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DOI: 10.1002/adma.200701205

Minimally Invasive Protein Delivery with Rapidly Dissolving

Polymer Microneedles**
By Sean P. Sullivan, Niren Murthy,* and Mark R. Prausnitz*

Biomolecules, including proteins, peptides, and vaccines, needles and, after insertion into the skin, the biocompatible
make up a large and potent portion of all new drugs and hold polymer dissolves within minutes to release the encapsulated
great promise for the future of therapeutics.[1,2] Although oral cargo, not requiring removal and leaving behind no biohazar-
delivery of these biotherapeutics would be desirable, there is dous sharps.
low bioavailability of biomolecules administered by this route Previous work has shown that microscopically piercing the
due to enzymatic degradation and poor absorption in the GI skin with micrometer-scale needles offers an effective and
tract, as well as first-pass metabolism of the liver.[3] As a re- convenient alternative for the delivery of biomolecules be-
sult, most biotherapeutics are administered by hypodermic in- cause of the efficient delivery[5,6], lack of pain[7–9], ease of use,
jection, which causes pain, can lead to infection, requires and the expected low cost of fabrication. Microneedles have
trained personnel, and often needs frequent, repeated injec- been shown to be able to deliver proteins, DNA, and vaccines
tions for the patient. Consequently, there exists the need for a in vivo, using devices small enough to be integrated into a
minimally invasive, self-administered delivery system for bio- low-profile, self-administered patch.[9–11]To date, most micro-
molecules. needles have been made of silicon or metal[12,13] with little
An attractive non-invasive option is the transdermal patch, work involving polymers.[14–16] There are, however, safety con-
which has been well-received for the delivery of nicotine, es- cerns if microneedles made of these materials break off in the
trogens, and other drugs.[4] However, delivery across intact skin, or if they are accidentally or intentionally reused. In con-
skin permits transport of small, lipophilic molecules only and trast, the use of biocompatible polymers could eliminate these
excludes transport of biotherapeutics, due to their large size. concerns, because the needles completely and safely dissolve
This study presents a novel, hybrid delivery approach to within the skin, and the needle free patch backing could be
achieve the delivery efficacy of injections and the safety and safely discarded, leaving no biohazardous sharps.
patient compliance of the patch. We designed and synthesized Achieving this goal presents significant material challenges.
rapidly dissolving polymer needles of micrometer dimensions The ideal polymer material would be strong enough to pene-
for the painless, self-administered delivery of biomolecules. In trate the skin, dissolve rapidly once in the skin, and be safely
this design, the drug is encapsulated within polymer micro- excreted by the body. Also, the fabrication process for these
microneedles should take place at ambient temperatures,
without organic solvents, and avoid damaging fragile biomole-
– cules during encapsulation. No current design allows for poly-
[*] Dr. N. Murthy mer microneedles to be fabricated in this manner. Previous
Department of Biomedical Engineering and studies have relied on either high-temperature molding pro-
Petit Institute of Bioengineering and Biosciences cesses that risk damaging biomolecules[15,16] or methods un-
Georgia Institute of Technology
315 Ferst Dr suitable for large-scale fabrication of micrometer struc-
Atlanta, GA 30332 (USA) tures.[14]
E-mail: [Link]@[Link] In this study, we have developed the first rapidly dissolving
Dr. M. R. Prausnitz polymer microneedles. This advance required the develop-
School of Chemical and Biomolecular Engineering
Georgia Institute of Technology ment of a new fabrication process to produce mechanically ro-
311 Ferst Dr bust microneedles that encapsulate biomolecules under gentle
Atlanta, GA 30332 (USA) processing conditions using methods suitable for inexpensive
E-mail: prausnitz@[Link]
mass production. Here, we detail the new fabrication process,
S. P. Sullivan
Department of Biomedical Engineering, Georgia Institute of based on room-temperature in situ polymerization, and study
Technology the mechanical, encapsulation, dissolution, and delivery prop-
315 Ferst Drive erties of the resulting polymer microneedles for the delivery
Atlanta, GA 30332 (USA)
of biomolecules to the skin.
