from covering that reservoir and a cathode. Thin film lithium
the surrounding electrolyte. Silicon dioxide is universally used rechargeable batteries are employed for this application
for a model protective covering (Santini et al., 1999). A plasma (Bates and Dudney, 1997). By the electrochemical
layer enhanced the chemical vapor deposition silicon dioxide is reaction, the anode membrane disintegrates and the
deposited over the entire electrode containing surface. The reservoir opens up, which permits the release of material
silicon dioxide situated over the portions of the anode, cathode inside it to diffuse out into the surrounding fluid. Each

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 Asian Journal of Biomaterial Research 2016; 2(1):22-28
reservoir on the prototype microchip can be triggered separately
because each anode has its own independent connection to the
power source. As the number of reservoirs on a microchip
becomes large, it should be feasible to connect each anode to the
power supply through a demultiplexer. The demultiplexer acts as
a "routing station" by directing power to a specific reservoir
based on a code sent to the demultiplexer by a microprocessor or
remote control (Bates and Dudney, 1997).
Control Circuitry and Power Source
The control circuitry system of the microchip device (Figure 5),
commonly comprises a timer, demultiplexer, microprocessor or
an input source. The microprocessor unit of the control circuitry
system of microchip activates and controls the desired reservoir
so that variety of the drugs may be filled in each specific
reservoir. Each reservoir may consist of a variety of drugs. A
biosensor unit can be used as a “trigger” or an input source to the
microprocessor. The microprocessor is a programmed map of the
drugs available in the reservoirs.
Each reservoir will be interlinked to each other through
multiplexing circuitry and be triggered by the microprocessor
unit. The input source of the control circuitry system can either be
a biosensor or a memory source or a remote control device. A
thin-film microbattery or lithium thin film battery can be
employed as a power source.
Figure 5. Schematic diagram of general circuit design
Capabilities of Battery and Power Requirements
This system incorporates a thin film solid state battery which was
developed in Oak Ridge National Laboratory (Bates and
Dudney, 1997). These thin film solid state batteries are
predictably less than 15 microns thick and occupy one centimeter
square of area (Santini et al., 1999). The power capacity of this
type of battery is 2mWh. A graphic representation of the battery
is illustrated in figure 6. This battery comprises a lithium metal
anode and LiCoO2 cathode. The lithium phosphorus oxynitride
can be utilized as an electrolyte between the anode and cathode
and platinum is used as the current collector.
The functions of the battery are likewise as common
Eveready or Duracell battery. Ion flow is throughout the
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26
electrolyte and electron flow is via external circuit. These
both are driven by a redox reaction between the anode and
the cathode materials. Besides 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 which are shown in
the following table. Calculations were based on the
following equations:
P=I V
V=IR
Where P = power, I = current, V = voltage, and R =
resistance
The power necessitated is still below the battery
capacity of 2mW-h. Thus, all of the reservoirs can be
liberated by employing only one lithium battery (Bates and
Dudney, 1997).
Figure 6. Schematic representation of thin film battery
Delivery Schedule
The microchip device contains numerous reservoirs which
can hold a range of drugs and can liberate them in varying
amounts. The drug delivery schedule is dependent upon the
patient need. For instance, with the capacity of battery, the
patient can be administered 25 ml (one reservoir) per day. In
this way drug can be released everyday for many years.
Device Testing
The Microchip drug delivery devices have been testified by
the discharge of the radio-labeled compounds and
therapeutic drugs and this release was monitored by liquid
chromatography and the scintillation counting techniques
correspondingly.
In vitro testing was accomplished with a flow cell
configuration, in which the chip is attached in a chamber of
phosphate-buffered saline (PBS). At regular intervals, the
PBS is replaced via inlet and outlet tubes and the collected
fractions are analyzed. In vivo testing was carried out again
by using both radio-labeled compounds and therapeutic
drugs. Both the blood and the urine are evaluated for the
detection of drug release.
Applications of Microchip
1. DNAchips for advancement in brain tumors diagnosis
 Asian Journal of Biomaterial Research 2016; 2(1):22-28
Present day methods which are employed for the treatment of
brain tumors are arduous and challenging due to their
heterogeneity and variable malignancy. The most common brain
tumors found in adults are Gliomas and its diagnosis is based on
subtle microscopic characteristics. Now there is no distinctive
marker or genetic signature by which outcome of each type of
glioma can be predicted.Agroup of researchers from the Institute
Curie and Inserm has exploited the technology of DNA chips,
which were able to recognize the tumors with the best prognosis,
whose chromosome has undergone a particular deletion. One of
these analytic methods is Comparative Genomic Hybridization
(CGH), which permits global assessment of the genome. It is a
tool to reconize genome regions that have been amplified or
deleted - very frequently in tumor cells.
2. In cancer therapy
By the assessment of the proteins in the blood, doctors find out
the patients' cancer risk and examine the health of the elder
people with chronic diseases. But the existing methods for
testing these proteins are require too much blood to be performed
regularly and are expensive too. Investigators looked forward to
make bedside diagnostics based on blood proteins a reality by
bringing down the cost of such tests. The diagnostic chip has
been developed by Caltech chemistry professor James Heath and
by Leroy Hood, the president and founder of the Institute for
Systems Biology, in Seattle. Heath and Hood have established a
company known as Integrated Diagnostics to commercialize the
blood chip (Haruyama, 2002).
