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UV-CURABLE PRESSURE SENSITIVE ADHESIVE
TRANSDERMAL DRUG DELIVERY PATCH BASED ON
PVP-PEGDA-PEG COPOLYMERIZATION
SARA FARAJI DANA
NATIONAL UNIVERSITY OF SINGAPORE
2013
UV-curable Pressure Sensitive Adhesive Transdermal Drug
Delivery Patch Based on PVP-PEGDA-PEG Copolymerization
Sara Faraji Dana
(M.Sc. of Chemistry, Mount Allison University, Canada)
(B.Sc. of Chemistry, Sharif University of Technology, Iran)
A Thesis Submitted
For The Degree of Master of Science
Department of Pharmacy
National University of Singapore
2013
i
Declaration
I hereby declare that the thesis is my original work and it has been written by me in its
entirety. I have duly acknowledged all the sources of information which have been used in
the thesis.
This thesis has also not been submitted for any degree in any university previously.
_________________
Sara Faraji Dana
14 March 2013
ii
Acknowledgements
I would not be able to fare well through this stage of my scientific journey without the
help of many people. I owe my gratitude to all who has contributed to this work one way or
another.
First and foremost, I must acknowledge my supervisor, Dr. Kang Lifeng, at Pharmacy
Department of NUS, whose support has been wonderful. Dr. Kang is a pleasure to work with;
he provides a good balance of direction and freedom to explore the possible avenues of
research one may wish. He clearly holds the best interests of his students at heart. Thanks to
his encouragement, positive attitude and guidance for my project which otherwise would not
have been accomplished.
I would like to express my gratitude and appreciation to Prof. Liu Xiang Yang for his
trust and permission, working with the delicate instruments in his biophysical lab at
Department of Physic. I would like to thank his group members, Nguyen Duc Viet, Nguyen
Anh Tuan, Toh Guoyang (William) and Xu Gangqin for their help teaching me how to use the
instruments.
I would like to extend my sincere thanks to professors and lecturers in Department of
Pharmacy who offered a peaceful and comfortable environment for studies and provided the
required facilities for a good research.
It is an honour for me to thank all my lab mates, Jaspreet Singh Kochhar, Pan Jing, Li
Hairui, and together with all other friends for their invaluable helps and creating such a
pleasant working atmosphere for me in the lab. I would like to take this opportunity to
express my gratitude to Chan Wei Ling (Kelly), Lye Pey Pey, NG Sek Eng, and Sukaman Bin
iii
Seymo for their fervent support.
I would also like to thank the SBIC-Nikon Imaging Centre at Biopolis for providing
the imaging facilities and special thanks to Ms Joleen Lim for the assistance provided in
demonstration the proper usage of Confocal Laser Scanning Microscope. I am also thankful
to Ms. Audrey Tay and Dr. Teo Wei Boon from PerkinElmer, Singapore for their help in
analysing ATR-FTIR samples.
At last, but not least, I thank the most important people of my life, those to whose
unconditional love I am indebted, my family. My deepest gratitude goes to my beloved
parents, Maman Maryam and Ahmad Baba, for their influential role in my life and their
sincere devoting of their lives to my progress, to Amir, my only brother for simply his
presence in my life and to Maziar, the love of my life, who did whatever he could to help me
concentrate on this work and for being a constant source of motivation and encouragement.
I humbly bow to my treasured mom and dad and dedicate this thesis to them as a little
sign of sincere appreciation and love for all their sacrifices.
iv
Table of Contents
Declaration................................................................................................................................. i
Acknowledgements .................................................................................................................. ii
Table of Contents .................................................................................................................... iv
Summary .................................................................................................................................. vi
List of Publications ................................................................................................................ vii
List of Tables ........................................................................................................................ viii
List of Figures .......................................................................................................................... ix
List of Abbreviations .............................................................................................................. xi
1 Introduction ...................................................................................................................... 1
2 Materials and Methods .................................................................................................. 10
2.1 Materials .................................................................................................................... 10
2.2 Fabrication of Pressure Sensitive Adhesive Films .................................................... 10
2.3 Preparation of Pig Skin Samples for Peel Tests ........................................................ 17
2.4 Hydrogels Characterization ....................................................................................... 17
2.4.1 Morphologies of PEGDA-Based Hydrogels ...................................................... 17
2.4.2 Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR)
Spectroscopy ..................................................................................................................... 18
2.4.3 Measurement of Film Thickness ........................................................................ 19
2.4.4 Drug Distribution ............................................................................................... 20
2.4.5 Measurements of Rheological Properties .......................................................... 20
2.4.6 Measurement of Mechanical Properties............................................................. 22
3 Results and Discussion ................................................................................................... 24
3.1 Microfabricated PSA hydrogels ................................................................................ 24
3.2 Morphological Characterization by SEM ................................................................. 28
3.3 Spectral Characterization of PSA Hydrogels ............................................................ 29
3.4 Control of thickness and Drug Distribution .............................................................. 32
v
3.5 Rheological Properties .............................................................................................. 35
3.5.1 Dynamic Strain Sweep Test. .............................................................................. 35
3.5.2 Dynamic Frequency Sweep Test. ...................................................................... 37
3.6 Viscoelastic Windows ............................................................................................... 40
3.7 Mechanical Properties ............................................................................................... 42
3.7.1 Tensile Testing. .................................................................................................. 43
3.7.2 Peel Testing. ....................................................................................................... 46
4 Conclusions ..................................................................................................................... 50
Future Work ........................................................................................................................... 51
Reference ................................................................................................................................ 54
Appendices and Supporting Information ............................................................................ 58
Appendix I ............................................................................................................................ 58
Appendix II .......................................................................................................................... 60
vi
Summary
We developed a new approach to fabricate pressure sensitive adhesive (PSA)
hydrogels for dermatological applications. These hydrogels were fabricated by using
polyvinylpyrrolidone (PVP), poly (ethylene glycol) diacrylate (PEGDA) and polyethylene
glycol (PEG) with/without propylene glycol (PG) via photo-polymerization. Hydrogel films
with the thickness of 130 to 1190 µm were obtained. The surface morphology and drug
distribution within the films were found to be uniform. The influence of different factors
(polymeric composition, i.e. PEG/PG presence, and thickness) on the functional properties
(i.e. rheological and mechanical properties, adhesion performance and drug distribution) of
the films was investigated. The viscoelastic, mechanical and adhesion (against glass and skin
substrates) behaviours of hydrogels were studied by rheological, tensile and adhesion strength
tests. Measurements were carried out on a porcine cadaver skin and glass surfaces as control,
to investigate the potential dermatological applications of these hydrogel adhesives. The
addition of plasticizers, namely PEG and PG, resulted in a simultaneous increase in elasticity
and tack of these hydrogels, due to formation of hydrogen bondings, which has a direct
correlation with their adhesive properties. The microfabricated hydrogel adhesives, modified
with PG, are potentially useful for industrial applications, due to the simple procedure,
precise control over film thickness, minimal usage of solvents and controllable mechanical,
rheological and adhesive properties.
vii
List of Publications
Sara Faraji Dana, Viet Nguyen Duc, Xiang-Yang Liu and Lifeng Kang, UV-curable
Pressure Sensitive Adhesives: Effects of Biocompatible Plasticizers on Mechanical and
Adhesion Properties, Soft Matter (Submitted, 2012)
Hairui Li, Yuan Yu, Sara Faraji Dana, Bo Li, Chi-Ying Li and Lifeng Kang, Novel
engineered systems for oral, mucosal and transdermal drug delivery, Journal of Drug
Targeting (Invited review, 2012)
viii
List of Tables
Table 1. PEGDA 258 weight percentage (%w) ratio in the precursor solution ....................... 14
Table 2. PEGMA weight percentage (%w) ratio in the precursor solution ............................. 14
Table 3. PEGDA 575 weight percentage (%w) ratio in the precursor solution ....................... 15
Table 4. Ratios of PVP:PEGDA:PEG:PG monomers (%w/w) in the precursor
solution ..................................................................................................................................... 16
ix
List of Figures
Figure 1. The schematic representation of PSA film fabrication ............................................. 11
Figure 2. Chemical structure of PEGMA macromer; Proposed crosslinking
mechanism for the reaction of UV curable PEGMA and PVP (dashed lines represent
hydrogen bonding between PEGMA and PVP monomers) ..................................................... 13
Figure 3. Chemical structure of monomers and the initiator used for preparing PSA
films ......................................................................................................................................... 25
Figure 4. Proposed crosslinking mechanism for the reaction of UV curable
monomers and formation of IPN; PEGDA macromers form a crosslinked network
by covalent bonding (responsible for mechanical strength) and PEGDA/PVP are
bonded to PEG/or PG via hydrogen bonding (responsible for adhesive properties) ............... 27
Figure 5. Scanning electron micrographs of (a) PVP-PEGDA, (b) PVP-PEGDA-
PEG, (c) PG incorporated PVP-PEGDA-PEG copolymer PSA films and (d)
Comparison of average number of separated phases per square micrometer in each
film ........................................................................................................................................... 28
Figure 6. ATR-FTIR spectra of macro-monomers, PEGDA and fabricated PVP-
PEGDA, PVP-PEGDA-PEG and PVP-PEGDA-PEG-PG copolymer PSA films
(solid arrow attributed to the hydroxyl stretching vibration bond, dash arrow is
attributed to the carbonyl stretching bond of PEGDA and dash circle is attributed to
the carbonyl stretching bond of PVP) ...................................................................................... 30
Figure 7. (a) Control of thickness in each film (number of spacers varied from 3, 5
and 7), (b) Reproducibility of films with different thickness (S1-S4 refer to four
samples of each thickness, each sample’s thickness was measured four times. P <
0.001, the error bar shows SD) ................................................................................................ 32
Figure 8. Quantification of distribution uniformity of Rhd B in PSA films with
different thickness using confocal microscopy: (a) Cross sectional view, (b) 3D
view and (c) Fluorescence intensity measurement in different parts of each film with
different thickness (number of spacers varied from 3, 5 and 7). P < 0.001, the error
bar shows SD ........................................................................................................................... 34
Figure 9. Log-log plot of shear moduli (G′, G′′, G*) vs. strain for (a) PVP-PEGDA-
PEG and (b) PG incorporated PVP-PEGDA-PEG copolymer PSA films with the
thickness of 910-1190 µm, fabricated with 7 spacers (frequency = 1 Hz, temperature
