Interpenetrating network hydrogels via simultaneous "click Chemistry" and atom transfer radical polymerization

Article abstract of DOI:10.1021/bm100268t

Simultaneous interpenetrating polymer networks (sIPNs) from concurrent copper(I)-catalyzed azide-alkyne cycloaddition "click chemistry" and atom transfer radical polymerization (ATRP) are described. Semi-sIPN of poly(ethylene glycol)/poly(2-hydroxyethyl methacrylate) (semi-PEG/PHEMA-sIPN) was first prepared via simultaneous "click chemistry" and ATRP from a mixture of poly(ethylene glycol)-diazide (N₃-PEG-N₃, M_n = 4000 g/mol), tetrakis(2-propynyloxymethyl)methane (TPOM), ethyl-2-bromobutyrate (EBB), CuBr, pentamethyldiethylenetriamine (PMDETA), and 2-hydroxyethyl methacrylate (HEMA) in dimethylformamide (DMF). Full sIPN of PEG/PHEMA (full-PEG/PHEMA-sIPN) was then prepared via simultaneous "click chemistry" and ATRP from a mixture of N₃-PEG-N₃ (M_n = 4000 g/mol), TPOM, EBB, CuBr, PMDETA, HEMA, and poly(ethylene glycol) diacrylate) (PEGDA, M_n = 575) in DMF. Both the semi- and full-sIPNs exhibit a fast gelation rate and high gel yield. The sIPNs also exhibit high swelling ratios and good mechanical and antifouling properties. The morphology and thermal behavior of the sIPNs were studied by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). These sIPNs could find applications as biomaterials for contact lenses, biomedical materials, artificial organs, and drug delivery systems.

Full text of DOI:10.1021/bm100268t

1810
Biomacromolecules 2010, 11, 1810–1817
Interpenetrating Network Hydrogels via Simultaneous “Click
Chemistry” and Atom Transfer Radical Polymerization
L. Q. Xu,†,‡ F. Yao,† G. D. Fu,*,† and E. T. Kang‡
School of Chemistry and Chemical Engineering, Southeast University, Jiangning District, Nanjing, Jiangsu
Province, People’s Republic of China 211189, and Department of Chemical and Biomolecular Engineering,
National University of Singapore, Kent Ridge, Singapore 809978
Received March 12, 2010; Revised Manuscript Received May 19, 2010
Simultaneous interpenetrating polymer networks (sIPNs) from concurrent copper(I)-catalyzed azide-alkyne
cycloaddition “click chemistry” and atom transfer radical polymerization (ATRP) are described. Semi-sIPN of
poly(ethylene glycol)/poly(2-hydroxyethyl methacrylate) (semi-PEG/PHEMA-sIPN) was first prepared via
simultaneous “click chemistry” and ATRP from a mixture of poly(ethylene glycol)-diazide (N3-PEG-N3, Mn )
4000 g/mol), tetrakis(2-propynyloxymethyl)methane (TPOM), ethyl-2-bromobutyrate (EBB), CuBr, pentameth-
yldiethylenetriamine (PMDETA), and 2-hydroxyethyl methacrylate (HEMA) in dimethylformamide (DMF). Full
sIPN of PEG/PHEMA (full-PEG/PHEMA-sIPN) was then prepared via simultaneous “click chemistry” and ATRP
from a mixture of N3-PEG-N3 (Mn ) 4000 g/mol), TPOM, EBB, CuBr, PMDETA, HEMA, and poly(ethylene
glycol) diacrylate) (PEGDA, Mn ) 575) in DMF. Both the semi- and full-sIPNs exhibit a fast gelation rate and
high gel yield. The sIPNs also exhibit high swelling ratios and good mechanical and antifouling properties. The
morphology and thermal behavior of the sIPNs were studied by scanning electron microscopy (SEM),
thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). These sIPNs could find applications
as biomaterials for contact lenses, biomedical materials, artificial organs, and drug delivery systems.
of attractive features with CuAAC, such as good tolerance for
a wide range of functional groups,26 but also the same copper
catalyst system.27 Combined CuAAC and ATRP in one-pot
synthesis has already been reported in the literature.28-31 The
influence of solvents, catalyst concentration, temperature, and
various azido reagents on simultaneous copper(I)-catalyzed
“click chemistry” and ATRP has been studied.32 Simultaneous
click reaction and ATRP in emulsion has also been reported.33
In this work, we demonstrate an alternative approach to the
preparation of semi-sIPNs and full-sIPNs via the simultaneous
reactions of “click chemistry” and ATRP. The interest in sIPN
of poly(ethylene glycol) (PEG) arises from the fact that PEG is
an uncharged, water-soluble, nontoxic, nonimmunogenic, and
widely used biomedical material.34-36 On the other hand, the
choice of poly(2-hydroxyethyl methaycrylate) (PHEMA) as the
other component of the IPNs arises from its hydrophilicity,
nontoxic nature, and biocompatibility with a large number of
existing biomedical and pharmaceutical applications.37,38 Semi-
PEG/PHEMA-sIPN was first prepared via simultaneous “click
chemistry” and ATRP from a reaction mixture of poly(ethylene
glycol)-diazide (N3-PEG-N3, Mn ) 4000 g/mol), tetrakis(2-
propynyloxymethyl)methane (TPOM), ethyl 2-bromobutyrate
(EBB), CuBr, pentamethyldiethylenetriamine (PMDETA), and
2-hydroxyethyl methacrylate (HEMA) in DMF. Full-PEG/
PHEMA-sIPN was also prepared via simultaneous “click
chemistry” and ATRP from the same reaction mixture, except
that the cross-linking agent, poly(ethylene glycol) diacrylate
(PEGDA), was also used.
