Development of a biocompatible and biodegradable hybrid hydrogel platform for sustained release of ionic drugs

Article abstract of DOI:10.1039/c4tb00576g

In this study, we reported the development of a new drug encapsulation strategy and a robust hybrid hydrogel platform for controlled and sustained release of small and large molecule ionic drugs. A biodegradable, biocompatible and temperature stimuli resp

Full text of DOI:10.1039/c4tb00576g

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ARTICLE
Development of a biocompatible and biodegradable
hybrid hydrogel platform for sustained release of
ionic drugs
Cite this: DOI: 10.1039/x0xx00000x
a
b
c
a, c,*
Received 00th January 2012,
Accepted 00th January 2012
Jun Wu, † Xin Zhao, † Dequn Wu, ChihꢀChang Chu
DOI: 10.1039/x0xx00000x
In this study, we reported the development of a new drug encapsulation strategy and a robust hybrid
hydrogel platform for controlled and sustained release of small and large molecule ionic drugs. A
biodegradable, biocompatible and temperature stimuli responsive hybrid hydrogel platform was
fabricated from arginine based unsaturated poly (ester amides) (ArgꢀUPEA), Pluronic diacrylate
www.rsc.org/
(PluronicꢀDA) and alginate by UV photoꢀcrosslinking method, combining the favorable properties of
hydrogel and polyelectrolyte complex. The hydrogels were systematically characterized, including the
swelling mechanics, mechanical property, biodegradation and interior morphology. In vitro
biocompatibility study showed that the hydrogels could support the cell attachment and proliferation
well. Some model drugs, such as hydrochloride salts of hydralazine, insulin and interleukinꢀ12, were
encapsulated into the hydrogels and the drug release behavior was investigated using HPLC, LCꢀMS,
BCA assay and ELISA assay. The obtained release profiles indicated that the Pluronic/Argꢀ
UPEA/alginate hybrid hydrogels could release ionic drugs over weeks in vitro via a sustained manner.
Hydrogels’ structureꢀfunction study indicated that the polymer structure, hydrogel composition and
environmental temperature had strong effects on the hydrogel property and their drug release profiles.
Introduction
Therefore, there is still a high demand for development of new
functional hydrogels that could release ionic drugs without
Different from microspheres and nanoparticles , hydrogels many drug size/type requirements (small or large molecules)
have attracted wide interests for controlled drug release because through a sustained and controllable manner while maximally
of their biocompatibility, high water content, organic solvent maintaining the original hydrogel properties.
1
ꢀ4
5
ꢀ12
free environment and permeability of molecules
.
Other
A potential solution is to introduce a secondary functional
advantages of hydrogel for drug delivery include easy and component or system into the hydrogels. One example is the
effective drug encapsulation and enhanced stability of many introduction of microspheres or nanoparticles into hydrogels for
6
16ꢀ19
types of proteins or nucleic acids . Furthermore, for the drug delivery applications
environmental stimuli responsive hydrogels, their drug release still had some limitations, such as the nonꢀsatisfactory loading
. However, the reported systems
1
6ꢀ19
behavior could be regulated by environmental stimuli, such as efficacy and release performance
. Based on the charged
. However, for most of the nature of ionic drugs, polyelectrolyte complex (PEC) has been
8
, 13, 14
temperature or pH changes
hydrogels, due to the large interior pore size and hydrophilicity, considered as one of the suitable candidates due to the reported
their releasing rates of ionic drugs (small and large molecules, ability to suppress the initial burst release and have extended
20ꢀ23
including proteins and nucleic acids) are normally rapid due to release behavior for proteins and other charged drugs
.
the 3D microporous structure of hydrogel and fast diffusion of Recently, PECs have been incorporated into hydrogels and the
drug molecules in aqueous environment. Some strategies or resulting hybrid hydrogels could deliver protein in a controlled
2
4, 25
systems have been developed for this shortcoming, such as and sustained manner
. However, for many reported PEC
1
5
cyclodextrin based hydrogels. But this kind of system hydrogel systems, some challenges still exist, including
normally has relative strict requirement for the drug types.
This journal is © The Royal Society of Chemistry 2013
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Journal Name
biocompatibility, biodegradability, manufacturing difficulty and Synthesis of Hydrogel Precursors
drug loading efficiency.