3. Microchip for Antidepressants
Depression is the fourth most important reason of disability in
the world. Newly, mechanical devices such as the
microprocessor-based Medication Event Monitoring System
(MEMS) have been developed. The assay of blood for drug and
its metabolites has also been used for dothiepin a ratio of
nordothiepin:dothiepin of greater than 1.1 denotes
noncompliance for a period of 48 h or longer. The MEMS system
facilitated us to detect the exact times at which opening of the
reservoirs occurred. The major benefit of implantable systems in
the treatment of chronic depression are that patients
psychologically become freed from having to continue to take
the medicines for months or years (Idbaih et al., 2005; George et
al., 2000).
4. Microfluidic cell treatment
Assessment of compounds existing in the living cells is a
significant part of the drug discovery process, but optimum drug
testing requires conditions that are as close to the physiological
context as possible (Haruyama, 2002). Micro fluidic devices
make it possible to manipulate single objects of cellular size and
thus analysis under controlled yet physiologically relevant
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27
environments can be obtained. Furthermore, by
parallelization of applied methods large numbers of cells
can be monitored concurrently i.e. under comparable
conditions (Haruyama, 2002).
5. Simplicity of release mechanism
The liberation of chemicals from the microchip is instigated
by fragmentation of the membrane. The membrane is
shattered by the application of an electric potential, which
cause the membrane to dissolve by simple electrochemical
reaction. The microchip device has no movable segments.
The absence of moving parts possibly enhances device
reliability by lowering the possibility of mechanical
breakdown (Idbaih et al., 2005; George et al., 2000).
6. Accuracy of dose
The microchip device comprise numerous reservoir, each
reservoir of microchip can be precisely filled with a small
amount of the drug by utilizing the microinjection or ink-jet
printing method. It is imperative that the amount of drug to
be delivered to a patient should match the amount
prescribed, specifically for highly potent compounds. The
amount of the drug administered from a microchip filled by
this printing technique can be firmly regulated and
accidental overdose can also be escaped because release
from active devices can only occur when an electric
potential will be applied to an anode. Larger doses can be
administered by simply opening several reservoirs at one
time (Idbaih et al., 2005; George et al., 2000).
7. Improve shelf-life
Several protein based drugs have a restricted stability or
shelf life. In this case the water permeation into these
protein drug formulations is one of the most common
causes. The membrane layering the packed reservoir of a
microchip will prevent the diffusion of water into these
reservoirs. Thus, the stability of protein drug can be
enhanced firstly by isolating the drug from the outside
environment (hermetically sealed) and secondly by storing
the microchip in their most stable form (solid, liquid or gel)
(Idbaih et al., 2005; George et al., 2000).
8. Potential for local delivery
The microchip device can be made infinitesimal to bring
about the local chemical delivery possible. The principal
benefit of local drug delivery is that high concentrations of
drug can be attained at the site where it is required while
keeping the systemic concentrations low. For instance,
BCNU (carmustine) is expansively used in the therapy of
malignant brain tumors. Large amount of BCNU must be
administered systematically to a patient to acquire its
minimal adequate concentrations at the tumor site in the
 Asian Journal of Biomaterial Research 2016; 2(1):22-28
brain which brings about damage to liver, spleen and kidney.
Insertion of polymer wafers containing BCNU at site of tumor
permits the local concentration of BCNU at tumor to be 1000
times higher than that attained by systemic delivery while
keeping systemic concentrations low (Santini et al., 2000).
9. Complex release patterns
The concomitant constant and pulsatile release (Complex
release patterns) can be acquired from the microchip. Any
complex chemical or drug release pattern can be broken down
into a combination of two parameters: release time and release
rate. A distinctive characteristic of controlled release microchip
is its capability to control both of these parameters (Santini et al.,
2000).
10. Compounds to be released
There are many substances which can be deposited inside the
reservoir unit of the microchip device and can be discharged
timely from the microchip. Each reservoir can be filled with a
different chemical or combination of chemicals. Chemicals
which are filled up in the reservoir can be either of solid, liquid or
gel form. Microfluidic devices such as pumps are restricted for
delivering liquids (Santini et al., 2000).
Conclusion
Conclusively, the upcoming trend demands innovative drug
delivery system like individualized remedy and the competence
to automate delivery system. The intended microchip for drug
delivery allows for storage and reliable controlled release of
multiple drugs. Microchip based implantable drug delivery
devices permit localized delivery by precise placement of the
device at the treatment site, release as per requirement (pulsatile,
adjustable continuous dosing and emergency administration ,
programmable dosing cycle) programmed delivery of multiple
drug and dosing in response to physiological response. This
device is less complicated and much more reliable than the
aforesaid devices that strive to manage drug release rate (i.e.
electro-mechanical or polymer systems). The microchip can be
fabricated by conventional microfabrication process and can also
be self-contained, which excludes the need for patient or doctor
intervention. The intended device illustrated (assuming one dose
per day) can last over a year; however, the releasing competence
relies on patient need.
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