1. Introduction
Interpenetrating polymer networks (IPNs), a kind of unique
“alloy” of cross-linked polymers, can exhibit entirely new and
sometimes surprising properties, such as tunable responsive
properties, enhanced mechanical properties, and improved
thermal stability.1-3 Because of these unique properties, IPNs
have found applications as biomedical materials.3-7 Traditional
synthesis of IPNs involves sequential polymerization of a
mixture of monomer and cross-linking agents in a swollen
network (sequential IPNs) or simultaneous one-step polymer-
ization of two different monomer-cross-linking agent pairs with
independent and noninterfering reaction mechanisms (sIPNs).3,8
The preparation of sIPN is often accomplished by polymerizing
one network via condensation polymerization, while the other
by free radical polymerization. The preparation of sIPNs thus
requires stringent conditions, such as functional group tolerance,
mild reaction conditions, and good reaction yields.1,9
“Click chemistry” is a powerful technique for preparing
macromolecules with complex architectures10-15 and functional
polymers for biomedical and pharmaceutical applications.16
Recently, “click chemistry”, especially copper(I)-catalyzed
azide-alkyne cycloaddition (CuAAC), has been widely used
in the preparation of hydrogel networks because of its reaction
specificity, quantitative yields, and good functional group
tolerance.17-19 Atom transfer radical polymerization (ATRP),
on the other hand, provides a unique tool for preparing nearly
monodispersed polymers with controlled molecular weight.20-23
Hydrogels have also been prepared via ATRP of multifunctional,
such as macromonomers,24,25 methacryloyloxy poly(ethylene
oxide) (PEO). Interestingly, ATRP not only shares a number
2. Experimental Section
2.1. Materials. The monomers, HEMA (97%) and PEGDA (Mn )
575 g/mol), were purchased from Acros Organic Co. of Geel, Belgium.
The monomers were used after removal of the inhibitors in a ready-
to-use disposable inhibitors-removal column. Propargyl bromide (80%),
* To whom correspondence should be addressed: Tel.: +86-25-52090625.
Fax: +86-25-52090625. E-mail: fu7352@seu.edu.cn.
† Southeast University.
‡ National University of Singapore.
10.1021/bm100268t
 2010 American Chemical Society
Published on Web 06/02/2010

Interpenetrating Network Hydrogels
Biomacromolecules, Vol. 11, No. 7, 2010 1811
PEG (Mn ) 4000 g/mol), and PMDETA (99%) were purchased from
Aldrich Chemical Co. and were used as received. Sodium azide (99%),
CuBr (99%), methane sulfonyl chloride, pentaerythritol, and bovine
serum albumin (BSA) were purchased from Shanghai Chemical Reagent
Plant.
2.2.5. Full- or Semi-sIPN Via Simultaneous “Click Chemistry”
and ATRP. 2.2.5.1. Preparation of Full-PEG/PHEMA-sIPN. A typical
procedure for the preparation of full-PEG/PHEMA-sIPN via simulta-
neous “click chemistry” and ATRP was carried out as follows. About
0.5 g (3.8 mmol) of HEMA, 0.54 g (0.95 mmol) of EGDA, 18.5 mg
(0.107 mmol) of PMDETA, 11.1 mg (0.057 mmol) of EBB, 0.3 g (0.075
mmol) of poly(ethylene glycol)-diazide, 10.8 mg (0.0375 mmol) of
tetrakis(2-propynyloxymethyl)methane, and 1.5 mL of DMF were
introduced into a 5 mL vial. The reaction mixture was purged with
argon for 20 min and 15.4 mg (0.107 mmol) of CuBr was added
quickly. The gelation of sIPN occurred in about 2 min. The mixture
was kept at 60 °C for another 24 h to obtain a uniform solid sIPN
hydrogel. The copper catalyst and DMF in the gel were removed in an
excess volume of 5% EDTA solution and maximum water absorption
was achieved by immersing the sIPN in deionized water.