PluronicꢀDA (F127ꢀDA) precursors were synthesized
In this study, for sustainable and controllable release of
ionic drugs, especially for the small molecule ionic drugs, a
multiꢀfunctional hybrid hydrogel system was developed,
containing cationic arginine based unsaturated poly (ester
amides) (ArgꢀUPEA), anionic alginate and thermoꢀresponsive
Pluronic. The hydrogel was fabricated from the mixture of
PluronicꢀDA, alginate and ArgꢀUPEA aqueous solutions by UV
photo crosslinking. Photo crosslinking has been widely used to
28
according to a previously reported method . The ArgꢀUPEAs
31, 32
were synthesized by the same procedures reported before
.
Briefly, the synthesis of ArgꢀUPEAs could be divided into the
following three steps: the preparation of unsaturated diꢀ
nitrophenyl ester of dicarboxylic acid ( ); the preparation of
tetraꢀ ꢀtoluenesulfonic acid salts of bis (Lꢀarginine), α, ωꢀ
alkylene diesters (II); and the synthesis of ArgꢀUPEAs (III) via
solution polycondensation of ( ) and (II). For the specific Argꢀ
p
ꢀ
I
p
I
6ꢀ11
prepare hydrogels
and it could realize better spatial and
UPEA, it’s named as xꢀUArgꢀyꢀz, while x and y is the CH2
number of diacid and diol part of the polymer repeating unit,
respectively. And z means the salt type. The more details about
temporal control over the reaction and gelation reactions can be
performed under very mild conditions, including aqueous
solution, room temperature, body pH, and even in situ in a
minimally invasive manner. Pluronics are biocompatible
polymers with lower critical solution temperature (LCST)
31
the ArgꢀUPEA could be found in previous report . The Argꢀ
UPEA and PluronicꢀDA precursors were purified first by
dissolving the precursors in distilled water and were dialyzed
against deionized water (MW cut off 4,000) under dark
environment for 2 days. After that, the solutions were
lyophilized for 2 days using a Virtis Freeze Drier (Gardiner,
NY) under vacuum at ꢀ48 °C.
2
6ꢀ29
behavior
and Pluronic based hydrogels have shown to
2
6ꢀ29
retain their temperature responsive property
. Anionic
alginate has excellent biocompatibility and has been widely
fabricated into hydrogels or utilized as one component of many
30
PEC systems . ArgꢀUPEAs are newly developed cationic,
water soluble and biodegradable polymers and ArgꢀUPEA Preparation of Hydrogels
3
1ꢀ34
based hydrogels have shown excellent biocompatibility
.
ArgꢀUPEA/PluronicꢀDA/alginate hybrid hydrogels were
prepared by the photoꢀpolymerization of two precursors (Argꢀ
UPEA and PluronicꢀDA) at different weight ratios in aqueous
solution with alginate and initiator. An example of the
fabrication of a hybrid hydrogel using 2ꢀUArgꢀ2ꢀS (S means
However, its drug delivery applications have never been
reported. In this study, ArgꢀUPEA would not only crosslink
with PluronicꢀDA to form the hydrogel scaffold, but also bring
positive charge to the resulting hybrid hydrogels and interact
with anionic alginate inside the hydrogel to form a 3ꢀD macro
PEC hydrogel. A small molecule ionic drug, hydrochloride salts
of hydralazine (Figure S1), was used as a model drug since it
has been used for cardiovascular therapy and wound healing .
Insulin and ILꢀ12 (an antiꢀtumor cytokine) were also selected in
this study as the model protein drug. ILꢀ12, insulin and
hydralazine were preꢀloaded into the hydrogels before photoꢀ
crosslinking. Then various hydrogel formulations have been
characterized in terms of in vitro release kinetics. In addition,
the physicochemical properties and biocompatibility of the
hydrogels were also systematically evaluated.
the salt type is pꢀtoluenesulfonic acid type) as ArgꢀUPEA was
given below: 0.10 g of 2ꢀUArgꢀ2ꢀS, 0.40 g F127ꢀDA and 5.0
mg of photoinitiator Irgacure 2959 (1.0 wt % of total amount of
precursors) were added into a glass vial and dissolved in 2.0
mL of deionized water to form a clear homogeneous solution.
Then 1.0 ml 4.0 wt% alginate deionized water solution was
added into the precursors’ solution and mixed well. The
solution mixture was then transferred to a customꢀmade 20 well
Teflon mold (diameter 12 mm and thickness ≈ 4 mm for each
well). Then the precursor solution in the mold was irradiated by
a longꢀwavelength UV lamp (365 nm, 100 W) for specified
time (normally 2ꢀ5 min) at room temperature. The irradiation
distance is 5ꢀ10 cm. After fabrication, the resultant hydrogels
were moved from the mold and dried in vacuum at room
temperature for 24 hours before further characterization. For
3
5
Experimental
Materials
Pluronic (F127, MW 12,600 and 70 % PEG content), drug loaded hydrogels, preꢀdetermined amount of drugs were
acryloyl chloride, triethylamine, sodium alginate, hydrochloride mixed with alginate solution first and then the mixture was
salt of hydralazine and insulin were purchased from Sigmaꢀ added to the precursor solution before photoꢀcrosslinking. All
Aldrich (St. Louis, MO) and used without further purification. other fabrication conditions were same.
