Microneedles in Drug Delivery system 2010-11 1. Introduction 1.1 The concept of minimally invasive drug delivery A discussion of minimally invasive drug delivery must begin with a consideration of what invasive delivery means. Administration of drugs via needles and syringes has been with us for more than a hundred years. For example, the first all-glass syringe patent was licensed to Becton Dickinson & Co. in 1898. Metal cannula needles on piston syringes have become the most prevalent ethical device-based drug delivery modality in existence, with multiple billions being used each year in many health care applications. Conventional needles, whether on syringes or catheters, represent the preeminent invasive delivery mode in existence. They are, however, also the most efficient and cost effective device-based system for administering agents into the systemic circulation and are presently the general method for delivering polypeptide agents, which are otherwise proteolyzed by the oral route. The reason, as discovered more than a century ago, is that a thin, sharp sterile metal pipe is an ideal way to breach the stratum corneum and deliver agents past the skin barrier into the micro-vascularization of the dermis or lower tissues and thence into the systemic circulation. Despite this, conventional needle-based delivery suffers many well- recognized drawbacks, not the least of which is the negative psychosocial connotation of drug administration via needles. Chetan N. Chauhan 1 SSPC, Mehsana
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Microneedles in Drug Delivery system 2010-11
1. Introduction
1.1 The concept of minimally invasive drug delivery
A discussion of minimally invasive drug delivery must begin with a consideration of
what invasive delivery means. Administration of drugs via needles and syringes has been
with us for more than a hundred years. For example, the first all-glass syringe patent was
licensed to Becton Dickinson & Co. in 1898. Metal cannula needles on piston syringes
have become the most prevalent ethical device-based drug delivery modality in existence,
with multiple billions being used each year in many health care applications.
Conventional needles, whether on syringes or catheters, represent the preeminent
invasive delivery mode in existence. They are, however, also the most efficient and cost
effective device-based system for administering agents into the systemic circulation and
are presently the general method for delivering polypeptide agents, which are otherwise
proteolyzed by the oral route. The reason, as discovered more than a century ago, is that a
thin, sharp sterile metal pipe is an ideal way to breach the stratum corneum and deliver
agents past the skin barrier into the micro-vascularization of the dermis or lower tissues
and thence into the systemic circulation. Despite this, conventional needle-based delivery
suffers many well-recognized drawbacks, not the least of which is the negative
psychosocial connotation of drug administration via needles. Other problems include the
pain of administration; safety concerns over the possibility of transmission of blood-
borne pathogens; the lack of compliance, the inability or dislike of patients to self-
administer via needles; and the lack of ease of use, especially for younger or elderly
patients. To address these needs, a number of new technologies have arisen or are in
development, whose inventors intend to provide trans-epidermal drug delivery by
circumventing the conventional needle and syringe.1
During recent years, transdermal drug delivery systems have shown a tremendous
potential for their ever-increasing role in health care. This has been mainly attributed to
the favourable properties of lack of first pass metabolism effects of liver, better patient
compliance, steady release profile and lowered pill burden in transdermal system.
However, the transdermal technology have limitations due to the inability of a large
majority of drugs to cross the skin at the desired therapeutic rates because of the presence
of a relatively impermeable thick outer stratum corneum layer. This barrier posed by
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Microneedles in Drug Delivery system 2010-11
human skin limits transdermal delivery only to lipophilic, low molecular weight potent
drugs.2 Researchers are trying to overcome this hurdle of poor permeability by the
following means:
1) Chemical Means: Chemical means include the prodrug approach and/or use of
chemical penetration enhancers that can improve the lipophilicity, and the consequent
bioavailability.
Chemical approach increases the lipophilicity and therefore increase the permeability of
drugs across skin, whereas the physical approaches disrupt the upper layers of skin
(stratum corneum) and reduce the resistance to the passage of drugs by creating minute
holes in the skin that are large enough for the passage of smaller drug molecules but
probably small enough not to damage the skin.
2) Physical Means: Physical means of transdermal drug delivery comprises of
iontophoresis, electroporation, and sonophoresis.