2.2.5.2. Preparation of Semi-PEG/PHEMA-sIPN. To prepare the
semi-sIPN, 0.74 g (5.7 mmol) of HEMA, 18.5 mg (0.107 mmol) of
PMDETA, 15.4 mg (0.107 mmol) of CuBr, 11.1 mg (0.057 mmol) of
EBB, 0.3 g (0.075 mmol) of poly(ethylene glycol)-diazide, 10.8 mg
(0.0375 mmol) of tetrakis(2-propynyloxymethyl)methane, and 1.5 mL
of DMF were introduced into a 5 mL vial (molar ratio of [HEMA]/
[EbiB]/[CuBr]/[PMDETA] ) 100:1:1:1). The reaction mixture was
purged with argon for 20 min and sealed. The gelation of sIPN occurred
in 2 min. The mixture was kept at 60 °C for a predetermined period of
time to obtain the uniform solid sIPN hydrogel. The copper catalyst
and DMF in the gel were also removed in 5% EDTA solution, and
maximum water absorption was achieved by immersing the sIPN in
deionized water.
2.2. Chemical Synthesis and Polymerization. 2.2.1. Synthesis
of Poly(ethylene glycol)-diazide (N3-PEG-N3). Poly(ethylene glycol)-
diazide was prepared from PEG according to the method reported in
the literature.39 About 10 g (2.5 mmol) of PEG (Mn ) 4000 g/mol)
was dissolved in 50 mL of dry pyridine. The solution was cooled to 0
°C, and 0.98 g (12.5 mmol) of methanesulfonyl chloride dissolved in
10 mL of dry dichloromethane was added dropwise over 20 min. The
mixture was allowed to return to room temperature and was stirred
another 12 h. After removal of the solvent in a rotary evaporator, the
residue was treated with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The solution was dried over MgSO4 for 10 h. The organic
solvent was removed by rotary evaporation. The product (8.9 g of pale
powder) was precipitated by addition of an excess amount of diethyl
ether. After that, a mixture of 8 g (2 mmol) of the as-prepared PEG
and 0.65 g (10 mmol) of sodium azide in 50 mL of dry DMF was
allowed to react at 85 °C for 24 h. The unreacted sodium azide was
removed by passing the reaction mixture through an alumina column,
and the filtrate was concentrated by rotary evaporation. The polymer
was precipitated from the concentrated DMF solution by addition of
diethyl ether and filtration. The product was studied by MALDI-TOF
mass spectroscopy and 1H NMR spectroscopy. The conversion ef-
ficiency of the hydroxyl groups into azide groups was about 93%. Yield:
90%; FTIR (cm-1): ν(NdN) ) 2098.
2.2.6. Degree of Swelling of Full- and Semi-sIPNs. The degree of
swelling of the sIPNs was measured as follow. Initially, the prepared
2.2.2. Synthesis of Tetrakis(2-propynyloxymethyl)methane. About
2.4 g (0.017 mmol) of pentaerythritol was added into a solution of
15 g (0.264 mmol) of KOH in 30 mL of anhydrous DMF. After stirring
at 5 °C for 30 min, 20 g (0.17 mmol) of propargyl bromide was slowly
added over a period of 20 min. The color of the solution turned brown
and the reaction mixture was stirring at 40 °C overnight. The reaction
mixture was quenched with water and extracted thrice with 50 mL of
ethyl ether. The organic layers were combined, washed with water,
then with brine, and dried over Na2SO4. After removal of the ethyl
ether by rotary evaporation, the adduct was further purified by passing
it through a silica gel column, using mixed ethyl acetate/hexane (2/8
in volume ratio) as the eluent. An orange solid of about 3.57 g was
sIPN was dried at 50 °C for more than 24 h, and the weight (weightdry gel
)
was recorded when the sample reached a constant weight. Then it was
immersed in deionized water for at least 24 h to allow the sIPN to
become fully hydrated. When the weight of the swollen sIPN reached
a stable value, it was again recorded (weightswollen gel). The degree of
swelling of hydrogels was calculated from the equation
degree of swelling ) weightswollen gel/weightdry gel - 1
{(
×
}
)
100%
Each value was the average value from five measurements.
2.2.7. Antifouling Properties of the Full- and Semi-sIPNs. Bovine
serum albumin (BSA) was diluted with a phosphate buffer solution
(PBS, pH 7.4) to prepare the 1% (mg/mL) solution. Prior to the
adsorption experiment, the hydrogels were equilibrated in PBS at the
physiological pH of 7.4 for 48 h. The protein absorption of the sample
was carried out by immersing the sample in the BSA solution at 25 °C
for 24 h. After the absorption, the BSA concentration in the solution
was determined by UV adsorption spectroscopy measurement at the
wavelength of 280 nm. The absorbed amount of BSA (mg/g) was
calculated from mass balance according to the following equation:
1
obtained. Yield ) 79%; H NMR (CDCl3, ppm): 4.13 (8H, -OCH2),
3.55 (8H, C(CH2)4), and 2.43 (4H, CH); FTIR (cm-1): ν(t CH) ) 3299.