= 23°C) ..................................................................................................................................... 36
Figure 10. Log-log plot of average shear moduli (G′ and G′′) vs. frequency for (a)
PVP-PEGDA-PEG and (b) PG incorporated PVP-PEGDA-PEG copolymer PSA
x
films with the thickness of 910-1190 µm, fabricated with 7 spacers (strain =
0.065%, temperature = 23°C) .................................................................................................. 38
Figure 11. Viscoelastic windows of PVP-PEGDA-PEG and PG incorporated PVP-
PEGDA-PEG copolymer PSA films with the thickness of 910-1190 µm, fabricated
with 7 spacers (white and black circles, respectively, refer to films without and with
PG incorporation)..................................................................................................................... 41
Figure 12. Stress-strain curve for (a) PVP-PEGDA-PEG and (b) PG incorporated
PVP-PEGDA-PEG copolymer PSA films (number of spacers varied from 3 to 7) ................ 45
Figure 13. Average peel test run of (a) PVP-PEGDA-PEG and (b) PG incorporated
PVP-PEGDA-PEG PSA films with the thickness of 910-1190 µm, from a rigid
substrate, i.e. glass, and a flexible substrate, i.e. cadaver pig skin, at a speed of 50
mm/min, and nominal peel angel of 180 degree. (C) Comparison of averaged 180
degree peel force for two different compositions from two different substrates ..................... 47
Figure 14. A horizontal diffusion cell assembly ...................................................................... 52
Figure 15. Fluorescence intensity of each film as measured by CLSM at different
depth intervals (2 µm), in three different parts of each film (two corners and one
center), a) L1 and L3 refer to number of spacers used for the fabrication (1 for films
with a thicknesses of 130-170 µm and 3 for films with a thickness of 390-510 µm,
respectively), b) L5 and L7 refer to number of spacers used for the fabrication (5 for
films with a thicknesses of 650-850 µm and 7 for films with a thickness of 910-
1190 µm, respectively) ............................................................................................................ 61
xi
List of Abbreviations
µm Micro meter
3D Three-dimensional
ATR-FTIR Attenuated total reflection Fourier transform infrared
AU Arbitrary unit
AVA Agri-food and veterinary authority
CLSM Confocal laser scanning microscope
EB Elongation at break
EtOH Ethanol
G" Viscous modulus
G* Complex modulus
G′ Elastic modulus
HHEMP 2-hydroxy-4'-(2-hydroxy-ethoxy)-2-methyl-propiophenone
HMPSA Hot-melt pressure sensitive adhesive
hr Hour
IACUC Institutional animal care and use committee
IPN Interpenetrating polymer network
LVER Linear viscoelastic region
mg Milligram
min Minute
ml Millilitre
Mn Number-average molecular weight
xii
PBS Phosphate buffered saline
PEG Polyethylene glycol
PEGDA Poly(ethylene glycol) diacrylate
PEGMA Poly(ethylene glycol) methacrylate
PG Propylene glycol
PSA Pressure sensitive adhesive
PVP Polyvinylpyrrolidone
Rhd B Rhodamine B
SD Standard deviation
SEM Scanning electron microscopy
TDDS Transdermal drug delivery system
TS Tensile strength
UV Ultraviolet light
VWs Viscoelastic windows
w/v Weight/volume
w/w Weight/weight
γ Shear strain
γ₀ Critical strain
1
1 Introduction
Pressure sensitive adhesives (PSAs) are a special class of tacky viscoelastic polymers
that adhere to substrates of various chemical nature under application of slight external
pressures over a short period of time (1-2 seconds).1, 2
To be qualified as a PSA, the polymer
needs a balance of elasticity and viscosity.3 It should possess both relative viscous flow under
applied bonding pressure to form a proper adhesive contact, and elastic cohesive strength,
which are necessary for resistance to debonding stresses.4
Generally, for the tight interaction of adhesive with the surface of a substrate, it
should be able to viscously flow into the surface cavities of the substrate.5 When the adhesive
makes a close contact with the surface of substrate because of its viscoelastic properties then
it will be able to make a greater amount of molecular interactions such as Van der Waals with
the substrate e.g. skin. Following the initial adhesion, the adhesive-substrate bonds can be
additionally enhanced by spatially tighter molecular interactions (i.e. hydrogen bonding,
hydrophobic interactions etc.).5, 6
Most of the biomedical substrates are comprised of complex arrays of biomolecules
with colocalized display of various interaction chemistries. Therefore, development of
polymeric systems capable of simultaneously forming multiple types of interactions with
substrates will extend the current scope of pharmaceutical applications of PSAs.
PSAs have found ever-expanding potential in biomedical applications during the
recent years. They have been proposed to be utilized in transdermal7 and transmucosal
8
therapeutic systems for programmed drug delivery9, tissue-adhesive wound healing
2
dressings10-14
, wound closures15
, surgical drapes4, transdermal patches
7, 16-19, moisture-
insensitive orthodontic primers20
and scaffolds for tissue engineering.4, 21
Tailoring PSAs for
various pharmaceutical applications however requires in depth understanding of physiology,
chemistry and physics of the substrates as well as precise engineering of the PSA film.
There are three main factors that determine the characteristics of a substrate for
adhesion. The first parameter is the chemical composition and structure of the substrate
surface that contributes to the thermodynamics of the adhesion. Second, mechanical
properties of substrate’s contact volume govern the dynamics of adhesion process while as a
third factor, surface morphology of the substrate controls the effective contact area. Although
all these three factors contribute to the work of adhesion, however, when comparing PSAs for
wet and dry surfaces, it’s the chemical composition of the substrate that plays the main role.22
Biological surfaces greatly vary in their hydration levels. The main difference
between skin and mucous membranes is that the latter is non-keratinized and is highly moist
because continuously produces mucus to prevent itself from becoming dry. This makes the
mucous membrane to behave as a rather hydrophilic substrate for adhesives. Whereas,
stratum corneum, the outer layer of the skin, is hydrophobic in nature to effectively act as a
barrier to transepidermal water loss. Although there are considerable levels of morphological
and mechanical differences between the skin and mucous membranes, the main factor to be
considered for the development of specific adhesives for each type of these substrates is their
surface chemical composition i.e. water content.23
As for skin applications, the performance prerequisites of medical PSAs are
challenging because they must be able to exhibit appropriate gel strength and sufficient
adhesiveness against varying skin types24
and at the same time they should be easily
3
removable from the skin surface without causing excessive irritation and leaving no residues
behind.
Most of the conventionally developed PSAs intended for adhesion to the skin are
basically hydrophobic in nature. These PSAs are based on natural and/or synthetic
hydrophobic monomers like polyisobutylenes, silicones and natural or synthetic rubbers. The
main disadvantage of PSAs solely made of hydrophobic components is that they lose their
tackiness upon presence of moisture on the substrate. This is a major problem for the
application of these PSAs on skin because the moisture accumulated due to sweating or other
dermal secretions in the adhesive-skin interface will cause loss of adhesion.25
To approach this problem, researchers have developed a class of adhesive polymers
named bioadhesives that are defined as adhesives capable of adhering to highly hydrated
biological surfaces such as mucosal tissues. To be considered bioadhesive, a PSA must
plasticize in the presence of water and remain adhered to the hydrated surface. This requires
the bioadhesive film to be made of hydrophilic elastomers.26
As a more specific class of
bioadhesives, those materials of this type that are designed to directly interact with mucosal
surface are referred as mucoadhesives. Since mucous membranes cover a significant portion
of the body’s available surface, mucosal path is a major direction for the development of
novel drug delivery systems.27
Similar to adhesion, an initial step in the process of bioadhesion is formation of a
series of interactions between surfaced molecular moieties of bioadhesive and the biological
substrate. Subsequently, polymeric chains of the bioadhesive interpenetrate into the bio-
substrate. It has been shown that by incorporation of specific ligands into the bioadhesives,
they can be guided to directly bind to the receptors on the cell surface rather than mucous gel
4
membrane.28
This enables targeted delivery of active pharmaceutical agents into the cells
since binding to cell surface receptors often results in endocytosis and internalization.
From another point of view, bio/mucoadhesion can be considered as a pressure-
sensitive character of adhesives toward hydrated biological substrates which provides several
advantages in using them in drug delivery systems. These advantages include but are not
limited to the followings:
1) Longer residence time of the formulation at the delivery site due to close contact
and adhesion. This will result in higher bioavailability at lower concentrations of
drug.
2) Possibility of targeted drug delivery to particular tissues or parts in the body by
incorporation of target-specific ligands in the bioadhesive
3) Controlled release of the active pharmaceutical agent which in combination with
extended residence time may result in lower administration frequency.
4) Possibility of avoiding the first-pass metabolism
5) Reduction in cost and dose-related side effects due to efficiency and localization
of the drug delivery29
A bioadhesive PSAs must be able to absorb a considerable amount of moisture to
avoid adhesion loss due to the accumulation of interfacial water. Being highly hydratable is
the characteristic property of hydrogels. Therefore, hydrogels are the candidates for the
synthesis of bioadhesive PSAs if they can be modified to show an appropriate degree of
viscoelasticity. Hydrogel polymers have been used to produce medical PSAs.4 The major
chemical systems used for medical PSAs are acrylate based hydrogels, due to their suitable
adhesive properties and low levels of skin irritation. Other polymer types, used as PSAs,
5
include silicone-based adhesives, polyvinyl ether-based adhesives and polyvinylpyrrolidone-
based adhesives.4, 30
In general, conventional hydrogels used as adhesives for medical applications are
developed by chemical or physical crosslinking. In these fabrication technologies, hydrogels
are either going through chemical reactions within an aggressive reaction environment (such
as pH fluctuations, i.e. acidic or basic solutions and high temperatures) or physical
interactions among the monomers, which both usually are accompanied with high amount of
solvents and chemical usage and normally are time-consuming. Although present
conventional crosslinking methods are well accepted for this purpose, there is plenty of room
for improvement.31
Solvent-free pressure sensitive adhesives, i.e., hot-melt PSAs (HMPSAs) and
radiation curable PSAs, are relatively new group of self-adhesive medical products and
increasing in importance due to environmental pressure on solvent-borne PSAs and the
performance shortcomings of aqueous systems.4, 30
At room temperature, HMPSAs are solid
materials but once heat is employed, they melt to a liquid state. The adhesive recovers its
solid form once cooled, and gains its cohesive strength. Therefore HMPSAs diverge from
other types of adhesives attaining the solid state through evaporation or removal of carrier
liquids (organic solvents or water) or by polymerization (ultraviolet (UV) radiation). The
HMPSA is made by plastification of thermoplastic elastomers through heat and homogeneous
incorporation of molten tackifying resins, oils and antioxidants into the polymer matrix to
achieve coating on the web at high temperatures. HMPSAs usually exhibit good adhesion to
substrates, and are less expensive than most solvent-based adhesives.5 However, they also
possess some drawbacks which generally include processing and safety challenges such as
6
the need for specially designed equipment, an elevated application temperature with higher
processing costs, and process sensitivity, as well as difficulty performing under high
temperatures, relatively poor oxidation stability and requirement of high peel force for
removal from the skin.4, 5
Similar to HMPSAs, radiation curable PSAs have also grown lately with
environmental factors demanding reduced solvent emissions and energy requirements. These
environmentally friendly adhesives are reactive compounds that contain almost no solvents
(or negligible amount) or other volatile substances. In addition, photo-polymerization enables
rapid conversion of monomer or macromer precursor solutions into a gel or solid under
physiological conditions potentially useful for medical applications.32
Photo-polymerization
is simply initiated by irradiation with light, such as UV light. The advantage of the photo-
polymerization method, unlike the conventional methods, is that there are no side products
such as wastes, fumes. Moreover, the UV irradiation technology is comparatively
inexpensive and does not need extra laboratory setup. Even though there are many
advantages in photo-polymerization, some drawbacks are still present, i.e. degradation upon
exposure to irradiation.10
By optimization of the polymerization conditions, such as
decreasing the irradiation time, it is possible to address the existing challenges.