[**] We thank Harvinder Gill, Michael Heffernan, Jung-Hwan Park and
Genggeng Qi for helpful discussions. MRP is the Emerson–Lewis To develop rapidly dissolving polymer microneedles, we
Faculty Fellow. This work was carried out at the Institute for Bioengi- first prepared master structures made of a polymeric photore-
neering and Bioscience and the Center for Drug Design, Develop- sist epoxy (SU-8) by a photolithography method. Then, we
ment and Delivery at Georgia Tech. This work was supported in part
by the Southeast Regional Center of Excellence for Emerging Infec- used these master structures to create reverse molds from
tions and Biodefense and the National Institutes of Health. polydimethylsiloxane (PDMS) (see Experimental Section). It

Adv. Mater. 2008, 20, 933–938 © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 933
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was possible to copy each master structure into hundreds of mechanical strength to the polymer, which is important for
molds and each mold could be reused to produce at least a microneedle insertion into skin. Second, PVP has high water
dozen microneedle arrays. PDMS was chosen as the mold ma- solubility, which facilitates rapid dissolution once inserted into
terial because it is flexible, lacks surface adhesion to the mas- the skin. Third, PVP already has a long history of clinical use
ter structure and allows the removal of the polymer micronee- as a blood plasma expander.[17,18] Finally, the vinyl pyrrolidone
dle array. These microneedle molds were then used to monomer is liquid at ambient conditions, which facilitates
fabricate replica microneedles by a new microfabrication pro- processing at mild temperatures without the need for an or-
cess developed in this study, which involves the room-temper- ganic solvent to fill the microneedle mold.
ature photopolymerization of a liquid monomer within the Using this approach, microneedles were produced to have a
microneedle mold. The gentle nature of this process allows range of micrometer-scale feature sizes, depending on the
the encapsulation of biomolecules within the microneedles, mold geometry. For example, the conical microneedles that
and its universality allows the production of needles from a are shown in Figure 1 measure 750 lm in length, 250 lm in
wide range of polymers and copolymers. We believe that this diameter at the base, and 5 lm in radius at the tip. These mi-
is the first example of an in situ polymerization of micronee- croneedles represent an excellent reproduction of the geome-
dles and represents a novel approach that could be broadly try of the master structure and the micromolds used to pre-
applied to in situ polymerization of other microstructures as pare them (data not shown). As discussed below, this in situ
well. micromolding approach produced similarly faithful reproduc-
We chose to synthesize microneedles by polymerizing tion results when creating microneedles of pyramidal geome-
monomeric vinyl pyrrolidone using ultraviolet light. The re- try, microneedles using a mixture of monomers to produce a
sulting polyvinylpyrrolidone (PVP) microneedles are shown copolymer structural material, and when encapsulating model
in Figure 1a–b. We used PVP as the structural material for mi- drugs within the microneedles.
croneedles for four reasons. First, the chemical backbone For the first generation of microneedles produced by this
structure of the vinyl pyrrolidone monomer contains a ring, new fabrication process, both the microneedles and their base
which increases intramolecular rigidity and thereby provides substrate were made of the same PVP polymer. Therefore,
using this process to encapsulate a
drug within the microneedles would
result in the drug being distributed
throughout the microneedles and
the base. However, any drug encap-
sulated in the base may not be effi-
ciently delivered into the skin be-
cause only the microneedles are
inserted into the skin. Thus, an
adaptation is required to encapsu-
late the drug exclusively within the
microneedles. In this adaptation,
after filling the mold with the mono-
mer and drug mixture, all liquid on
the base of the mold is carefully pi-
petted off, leaving liquid only in the
cavities of the mold, which then
forms the microneedles. Then, a liq-
uid monomer solution with no sus-
pended drug is placed on the mold
to form the base substrate and the
setup is placed under ultraviolet
light where photopolymerization
takes place. This produces micro-
needles with drug exclusively encap-
sulated within the microneedles and
not the base. Figure 1c–d show a
representative PVP microneedle ar-
ray with sulforhodamine encapsu-
Figure 1. PVP polymer microneedles made by a new in situ polymerization process. a) Overhead view lated only within the microneedles,
and b) side view of pure PVP microneedles. c) Overhead view and d) side view of PVP polymer micro- which have the same sharpness as
needles with sulforhodamine encapsulated within microneedles and not within the base substrate.