2.2.3. PEG-Based Network from “Click Chemistry”. About 0.1 g
(0.025 mmol) of poly(ethylene glycol)-diazide, 3.6 mg (0.0125 mmol)
of tetrakis(2-propynyloxymethyl)methane, 8.7 mg (0.05 mmol) of
PMDETA, and 1 mL of DMF were introduced into a small vial. After
the mixture turned clear, the vial was degassed with argon for 20 min,
and 7.2 mg (0.05 mmol) of CuBr was quickly added under ultrasonic
agitation. The gelation point was reached in 1 min, and the reaction
was allowed to continue for another 24 h at 60 °C. A uniform hydrogel
was obtained upon removal from the vial. The gel was transferred to
an EDTA (5%) solution to remove the copper ions and DMF. Finally,
the gel was immersed into a large volume of pure deionized water to
allow the water absorption.
qe ) (C0 - Ce) · V/m
where qe is the equilibrium absorption capacity, m (g) is the mass of
fully swollen gel, V (mL) is the volume of BSA solution, and C0 (mg/
mL) and Ce (mg/mL) are the initial and equilibrium protein concentra-
tions, respectively.
2.2.4. PHEMA-co-PEGDA Network from Atom Transfer Radical
Polymerization. A typical polymerization procedure was carried out
as follow: 0.5 g (3.8 mmol) of HEMA, 0.54 g (0.95 mmol) of EGDA,
9.9 mg (0.057 mmol) of PMDETA, 11.1 mg (0.057 mmol) of EBB,
and 1 mL of DMF was introduced into a dry and clean vial (molar
ratio of [HEMA]/[EGDA]/[EBB]/[CuBr]/[PMDETA] ) 66.7:16.6:1:
1:1). The mixture was degassed with argon for 20 min, and then 8.2
mg (0.057 mmol) of CuBr was added into the vial. Gelation was reached
in 45 min. After gelation, the reaction was allowed to proceed at 60
°C for another 24 h before being terminated via exposure to air. Finally,
the copper catalyst and DMF were removed by immersing the gel into
an excess volume of 5% EDTA solution.
2.2.8. Characterization. The chemical structures of tetrakis(2-
1
propynyloxymethyl)methane was characterized by H NMR spectros-
copy on a Bruker ARX 300 MHz spectrometer, using CDCl3 as the
solvent, in 1000 scans at a relaxation time of 2 s. Matrix-assisted laser
desorption ionization time-of-flight mass spectrometry (MALDI-TOF-
MS) were recorded using a Bruker AutoFlex II apparatus. Fourier
transform infrared (FT-IR) spectra were obtained from a MAGNA-IR
750 spectrometer (Nicolet Instrument Co.). The sample was dispersed
in a KBr pellet. The swollen hydrogels were frozen rapidly at -80 °C
and then dried in a freeze-dryer. The thermal stability of the full-PEG/

1812 Biomacromolecules, Vol. 11, No. 7, 2010
Xu et al.
Scheme 1. Preparation of Semi-PEG/PHEMA-sIPN and Full-PEG/PHEMA-sIPN via Simultaneous “Click Chemistry” and Atom Transfer
Radical Polymerization (ATRP)
PHEMA-sIPN, semi-PEG/PHEMA-sIPN, PEG-based network, and
PHEMA-co-PPEGDA network were determined on a thermogravimetric
analyzer (TA SDT Q-600). The DSC measurements were performed
on a Pekin Elmer DSC7 calorimeter under a nitrogen atmosphere, at a
heating rate of 10 °C/min. The absorption and transmittance spectra of
the prepared hydrogels were measured on a Hitachi U-4100 UV-visible
spectrophotometer. The hydrogel sample with a thickness of 0.5 cm
was fixed on the inner wall of a quartz cell. The morphology of the
sIPNs was studied on a scanning electron microscope (Hitachi X-650
SEM) at an accelerating voltage of 5-20 kV and an object distance of
about 8 mm. Tensile testing was performed using an Instron Model
5844 tensile tester at room temperature. The extension speed was set
to a constant stretching rate of 0.01 mm/s until the failure of the sample.
The true stress and strain were calculated from the load and extension
data recorded by the software Testworks.
and semi-PEG/PHEMA-sIPN via simultaneous “click chemis-
try” and ATRP. The increase in the amount of Cu(I) catalyst
can reduce the gelation time. By increasing the concentration
of CuBr from 20 to 100% (relative to the mole concentration
of azido and alkynyl groups), the respective gelation time
decreases from about 38 to 2 min and about 42 to 2 min. A
similar observation has been reported.40,41 The fact that, in the
presence of limited Cu(I) catalysts, the gelation time of PEG-
based network is shorter than that of the semi-PEG/PHEMA-
3. Results and Discussion
3.1. Preparation of Interpenetrating Polymer Networks
(sIPNs) from Simultaneous “Click Chemistry” and Atom
Transfer Radical Polymerization (ATRP). Full- and semi-
sIPNs were prepared from the simultaneous reactions of (i)
“click chemistry” of N3-PEG-N3 (Mn ) 4000 g/mol) and TPOM
to generate the network with 1,2,3-triazole linkage and (ii) ATRP
of HEMA, or PEGDA and HEMA, to form the respective semi-
and full-sIPNs (Scheme 1). Figure 1 shows the optical images
of the pristine PEG network from “click chemistry”, PHEMA-
co-PPEGDA network from ATRP, semi-PEG/PHEMA-sIPN,
and full-PEG/PHEMA-sIPN, respectively.
The gelation effect is very important in the investigation of
sIPN formation from simultaneous ATRP and “click chemistry”.