Various functional hydrogels for use in transdermal drug delivery systems (TDDS)
and scaffolding of tissues have been prepared with monomers or macromers (Fig. 3), such as
poly(ethylene glycol) diacrylate (PEGDA)21, 33
, polyvinylpyrrolidone (PVP)34-36
,
polyethylene glycol (PEG).21, 35
In medical applications, the PSA hydrogels are usually in direct contact with skin,
thus the biocompatibility and non-toxicity are two main factors to consider.12, 21
PVP
7
monomer is a well-known bioadhesive polymer with proper biocompatibility and capacity of
H-bond formation; hence, this polymer can be used as one of the main components of pseudo
hydrogel preparation for temporary skin covers, wound dressings or TDD patches.
To improve PVP hydrogels mechanical properties, plasticizers and crosslinking
agents can be added.10, 37
PEG34, 38
and propylene glycol (PG) (Fig. 3)34, 39
, as hydrophilic
plasticizers, have been used to prepare hydrogels because of their hydrophilicty and
biocompatibility. Plasticizers are known to cause a reduction in polymer-polymer chain
secondary bonding, forming secondary bonds with the polymer chains instead.38
Many of the
polymers used in pharmaceutical formulations are brittle and require the addition of a
plasticizer into the formulation. Plasticizers are added to pharmaceutical polymers intending
to improve film forming and the appearance of the film, preventing film from cracking,
obtaining desirable mechanical properties, i.e. increase of elongation at break (EB),
adhesiveness, toughness, film flexibility and processability and on the other hand, decrease of
tensile stress (TS) and hardness.40
Upon addition of plasticizer, enhancement in the
flexibilities of polymers is the result of loosening of tightness of intermolecular forces. The
plasticizers with lower molecular weight can penetrate more easily into the polymeric chains
of the film forming agent, therefore can interact with the specific functional groups of the
polymer.38
PG and PEG are frequently employed in TDDS to plasticize the polymeric films.34
Feldstein et al. reported fabrication of PVP-PEG PSA hydrogels via solvent casting
technique. In this technique the high molecular weight PVP and low molecular weight PEG
monomers are crosslinked physically, via hydrogen bonding. Neither PVP nor PEG is
individually adhesive, but the yielded hydrogels were quite adhesive which was due to
hydrogen bonding among the monomers. The current technique was reported to be time-
8
consuming and the hydrogels possess poor mechanical properties (lack of elasticity).41
Crosslinking agents, i.e. PEGDA42
, are also added for the improvement of the
mechanical properties. As the previous works reported N-vinylpyrrolidone and PEGDA can
be radically copolymerized in the presence of a redox system by chemical crosslinking which
is the formation of covalent bondings.43
The yielded PVP-PEGDA product did not possess
almost any adhesiveness, and also the film itself was very brittle due to absence of hydrogen
bonding and presence of just covalent bonding (lack of viscosity).
Relatively hydrophilic and water soluble PEGDA macromers which possess
polymerisable C=C bonds at their chain ends, are easily photo-crosslinked by themselves,
forming a solid network through radical polymerization. The chemical crosslinkings between
PEGDA macromers lead to the formation of covalent bondings and subsequently creating
three-dimensional (3D) acrylate polymeric networks. This polymeric network can be used as
a matrix for drug delivery, and as a matrix for encapsulation of biological material. The
yielded PEGDA hydrogels were brittle and had no adhesiveness due to lack of viscosity
(presence of hydrogen bonding). 21, 44
The main drawbacks of these aforementioned hydrogels, PVP-PEGDA, PEGDA and
PVP-PEG, were their poor mechanical properties (i.e. PVP-PEG) and lack of adhesiveness
(i.e. PVP-PEGDA and PEGDA hydrogels). In this study, we fabricated PSA hydrogel films
which benefit from both hydrogen bondings, to gain proper adhesive properties, and covalent
bondings, to achieve chemical crosslinking for the enhancement of mechanical strengths.
Photo-polymerization technique was utilized to minimize the usage of chemical solvents and
fast curing. We synthesized a photo-crosslinked PVP-PEGDA-PEG and also PVP-PEGDA-
PEG-PG hydrogels with the photo-polymerization technique. For radical polymerization to
9
start, 2-hydroxy-4′-(2-hydroxy-ethoxy)-2-methyl-propiophenone (HHEMP) served as the
initiator, which produces radicals upon UV irradiation. Since the crosslinking of polymers
(PEGDA in this case) occurs due to covalent binding, the resulting hydrogels are
mechanically strong. Electrostatic interaction between PEGDA/PVP macro-monomers and
PEG/PG happens because of hydrogen bonding and hydrophobic interactions without
interfering with the UV-mediated photo-polymerization of acrylate groups of PEGDA,
resulting in proper adhesive properties (Fig. 4).
To fabricate PSA films with different thickness, different casting systems were
designed for different kinds of PSAs.5 A uniform thickness of the water-based and solvent-
based PSAs films can be produced by using either of the following techniques; the film-
casting knife35, 38, 41
, solution casting method9, 10
, reverse roller coater45
, and automated thin
layer chromatography plate scraper.46
In addition, it was reported that evenly casted HMPSAs
with different thicknesses were produced using slot orifice coater.45
In our study, the control
over thickness was simple and efficient. Different thicknesses in the range of 100 µm to 1
mm were governed by increasing of number of stacked coverslips in the fabrication process.
It was demonstrated in this study that the microfabricated hydrogel PSAs are potentially
useful for dermatological applications.
10
2 Materials and Methods
2.1 Materials
Poly(ethylene glycol) diacrylate (PEGDA, Mn 575), 2-hydroxy-4′-(2-hydroxy-
ethoxy)-2-methyl-propiophenone 98% (HHEMP) and polyvinylpyrrolidone (PVP, Mn
360,000) were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Polyethylene
glycol (PEG, Mn 200), and rhodamine B (Rhd B) were purchased from Alfa Aesar Co.
(Heysham, Lancashire, UK). Ethanol 95% denatured with 5% Methanol (EtOH) and
propylene glycol (PG) were purchased from Shell Eastern Chemicals Co. (Singapore) and
Aik Moh Paint & Chemicals Inc. (Singapore), respectively. All chemicals used were reagent
grade and were utilized as supplied without further purification. Ultrapure, deionised water
(Millipore Direct-Q, Molsheim, France) was used in this study. The cadaver porcine skin was
obtained from a local abattoir in Singapore.
2.2 Fabrication of Pressure Sensitive Adhesive Films
Before PSA fabrication, the glass coverslips and glass slides were immersed in 95%
Ethanol solution for 2 hrs for cleaning the surface from contaminations and dried for 30
minutes at 37°C.
To fabricate PSAs, fabrication cast was prepared by using two coverslips (Technische
Glaswerke Ilmenau GmbH, Germany, 130-170 µm thickness, 22×22 mm) supported on either
edges of the same side of a glass slide as “spacers” (Continental Lab Product Inc., San Diego,
CA, USA, 1-1.2 µm thickness, 25.4×76.2 mm) and placing another coverslip on the top to
create a cavity in the centre, as shown in Fig. 1.
11
Figure 1. The schematic representation of PSA film fabrication
UV crosslinkable PEGDA solution, containing 0.5 %w/w of the HHEMP photo-
initiator was added to the 25 %w/v solution of PVP in EtOH. To prepare different films with
various adhesive properties, the resulting mixture was added to PG and/or PEG. The final
12
PVP-PEGDA-PEG or PVP-PEGDA-PEG-PG precursor solution was placed on the glass
slide using a micropipette and was drawn up by capillary action into the gap between the
coverslips and the glass slides.
The set up was then irradiated with high intensity ultra violet light of 350-500 nm for
1-7 seconds (this timing depend on the thickness of the film), with a UV distance of 6 cm, at
an intensity of 12.4 W/cm2 using the EXFO OmniCure S200-XL UV curing station (EXFO,
Photonic Solutions Inc., Canada), please see Appendix I.47
The fabricated PSA films were further developed to remove the uncross-linked
macromer/monomers by washing them thoroughly with deionized water. Solvent removal is
not necessary because the fabrication method used here is solvent free (or contains negligible
amounts of solvents).
As the fabricated PSA films were about to be used for mechanical tests, i.e. peel
testing, we had to avoid touching the films as much as possible once the films were separated
from the glass slide to minimize any loss of adhesiveness. Therefore, immediately after
curing the polymer, the top coverslip was carefully removed. One corner of the fabricated
film was lifted using a coverslip and deionized water was sprayed beneath the film. Running
water underneath the film facilitated the detachment of the film from the glass slide and
prevented occurrence of any rip in the film. The film was put on a piece of Parafilm via the
same side of the film that was detached from the glass slide. The film was left on the Parafilm
to air-dry. The dried PSA films were then placed in the desiccator until further use. It should
be noted that throughout the experiments we used the untouched face of the film (facing the
air) for the characterization tests.
Initially for the fabrication of microfabricated hydrogel films, we utilized different
13
PEG-based monomers with different ratios to investigate which monomers is suitable for our
purpose, to form a film with better mechanical properties.