On the other hand hypodermic needles are effective at bolus delivery of drugs, but cause
pain during insertion and are not ideally suited for delivery over extended periods.
Transdermal patches address these shortcomings.
Chetan N. Chauhan 2 SSPC, Mehsana
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1.2 Mechanism of skin penetration
The thickness of the stratum corneum is approximately 10 to 20 microns. Therefore the
minimum distance breached by minimally invasive transdermal systems must be about 20
microns. During tissue damage, adenosine triphosphate (ATP) is released from damaged
cells. ATP is a ubiquitous cellular energy storage compound, which when released
extracellularly potentiates input nociceptors (pain receptors) via direct stimulation of
neurons. The effect appears to provide a local signal for tissue destruction, which in turn
stimulates remedial physiological responses such as inflammation, etc. Pain may also
result from tissue distension caused by drug injection, skin damage (and ATP release), or
direct damage to nerves. Researchers are approaching the challenge of pain reduction by
several techniques that are linked by one unifying strategy: limiting the extent of
mechanical insult to skin to the first 50 microns of tissue.
The mechanical stress–strain relationships of skin complicate the practical manipulation
of the stratum corneum, epidermis, and upper dermal layers. The mechanics of skin, and
other soft tissue such as arteries, muscle, and ureter, do not display single-value
relationships between stress and strain and are therefore classified as inelastic materials.
When tissues in this group are held at constant strain, they display stress relaxation, and
when held at constant stress they creep.2, 3
Historically this relationship has required uniaxial application of mechanical force to
breach skin (as in needle penetration), and has made sensation-free clinical manipulation
(containment, preparation, and breach) of skin tissue difficult. In general the new skin
breach technologies described in this communication require either direct uniaxial
application of mechanical energy or thermally/mechanically induced changes in the
physical properties or structure of skin. They differ from classical approaches in that they
attempt to target the epidermis and upper dermal layers devoid of nosiceptors while
gaining access to the circulatory and immune systems via the dermal capillary bed and
epidermis, respectively. If successful, these approaches may greatly reduce or eliminate
the mechanical stimulation of pain responses during delivery.
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1.3 Microneedles as a system for minimally invasive transdermal delivery
The development of microneedles for transdermal drug delivery came about as an
approach to enhance the poor permeability of the skin by creating microscale conduits for
transporting across the stratum corneum. Microneedle technology has been developed as
an advanced technique for penetration of large molecular weight and/or hydrophilic
compounds. Micron scale needles assembled on a transdermal patch have been proposed
as a hybrid between hypodermic needles and transdermal patches to overcome the
individual limitations of both the injections as well as patches. Microneedles are so called
because they are of micrometre (millionths of a metre) scale.
Microneedle technique has been successfully used to deliver a variety of compounds
including macromolecules and hydrophilic drugs into the skin. As microneedle system
bypasses the stratum corneum barrier of the skin, permeability enhancement of two to
four orders of magnitude has been observed for small molecules like calcein and also for
the relatively larger compounds like proteins and nanoparticles. The technology that are
long and robust enough to penetrate the layer of the stratum corneum but short enough to
avoid stimulating the nerves has the potential to make the transdermal delivery of drugs
more effective. Therefore, the main aim of the microneedle technology is to combine the
efficacy of the hypodermic needle with the convenience of a transdermal patch.
Figure 1: Layers of the Human Skin
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In modern medical applications, there is a need for very small hypodermic needles that
are economical to fabricate. Currently, the smallest needles commercially available, 30
gauge needles, have a 305 mm outer diameter with a wall thickness of 76 mm.
Traditional machining methods make it unfeasible to create needles with a diameter
less than 300 mm. Microneedles on the other hand can be any size and geometry since
they are defined lithographically. Microneedles are designed to be high performance
minimally invasive conduits, through which drug solutions may pass into the body. In
order to be minimally invasive, the needles are designed to be as small as possible.