Because “click chemistry” and ATRP share the same catalyst
system, the concentration of Cu(I) catalyst plays an important
role in the gelation effect. Simultaneous ATRP and “click
chemistry” with varying concentration of Cu(I) catalyst were
carried out to obtain the optimal gelation effect. Figure 2 shows
the dependence of gelation time on the molar ratio of CuBr/
azide groups of the pristine PEG network from “click chemistry”
Figure 1. Photographs of (a) the PEG-based network from “click
chemistry”, (b) the PHEMA-co-PPEGDA network from ATRP, (c)
semi-PEG/PHEMA-sIPN via simultaneous “click chemistry” and
ATRP, and (d) full-PEG/PHEMA-sIPN via simultaneous “click chem-
istry” and ATRP.

Interpenetrating Network Hydrogels
Biomacromolecules, Vol. 11, No. 7, 2010 1813
concentration of the azide and alkyl groups. Although the side
reaction between the azide groups and vinyl monomers can
proceed at a finite rate,42 this side reaction is much slower than
the reaction involving “click chemistry”. Thus, the effect of the
side reaction between the azide and the vinyl groups is
negligible. In Figure 3, the increase in concentration of CuBr
leads to an increase in CuAAC efficiency of both the pristine
PEG network and semi-PEG/PHEMA-sIPN. At the CuBr/azide
ratio of about 0.2, the CuAAC efficiency of pristine PEG
network is about 50%, which is higher than that (40%) of semi-
PEG/PHEMA-sIPN. When the CuBr/azide ratio is increased to
1.0, the CuAAC efficiency in semi-PEG/PHEMA-sIPN reaches
92%, which is comparable to that (94%) of the pristine PEG
network. These results indicate that sufficient catalyst concentra-
tion in the reaction mixture is critical to both “click chemistry”
and ATRP in a one-pot synthesis. An additional increase in the
amount of CuBr will not improve the CuAAC efficiency
remarkable but will lead to a poor control of ATRP. Thus, in
this study, the molar ratio of [CuBr]/[azido]/[alkynyl] is fixed
at 1:1:1.
Figure 2. Dependence of gelation rate on the molar ratio of CuBr/
azide groups: (a) the PEG-based network from “click chemistry” with
molar ratio of [azido]/[alkynyl] ) 1:1 in 1.5 mL of DMF at 60 °C and
(b) semi-PEG/PHEMA-sIPN via simultaneous “click chemistry” and
ATRP with molar ratio of [azido]/[ alkynyl]/[HEMA]/[EBB] ) 1:1:100:1
in 1.5 mL of DMF at 60 °C.
Semi-PEG/PHEMA-sIPN was prepared via simultaneous
“click chemistry” and ATRP from a reaction mixture of N3-
PEG-N3 (Mn ) 4000 g/mol), TPOM, EBB, CuBr, PMDETA,
and HEMA in DMF. The PEG gel fraction of semi-PEG/
PHEMA-sIPN was obtained from a control experiment with the
same reaction conditions as that for the preparation of semi-
PEG/PHEMA-sIPN, albeit in the absence of EBB. The gel
fraction of semi-PEG/PHEMA-sIPN was obtained from the
relation: gel fraction ) massdried gel/masspolymer precursors. The data
in Table 1 show that the PEG gel fraction of semi-PEG/
PHEMA-sIPN was about 90%, which was slightly lower than
that (94%) of the pristine PEG-based network. The conver-
sion of PHEMA was calculated from the expression of
[massdried gel of semi-PEG/PHEMA-IPN - massdried gel of control experiment]/
massHEMA. The data in Table 1 also show that at the reaction
time of 12 h, the conversion of HEMA is about 0.43. With the
increase in reaction time from 12 to 24 h, the gel fraction of
PEG remains unchanged, while the conversion of HEMA
increases from 0.43 to 0.59. Part of the Cu(I) catalyst forms
the Cu(I) acetylide complex with alkyne for “click chemistry”,
and the remaining part reacts with EBB to generate the radicals
and Cu(II) for ATRP.22,43 In fact, the rate of “click chemistry”
was very fast. A 90% click conversion can be achieved in 5
min.32 Thus, in the first few minutes, “click chemistry” was
the predominant reaction. In a control experiment for the
preparation of semi-PEG/PHEMA-sIPN, the reaction was
stopped at 3 min when the gel point was reached, and the
unreacted molecules were extracted from the hydrogel. FTIR
studies show that the hydrogel is composed mainly of a PEG-
based network and no PHEMA polymer was found in hydrogel.
When the gel point of PEG was reached and most of the click
reactions had been completed, the polymerization became
dominated by ATRP of HEMA. At this stage, polymerization
may be considered as the ATRP of HEMA in a PEG-based
network.