PEGDA with two different molecular weights (PEGDA Mn 575 and PEGDA Mn 258)
and poly(ethylene glycol) methacrylate (PEGMA Mn 526, Fig. 2), were used together with
PVP for the fabrication of the films.
Figure 2. Chemical structure of PEGMA macromer; Proposed crosslinking mechanism for the reaction of
UV curable PEGMA and PVP (dashed lines represent hydrogen bonding between PEGMA and PVP
monomers)
14
The PVP films obtained with PEGDA 258 (Table 1) and PEGMA 526 (Table 2) were
much more fragile than the films obtained with PEGDA 575 and for the ratios below 1:9,
hardly formed any film.
Table 1. PEGDA 258 weight percentage (%w) ratio in the precursor solution
Table 2. PEGMA weight percentage (%w) ratio in the precursor solution
PEGMA macromers possess C=C bond at one end of their chain. The crosslinking
occurs when this reactive vinyl chain ends of PEGMA are polymerized by themselves,
15
forming a solid network through radical polymerization. The chemical crosslinkings between
them (PEGDA macromers) lead to the formation of covalent bondings.
Based on the proposed mechanism for photo-polymerization of PVP-PEGMA and due
to the structure of PEGMA, its crosslinking with PVP is physical because of hydrogen bond
formation between hydroxyl group of PEGMA and the carbonyl group from PVP (Fig. 2).43
Since PEGDA 575 showed better results and processability during the fabrication
procedure and the fabricated films exhibited proper mechanical properties, e.g. ability to
peeled off the fabrication set up without any damage to the films and flexibility, it was
chosen to be used as the macromer for this study along with other base monomers, i.e. PVP
and PEG/or PG. The different ratio of PEGDA 575 used for the fabrication of films is shown
in Table 3.
Table 3. PEGDA 575 weight percentage (%w) ratio in the precursor solution
16
Different ratios of PEGDA macromer and PVP, PEG/or PG monomers, were used in
order to obtain microfabricated PSA hydrogel films with the best viscoelasticity and adhesive
properties. The “thumb tack test”48
, a qualitative test, was applied for the preliminary
determination of the adhesion property of the fabricated hydrogels. For each PSA film
obtained from selected precursor solution mixture of monomers, a thumb was simply pressed
against the film and the relative tack property was evaluated and compared to other films to
decide the best monomers mixture ratios. Based on the qualitative observations from the
thumb tack test, the best precursor solution ratio of monomers was found to be 1:7:2 and
1:7:2:0.5 respectively for PVP-PEGDA-PEG and PVP-PEGDA-PEG-PG PSA hydrogel films
(Table 4).
Table 4. Ratios of PVP:PEGDA:PEG:PG monomers (%w/w) in the precursor solution
17
2.3 Preparation of Pig Skin Samples for Peel Tests
Pig skins excised from ear were used in our experiments. The hair of cadaver porcine
ear skin were first removed using an electric hair clipper Philishave 241 (Philips, Hong
Kong) followed by hair removal cream Veet (Reckitt Benckiser, Poland) to completely
remove the hair.49
The skin samples were gently cleaned with a Kimwipe tissue paper
(Kimberly-Clark, Roswell, GA, USA) and subcutaneous fat was removed using a scalpel.
The defatted skin samples were cut into small pieces (with the dimension of 30×50 mm) and
conserved frozen at -80°C until they were used. Prior to peel adhesion tests, the frozen skin
samples were thawed at room temperature (23°C) for 30 minutes.50
The thawed pig skin was
blotted with Kimwipe tissue paper and affixed under mild tension on a glass slide using paper
clips. The microfabricated pressure sensitive adhesive films were adhered to the skin with the
force of a thumb before peel strength measurements were done.
All animal procedures were carried out in compliance with relevant regulations
approved by the Institutional Animal Care and Use Committee (IACUC), National University
of Singapore (NUS). Approval to collect the porcine skin from local abattoir was granted by
Agri-Food and Veterinary Authority (AVA) of Singapore.
2.4 Hydrogels Characterization
2.4.1 Morphologies of PEGDA-Based Hydrogels
Microstructure and surface morphology of microfabricated hydrogel adhesive films
were evaluated by a Scanning Electron Microscopy (SEM, JEOL JSM-6700F) analysis
18
operating in the high vacuum/secondary electron imaging mode at an accelerating voltage of
5 kV. The hydrogels specimens were placed in a 50°C oven for 2 hrs so that the samples
became completely dry prior to morphological observation. Thereafter, the hydrogel samples
were sputter coated with a thin layer of gold alloy to improve the surface conductivity. To
compare the microstructure of microfabricated hydrogel films of different compositions
(PVP-PEGDA, PVP-PEGDA-PEG and PVP-PEGDA-PEG-PG films), the number of
separated phases per square micrometer were counted in at least 35 subdivisions of each SEM
image and averaged. (Note: to ensure that the hydrogel specimen composition will not be
affected upon oven drying (50°C), we placed another sample in desiccator so that silica gels
absorb moisture present in the hydrogel. SEM images of both drying ways were similar; the
only difference was the time that SEM instrument needed to reach high-vacuum, as it was
longer for the desiccators dried sample).
2.4.2 Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR)
Spectroscopy
Pure PEGDA macromer, and PVP, PEG and PG macromers and hydrogels of
PEGDA, PVP-PEG, PVP-PEGDA, PVP-PEGDA-PEG and PVP-PEGDA-PEG-PG were
analyzed by ATR-FTIR to investigate the interactions between the monomers. The ATR-
FTIR spectra were acquired using a PerkinElmer Spotlight 400 FTIR Imaging System (Perkin
Elmer, Shelton, CT USA) with an ATR accessory having a diamond crystal over the range of
4000-600 cm-1
.
To examine the chemical structure of microfabricated hydrogel adhesive films, each
film was placed on top of the crystal and a pressure arm was positioned over the sample to
19
exert a force of ~ 80 N on the sample. And for analysing liquid samples (i.e. PEGDA, PG and
PEG monomers), a drop of liquid was placed on top of and covering the diamond crystal. No
additional sample preparation was required for ATR-FTIR analysis. Removal of ethanol from
prepared hydrogel films was ascertained by ATR-FTIR spectroscopy in the absence of
methylene group stretching vibrations at around 2974 and 1378 cm-1
.
The structure of PEGDA, PVP-PEG and PVP-PEGDA-based hydrogels were
confirmed by ATR-FTIR analysis. PVP-PEG hydrogel, which was used as a control sample
in the ATR-FTIR analysis, was prepared according to Feldstein et al. by solvent casting
method. PVP and PEG were separately dissolved in common solvent, ethanol, and then
mixed before they were poured into the Teflon mold (2 cm deep), followed by the solvent
evaporation at ambient temperature (23°C) for 7 days. The resulted films were then placed in
desiccators.2
2.4.3 Measurement of Film Thickness
In the fabrication process of the pressure sensitive adhesives films, the number of
spacers governs the thickness of films. Each coverslip is approximately 150 µm thick.
Increased spacer thickness was achieved by increasing the number of coverslips stacked on
either side of the base glass slide as shown in Fig. 1. Depending on the number of spacers
used for the fabrication (1, 3, 5 and 7 spacers), the expecting thickness of films would vary
from 130-170 µm to 910-1190 µm. The microfabricated hydrogel adhesive films were
imaged using a Nikon microscope (Nikon, SMZ 1500, Tokyo, Japan) to quantify the
thickness characteristics of each film. For this purpose, the thickness of each film was
measured at five different sections (four corners and the middle). To show the thickness
20
reproducibility for each film, four films with the same number of spacers were fabricated and
their thickness was measured for four times.
2.4.4 Drug Distribution
To check the distribution uniformity of drugs within the PSA hydrogel films, the
model drug Rhd B (0.09 wt%), was incorporated into the PEGDA-based PSA films by
dissolving it in the polymer precursor solution before UV irradiation. Fabrication of the PSA
hydrogels at small polymerization time of 1-7 seconds (this timing depend on the thickness of
the film) is expected not to compromise the stability of incorporated drug (i.e. model drug
Rhd B) as the exposure to UV is minimized.
To assess the quality of drug distribution in films, Nikon microscope (Nikon, SMZ
1500, Tokyo, Japan) and Confocal Laser Scanning Microscope (CLSM, A1R-Nikon, Tokyo,
Japan) were used to capture the fluorescence cross sectional and three-dimensional image of
each film respectively. The intensity of fluorescence in each film was optically scanned at
different depth intervals (2 µm) in three different parts (two corners and one center) using
CLSM to reconfirm the uniformity of drug distribution within PSA films (please see
Appendix II).
2.4.5 Measurements of Rheological Properties
The rheological properties of the PSA hydrogels were determined with Bohlin Gemini
rotational rheometer (Bohlin Gemini HR nano, Bohlin Co., UK) equipped with 20 mm
diameter parallel plates. The hydrogel sample was placed between an upper plate fixture of
20 mm parallel plate and a stationary surface before being subjected to sinusoidal
21
oscillations. Gap between the two surfaces was set according to the thickness of each film,
i.e. 910-1190 µm (fabricated with 7 spacers).