Needles are also designed to be extremely sharp, with submicron tip radii. This allows
the needles to be effectively inserted into the skin. The stress on the skin is inversely
proportional to the area over which the force is applied.3, 29, 31
Therefore as tip radii decreases the stress imposed at a constant force increases and
allows lower forces to be used for needle insertion. In addition, the small size of the
needles cause less compression of the tissue as needles are inserted which leads to less
compression of pain receptors and a decrease in insertion discomfort. The small size of
the microneedles also decreases the chance that the needle will be inserted close to a
pain receptor. The decrease in tissue damage also decreases the likelihood of infection
occurring at the site of insertion. Internal features of the microneedle, such as in-line
microfilters, which are defined as part of the needle during a lithography step, may also
be used to effectively filter any foreign matter including bacteria from the fluid being
injected. This decreases the chance that a contaminated solution may be inadvertently
injected.
One of the largest barriers to the commercialization of technology is the cost and
effectiveness of producing the technology. Since microneedles are produced in a highly
parallel batch process there is great potential that the individual cost per needle is
lowered. Molded needles which do not sacrifice the mold wafers lead to an increased
cost savings, since the mold may be used over and over. This leads to a high quality
reproducible device that opens up a new option for drug delivery applications that has
few cost and fabrication barriers to being employed in the marketplace.5
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2. Advantages & Disadvantages
2.1 Advantages
The major advantage of microneedles over traditional needles is, when it is inserted into
the skin it does not pass the stratum corneum, which is the outer 10-15 μm of the skin.
Conventional needles which do pass this layer of skin may effectively transmit the drug
but may lead to infection and pain. As for microneedles they can be fabricated to be long
enough to penetrate the stratum corneum, but short enough not to puncture nerve endings.
Thus reduces the chances of pain, infection, or injury. 5
In terms of processing there are also many advantages. By fabricating these needles on a
silicon substrate because of their small size, thousands of needles can be fabricated on a
single wafer. This leads to high accuracy, good reproducibility, and a moderate
fabrication cost
Microneedles have a significant advantage over other approaches to transdermal drug
delivery such as electroporation, ultrasonic delivery, or chemical modifiers/enhancers all
of which rely on decreasing the permeation barrier of the stratum corneum, the outermost
layer of the skin. Microneedles mechanically penetrate the skin barrier and allow the
injection of any volume of fluid over time. Microneedles have the ability to be precisely
inserted to inject therapeutics any particular distance below the stratum corneum. This
allows precise localization of a high concentration drug solution in order to obtain
effective absorption into the bloodstream or to stimulate particular clusters of cells in or
near the skin. Therefore, the drug delivery does not depend on transient delivery of
therapeutics across the skin. The delivery is independent of the drug composition and
concentration and merely relies on the subsequent drug absorption into the bloodstream,
which occurs at a much faster rate than permeation of a solution across the skin. This also
allows complex drug delivery profiles. Since drug is actively injected into a patient the
dosage may be varied with time. In addition, by employing multiple needles or effective
fluid control with mixing of solutions multiple drugs may be injected simultaneously
specific to a patient’s personal needs. Needles may also be used to transdermally sample
body fluids for analysis. 4
The extreme miniaturization of fluidic devices enables portable devices for
personalized medicine allowing continuous metabolite monitoring with drug delivery in
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response to metabolite levels. This has tremendous advantages over existing
technologies. It allows patients more freedom in their treatment since they are no longer
dependent on a facility to provide an outpatient service which often results in a bolus
injection or a period of intravenous drug delivery while a patient is at the facility with
little or no therapy between treatments. It also allows a lower drug dosage to be injected
over a longer period of time to maintain a constant blood concentration. A bolus
injection on the other hand leads to a rapid increase in blood concentration, often to
toxic levels, followed by a decay period as the drug is metabolized. This time varying
high concentration injection is often responsible for many side effects associated with a
large number of therapeutics. By maintaining a constant blood concentration below
toxic levels, side effects associated with a high concentration bolus injection may be
reduced. Further, the ability of microneedles to deliver therapeutics at a slow,
controlled rate will make unnecessary the injection of a large bolus in the first place.
This allows the delivery of therapeutics to a depth just below the stratum corneum and
yet still above the nerve bed in the skin. A bolus must be injected deeply into the tissue so
it does not leak out the hole punched in the skin to deliver it. Microneedles make this
form of therapeutic delivery unnecessary.