Each microneedle measures 750 lm in height, 250 lm in base diameter, and 5 lm in tip radius. the PVP microneedles shown in Fig-

934 [Link] © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2008, 20, 933–938
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ure 1a–b. This adaptation is especially important when deliv- As shown in Figure 2b, the mechanical strength (fracture
ering expensive biomolecules and in scenarios where precise force) of the copolymer PVP-MAA containing just 1% MAA
dosing is required. is nearly double the mechanical strength of the homopolymer
PVP microneedles are hypothesized to be sharp and strong PVP and increases as the methacrylic acid content is increased
enough to insert into the skin without breaking. We tested this (ANOVA, p<0.001, p = probability value), such that PVP-
hypothesis by inserting 100-microneedle arrays into porcine MAA microneedles containing 25% MAA exhibit almost a
skin in vitro and then staining the skin after removing the mi- four-fold increase in strength. Still greater MAA content did
croneedles to identify the sites of insertion. Figure 2a shows a not significantly increase the mechanical strength (ANOVA,
representative image of the skin surface after microneedle in- p>0.05). Stronger polymer microneedles could be advanta-
sertion and staining. This image shows that all 100 micronee- geous for drug delivery to tougher tissue sites of the body
dles inserted into the skin. Subsequent microscopic examina- where insertion is more difficult.
tion of the microneedles showed that the needles were not In addition, studies showed that the dissolution rate de-
broken or deformed during the insertion process (data not creases with increasing MAA content, such that PVP-MAA
shown.) microneedles containing 25% MAA dissolve after approxi-
It is important to determine the microneedle dissolution ki- mately 2 h within porcine skin in vitro (data not shown). Poly-
netics in order to know the length of time the microneedles mer microneedles with fast dissolution rates would be attrac-
need to be left in skin prior to removal of the base. The disso- tive for rapid delivery scenarios, such as vaccinations, where
lution kinetics of PVP microneedles were measured by insert- microneedles can be inserted, removed, and discarded with-
ing the needles into porcine skin in vitro and inspecting them out making the patient wait. Polymer microneedles with
after removal, which showed that the entire PVP microneedle slower, controlled dissolution rates could be desirable for situ-
array was dissolved in the skin within one minute (data not ations where controlled release of a drug over time is optimal.
shown). In this scenario, a microneedle patch could be held in place on
Although PVP microneedles are strong enough to insert the skin with an adhesive layer, similar to ones used by con-
into skin and then rapidly dissolve within the skin, it could be ventional transdermal patches. Alternatively, these slower dis-
important to increase microneedle mechanical strength, pro- solving microneedles could be designed in the future to
long dissolution time, or otherwise tune microneedle proper- quickly deposit within the skin by separating the base from
ties for specific needs. To achieve this control over micronee- the microneedles, which then dissolve slowly over time within
dle properties, we fabricated microneedles by copolymerizing the skin.
two liquid monomers, vinyl pyrollidone (VP) and methacrylic Concerning safety, gel permeation chromatography analysis
acid (MAA), to form poly(vinylpyrrolidone-co-methacrylic of PVP microneedle dissolution products determined that the
acid) (PVP-MAA). We chose MAA as the second monomer average molecular mass of PVP is 8970 Da with a polydispers-
because it is nontoxic, is liquid in monomeric form, has been ity of 1.42. Given that PVP with molecular mass less than
used in the past for drug delivery purposes, and has a high me- 20000 Da has been shown to be safe for human use because
chanical strength due to the rigidity of its chemical back- of efficient clearance by the kidney after subcutaneous injec-
bone.[19] In addition, a copolymer of PVP-MAA could have tion,[17] the low measured molecular mass suggests that PVP
additional mechanical strength from hydrogen bonding be- microneedle dissolution products can be safely excreted from
tween the side chains of the VP and MAA monomeric units the body. In addition, microneedles of various designs have
of the polymer.[20] been shown to cause little or no pain and to be well tolerated
by human subjects.[7,9] Microneedles
with geometries similar to those used in
this study have also been shown to
cause minimal pain.[8]
Fracture Force (N/needle)

0.5
As shown in Figure 2a, PVP micro-
0.4
needles are sharp and strong enough to
0.3 insert into the skin. However, this does
not determine the depth of insertion.