2.4.5.1 Dynamic Strain Sweep Tests
In a dynamic strain sweep test conducted at 1 Hz and 23°C with Bohlin Gemini
rotational rheometer, elastic or storage modulus G′ (a measure of elasticity), loss modulus G′′
(a measure of viscosity), and complex modulus G* (viscoelasticity, G*= [(G′)2 (G′′)
2]
1/2)
versus strain profiles were generated as strain increased from 0.0001 to 100 percent. The
linear response region or Linear Viscoelastic Region (LVER) for the dynamic frequency
experiments was determined with a strain sweep, whereby a range of incremental shear
stresses (1-106 Pa) were applied on the samples. Critical strain, the onset of hydrogel film
rupture, was considered as the strain level where G′ began to drop.10, 51, 52
2.4.5.2 Dynamic Frequency Sweep Tests
The dynamic viscoelastic behaviour of hydrogels of PVP-PEGDA-PEG and PVP-
PEGDA-PEG-PG were also investigated using the same rheometer. A parallel plate geometry
(20 mm diameter) was used for the measurements under small strain amplitude (0.065
percent) to maintain intact gel structure (within the LVER). Dynamic frequency sweep tests
were carried out at 23°C to observe the G′ and G′′ as a function of a wide range of oscillation
frequencies (0.01-100 Hz). In each case, measurements were reproduced using three samples
of the same composition and G′ and G′′ were plotted vs. frequency.1
22
2.4.5.3 Viscoelastic Windows (VWs) of PSA Films
The Bohlin Gemini HRnano rheometer was used to measure G′ and G′′ values of
different PSA films at 0.01 and 100 radian per second (rad/s) oscillation frequency, at 23°C
and under 0.065 percent strain amplitude (Note: 0.01 rad/s= 0.0016 Hz and 100 rad/s=16 Hz,
since 1 rad/s = 1/2π Hz). By plotting the following four coordinates (quadrant) on the log-log
cross plot of G′ and G′′, their viscoelastic windows were constructed: (i) G′ at 0.01 rad/s, G′′
at 100 rad/s; (ii) G′ at 100 rad/s, G′′ at 0.01 rad/s; (iii) G′ at 0.01 rad/s, G′′ at 0.01 rad/s; (iv)
G′ at 100 rad/s, G′′ at 100 rad/s.53,54
2.4.6 Measurement of Mechanical Properties
2.4.6.1 Tensile Tests
Tensile tests were carried out with an Instron 5848 Microtester (Massachusetts, USA),
using a 5 N load cell at room temperature (23°C). The hydrogel samples were cut into a
rectangular shape, with a gauge length of 25 mm, width of 11 mm and different thicknesses
(varied from 390-510 µm to 910-1190 µm). Samples were placed between the clamps and
subjected to tension until the hydrogels lost their integrity. The tensile strain was measured as
the change in the length of the film divided by the initial length of the film. The tensile stress
was obtained by dividing the force by the original cross-sectional area of the film. Using
these data, the stress-strain curve was plotted for each measurement to represent the
mechanical properties of hydrogel.3
23
2.4.6.2 Peel Adhesion Tests
An Instron 5848 Microtester (Massachusetts, USA) was used to measure peel
strengths of PSA films (11 mm width, 45 mm length, with two different thickness of 650 µm
and 900 µm) against either a rigid (glass slide) or a flexible (cadaver porcine skin) surface at
room temperature (23°C) with a 5 N load cell. Rigid substrates (i.e. glass slide) were tested
for comparison with skin. Peeling was carried out at a rate of 50 mm/min and a peel angle of
180° (no backing layer was used in the peel testing). Peel strengths were measured in
triplicate, as continuous peel tests over 1 minutes.6 Glass slide was cleaned with acetone and
the skin was carefully wiped out with tissue paper between each peel experiment.55
24
3 Results and Discussion
3.1 Microfabricated PSA hydrogels
The aim of our study is to develop a one-step photo-polymerization method of
fabricating microstructure PSA hydrogel films at the shortest possible polymerization time
and study the rheological and mechanical properties. The photo-polymerization methods used
to date involved long exposure times to UV, which can compromise the stability of the
incorporated drugs, such as proteins, peptides, etc.56, 57
In our approach, microfabricated PSA
hydrogels were obtained at low polymerization time of 1-7 seconds (this timing depend on
the thickness of the film) which is expected not to compromise the stability of incorporated
drug as the exposure to UV is very short (Fig. 1).
Moreover, as photo-polymeric reactions can also be influenced by the intensity of the
light source used, so we aimed to find the right combination of polymerization time and the
UV intensity for fabricating PSA hydrogels.58
It was found that a combination of
polymerization time of 1-7 seconds and intensity of 12.4 W/cm2 was suitable for our method.
The PEGDA macromer and PVP, PEG and PG monomers, as shown in Fig. 3, were
selected for this fabrication approach based on their biocompatibility and their UV curability.
The fabrication process involved free radical polymerization using HHEMP as the photo-
initiator.
UV irradiation of the PVP-PEGDA-PEG and PVP-PEGDA-PEG-PG polymer
precursor solutions resulted in copolymerization of the monomers and the formation of white,
translucent, adhesive and flexible films, presumably in which PEGDAs covalently were
bonded together (reason of proper mechanical strength of the film), while PG and/or PEG
25
were physically crosslinked to PVP monomers and/or PEGDA via hydrogen bonding (reason
of proper adhesive properties), as both PG and PEG are hydrogen donors.
Figure 3. Chemical structure of monomers and the initiator used for preparing PSA films
According to the proposed mechanism for the photo-polymerization, the HHMP
photo-initiator molecules dissociated into radicals by means of UV light absorbance at the
outset of the reaction, demonstrated in Fig. 4. Subsequently, the formed initiator radicals
react with the PEGDA macromer generating active center, which could propagate through
PEGDA carbon-carbon double bonds to form kinetically growing, reactive chains. It is also
possible that the radical formation propagates through a pendant vinyl group of PEGDA by
which a 3D polymeric network of hydrogels will form.44
As for PVP monomers, following
26
the UV irradiation they just get entrapped in the PEGDA 3D hydrogel network.. Besides,
PEGDA and entrapped PVP could be physically crosslinked with PG/or PEG through
noncovalent crosslinking which leads to the formation of hydrogen bonding networks.43
Therefore an interpenetrating polymer network (IPN) will form, composed of 3D crosslinked
PEGDA network (covalent bonding), linear PVP polymer (entrapped in the 3D network), PG
and/or PEG (hydrogen bonding with PEGDA/or PVP).
Using different numbers of spacers (varied from 1 to 7), we were able to make
hydrogels in different dimensions (maximum 2022 mm, with the thickness varying from
130 µm to 1190 µm). The transparency of the films was variable depending on the gel
thickness. The thicker the microfabricated pressure sensitive adhesive hydrogels, the more
opaque the films.
Before performing the tensile tests on the microfabricated PSA hydrogels, the “thumb
tack test”48
was applied for the preliminary determination of the adhesion property of the
hydrogels. The thumb was simply pressed against the microfabricated PSA films and the
relative tack property was evaluated. Based on the qualitative observations from the thumb
tack test, it was clear that the PG incorporated PVP-PEGDA-PEG microfabricated hydrogels
had better adhesive properties comparing to the PVP-PEGDA-PEG, as they had more affinity
to the glass slide and the resistance toward peeling off was higher. To confirm this, further
tests were conducted to characterize the morphological, mechanical and rheological
properties of the microfabricated films.
27
Figure 4. Proposed crosslinking mechanism for the reaction of UV curable monomers and formation of
IPN; PEGDA macromers form a crosslinked network by covalent bonding (responsible for mechanical
strength) and PEGDA/PVP are bonded to PEG/or PG via hydrogen bonding (responsible for adhesive
properties)
28
3.2 Morphological Characterization by SEM
Fig. 5(a), (b) and (c) represent the microstructure morphologies of PVP-PEGDA non-
adhesive hydrogel, PVP-PEGDA-PEG and PG incorporated PVP-PEGDA-PEG
microfabricated pressure sensitive hydrogels, respectively. It can be seen from these
micrographs that in comparison with the PVP-PEGDA and PVP-PEGDA-PEG hydrogels, the
surfaces of the PVP-PEGDA-PEG-PG hydrogels possess a denser porous-network structure.
Figure 5. Scanning electron micrographs of (a) PVP-PEGDA, (b) PVP-PEGDA-PEG, (c) PG incorporated
PVP-PEGDA-PEG copolymer PSA films and (d) Comparison of average number of separated phases per
square micrometer in each film
29
Fig. 5(d) shows the comparison between the microstructure of microfabricated
hydrogel films of different compositions (PVP-PEGDA, PVP-PEGDA-PEG and PVP-
PEGDA-PEG-PG films) in regard to the existent number of separate phases per square
micrometer for at least 35 subdivisions of the each SEM image. It was observed that the
average density of the separate phases of PVP-PEGDA films is increased by incorporation of
PEG and PG. From the analysis of all reproduced SEM micrographs of the fabricated
hydrogels, it is shown that the morphology of films became increasingly more packed and
dense by incorporation of PEG and PEG/PG monomers into the fabricated PVP-PEGDA
hydrogels. The difference in morphology between the PVP-PEGDA-PEG and PVP-PEGDA-
PEG-PG hydrogels shown in Fig. 5(b) and (c), could be explained as the influence of PG and
increasing the number of hydrogen bondings. Here, PG is performing the role of partial
crosslinking agent via hydrogen bonding, which causes denser cross-linking network
structure in PVP-PEGDA-PEG-PG films. These observations are also in agreement with the
hypothesis that hydrogels with a maximum number of electrostatic interactions (hydrogen
bonding in this case) have a tighter structure and improved network stability.9
3.3 Spectral Characterization of PSA Hydrogels
One of the reliable ways to detect hydrogen bonding between polymers is ATR-FTIR
spectroscopy, in the analysis of which, a shift to lower frequencies and drastic increase in
absorbance in the frequency range of 2500-4000 cm-1
is taken as evidence for the occurrence
of hydrogen bonds involving O-H functional groups as donors and C=O as acceptors. This
effect is often accompanied by the broadening of O-H and C=O stretching peaks.59, 60
By
comparing the ATR-FTIR spectra of pure PEGDA macromer and PG, PEG and PVP
30
monomers, PEGDA hydrogels and PVP-PEGDA, PVP-PEGDA-PEG and PG incorporated
PVP-PEGDA-PEG hydrogels, shown in Fig. 6, an effect similar to the extensive hydrogen
bond formation can be observed.
Figure 6. ATR-FTIR spectra of macro-monomers, PEGDA and fabricated PVP-PEGDA, PVP-PEGDA-
PEG and PVP-PEGDA-PEG-PG copolymer PSA films (solid arrow attributed to the hydroxyl stretching
vibration bond, dash arrow is attributed to the carbonyl stretching bond of PEGDA and dash circle is
attributed to the carbonyl stretching bond of PVP)
Physical crosslinking (hydrogen bonding) degree was measured from the ATR-FTIR
spectra of copolymers (i.e. PVP-PEGDA-PEG and PVP-PEGDA-PEG-PG) in carbonyl and
31
hydroxyl stretching vibration regions. The degree of hydrogen bonding interactions can be
deduced from changes in the peak position of the C=O stretching band (shown by dash arrow
for PEGDA and dash circle for PVP) and O-H stretching vibration band (shown by solid
arrows), where as demonstrated in Fig. 6, hydrogen bonding is evidenced by a shift to lower
wavenumbers and broadening.60, 61
In Fig. 6(c) and (d), the band in 1690 cm-1
and the sharp
band in 1760 cm-1
region represent the C=O stretching band of PVP and PEGDA
respectively. These bands can be attributed to carbonyl groups that are free, but bound by
PVP-PVP or PEGDA-PEGDA dipole interactions. In PVP-PEGDA-PEG Fig. (g) and PVP-
PEGDA-PEG-PG Fig. (h), although we did not observe any shift to lower wavenumbers,
slight broadening of C=O stretching bands was noticed, which is attributed to the C=O
stretching band of either PVP or PEGDA (or both) hydrogen-bonded to PEG/or PG.62
On the other hand, the mechanical strength provided by the crosslinked PEGDA
molecules is critical for PSA, especially while handling the films. The covalent bonding
between PEGDA molecules can be attributed of the C=C stretching band of the acrylate
group visible at the 1635 cm-1
in un-crosslinked macromer but is lost when PEGDA
molecules are photo-crosslinked (due to conversion of carbon-carbon double bond to carbon-
carbon single bond), as seen in the Fig. 6(d) and (e).21, 63
This phenomenon however gets
masked due to the C=O stretching of PVP in Fig. 6 (f), (g) and (h).