Other advantages include: 8
Precise volumes of fluid moved rapidly and efficiently
Reduce the amount of drug used
Localize the delivery of potent compounds
Deliver otherwise insoluble or unstable therapeutic compounds
Reduce the chances of missing or erring a dose
Multiple injections can be avoided
Ability to administer the drug at the specific target site
Rapid onset of action
Possible self administration
Efficacy and safety comparable to approved injectable products
Improved patient compliance
Good stability
Cost effective
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2.2 Current limitations of microneedles
Biological Response
Future work needs to be performed to determine the biological response to microneedles.
The first response to tissue distress from needle insertion is an inflammatory response at
the insertion site. Also, constriction of capillaries may occur which may affect drug
absorption. During this time tissue edema may also occur, which may affect fluid
delivery from the needles, with the migration of leukocytes to the injury site. Protein
adsorption to the surface of the silicon will promote adhesion of leukocytes to the
needles. However, surface modifications of silicon surfaces to reduce protein adsorption
is an active area of research. Some surface modifiers include: silicon carbide,
polyethylene glycol (PEG), or plasma enhanced chemical vapor deposition (PECVD) of a
Teflon-like fluoropolymer. Any of these coatings could be incorporated into needle
fabrication to improve biocompatibility.
Since microneedles are designed for short term intradermal drug delivery, fibrous
encapsulation is not expected because the needle is not inserted long enough for
encapsulation to occur. However, there is the chance that the body may try to extrude the
needle by pushing it out over time. Therefore, mechanical reinforcement may be required
to keep the needle in place.2
Breakage Versus Piercing Ability
Due to the small size of microneedles, strength and robustness are the major factors in
determining the range of their applications. Needles must be able to tolerate forces
associated with insertion, intact removal and normal human movements if they are to be
integrated into portable biomedical devices. Namely, materials such as silicon are strong
and can easily pierce the skin but they are also brittle materials which fracture easily.
Metal and polymer needles on the other hand are not stiff so they can absorb larger
stresses by plastically deforming. However, this ability also makes piercing the skin more
difficult. Metal deposition also uses thin film processing techniques, and therefore the
metals are mechanically weaker than bulk hardened metals such as stainless steel. A
hybrid microneedle such as the parylene coated silicon needle appears to be most
promising because it balances the advantages of each material. A silicon tip could be held
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rigid during insertion and then released allowing the polymer tube to absorb the stress
associated with movement. Since the silicon tip is so much smaller than a whole needle it
will experience smaller stresses and will be less likely to fracture. In addition, even if the
tip does fracture it will be held together by the polymer coating. Another approach is to
develop new polymer processing techniques which can be used to generate needles. If a
semi-crystalline polymer is used, then it may be strong enough to allow needle insertion,
but also have enough of the polymer in an amorphous phase to absorb mechanical stress.
Another way to take advantage of material limitations is to precisely control the stresses
and forces the needle experiences. This could be accomplished by having a
microfabricated insertion actuator to control the insertion force. This could consist of a
microfabricated linear stepper motor or piezoelectric actuator. Both would allow precise
positioning and direct insertion of the needles axially without any bending moment to
deform or fracture the needles. Piezoelectric actuators could also produce ultrasonic
vibrations to decrease the amount of force required for insertion.4
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3. Applications
3.1 Diabetes
Microfluidic devices and sampling through a microneedle allows a feedback loop
between a sensor which monitors the glucose levels in the body and a delivery module
which can deliver insulin in a time varying fashion as needed. This more closely
mimics the body’s natural regulation of sugar leading to fewer complications associated
with the treatment.2
3.2 Chemotherapy
When a patient undergoes chemotherapy they often receive a fixed drug dosage in a
session. By delivering the chemotherapeutic agents continuously through a
microneedle, the patient may receive therapy over a longer period of time. It could also
lead to a lower dosage of the toxic drugs, which must be injected at any one time.
Lowering chemotherapy dosages may lead to an overall lessening of the severity of side
effects. By incorporating a longer treatment period with fewer side effects, it could
shorten the overall number of treatments and recovery time to combat the disease.