0.2
As a result of the elastic nature of the
0.1 skin, even microneedles that are strong
0
and sharp enough to insert will deform
0 20 40 60 80 the skin surface prior to insertion. Be-
b MAA content (%) cause delivery from these polymer mi-
croneedles requires needle dissolution
within the skin to release the encapsu-
Figure 2. Insertion capabilities and mechanical properties of polymer microneedles. a) Evidence of lated cargo, it is important to determine
insertion of PVP polymer microneedles into porcine cadaver skin via skin marking test. b) Plot the depth of insertion. In addition, it
showing the mechanical strength (fracture force) of the copolymer PVP-MAA microneedles increas-
ing with increasing methacrylic acid (MAA) content. could be beneficial to deliver drugs to

Adv. Mater. 2008, 20, 933–938 © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim [Link] 935
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specified depths within the skin, for example, targeting den-

dritic Langerhans cells found in the epidermis for vaccination
purposes.[21] To determine the depth of insertion, polymer mi-
croneedles were inserted into porcine cadaver skin in vitro,
and histological sections were processed from the frozen sam-
ples. Figure 3a shows a cross section of skin after insertion of
a PVP microneedle with encapsulated sulforhodamine. Fig-
ure 3b shows the same tissue sample after needle removal and
staining with hematoxylin and eosin to visualize the layers of
the skin and the hole left by microneedle insertion. The
a b
750-lm-long microneedles inserted almost completely into
the skin, which suggests that the encapsulated drug would be
efficiently delivered.
The ultimate goal of this study was to produce polymer
microneedles that can successfully encapsulate and deliver ac-
tive biomolecules. To assess this objective, red-fluorescent bo-
vine serum albumin was encapsulated within PVP polymer
microneedles and delivered to porcine skin. Figure 3c shows a
histological section prepared 15 min after microneedle inser-
tion. The fluorescent protein has been delivered to both the
dermis and epidermis and it has diffused a short distance away
from the insertion site. This demonstrates the ability of the
new polymer microneedles to deliver a biomolecule to the
skin.
To assess if biomolecules can retain activity after encapsula-
tion within polymer microneedles, we encapsulated another
model protein, b-galactosidase, in PVP microneedles; dis-
solved them in PBS; and measured enzymatic activity of the
resulting solution. The normalized activity of b-galactosidase
after encapsulation and release from polymer microneedles
was 0.99±0.01, (n=5) which was statistically indistinguishable
from i) a solution of b-galactosidase in PBS (1.00±0.00) and ii)
a solution of b-galactosidase in PBS containing dissolved PVP
from empty microneedles (0.99±0.01). This demonstrates that
the in situ polymerization, fabrication, and microneedle disso-
lution processes are gentle enough to retain the activity of an
encapsulated biomolecule. To validate this result further, Fig-
ure 3d shows a histological section of porcine skin after deliv-
ery of b-galactosidase from PVP microneedles and exposure
to X-gal (5-bromo-4-chloro-3-indolyl-beta-D-galacto-pyrano-
side). The enzymatic conversion of the X-gal substrate to a
blue product by b-galactosidase demonstrates that the b-ga-
lactosidase delivered into the skin is enzymatically active. Figure 3. Microneedle insertion and protein delivery into skin. a) Fluores-
These findings suggest that rapidly dissolving polymer mi- cence microscopy image of a PVP polymer microneedle with encapsu-
lated sulforhodamine inserted into porcine skin. b) Bright-field microsco-
croneedles offer an exciting new drug-delivery alternative to
py image of the same skin section after microneedle removal, stained
the hypodermic needle. They combine the painless, self-ad- with hematoxylin and eosin, showing the depth of microneedle insertion.