Mouse ILꢀ12 and mouse ILꢀ12 ELISA kit were purchased from
Equilibrium Swelling Ratio & Swelling Kinetics of Hydrogels
R&D systems. Water soluble UV initiator: 2ꢀHydroxyꢀlꢀ [4ꢀ
(
2
hydroxyethoxy)
959), LꢀArginine
monohydrate, fumaryl chloride, ethylene glycol, 1, 4ꢀbutanediol ×100 %, where W is the weight of a swollen hydrogel at
phenyl]ꢀ2ꢀmethylꢀlꢀpropanone
(Irgacure
The equilibrium swelling ratio (Q ) of the hydrogel is
eq
(LꢀArg), pꢀtoluenesulfonic
acid calculated by the following equation: Qeq = [(W ꢀW )/ W ]
e
d
d
e
and pꢀnitrophenol were all purchased from Alfa Aesar (Ward equilibrium and W is the weight of the corresponding dry
d
Hill, MA) and used without further purification. Other hydrogel at t = 0. All swelling ratio results were obtained from
chemicals and reagents if not otherwise specified were triplicate samples and data were expressed as the means ±
purchased from SigmaꢀAldrich (St. Louis, MO).
standard deviation. The swelling kinetics of the Argꢀ
2
| J. Name., 2012, 00, 1-3
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UPEA/F127ꢀDA/alginate hydrogels was measured over a hydrogel was selected as the hydrogel control. The cells used
period of 4 days at room temperature. Each dry Argꢀ for this study were BAECs and Detroit 539 human fibroblast.
UPEA/F127ꢀDA/alginate hydrogel sample was weighed and The purified swollen hydrogels were cut into round shape with
immersed in 20 mL of solutions with different parameters for the diameter that just filled the well of 24ꢀwell cell culture
predetermined periods. Before weighing, the samples were plates at 37 °C in cell culture media. Before being put into the
taken from the solutions and blotted with filter papers to 24ꢀwell cell culture plates, the hydrogels were sterilized under
remove excess surface water. The swelling ratio (Q) of the UV light (in the cell culture hood) for 2 h. After that, the
hydrogel at time t is calculated by the following equation: Q = hydrogels were washed twice by PBS buffer and cell culture
[
(W ꢀW )/ W ] ×100 %. W is the weight of the corresponding media. Then, the hydrogels were placed into the wells of the
t d d t
dry hydrogel at time t.
cell culture plate and fixed by sterilized rubber ring which has
the same diameter as the well of cell culture plate. BAECs or
fibroblast cells were seeded at an appropriate cell density
Compressive Modulus of Hydrogels
The mechanical property of the ArgꢀUPEA/F127ꢀ (10,000 cells/well) and incubated overnight. After 48 h
DA/alginate hydrogels was measured by a 2980 Dynamic incubation, the cell attachment and proliferation on the
Mechanical Analyzer (DMA) (TA Instruments Inc., New hydrogel surface was record by an optical microscope.
Castle, DE) in a ‘‘controlled force’’ (CFꢀmode) mode. The
Controlled Release of Ionic Drugs via Hydrogels
swollen hydrogel samples in circular disc shape were
submerged in distilled water and mounted between the movable
compression clamp (diameter 30 mm) and the fluid cup with a DA/alginate hydrogels was carried out in a PBS buffer at 37
.1 N preloading force. A force ramp from 0.1 N at a rate of 0.3 or room temperature. Hydralazine was preloaded into the
For hydralazine, its release from the ArgꢀUPEA/Pluronicꢀ
°
C
0
or 0.5 N/min was applied. All measurements were carried out at hydrogel samples according to the following protocol: preꢀ
room temperature. The compression elastic modulus (E) of the determined amount of hydralazine was directly mixed alginate
swollen hydrogel was extracted by plotting the compressive first, the mix with ArgꢀUPEA, PluronicꢀDA precursors and
tress versus strain. All compression elastic modulus data in this photoꢀinitiators in distilled water, and the solution mixture was
study were obtained from triplicate samples and data were UV irradiated for 3ꢀ5 mins to form drug loaded hydrogels. The
expressed as the means ± standard deviation.