There are also many cell based therapies which could be delivered continuously
through a microneedle. Antitumor effector cells which attack melanomas have been
extensively studied. These cells have been shown to reduce the size of both solid and
hematologic human tumors. However, if cells are injected intravenously they are not
always localized to tumors and the liver and spleen destroy a large majority of the cells.
If the injection is directly into or around tumors (intralesionally), they will be localized
to attack the tumor. The microneedles do very little tissue damage, so a patient can
receive continuous therapy. Also, the needles have less chance of damaging tumors and
causing the tumor to metastasize than larger needles. 2, 9
3.3 Vaccinations, Pain relievers and Antibiotics
Currently there are many medications, such as the Hepatitus B vaccine, which require
several shots over a period of time. Quite often, people will receive the first or second
shot but fail to return for subsequent shots. Patients also take antibiotics until their
symptoms subside but then do not finish their pills. This is leading to a dramatic
increase in antibiotic resistant bacteria strains. Analgesics such as Sufanta (Sufentanil
Citrate), Sublimaze (Fentanyl Citrate), and Dilaudid (Hydromorphone) have doses of
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less than 3 ml per hour. By delivering these pain relievers continuously, a patient can
obtain the benefits of the analgesic without being hindered by a intravenous drip.
Delivery of all of these medications in a continuous fashion greatly simplifies the
therapy. A patch device could be applied once a day or every few days and supply the
patient with enough medication for a given time period. In addition, the drug could be
kept in a lyophilized powder. The powder would be reconstituted with water, dosed,
and delivered as needed by the patient. 2
3.4 Catheterized Instrumentation
Microneedles may be placed on the end of a catheter for intervascular delivery. The
needle could be used to breach blood vessel walls in order to inject precise dosages of
drugs to the surrounding tissue. They may be used to inject clot-dissolving drugs
directly into a coronary arteriosclerosis such as alteplase (a genetically engineered form
of one of the body's own plasminogen activator proteins) or Streptokinase (a
plasminogen activator produced by streptococcus bacteria)20
3.5 Blood glucose measurements
Recent advancement involves the instrument in which a patient will load the cartridge
into the electric monitor and simply press the monitor against the skin. This action will
cause the microneedle to penetrate the skin and drain a very small volume of blood(less
than 100 nanolitres) into the disposable. Chemical agents in the disposable react with the
glucose in the blood to give a colour. The blood glucose concentration will be measured
either electrochemically or optically and the resultant value displayed on the monitor.
The use of hollow microneedles allows the delivery of medicine, insulin, proteins or
nanoparticles that would encapsulate a drug or demonstrate the ability to deliver a virus
for vaccination. An assay of needles can be designed to puncture the skin and deliver the
drug much like a nicotine patch for individuals who are trying to quit smoking.38
3.6 Skin therapy
Microneedle skin therapy is s till in testing development but it seems to show much
promise. Microneedle therapy is a way to rejuvenate the skin without destroying the
epidermis. It is similar to laser treatment but with less damage. Microneedles penetrate
the epidermis and break away old collagen strands. The collagen strands that are
destroyed create more collagen under the epidermis. This leads to youthful looking skin.
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The only disadvantage of this method is that it causes blood oozing, which laser
treatments do not. It does however have advantages such as: increased collagen, non sun-
sensitivity upon treatment, no breaking of the epidermis, lower cost, and ease of
application.20
3.7 Eye Treatment
Microneedles can be used to deliver drugs to the eye through a minimally invasive
procedure. The needles used to penetrate the eye only go as deep as half a millimetre into
the eye tissue. This means that the needles do not penetrate far enough to cause as much
damage as traditional needles. As a result, they can be applied to the eye using only local
anaesthetic. This technique has the potential to revolutionise the way of treating common
eye conditions such as glaucoma, macular degeneration and diabetic retinopathy.
Other applications of microneedles include: 26, 24, 39
Cell manipulation.
Interconnection between microscopic and macroscopic fluidic systems.