ministrative abilities of the transdermal patch with the ability c) Fluorescence microscopy image showing delivery of fluorescently la-
to deliver biotherapeutics, which, in most cases, is only possi- beled bovine serum albumin by PVP polymer microneedles to porcine
skin. d) Bright-field microscopy image of delivery of enzymatically active
ble in current clinical practices using hypodermic needles. The
b-galactosidase via PVP polymer microneedles to porcine skin. The blue
polymer microneedles created by the new in situ polymeriza- color represents the enzymatic conversion of X-gal by the delivered b-ga-
tion fabrication process developed in this study dissolve in the lactosidase.
skin within a minute, thereby delivering the encapsulated car-
go and leaving behind no biohazardous sharps associated with
dirty needles. The gentle nature of this new fabrication pro- systems, which could lead to the creation of other molded
cess allows for the encapsulation of fragile biomolecules and drug-delivery devices. In addition, this process allows tuning
its universality allows for the use of many different copolymer of the mechanical strength and dissolution rate of the structur-

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al polymer material depending on the delivery site and the Polymer Microneedles with Encapsulated Sulforhodamine and
time course for the molecule to be delivered. These polymer Other Compounds: A modified process was developed to encapsulate
model drugs within the microneedles, but not within the base sub-
microneedles were shown to successfully insert into the skin strate (Fig. 4b). Sulforhodamine (Molecular Probes, Eugene OR) was
and delivered an encapsulated active protein. This new drug- added at a concentration of 10–4 M to vinyl pyrrolidone monomer con-
delivery platform shows future promise for the delivery of a taining 1.5 wt% AIBN initiator. This mixture was applied to the mold
range of biomolecules, including vaccines, proteins, peptides, and a vacuum was applied to pull the monomer drug mixture into the
microneedle holes. Next, the solution that remained puddled on the
and nucleotides.
surface of the mold was gently removed with a micropipette and re-
turned to the stock solution for re-use. Then, 200 lL of a solution of
the vinyl pyrrolidone monomer and AIBN initiator was applied to the
Experimental PDMS microneedle mold to make up the base substrate. Finally, the
system was placed under the UV lamp where photopolymerization
occurred, resulting in a polymer microneedle array with needles made
Polymer Microneedle Fabrication: As described previously [16], mi-
of PVP and encapsulated sulforhodamine and a base substrate made
croneedle master structures were created using a lens-based technique
only of PVP. The same fabrication process was used to preferentially
to produce microneedles made of SU-8 epoxy photoresist (Fig. 4a).
encapsulate fluorescently labeled bovine serum albumin (Molecular
Arrays of 225 (15×15) conical microneedles were made with 250 lm
Probes) and the enzyme b-galactosidase (Sigma–Aldrich) in the mi-
base diameter, 5 lm tip radius, and 750 lm height. Additionally, mas-
croneedles.
ter-structure arrays of 100 (10×10) pyramidal microneedles were fab-
Fracture Force Test: The mechanical strength of the copolymer
ricated to have a 300 lm base width, 5 lm tip radius, and 650 lm
PVP-MAA microneedles was tested for the following molar mono-
height. Next, microneedle molds were made from polydimethylsilox-
meric ratios (VP/MAA): 100/0, 99/1, 90/10, 75/25, 50/50, 25/75. In this
ane (10 mm thick, Dow Corning 182 Sylgard, Midland MI) to exactly
experiment, the failure force under axial load was measured using a
inverse-replicate the master structures. This was done by pouring
displacement force test station (Model 921A, Tricor Systems, Elgin,
PDMS over the microneedle master structure and allowing the poly-
IL) following established protocols [16,22]. Force versus displacement
mer to cure overnight.
curves were generated by pressing the array of microneedles
Polymer microneedles were created using the following new photo-
(20–25 needles per array) against a hard metal surface at a rate of
polymerization process. A mixture of the liquid monomer, vinyl pyr-
0.5 mm s–1. The average microneedle fracture force was calculated by
rolidone (200 lL, Sigma–Aldrich, St Louis MO), and free-radical ini-
dividing the maximum fracture force by the number of needles.