As it has been established by ATR-FTIR spectroscopy of the copolymers spectra, Fig.
6(g) and (g), the physical crosslinking is due to hydrogen bondings between the proton
donating hydrogen atoms of PEG/or PG terminal hydroxyl groups and the electronegative
oxygen atoms of carbonyl groups in PVP/or PEGDA.64
The PG and PEG monomer spectra,
Fig. 6(a) and (b), have a broad, singlet O-H peak at around 3580-3400 cm-1
due to one
32
reactive OH group at each end of PG and PEG molecules. Therefore, each PG or PEG
molecule is capable of forming two hydrogen bonds with the carbonyl groups in PVP/or
PEGDA repeat units, acting as a physical crosslinker of PVP/or PEGDA chains. Due to
hydrogen bonding, the hydroxyl stretching vibration band of PG and PEG, Fig. 6(a) and (b),
broaden and shift to a lower wavenumbers, ~ 3700-3200 cm-1
, as observed in PVP-PEG (e),
PVP-PEGDA-PEG (g) and PVP-PEGDA-PEG (h) spectra.61
3.4 Control of thickness and Drug Distribution
The robustness of our approach to microfabrication and controlling the thickness of
the polymeric films under study was evidenced by the linear relationship between the number
of utilized spacers for the fabrication of the films (1, 3, 5 and 7 spacer) and their measured
thickness as depicted in Fig. 7(a).
Figure 7. (a) Control of thickness in each film (number of spacers varied from 3, 5 and 7), (b)
Reproducibility of films with different thickness (S1-S4 refer to four samples of each thickness, each
sample’s thickness was measured four times. P < 0.001, the error bar shows SD)
33
Fig. 7(b) shows the thickness reproducibility for each of four samples of
microfabricated PVP-PEGDA-PEG pressure sensitive hydrogel films with the same number
of spacers (1, 3, 5 and 7 spacers).
Incorporation of Rhd B as a model drug into the PSA films during the fabrication
yielded uniformly distributed microfabricated PVP-PEGDA-PEG-Rhd B films. This was
testified by cross sectional and three-dimensional imaging analysis of various films with
different thicknesses (390-510 to 910-1190 µm) as shown in Fig. 8(a) and (b). Estimation of
Rhd B content by fluorescent intensity measurement at different spots of each film indicated
that the model drug is distributed uniformly, throughout the films, as shown in Fig. 8(c).
34
Figure 8. Quantification of distribution uniformity of Rhd B in PSA films with different thickness using
confocal microscopy: (a) Cross sectional view, (b) 3D view and (c) Fluorescence intensity measurement in
different parts of each film with different thickness (number of spacers varied from 3, 5 and 7). P < 0.001,
the error bar shows SD
35
3.5 Rheological Properties
In the rheological study on our PSA hydrogel films (two different compositions, i.e.
PVP-PEGDA-PEG and PG incorporated PVP-PEGDA-PEG) we employed both dynamic
strain sweep and dynamic frequency sweep tests.
3.5.1 Dynamic Strain Sweep Test. In the dynamic strain sweep test, the
viscoelasticity of films were measured over a wide range of shear rates (0.0001-100% strain).
Oscillatory deformation is applied to the PSA films and the material response is monitored at
a constant frequency (1 Hz) and temperature (23°C). The strain dependence of G′, as an
rheological property of gels, is a measure of the brittleness and rigidness of the junctions
within the structure.65
Fig. 9 shows the change of the moduli (elastic (G′), viscous (G′′) and complex (G*)
modulus) of the PVP-PEGDA-PEG (a) and PVP-PEGDA-PEG-PG (b) PSA hydrogel films,
with the thickness of 910-1190 µm (fabricated with 7 spacers), as functions of various
oscillating strain amplitudes, γ. The strain corresponds to the deformation of the networks
caused by the applied shear stress. The elastic modulus remains stable under small strains and
decreases abruptly, i.e. onset of nonlinearity, when γ surpasses a certain value γ₀ (so called
critical strain) which indicates bond breakage within the networks of hydrogels.65, 66
As observed in Fig. 9 (a) and (b), the PVP-PEGDA-PEG and PVP-PEGDA-PEG-PG
microfabricated PSA hydrogels can withstand up to 0.5% and 0.8% of the strain,
respectively. Below the critical strain, the mesh-like microstructure of the films is intact and
above this, it crumbled. This shows that the three-dimensional microstructure of PSA films,
36
with or without PG in the composition, can withstand a strain up to the critical strain value,
i.e. 0.8% and 0.5% respectively, without showing any change in elasticity. However, the
three-dimensional network cannot stand any further increase in the applied strain and
ultimately it collapses. This collapse is reflected in the decrease of the elastic modulus of the
hydrogel.
Figure 9. Log-log plot of shear moduli (G′, G′′, G*) vs. strain for (a) PVP-PEGDA-PEG and (b) PG
incorporated PVP-PEGDA-PEG copolymer PSA films with the thickness of 910-1190 µm, fabricated with
7 spacers (frequency = 1 Hz, temperature = 23°C)
The length and position of the LVER of the elastic modules can be used as a measure
of the stability of a PSA structure over a range of strain and as an indication of the ability to
resist flow, since structural properties are best related to elasticity.51
As observed in the Fig.
9(b), the PG incorporated films have longer LVER and higher critical strain values
comparing to films without PG incorporation, Fig. 9(a). Therefore, PG incorporated PSA
films have a higher rheological stability and elasticity (flexibility).
37
3.5.2 Dynamic Frequency Sweep Test. This test describes the structure type of
the PSA films according to their moduli (G′ and G′′). Using the dynamic frequency sweep
test, the effect of frequency on the viscoelastic properties of hydrogels as a function of time
was studied. The values of G′ and the G′′ can be used to confer the behaviour of PSA films
under a certain strain. If G′ > G′′, then the material is more solid-like than liquid-like.51
The frequency sweep rheological test was done in LVER area with constant
deformation (γ = 0.065%) and changing frequency from 0.1 Hz to 100 Hz. Relying on the
data acquired from the dynamic strain sweep tests, Fig. 9, we chose the strain amplitude of
0.065% to run the dynamic frequency sweep test on the films, as it was the middle value of
the LVER area.
Fig. 10(a) shows viscoelastic properties of the PVP-PEGDA-PEG hydrogels, whereas
Fig. 10(b) displays the viscoelastic properties of the PG incorporated PVP-PEGDA-PEG
hydrogels. As presented in the figure, for all the microfabricated PSA hydrogel films, G′ was
greater than G′′ over the entire frequency range, which is consistent with the solid-like, elastic
nature of the hydrogels. in other words hydrogel behaved as a viscoelastic solid. As perceived
in the figure, the G′ and G′′ of the PSA hydrogels are fairly independents of frequency over a
wide range of frequencies. The nearly independent and weak dependence of G′ and G′′ with
frequency, accordingly, is due to both the covalent network (chemical crosslinking between
PEGDA macromers) and physical nature of the network due to hydrogen bonding (physical
crosslinking between PVP/or PEGDA and PEG/or PG) as it is explained in Fig. 4.
Both hydrogel films, as shown in Fig. 10, retained their predominating elastic nature
(up to 10 Hz of frequency) as G′ are about ten times higher than G′′. But, with a higher
frequency of more than 10 Hz, G′′ gradually approach nearer to the G′, shifting slightly more
38
toward viscous nature. The upturn in G′′ for both hydrogel compositions, at the higher
frequencies suggests the onset of a structural change in the hydrogel network, which is most
likely viscous flow.1, 10
Figure 10. Log-log plot of average shear moduli (G′ and G′′) vs. frequency for (a) PVP-PEGDA-PEG and
(b) PG incorporated PVP-PEGDA-PEG copolymer PSA films with the thickness of 910-1190 µm,
fabricated with 7 spacers (strain = 0.065%, temperature = 23°C)
39
The presence of PEG and PEG-PG in the composition of the PSA films, play
significant roles in maintaining the viscoelasticity of the hydrogels besides the adhesive
properties. Frequency sweeps over at least three decades of frequency were used to provide
an indication of the type of gel formed in our PSA films as a correlation to the proposed
mechanism earlier in the study.
As it was shown in Fig. 4, we have both covalent bondings and hydrogen bondings in
the structure of the microfabricated PSA hydrogels. According to the moduli trends of our
microfabricated PSAs, shown in Fig. 10(a) and (b), they could be classified as a well-
structured (gelled) system, due to earlier noted results (i.e. G′ > G′′ and almost independency
of frequency). Therefore, the PVP-PEGDA-PEG and PG incorporated PVP-PEGDA-PEG
microfabricated PSA hydrogels can be considered as much of chemical (cross-linked) gels as
physical (noncovalent linkages) gels. To some extent, Fig. 10, represents the effect of PG
incorporation on the storage modulus (G′), which denotes elastic property and the loss
modulus (G′′) which represents viscous property of hydrogels with respect to frequency.
From comparison of (a) and (b), it is clear that before PG incorporation G′ and G′′ are
lowered. This indicates that the PG incorporated PVP-PEGDA-PEG hydrogel films are more
elastic because PG is responsible to develop more physical cross-linking (hydrogen bonding)
in the hydrogels. The result of dynamic frequency sweep test, Fig. 10(b) also correlates with
the result from dynamic strain sweep test shown in Fig. 9(b); in that PG incorporated PSA
hydrogel film possesses higher stability and elasticity (flexibility). PG incorporated PVP-
PEGDA-PEG PSA films, as a viscoelastic material, exhibit both elasticity of solids and
viscosity of liquids.