Figure 3. Dependence of the hydrogel yields on the molar ratio of
CuBr/azide groups of (a) the PEG-based network from “click chem-
istry” with a molar ratio of [azido]/[alkynyl] ) 1:1 in 1.5 mL of DMF at
60 °C for 24 h and (b) the semi-PEG/PHEMA-sIPN via simultaneous
“click chemistry” and ATRP with molar ratio of [azido]/[ alkynyl]/
[HEMA]/[EBB] ) 1:1:100:1 in 1.5 mL of DMF at 60 °C for 24 h.
sIPN suggests that a part of Cu(I) catalysts is used to initiate
the ATRP process, thus, reducing the catalyst concentration for
the “click chemistry”.
The introduction of ATRP into the “click chemistry” might
affect the molecular structure of the PEG network and the
efficiency of CuAAC. Thus, the CuAAC efficiency of pristine
PEG network and semi-PEG/PHEMA-sIPN were studied. The
CuAAC efficiency can be calculated from the residual of azide/
acetylene groups. According to the method reported,17 postgel
“click chemistry” of the azide-functionalized chromophores (3-
azido-7-hydroxycoumarin) was performed, followed by UV
absorption analysis to determine the amount of the unreated
alkyne groups in the gels. Figure 3 shows the dependence of
CuAAC efficiency on the CuBr/azide molar ratio of pristine
PEG network prepared with an [azido]/[alkynyl] molar ratio of
1:1 in 1.5 mL of DMF at 60 °C for 24 h, and of semi-PEG/
PHEMA-sIPN prepared with an [azido]/[alkynyl]/[HEMA]/
[EBB] molar ratio of 1:1:100:1 in 1.5 mL of DMF at 60 °C for
24 h. Thus, the CuAAC efficiency is enhanced by the increase
in catalyst concentration. The CuAAC efficiency of semi-PEG/
PHEMA-sIPN is lower than that of the pristine PEG-based
network, especially when a low concentration of CuBr is used.
This result is consistent with the fact that introduction of ATRP
reduces the amount of Cu(I) for CuAAC and dilutes the
Full-PEG/PHEMA-sIPNs were also prepared via simulta-
neous “click chemistry” and ATRP from a reaction mixture of
N3-PEG-N3 (Mn ) 4000 g/mol), TPOM, EBB, CuBr, PMDETA,
HEMA, PEGDA (Mn ) 575), and DMF. The PEG gel fraction
of full-PEG/PHEMA-sIPN was obtained from a controlled
experiment carried out under the same reaction condition as
that used for the preparation of full-PEG/PHEMA-sIPN, albeit
in the absence of EBB. The gelation was reached in 2 min and
a PEG gel fraction of about 88% in full-PEG/PHEMA-sIPN

1814 Biomacromolecules, Vol. 11, No. 7, 2010
Table 1. Characterization of the Interpenetrating Networks
Xu et al.
sample
gel fraction
swelling degreef (%)
max. stressf (kPa)
max. extension to breakf (%)
PEG-based network
0.94
0.77
1570 ( 110
120 ( 10
630 ( 17
60 ( 5
920 ( 30
960 ( 28
1430 ( 36
1480 ( 41
800 ( 59
20 ( 3
480 ( 29
650 ( 33
600 ( 25
760 ( 41
PHEMA-co-PPEGDA network
semi-PEG/PHEMA-sIPN1a
semi-PEG/PHEMA-sIPN2b
full-PEG/PHEMA-sIPN1c
full-PEG/PHEMA-sIPN2d
0.90/0.43e
0.90/0.59
0.88/0.60
0.88/0.64
1330 ( 90
1230 ( 95
870 ( 70
1090 ( 85
a Molar feed ratio of [HEMA]/[EBB]/[CuBr]/[PMDETA]/:[N3-PEG-N3]/[TPOM] ) 100:1:1:1:0.5:0.25. The reaction was carried out at 60 °C, and the reaction
time was fixed at 12 h. b Molar feed ratio of [HEMA]/[EBB]/[CuBr]/[PMDETA]/[N3-PEG-N3]/[TPOM] ) 100:1:1:1:0.5:0.25. The reaction was carried out at
60 °C, and the reaction time was fixed at 24 h. c Molar feed ratio of [HEMA]/[EGDA]/[EBB]/[CuBr]/[PMDETA]/[N3-PEG-N3]/[TPOM] ) 66.7:16.6:1:1:1:
0.5:0.25. The reaction was carried out at 60 °C, and the reaction time was fixed at 12 h. d Molar feed ratio of [HEMA]/[EGDA]/[EBB]/[CuBr]/[PMDETA]/
[N3-PEG-N3]/[TPOM] ) 66.7:16.6:1:1:1:0.5:0.25. The reaction was carried out at 60 °C, and the reaction time was fixed at 24 h. e PEG and PHEMA gel
fractions. f The value is the average of five measurements.