tiator, AIBN (azobisisobutyronitile 1.5 wt%, Sigma–Aldrich), was
Imaging Microneedle Insertion: To identify sites of microneedle in-
applied to the PDMS mold, covering the entire array. The system was
sertion, a PVP microneedle array was inserted into pig skin in vitro
placed inside a vacuum oven (VWR, Cornelius OR) under a 30 mm
with approval from the Georgia Tech IACUC. Institutional Animal
Hg (1 mm Hg = 133.32 Pa) vacuum for 2 min at room temperature
care and Use Commitee. The array was removed and a hydrophobic
(22–23 °C) to fill the liquid mixture into the microneedle mold. Next,
dye (0.4% Trypan blue solution, Sigma–Aldrich) was placed on the
the system was placed under a UV lamp (100 W, 300 nm, BLAK
skin for 5 min to stain the sites of microneedle penetration. The skin
RAY, Upland CA) for 30 min at room temperature to induce photo-
was then washed thoroughly under water to remove excess dye from
polymerization. Finally, the polymer microneedle array was gently
the surface. Finally, the skin was imaged by stereomicroscopy (Olym-
peeled out of the mold. Microneedles made of the copolymer poly(vi-
pus SZX9, Japan) to identify the microneedle insertion locations.
nylpyrrolidone-methacrylic acid) were created in a similar manner
To determine depth of microneedle insertion, a polymer micronee-
with a mixture of the liquid monomers, vinyl pyrrolidone and
dle array was applied to pig skin in vitro. Next, the microneedles em-
methacrylic acid, used.
bedded in the skin were flash-frozen in situ in liquid nitrogen. The
sample was cut into 10-lm sections using a microcryostat (MICROM
HM560, Waldorf Germany) and these sections were stained using he-
matoxylin and eosin. Finally, the histological sections were examined
by stereomicroscopy to determine the depth of insertion.
(1) Delivery of Fluorescent Labeled Protein: Polymer microneedles
(7) were made of PVP with 0.2 wt% Texas Red bovine serum albumin
preferentially encapsulated within the microneedles. The base of the
(5A)
(2)
microneedle array was made of PVP. The microneedle array was in-
serted into pig skin and left for 1 min. The array was then removed and
inspected by bright-field and fluorescence microscopy to confirm that
(3) the microneedles had completely dissolved within the skin and only
(6)
(4) (5B) the base remained. After 15 min, the skin was flash-frozen using liquid
nitrogen and cut using the microcryostat into sections of 10 lm. The
sections were examined by fluorescence microscopy (Nikon E600W,
Japan) to image the extent and distribution of protein delivery.
a b Enzyme Encapsulation and Activity Assay: The activity of b-galac-
tosidase was measured after encapsulation within polymer micronee-
dles to determine if the fabrication and dissolution processes damage
Figure 4. New in situ fabrication process for polymer microneedles.
the enzyme. A “dose” of 1.0 mg of b-galactosidase was encapsulated
a) PDMS is poured onto the microneedle master structure (1); the PDMS
within an array of PVP microneedles. The microneedles were then
microneedle mold is cured and peeled off (2); the liquid monomer and
dissolved in cold (4 °C) PBS, and the activity of the released enzyme
drug are pipetted onto the mold (3); a vacuum is applied to pull the solu-
was measured, using the manufacturer’s protocol [23]. This involves
tion into the microneedle mold (4); and the system is placed under a UV
creating an enzymatic reaction with nitrophenol and monitoring the
lamp to polymerize the microneedles, which are subsequently peeled out
product by absorbance at 410 nm. Positive controls were tested, con-
of the reusable mold (5A). b) Excess solution is removed from the sur-
taining b-galactosidase in cold PBS, and b-galactosidase in PBS con-
face (5B); a liquid monomer solution with no drug is applied to the sur-
taining previously dissolved, placebo PVP microneedles.
face (6); and the system is placed under a UV lamp to polymerize the mi-
Delivery of enzymatically active b-galactosidase was also studied in
croneedles, which are then peeled off (7).
pig skin in vitro. In this case, an array of PVP microneedles containing

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