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4. Classification – Types & Approaches
Microneedles can be classified into various types as shown below:
4.1 Types of Microneedles:
Figure 2: Classification of Microneedles
4.1.1 Solid Microneedles
Solid microneedles are designed to create micron-size pores in the tissue, which act as
direct pathways allowing drug molecules or particles to transport into the tissue. These
microneedles tend to have sharp tips and have good mechanical strength. They can be
mass-produced at low cost. These are of various types and as shown above, can be
fabricated from various materials: 9, 15, 22
4.1.1.1 Silicon Microprobes 18, 27
In the early phase of microneedle development, pyramidal silicon microprobes were
found. Using a spin casting method, a photoresist is placed onto a silicon-dioxide coated
wafer; the wafer is then brought in contact with a photomask and is exposed to UV light.
The transferred pattern is then etched into the silicon dioxide masking layer. The
photoresist is then removed and the wafer is anisotropically wet-etched in potassium
hydroxide solution to create arrays of pyramidal probes. With the goals of delivering
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genetic materials to cells, these microprobles are ten to hundreds of microns in height and
have very sharp tips. 28, 41
4.1.1.2 Silicon microneedles
Figure 3: Silicon Microneedles
The simplest forms of the microneedles are solid spikes. Besides being solid, their
unifying characteristics include being very sharp and usually had fairly simple fabrication
schemes. Using a deep-reactive ion etching method, silicon microneedles were
fabricated. The fabrication steps include depositing a chromium masking layer onto a
silicon wafer, patterning it using photolithography into dots with the size of the desired
needle base. The wafer is etched with an oxygen/fluorine plasma mixture to create the
high aspect ratio silicon microneedles. These needles were used to create micron-scale
holes in the skin through which molecules can be more easily transported. Silicon is
preferred material for fabrication because it has the following characteristics.16, 43
Silicon is abundant, inexpensive, and of high purity and perfection
Silicon processing is highly amenable to miniaturization
Photolithographic patterning allows for rapid evaluation of design ideas
Batch-fabrication results in high volume manufacturing at low unit cost
Silicon is also a biocompatible material (essential for blood testing)
Henry et al. (1998) conducted the first study to determine if silicon microneedles could
be used to increase transdermal drug delivery. The penetration of microneedles through
the upper layer of skin (stratum corneum) created direct pathways for molecules that
would not normally be able to diffuse through skin barrier due to size or water solubility.
In addition, Kaushik et al. (2001) tested the pain level associating with the insertion of
silicon microneedle arrays into human skin in vivo. The study showed that the
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microneedles caused an insignificant amount of pain compared to conventional
hypodermic needle insertion, and no subjects reported any adverse reactions.
4.1.1.3 Metal Microneedles
Metal is considered a better alternative material for microneedles since it has good
mechanical strength, is relatively inexpensive and can be fabricated with ease. Solid,
stainless steel microneedles can be made by a laser-cutting technique. The resulting
needle structures are bent out of the sheet, and electropolished. The needles can be in
either single microneedles or multi-needle array form. Martanto et al (2004) used
stainless steel solid microneedles to deliver insulin to diabetic hairless rats in vivo. Needle
arrays were inserted into the rat skin using a high-velocity injector. A solution of insulin
was placed on top of the microneedle arrays and left in place for 4 h. Over this time
period, blood glucose level steadily decreased by as much as 80% compared to the
control subject.18, 36
4.1.1.4 Polymer microneedles
Polymers have also been used to form arrays of microneedles. In comparison to silicon
counterparts, polymer microneedles offer the mechanical advantage of improved
resistance to shear induced breakage. Unfortunately, this comes at the cost of reduced
sharpness at the tip of the microneedle due to low modulus and yield strength of the
polymers. Chemically, biodegradable polymers allow additional functionality of the
microneedles themselves. Rather than simply piercing the skin to create pathways for
therapeutic molecules, the microneedles themselves become drug depots implanted in the
skin.2, 34
4.1.2 Hollow Microneedles
Skin permeability can be dramatically increased by the holes created from solid
microneedles insertions. However, it is still necessary to have more controlled and
reproducible transport pathways to delivery drugs into the tissue. The fabrication of
hollow microneedles that allow transport through the hollow shaft of the needle was
based on this need. The inclusion of a hollow lumen in a microneedle structure expands
its capabilities dramatically and can offer the following advantages:
The ability to deliver larger molecules and particles;
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Deliver material in a convective transport fashion (for example, pressure-driven
flow) instead of passive diffusion;
Minimize the cross-contamination of the deliverables and its surrounding.