was obtained (gel fraction ) massdried gel/masspolymer precursors). To
study the formation of PHEMA/PEGDA networks in simulta-
neous “click chemistry” and ATRP, another controlled experi-
ment under the same reaction condition as that used for the
preparation of full-PEG/PHEMA-PEGDA-sIPN, except using
PEG (Mn ) 4000 g/mol) instead of N3-PEG-N3, was carried
out. In the controlled experiment of ATRP of PEGDA and HEMA,
the gelation was achieved at a reaction time of about 45 min. The
polymerization rate of PEGDA was relatively slow25 and the living
character of polymerization was maintained in the first 20 min. In
the process of simultaneous “click chemistry” and ATRP, gelation
commenced in about 2 min. Prior to gelation, the ATRP process
proceeds in a controlled manner. However, as the reaction proceeds,
the concentration of radical may start to increase. The increase in
concentration of radicals can be attributed partially to the release
of Cu(I) from the Cu(I) acetylide complex due to the completion
of “click chemistry” and partially to the reduction in radical
deactivation because of the decrease in mobility of the Cu(I) and
Cu(II) species arising from the increase in system viscosity. The
increase in radical concentration results in a high ATRP rate and
promotes the formation of PEGDA and PHEMA networks. Thus,
in the full-PEG/PHEMA-sIPN, the networks of PEG and PEG/
PHEMA were generated sequentially. The gel fraction of PHEMA
Figure 4. UV-visible transmittance spectra of (a) the PEG-based
network from “click chemistry”, (b) PHEMA-co-PPEGDA network from
ATRP, (c) semi-PEG/PHEMA-sIPN via simultaneous “click chemistry”
and ATRP, and (d) full-PEG/PHEMA-sIPN via simultaneous “click
chemistry” and ATRP. PEGDA ) poly(ethylene glycol) diacrylate.
than that of the pristine PEG network from “click chemistry”.
The MEB of the pristine PEG network is about 800%, while
the MEB’s of full-PEG/PHEMA-sIPN and semi-PEG/PHEMA-
sIPN are about 760 and 650%, respectively. The decrease in
MEB can be attributed to the relatively lower gel fraction (gel
yield) of full- and semi-sIPN in comparison to that of the PEG-
based network (Table 1). A higher gel yield means fewer
disfigurements in the network, leading to a higher tensile stress.
The optical properties of the as-prepared sIPNs were studied.
Figure 4 shows the transmittance of pristine PEG network from
“click chemistry”, PHEMA-co-PPEGDA network from ATRP,
semi-PEG/PHEMA-sIPN and full-PEG/PHEMA-sIPN, respec-
tively. In the ultraviolet range, the transmittances of full-PEG/
PHEMA-sIPN and PEG-based network are higher than those
of the semi-PEG/PHEMA-sIPN and PHEMA-co-PPEGDA
network. At the wavelength of 280 nm, the respective transmit-
tances of the PEG-based network and full-PEG/PHEMA-sIPN
are 23 and 20%, which are higher than that of semi-PEG/
PHEMA-sIPN (3%) and that of PHEMA-co-PPEGDA network.
In the visible region, both the full-PEG/PHEMA-sIPN and PEG-
based network exhibit relatively constant transmittances of about
63 and 79%, respectively, while the transmittance of the semi-
PEG/PHEMA-sIPN increases with the increase in wavelength.
At 400 nm, the transmittance of semi-PEG/PHEMA-sIPN is
only 28%. However, the transmittance increases dramatically
to 75% at 800 nm.
was calculated from the equation [massdried gel of full-PEG/PHEMA-IPN
-
massdried gel of control experiment]/massHEMA. The data in Table 1 show that
as the polymerization time is increased from 12 to 24 h, the PHEMA
fraction increases correspondingly from 0.60 to 0.64.
3.2. Physical Properties of the sIPNs. All the sIPNs
prepared exhibit a high degree of swelling. The data in Table 1
shows that the degrees of swelling of the prepared semi- and
full-sIPN are 1230 and 1090%, respectively. They are higher
than that of the PHEMA-co-PPEGDA network (120%) but
lower than that of PEG-based network (1570%). The ability of
the polymer chains to relax fully has allowed the formation of
bigger pores and cavities, as well as given rise to a higher degree
of water adsorption by the pristine PEG networks from “click
chemistry”. For full-PEG/PHEMA-sIPN, the PEG network and
PHEMA-co-PPEGDA network are entangled, restricting the full
stretching of the network lattice and resulting in a lower degree
of water adsorption. For semi-PEG/PHEMA-sIPN, the hydro-
philic PHEMA can stretch freely within the network lattice. The
extension of PEG chains is also much easier than those of full-
PEG/PHEMA-sIPN. Thus, the degree of swelling of semi-PEG/
PHEMA-sIPN is approaching that of the PEG network.
Both full- and semi-sIPNs exhibit improved mechanical
properties over those of the PEG network from “click chemistry”
and PHEMA-co-PPEGDA network from ATRP (Table 1). The
entanglement of networks by low molecular weight segments
between the cross-linking points (Mc) and mesh size have
significantly increased the tensile stress of sIPNs. The maximum
extension to break (MEB) of sIPNs, however, is slightly lower
The morphology of sIPNs was also studied. Figure 5a,b shows
the cross-sectional scanning electron microscopy (SEM) images
of the freeze-dried samples of PHEMA-co-PPEGDA network
from ATRP, PEG-based network from “click chemistry”, semi-
PEG/PHEMA-sIPN, and full-PEG/PHEMA-sIPN, respectively.