drug loaded hydrogels were then placed inside small vials
containing 10.0 mL PBS solution (one piece of hydrogel per
vial). The vial was incubated at 37 °C or room temperature with
In vitro Enzymatic Biodegradation of Hydrogels
The in vitro biodegradation of the ArgꢀPEA/F127/alginate a constant reciprocal shaking (ca. 100 rmp). The hydralazine
hybrid hydrogels was evaluated. Briefly, freshly prepared and contents were then analyzed by a high performance liquid
purified hydrogel was placed into a glass vial containing 10 mL chromatography (HPLC). The following are the details of
PBS buffer (pH 7.4, 0.067 M) or 0.1 mg/mL trypsin in 10.0 mL measuring hydralazine concentration via HPLC. To determine
PBS buffer. The hydrogel was then incubated at 37 °C with a the release amounts of the drug at predetermined time points,
constant reciprocal shaking (ca. 100 rpm). The trypsin solution 50 µL of the immersion solution was removed from the vial and
was changed every other day and at each measuring time point. added into a HPLC vial followed by adding 950 µL PBS buffer
At the end of predetermined period, the hydrogels were to dilute the solution. The solution was thoroughly vortexed
removed (or collected by filtration if broken into small parts), before tested by a HPLC (HP 1100 model, Palo, Alto, CA,
then washed with 10 mL distilled water for 5 minutes for 3 USA) equipped with a diode array detector. A C18 reversed
times, and then dried in freeze drying machine for 24 h to phase column (5 um, 4.6X250 nm, Alltech Adsorbosphere XL)
completely remove the residue water.
was used as the stationary phase, while the mobile phase
consisted of acetonitrile and water (pH 3.0) in the volume ratio
Interior Morphology of Hydrogels
6
3:37. The injection volume was 50 or 100 µL based on the
Interior morphology of ArgꢀUPEA/PluronicꢀDA/alginate released hydralazine concentration and the mobile phase was
hydrogels was investigated by scanning electron microscope pumped at a flow rate of 2.0 mL/min. Detection was at 365 nm
(
SEM). The swollen hydrogel samples, after reaching their with a UV detector. ChemStation (Palo, Alto, CA, USA)
maximum swelling ratio in distilled water at room temperature, software was used for data analysis. All drug release tests at
were quickly frozen in liquid nitrogen and then freezeꢀdried each time point were carried out in triplicate and variation was
under vacuum at ꢀ48 °C for 3 days until all water inside the expressed as a standard error of the mean. The confirmation of
hydrogel was sublimed. The freezeꢀdried hydrogel samples hydralazine chemical structure was carried out by GCꢀMS
were then cut and fixed on aluminum stubs and then coated method and the major diagnostic MS fragments were analyzed.
with gold for 30 seconds for interior morphology observation For insulin and ILꢀ12 release study, the released contents were
with a SEM instrument (Leica S440, Germany).
measured by BCA assay and ELISA assay, respectively. All
other steps were same as the protocol for hydralazine release
study.
Cell attachment and proliferation on hydrogel surface
The cell attachment on the ArgꢀUPEA/F127ꢀDA/alginate
hybrid hydrogel surface was evaluated and pure F127ꢀDA
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Jou4TrnB0al Name
Results and Discussion
to work as a polymer surfactant buffer to reduce the interactions
between positively charged ArgꢀUPEA and negatively charged
To achieve sustained release of ionic therapeutics, especially alginate. The specially designed ArgꢀUPEAs have good water
for small molecule ionic drugs, we developed a novel solubility (> 2.0 wt%) and the molecular weight is below 15.0
biocompatible and biodegradable hybrid hydrogel platform KDa. After testing, it’s been confirmed that mixing of Argꢀ
utilizing a new simple fabrication strategy, which would UPEAs and alginate would not form visible insoluble or
maximally keep the original hydrogels properties and be precipitated complexes. And the large amount of the Pluronicꢀ
suitable for a variety of ionic drugs with different MW range. DA would further reduce the interaction and avoid the
This hybrid hydrogel system would not only combine the formation of insoluble or precipitated complexes of ArgꢀUPEA
favorable properties of hydrogel and PECs, but also utilize the and alginate. During the mixing step, the ArgꢀUPEAs would
special characteristics of arginine (high pKa) and Pluronic mix with PluronicꢀDA first, then the alginate with drug would
(
temperature responsive). The wide variety of hydrogel be added for further mixing. Since the charge density of Argꢀ
components (various precursors) and material parameters UPEA and alginate is around 2.5 mol/kg and 5.7 mol/kg,
molecular weight, composition ratio, type and degree of cross respectively, the weight ratio of ArgꢀUPEA to alginate was
(
linking) may allow us to engineer the hydrogels with a wide fixed at 2.5 in this report so that the PEC could be formed well
range of ionic drug release kinetics. And the understanding of while the net charge of the hydrogel is a little bit positive,
these structureꢀfunction relationships would be very helpful to which would be good for the cell attachment and proliferation.
develop new generations of hydrogels having finely The naming of the hybrid hydrogel in this study is: Argꢀ
controllable and sustained drug release performance.