40
3.6 Viscoelastic Windows
The concept of viscoelastic windows (VW) has been proposed by Chang to identify
different types of PSAs. Such VWs are constructed from the values of dynamic storage
modulus (G′) and dynamic loss modulus (G′′) at frequencies of 0.01 rad/s and 100 rad/s
(equivalent to 0.0016 Hz and 16 Hz respectively). These two frequencies are selected because
the range covers majority of the time scales that correspond to the uses of PSAs at different
application rates in performance tests. Chang67
reported that for most PSAs, at room
temperature within the selected frequencies, G′ and G′′ falls between 103 and 10
6 Pa.
Moreover, there is a unique correlation between the location of their VWs and the adhesion
performance of the PSAs.
According to the four quadrant concept, different types of PSAs are categorized based
on the location of their VWs on the log-log cross plot of G′ and G′′. The proposed four
quadrants by Chang, 1) top-left hand quadrant of high G′ and low G′′, 2) top-right hand
quadrant of high G′ and high G′′, 3) lower left hand quadrant of low G′ and low G′′, and 4)
lower right-hand quadrant of low G′ and high G′′, are the characteristic VWs for 1) non-PSA
or release coatings, 2) high shear PSAs, 3) removable and medical PSAs, and 4) quick and
cold stick PSAs, respectively.53,54
For our study, we also evaluated the G′ and G′′ values of both microfabricated PSA
films, i.e. PVP-PEGDA-PEG and PG incorporated PVP-PEGDA-PEG films, at 0.01 and 100
rad/s oscillation frequency, 23°C and under 0.065 percent strain amplitude. By means of the
viscoelastic window concept proposed by Chang and harness of the G′ and G′′ data, the
window for each of the microfabricated PSAs was constructed to define in which quadrant
they will appear. Depending on the appearance of their VWs in any of the four quadrant types
41
of PSAs, they possess different viscoelastic characteristics.
Fig. 11 illustrates the corresponding VWs for the microfabricated PVP-PEGDA-PEG
and PG incorporated PSA hydrogel films, with the thicknesses of 910-1190 µm (fabricated
with 7 spacers). As it is shown in the figure, the VWs for both compositions of our films
appear in quadrant 3 (bottom left-hand quadrant), possessing low G′ and low G′′ values. This
quadrant corresponds to low bonding modulus and low dissipation, which is referred to the
removable and medical-type PSAs. The two mentioned distinct characteristic properties, low
G′ and low G′′, make these PSAs very contact-efficient and give them more elasticity or
better removability, respectively.
Figure 11. Viscoelastic windows of PVP-PEGDA-PEG and PG incorporated PVP-PEGDA-PEG
copolymer PSA films with the thickness of 910-1190 µm, fabricated with 7 spacers (white and black
circles, respectively, refer to films without and with PG incorporation)
By comparing the VWs of the PG incorporated microfabricated PSA films, Fig. 11,
with those PSAs without PG, one notes that the PG containing films tend to occupy the lower
42
(better conformability) and farther right (better flow) area of Quadrant 3, where medical
PSAs are usually located. While the window for the PVP-PEGDA-PEG hydrogels lays closer
to the top left of quadrant 3, where removable PSAs are positioned.53, 67
Earlier results from
studies of PSAs have revealed that good adhesive performance happens when the G′ is low at
low frequency rates (i.e. 0.01 rad/sec) and a rather high slope exists for G′ as the frequency is
increased (i.e. 100 rad/sec). The trends for our microfabricated PSAs, Fig. 11, are in line with
the results from the earlier studies, showing that the fabricated adhesive films, especially the
PG incorporated film, have good adhesive performance.
It must be considered that the reference temperature for the medical adhesive is the
skin temperature, ~33°C, rather than 23°C at which the measurements were carried out in this
work. Consequently, due to the higher reference temperature, the bonding modulus of the
microfabricated PSAs becomes even lower (i.e., more conformable). This is considered
desirable for film-skin contact because of the uneven, frequently varied, and habitually
contaminated nature of the skin surface.67
3.7 Mechanical Properties
For the characterization of PSA films, the tensile strength (TS) and the elongation to
break (EB%) are two important mechanical properties in terms of their resistance to abrasion
and flexibility, respectively. Films tailored for dermatological applications must be flexible
enough to follow the movements of the skin and sustain a comfortable feel, and at the same
time withstand the mechanical abrasion caused by bodily movement (especially on curved
areas, such as knees and elbows) or external objects for example clothes.9, 68
Hence, PSA
43
films with higher EB% (strain percentage) and TS (stress, MPa or N/mm2) are preferred for
the TDD applications.
3.7.1 Tensile Testing. The tensile test was done on microfabricated PSA hydrogel
films. Tensile stress vs. strain curves for the microfabricated PVP-PEGDA-PEG and PG
incorporated PVP-PEGDA-PEG hydrogels (fabricated with 3, 5 and 7 number of spacers) are
shown in Fig. 12(a) and (b), respectively. The PSA hydrogel films of both compositions
fabricated with one spacer had a thickness range of 130-170 µm, which were too delicate to
be suitable for tensile measurements, due to difficulty in handling. Representative stress-
strain curves for microfabricated PSA hydrogels with two different compositions and with 3
different thicknesses showed distinctly different profiles, although all exhibited a toe and
linear elastic region and scaffolds experienced necking before deformation.
The PG incorporated PVP-PEGDA-PEG hydrogels, with 3, 5, or 7 spacers, exhibited
ultimate tensile strength of 0.06-0.12 MPa and a reasonable elongation to break of 65-85%,
Fig. 12(b). The high elongation is attributed to ability of the physical cross-links to dissipate
energy. In comparison, the PVP-PEGDA-PEG, fabricated with 3, 5, or 7 spacers,
demonstrated a tensile strength between 0.09 and 0.18 MPa and a percent elongation at
failure between 35-55%. These results can be explained as a consequence of the less
impacted structure and absence of PG in the structure, which made the sample more brittle
and less elastic and flexible.
Hydrogel composition was shown to have an observable impact on the tensile
properties of the PSAs. There is a correlation between the morphology of hydrogels and the
stress-strain curves. For PG incorporated PVP-PEGDA-PEG films the morphology was more
44
impacted with denser distribution of the separated phases, Fig. 5(c), compared to the
hydrogels without PG, Fig. 5(b). The stress-strain curve of PG incorporated PVP-PEGDA-
PEG hydrogels with more compacted structure showed approximately 1.5-fold higher tensile
strain (i.e., elongation) than the corresponding hydrogels without PG, as shown in Fig. 12(a)
and (b) respectively.
Also by looking at each plot individually, it can be concluded that for each
composition by increasing the thickness of microfabricated films from 390-510 µm to 910-
1190 µm, the elasticity decreases and deformation point appear earlier.
Overall, the incorporation of PG reduced the ultimate tensile stress comparing to the
hydrogels without PG as shown in Fig. 12(b). As expected, the ultimate tensile strain (EB%)
of the PG incorporated hydrogels exhibited opposite trends compared with the ultimate stress
(TS).
Based on these evaluations, it is found that although incorporation of PG in the PSA
films adversely affects the TS when compared with the films without PG, the advantage of its
presence in the films by increasing EB% is more obvious which had a significant effect on
the elasticity of the PSA films. A small change in the tensile stress magnitude leads to a
larger change in the tensile strain percentage of PG incorporated hydrogel films, showing
they possess a larger elastic region, and the deformation occurs later (up to 85% before
deformation), which makes these films a better, ductile films comparing to those without PG.
Enhancement of EB% by PG incorporation, as a plasticizer, may be attributed to its
placement in between of PVP-PEGDA polymer chains through hydrogen bonding which will
space the polymer chains apart. This leads to weakening of the polymer intermolecular
binding, allowing the polymer molecules to move more freely resultant in an increase in the
45
flexibility of hydrogel films and a decrease in tensile strength.69, 70
Figure 12. Stress-strain curve for (a) PVP-PEGDA-PEG and (b) PG incorporated PVP-PEGDA-PEG
copolymer PSA films (number of spacers varied from 3 to 7)
This indicates that incorporation of PG into our PSA films always increases the
flexibility of the films and that utilizing more number of spacers in fabrication (increasing of
46
the thickness) produces the highest increase in the EB%. It should also be noted that PVP-
PEGDA-PEG films exhibit a lower flexibility when compared with PG incorporated PVP-
PEGDA-PEG films with the same thickness. According to the presented results of TS and
EB% attained from stress-strain curves, PG incorporated PVP-PEGDA-PEG film with the
thickness of 390-510 µm (fabricated with 3 spacers) is the film presenting the best functional
properties for the potential dermatological applications because it presents a better overall
tensile strength and elasticity as it can be stretched to almost 85% of its original length.9
3.7.2 Peel Testing. The peel adhesion testing was accomplished at a peel angle of
180° and a fixed rate of 50 mm/min. Three different microfabricated PSA hydrogel samples
of each condition (i.e. change of composition and thickness) were tested. The peel strengths
and the displacement of the films against both rigid (i.e. glass slide) and flexible (i.e. cadaver
porcine skin) substrates were recorded by the testing machine. The maximum detachment
force is noted and considered as a measure of adhesive force. The peel force of each film is
plotted as a function of its displacement.6, 17, 48
The results of the peel testing for PVP-PEGDA-PEG and PG incorporated PVP-
PEGDA-PEG films (with the thickness of 910-1190 µm, fabricated with 7 spacers), against
both substrates, glass slide and skin, are shown in Fig. 13(a) and (b) respectively. As it can be
observed from the figures, incorporation of PG into the films considerably increased the peel
strengths of the PSA films comparing to that without PG. The maximum peel force against
glass slide was 0.79 N, 0.42 N and 0.59 N, 0.3 N against skin sample, respectively, for PSA
films with PG and without PG. According to the data collected, PG incorporation has a
noticeable influence on the peel strengths of the microfabricated PSA films.
47
Figure 13. Average peel test run of (a) PVP-PEGDA-PEG and (b) PG incorporated PVP-PEGDA-PEG
PSA films with the thickness of 910-1190 µm, from a rigid substrate, i.e. glass, and a flexible substrate, i.e.
cadaver pig skin, at a speed of 50 mm/min, and nominal peel angel of 180 degree. (C) Comparison of
averaged 180 degree peel force for two different compositions from two different substrates
48
The low peel strength of the PVP-PEGDA-PEG hydrogel films with no PG
incorporated is consistent with the morphology observed in SEM experiments. The increased
number of voids present in the PVP-PEGDA-PEG films, Fig. 5(b), in other words the less
packed structure of these films, lowered both the localized adhesive thickness and the contact
area which leads to a reduction in the peel strength. While the PVP-PEGDA-PEG adhesive
films had a similar thickness to that of the other samples (i.e. PG incorporated PVP-PEGDA-
PEG PSA films), due to the less dense structure, the amount of adhesive on the surface of
substrate was reduced. The reduced contact area also decreases the amount of mechanical
interlocking. The combination of these properties would lower the peel strength on any PSA
as it does for the PVP-PEGDA-PEG PSA films.