The PHEMA-co-PPEGDA network (Figure 5a) has a homoge-

Interpenetrating Network Hydrogels
Biomacromolecules, Vol. 11, No. 7, 2010 1815
Figure 5. SEM images (cross-section view) of (a) the PHEMA-co-PPEGDA network from ATRP, (b) PEG-based network from “click chemistry”,
(c) semi-PEG/PHEMA-sIPN via simultaneous “click chemistry” and ATRP, and (d) full-PEG/PHEMA-sIPN via simultaneous “click chemistry”
and ATRP.
neous and dense morphology, while the PEG-based network
(Figure 5b) is highly porous with pore sizes ranging from 90 to
150 µm. The morphology of semi-PEG/PHEMA-sIPN (Figure
5c) and full-PEG/PHEMA-sIPN (Figure 5d) is similar to that
of the PEG-based network, and the pore sizes are in the range
of 60-90 µm. The SEM results are thus consistent with the
swelling results, that is, the more porous the structure, the higher
the degree of swelling.
3.3. Thermal Properties. The thermal stability is very
important for materials aiming for biomedical applications. For
the thermally unstable biomaterials, thermal treatment during
the process of manufacturing and long-term usage at 37 °C can
lead to degradation of their mechanical properties and alteration
of their cytotoxicity and biocompatibility.44 Thus, the thermal
Figure 6. Thermogravimetric analysis (TGA) of (a) the PEG-based
network from “click chemistry”, (b) semi-PEG/PHEMA-sIPN via
simultaneous “click chemistry” and ATRP, (c) full-PEG/PHEMA-sIPN
properties of sIPNs were also studied. Figure 6 shows the
thermogravimetric analysis (TGA) results of the pristine PEG
network from “click chemistry” (curve a), semi-PEG/PHEMA-
sIPN (curve b), full-PEG/PHEMA-sIPN (curve c), and the
PHEMA-co-PPEGDA network from ATRP (curve d). The
weight loss of semi-PEG/PHEMA-sIPN and full-PEG/PHEMA-
sIPN commences at the temperature of about 290 °C, which is
lower than that (350 °C) of the pristine PEG network but is
higher than that (250 °C) of the PHEMA-co-PPEGDA network.
The network from ATRP consists of a dense cluster of multiple
acrylate groups within a weakly cross-linked matrix.45 Thus,
the introduction of easily decomposable composition (network
or linear polymer from ATRP) reduces the thermal stability of
semi- and full-PEG/PHEMA-sIPNs.
The differential scanning calorimetry (DSC) thermograms of
sIPNs were investigated in the temperature range of 0 to 200
°C. The results are shown in Figure 7. There were two transitions
in the DSC curves of semi-PEG/PHEMA-sIPN and full-PEG/
PHEMA-sIPN. The first weak endothermic peak appeared at
around 50 °C is associated with the melting temperature (Tm)
of the PEG network, which is comparable to that (55 °C) of
via simultaneous “click chemistry” and ATRP, and (d) PHEMA-co-
PPEGDA network from ATRP.
the pristine PEG-based network. The second endothermic peak
at around 88 °C is attributable to the glass transition temperature
(Tg) of PHEMA and the PHEMA-co-PEGDA network. The
DSC results are thus consistent with the structures of semi-
PEG/PHEMA-sIPN and full-PEG/PHEMA-sIPN prepared by
simultaneous ATRP and “click chemistry”.
3.4. Antifouling Property of the sIPNs. For application as
biomaterials, such as soft contact lenses, the ability to resist
protein adsorption (or the antifouling property) is very important.
The antifouling properties of pristine PEG network, PHEMA-
co-PPEGDA network, full- and semi-PEG/PHEMA-sIPNs
against the plasma protein, BSA, were studied. Figure 8 shows
the amount of absorbed protein on the hydrogel samples after
equilibrating in 1% (mg/mL) PBS of BSA at the physiological
pH of 7.4 for 48 h. The PHEMA-co-PPEGDA network exhibits
a higher BSA absorption (11.3 mg/g-1) than the pristine PEG

1816 Biomacromolecules, Vol. 11, No. 7, 2010
Xu et al.
and good thermal stability, as well as good antifouling
properties. The so-prepared semi-PEG/PHEMA-sIPN and
full-PEG/PHEMA-sIPN are, thus, potentially useful as
biomedical materials and vehicles for drug delivery. The
synthesis method also provides a versatile platform for
preparing other functional semi- or full-sIPNs by using
different monomers and different azide/acetylene functional
polymer pairs.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China Grant 20804009
and the Key Project of Chinese Ministry of Education Grant
108062. This work was also supported by the Program for
New Century Excellent Talents in University Grant NCET-
08-0117 and the Southeast University Foundation Grants
400741012 and 4007041023.
Figure 7. Differential scanning calorimetry (DSC) of (a) the PHEMA-
co-PPEGDA network from ATRP, (b) semi-PEG/PHEMA-sIPN via
simultaneous “click chemistry” and ATRP, (c) full-PEG/PHEMA-sIPN
via simultaneous “click chemistry” and ATRP, and (d) PEG-based
network from “click chemistry”.
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