A variety of hollow microneedles has been fabricated and has demonstrated success in
transdermal drug delivery. As expected these benefits come at the cost of increased
complexity.
Figure 4: Hollow Microneedles
4.1.2.1 Silicon hollow microneedles
The most logical technique for the inclusion of a lumen in the silicon spikes presented is
the addition of an etching step to form a fluidic channel using standard photolithography
and isotropic-anisotropic etching combination. The fabrication steps include coating
silicon dioxide on a silicon wafer, patterning the backside of the wafer and etching
through the wafer stopping on the upper oxide layer to define the needle lumen. Silicon
nitride was then deposited, and a larger circular mask was patterned on the front side and
underetched to create the tapering effect of the microneedle. After both silicon dioxide
and silicon nitride layers were removed, symmetrical and asymmetrical needle structures
can be achieved by adjusting the relative position of the isotropic and anisotropic etching
axis. The hollow silicon structures have been created in three-dimensional arrays out of
the substrate plane. 10, 18
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4.1.2.2 Metal hollow microneedles
Hollow metal microneedles can be creating using laser micromachining (Davis 2003).
Microneedles with straight walls (i.e. that is not tapered) are fabricated using molds with
cylindrical holes created either by reactive ion etching (RIE) through silicon wafers or
lithographically defining holes in SU-8 photoresist polymer. A thin coating of metal was
then electrodeposited onto the molds to produce the desired microneedles. Tapered
hollow needle was fabricated either by obtaining a mold from a silicon master or laser
drilling tapered holes into polymer sheets, followed by electrodeposition of a thin metal
coating onto the mold. 18, 21
4.1.2.3 Glass hollow microneedles
Hollow, glass microneedles can be quickly produced with different geometric parameters
for small-laboratory use. These needles are physically capable of insertion into the tissue
without breaking, having a larger drug loading dose and permitting visualization of the
deliverables. Thin glass capillaries were placed within a micropipette puller, and could
have either a blunt or a beveled tip, which allowed ease of needle insertion into the tissue.
Coupling with an insertion apparatus, the insertion depth of the needle into the tissue can
be controlled precisely. 40, 44
McAllister et al. (2003) used single glass microneedles inserted into the skin of diabetic
hairless rats in vivo to deliver insulin during a 30-min infusion period. The needles had a
tip radius of 60 μm and were inserted into the tissue of a depth of 500-800 μm. The
results indicated an up to 70% drop in blood glucose level over a 5-h period after the
insulin was administered. Using single, beveled-tip microneedles, Martanto et al. (2006)
examined the effect of different experimental parameters on microinfusion through
hollow glass microneedles into human skin in vitro. The study reported that partial
retraction of the needle within the tissue increased delivery flow rate 10-fold compared to
that without retraction. Infusion rates could also be increased at a greater insertion depth,
a larger infusion pressure, a beveled-tip instead of a blunt tip and the addition of
hyaluronidase enzyme. 21
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4.1.3 Other types of microneedles
Besides solid and hollow microneedles, various other types of microneedles were
fabricated using different materials such as biodegradable polymers, polysilicon and
sugar with additional functionalities. Because of their biocompatible nature with the
tissue, biodegradable polymer microneedles were developed. These needles were
fabricated by initially making master structures using lithography-based methods,
creating inverse structures from the master molds, and finally producing replicate
microneedles by melting biodegradable polymer formulations (i.e. poly-lactic acid, PLA,
or poly-lactic-co-glycolic acid, PLGA) into the molds. The resulting microneedles can be
loaded with molecules, drugs, DNA or proteins. Unlike solid and hollow microneedles,
polymer microneedles themselves serve as the drug implants after insertion into the
tissue. 30, 37
Microneedles made out of maltose mixed with ascorbate were developed for transdermal
delivery of drugs. The lengths of these needles were ranging from 150 μm to 2 mm. A
clinical experiment was performed to test the biosafety and basic tolerance of these
microneedles. The tests showed the sugar-based microneedles spontaneously dissolved
and released ascorbate into epidermis and dermis of human skin. No dermatological
problems were reported. Aside from being a drug delivery tool, microneedles can also be
used as a biosensor. One major reason for loss of biosensor activity is through the settling
of large molecular weight compounds onto the sensor and affecting senor signal stability.