It is also apparent that the peel strength of either of the compositions encounters a
reduction when the substrates changed from glass to skin. As for the PG incorporated films,
maximum peel force reduced from 0.79 N to 0.59 N and for the films without PG
incorporation, maximum peel force reduced from 0.42 N to 0.3 N by switching the substrate
from glass to skin.
The peel strengths average of all the three measurements for each film type (PVP-
PEGDA-PEG with or without PG incorporation), against both surfaces were recorded in
Newton and is shown in Fig. 13(c) for a better comparison. As noted, the PG incorporated
films possess the highest peel strength against the rigid surfaces and the PSA films without
PG possess the smallest peel strength against the flexible surface.
Removal of the PSA films from different substrates involves the work done in the
extension of the adhesive, distortion of the backing during the stripping action and the
separation of the adhesive/surface interface.5, 6
As for our studies no backing layer was
49
involved and just the adhesive films, PVP-PEGDA-PEG and PG incorporated PVP-PEGDA-
PEG PSA, were used in the peeling test. The debonding of our adhesive films was via
“Adhesive failure Case I” mode which means when the PSA films were peeled away from
either of substrates, i.e. glass and pig skin cadaver, they were stripped cleanly, leaving no
visible adhesive residue on the substrates.6
Generally, a PSA should be able to flow into the cavities of the substrate (so called
viscosity), in order to interact tightly with the surface of the substrate.5 When it makes a close
contact with the surface of substrate because of its viscoelastic properties then it will be able
to make molecular interactions such as Van der Waals forces with the skin or substrate. The
PSA-skin bonds can be built by stronger interactions (i.e. hydrogen bonding), following the
initial adhesion.5, 6
So, enhancements of adhesion by incorporation of PG may be attributed to
the improvement of viscoelastic properties of films and hence a better wetting effect. And
also it may be due to enhancement of the number of hydrogen bonding in the polymer
network, as PG has two hydroxyl groups in its structure.
Besides peel strength measurements for two different compositions of films (without
and with PG incorporation) against both soft and hard surfaces, the effect of varying the
thickness of adhesive while keeping other factors constant was also studied. The effect of
adhesive thickness, either 650-850 µm or 900-1190 µm thick, on peel strength was almost
negligible.
Thus, according to these results, it was noted that the peel force would increase with
the incorporation of PG, and/or utilizing a hard substrate instead of a flexible one, but not
with the change of the film thickness from 650-850 µm (5 spacers) to 900-1190 µm (7
spacers).
50
4 Conclusions
To develop a suitable pressure sensitive adhesive film for dermatological applications,
we devised photo-crosslinked PVP-PEGDA-PEG hydrogels. The PSA films were
successfully fabricated by photo-polymerization of PVP, PEGDA and PEG polymers
with/without PG. The resulted PSA hydrogel films thickness is controllable, with a densely
phase-separated and uniform surface morphology. These hydrogels were capable of
undergoing UV irradiation and formation of the films within a few seconds with minimal
usage of solvents compared with those prepared with conventional methods. Both the lack of
solvents and the quick cure speed are key features of this green approach to chemical
processing. Furthermore, there was a precise control over the thickness of the films. The
simple fabrication process enabled us to control the adhesive properties, such as gel strength
and adhesiveness, by manipulating the preparative composition and conditions.
Employing simultaneous optimizations (various thicknesses, PG incorporation), the
optimal formulation of photo-crosslinked hydrogels, i.e. PVP-PEGDA-PEG-PG, for potential
use as dermatological adhesives was successfully established. The PVP-PEGDA-PEG-PG
films are shown to be more flexible and adhesive than the correspondent PVP-PEGDA-PEG
films. Increasing the thickness of the films decreased the flexibility and elongation at break
percentage of the films, but has no effect on the adhesiveness of the films. Incorporation of
PG, as a plasticizer, into the PVP-PEGA-PEG hydrogel provided the best film properties. The
optimized film has shown suitable mechanical and rheological properties, i.e. flexibility,
resistance and bioadhesion, which make it a promising adhesive hydrogel film for
dermatological applications.
51
Future Work
As a future work, the development of these microfabricated, photo-crosslinked PVP-
PEGDA-PEG hydrogel films modified with PG, will be further investigated with the
incorporation of different drugs and by determination of the drug release profiles and drug
permeation studies through the skin in order to assess the viability of using these films as
adjustable dermatological drug delivery systems.
Encapsulation of drugs in microfabricated PSA hydrogels: Different model drugs,
such as Rhd B, lidocaine, will be encapsulated in the hydrogel matrix of PVP-PEGDA-PEG-
PG PSA films. The amount of drug encapsulated in the hydrogel films can be calculated from
the percent weight of the drugs in the precursor solution and the weight of microfabricated
films.
In vitro release profile of drugs from PSA hydrogel films: Following the
encapsulation of drugs, e.g. model drug Rhd B, in the PSA hydrogel films, the in vitro release
from hydrogel matrix can be tested. The PSA films will be immersed in PBS and the release
solutions should be periodically sampled. Once done with the sampling, each sample should
be pipetted into the wells of Corning 96 well plate and analyzed by absorbance measurements
in a microplate reader. The cumulative percentage release is then will be calculated.
In vitro drug permeation studies from PSA hydrogel films through the skin:
Complementing the in vitro release profile of model drugs, e.g. Rhd B, from PSA hydrogels,
the next step is to study the drug permeability from microfabricated hydrogels across cadaver
pig skin in an in vitro setting using horizontal diffusion cell (Fig. 14).
52
Figure 14. A horizontal diffusion cell assembly
Investigation of drug stability upon UV exposure: Although, fabrication of the PSA
hydrogels at small polymerization time of 1-7 seconds is expected not to compromise the
stability of incorporated drug (e.g. model drug Rhd B) as the exposure to UV is minimized.
As a part of our future work, we plan to investigate the UV stability of different drugs
incorporated into the PSA films. Since the model drug Rhd B was incorporated into the
PEGDA-based PSA films by dissolving it in the polymer precursor solution before UV
irradiation, we intend to check the drug composition before and after UV radiation to trace
any possible degradation.
We expect that our method of fabrication ensures higher drug stability than previously
used methods in fabrication of PSA films due to solvent-free process, and fast
polymerization. However, we aim to fabricate PSA films encapsulating different drugs, and
testing their stability post fabrication. Spectroscopy techniques will be used to analyze the
change in encapsulated drug conformation upon exposure to UV light.
53
Assessment of potential toxicity and irritation: Despite PEGDA, PVP, PEG and
PG have a long history of use in drug delivery systems, their composite polymer still needs to
be assessed for toxicity and irritation potential. It is necessary to evaluate the toxicity
potential of polymeric materials, various formulation components and physicochemical
changes that might happen during the fabrication. The methodology will involve dermal
sensitivity analysis using reconstituted epidermal tissues and in vitro cell viability studies
using representative hepatic and renal cells on suitable platforms. Finally, clinical studies in
human volunteers for assessing the dermal irritation associated with the PSA hydrogel films
will be carried out.
54
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58
Appendices and Supporting Information
Appendix I
Furthermore, the fabrication process was also optimized by performing trials of
different variable settings, i.e. adjustment of UV light strength (0.6-12.4 W/cm2), UV
exposure time (differing from 1-30 seconds) and UV light distance (2-10 cm).
It was observed that as the UV light distance from the setting stage was increased
(from 2 to 6 cm), due to increase of UV irradiation area, larger portion of the fabrication set
up was being photo-polymerized. On the other hand, increase of the distance between the UV
light and the fabrication setup, above 9 cm, resulted in the formation of non uniform films.
With the intensity lower than 4 W/cm2, no PSA hydrogel films were formed and
between the intensities of 4–8 W/cm2, hydrogels formed were observed to be uneven and the
uniformity of thickness was poor. The uniform PSA film structures were obtained at all
intensities above 8 W/cm2. The microfabricated PSAs at 12.4 W/cm
2 were found to possess
the optimum mechanical properties.
Moreover, fabrication of PSA hydrogel films were attempted at different
polymerization durations ranging from 1 second to 30 seconds, keeping the UV light intensity
constant (12.4 W/cm2) and with two fixed distances from UV light source, i.e. we tried both 6
cm and 4 cm. It was noticed that the photo-polymerization of the precursor solution required
minimum UV exposure duration of 3 seconds. At polymerization durations longer than 15
seconds, the microfabricated films were slightly difficult to detach from the setup.
Eventually, 6 cm distance from UV light source and 1-7 seconds of polymerization
time (the time was increased from 1 second to 7 seconds, upon increasing the spacer
59
thickness. We manipulated the spacer thickness by increasing the number of coverslips, i.e.
1-9 coverslips) at the UV intensity of 12.4 W/cm2 were set as optimum conditions for the
fabrication process of the PSA films.
60
Appendix II
As mentioned before for model drug experiments, 4500 µg of Rhd B was added to the
PVP-PEGDA-PEG precursor solution before UV irradiation. The yielded PVP-PEGDA-
PEG-Rhd B films were then analyzed by CLSM to assess the quality of drug distribution and
the intensity of fluorescence in each film at different depth intervals (2 µm increments) and
three different spots to reconfirm the uniformity of drug distribution within PSA films.
As shown in Fig. 15 (a) and (b), the Rhd B incorporated PSA films, with different
thicknesses (130-5170 to 910-1190 µm), showed a similar trend at different spots on different
films and the maximum fluorescence intensity for all of them is about 4095 AU.
61
Figure 15. Fluorescence intensity of each film as measured by CLSM at different depth intervals (2 µm),
in three different parts of each film (two corners and one center), a) L1 and L3 refer to number of spacers
used for the fabrication (1 for films with a thicknesses of 130-170 µm and 3 for films with a thickness of
390-510 µm, respectively), b) L5 and L7 refer to number of spacers used for the fabrication (5 for films
with a thicknesses of 650-850 µm and 7 for films with a thickness of 910-1190 µm, respectively)