A microdialysis microneedle is fabricated that is capable of excluding large MW
compounds 19
4.2 Delivery Strategies
A number of delivery strategies have been employed to use the microneedles for
transdermal drug delivery. These include:
4.2.1 Poke and patch approach
This method uses microneedles to make holes and to apply a transdermal patch to the
skin surface.5 Transport can occur via diffusion or possibly iontophoresis if an electric
field is applied.
Chetan N. Chauhan 18 SSPC, Mehsana
Microneedles in Drug Delivery system 2010-11
Insulin delivery using poke and patch approach:
Insulin was delivered to diabetic hairless rat’s in-vivo. Microneedle arrays were inserted
into the skin using a high velocity injector and shown by embed fully within the skin. A
solution of insulin was placed on the top of the microneedle array and left in place for 4
hours. Over this time period blood glucose levels steadily decreased by as much as 80%.
Insulin placed on the skin surface without microneedles did not have any significant
effects. 5, 20
4.2.2 Coat and poke
Another approach is coat and poke where the needles are first coated with the drug and
then inserted into the skin. There is no drug reservoir on the skin surface; the entire drug
to be delivered is on the needle itself.
A variation on this method is the dip and scrape where microneedles are first dipped into
the drug solution and then scrapped across the skin surface to leave behind the drug
within micro abrasions created by microneedles.5
Protein vaccine delivery using coat and poke method
Examination of microneedles to deliver ovalbumin as model protein was done using coat
and poke method. Antigen release from the needle surface was found to occur quickly
where upto 20mg could be released in five sec. 20
4.2.3 Biodegradable microneedles
It involves injecting the drug through the needle with a hollow bore. This approach is
more reminiscent of an injection than a patch.
Chetan N. Chauhan 19 SSPC, Mehsana
Microneedles in Drug Delivery system 2010-11
5. Microfabrication
MEM is an acronym for Microelectromechanical systems. These gained popularity in the
1960’s in the microelectronics industry when sensors were integrated with the electronic
circuits. These are systems that have either mechanical or electric devices typically
containing sub millimeter feature sizes. Slowly, the field of MEMS became distinct
division from microelectronics and commercial products became available.
They are used to make pressure, temperature, chemical and vibration sensors, light
reflectors and switches as well as accelerometers for airbags, vehicle control, pacemakers
and games. The technology is also used to make inkjet print heads, microactuators for
read/write heads and all-optical switches that reflect light beams to the appropriate output
port.13, 35
5.1 General fabrication of microneedles
The various patterns used in depositing layers and doping regions on the substrate are
defined by a process called lithography. 45
Simply put, the lithography process generally consists of the following steps.
A layer of photo resist (PR) material is first spin-coated on the surface of the wafer.
The resist layer is then selectively exposed to radiation such as ultraviolet light,
electrons, or x-rays, with the exposed areas defined by the exposure tool, mask, or
computer data.
After exposure, the PR layer is subjected to development which destroys
unwanted areas of the PR layer, exposing the corresponding areas of the
underlying layer.
Depending on the resist type, the development stage may destroy either the
exposed or unexposed areas. The areas with no resist material left on top of them
are then subjected to additive or subtractive processes, allowing the selective
deposition or removal of material on the substrate.
Photo resist materials consist of three components:
A matrix material (also known as resin), which provides body for the photo resist
The inhibitor (also referred to as sensitizer), which is the photoactive ingredient
The solvent, which keeps the resist liquid until it is applied to the substrate.