UPEA/F127ꢀDA/alginate (m/n, w/w). The m/n is the weight
ratio of ArgꢀUPEA to F127ꢀDA (the weight ratio of Argꢀ
UPEA/alginate has been fixed at 2.5).
Synthesis of Precursors
In this report, Pluronics were chosen as a precursor
component due to their excellent biocompatibility, water
solubility, low toxicity, low immunogenicity and temperature
2
6ꢀ29
responsive property
. Among a variety of Pluronics, F127
was chosen because of its suitable chain length for chemical
modification and hydrogel fabrication. The synthesis scheme of
the F127ꢀDA could be found in the supporting information
(
Figure S2).
Unsaturated diꢀ
Monomer , diꢀ ꢀNitrophenyl Fumarate (NF), x=2) was
ꢀnitrophenol as
ꢀtoluenesulfonic acid salt
of Lꢀarginine diesters (Monomer II) were prepared in this
study: tetraꢀ ꢀtoluenesulfonic acid salt of bis (Lꢀarginine)
ethane diesters Argꢀ ꢀS (y=2); tetraꢀ ꢀtoluenesulfonic acid salt
of bis (Lꢀarginine) butane diesters, Argꢀ ꢀS (y=4). ArgꢀUPEAs
were prepared by the solution polycondensation of ( ) and (II
monomers (NF and Argꢀ2ꢀS, Argꢀ4ꢀS) at different
p
ꢀnitrophenyl ester of dicarboxylic acid
(
I
p
prepared by reacting fumaryl chloride with
p
3
1
previously reported . Two types of
p
p
Figure 1, Illustration of the 3ꢀD structure of drug loaded
hydrogel (left) and precursors, chemical structure of ArgꢀUPEA
and F127ꢀDA, and the photo image of 2ꢀUArgꢀ2ꢀS/F127ꢀ
DA/alginate (1:4, w: w) hydrogel (swollen (left) and dry
2
p
4
I
)
(
right))
3
1
combinations . The ArgꢀUPEAs synthesized with different
combinations of diacids and diols building blocks were: 2ꢀ
UArgꢀ2ꢀS, 2ꢀUArgꢀ4ꢀS. The two ArgꢀUPEAs synthesized here
have high water solubility (> 2 wt%) and low hydrophobicity
and they would not form visible precipitates with alginate in
Photoꢀcrosslinking time was suggested to be as short as
possible so that the bioactivity of the therapeutics would not be
affected. For this goal, a powerful 100W UV light is used so
that the photoꢀcrosslinking could be completed within mins.
After optimization, the crosslinking time was set at 2ꢀ5 mins,
depending on the composition of the hydrogel. More Argꢀ
UPEA component in the hydrogel would need a little bit longer
time due to the relative weak reactivity of the double bonds of
ArgꢀUPEA. Figure 1 showed the chemical structure of Argꢀ
UPEA and F127ꢀDA, illustration of 3ꢀD structure of ionic drug
loaded hybrid hydrogel (left) and the photo image of a 2ꢀUArgꢀ
aqueous solutions. Other ArgꢀUPEAs with longer CH segment
2
in the repeating unit were not used in this study due to their low
water solubility and high hydrophobicity. The synthesis scheme
of the monomers and polymers could be found in the
supporting information (Figure S3).
Fabrication of Hydrogels
In this report, PluronicꢀDA was selected as a coꢀprecursor
to facilitate photoꢀcrosslinking of ArgꢀUPEA with Irgacure
2
ꢀS/F127ꢀDA/alginate hydrogel (swollen (left) and dry (right)).
All the fabricated ArgꢀUPEA/F127ꢀDA/alginate hydrogels in
this report were transparent or light white after reaching their
swelling equilibrium. The successful fabrication of Argꢀ
2
959 as the photo initiator in an aqueous system. Besides the
previously mentioned functions of PluronicꢀDA, one more
important role of PluronicꢀDA in the hydrogel fabrication was
4
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UPEA/F127ꢀDA/alginate hybrid hydrogels was confirmed by showed the equilibrated swelling ratios at room temperature for
elemental analysis (Table 1). By measuring the nitrogen the hybrid hydrogels with varied compositions. F127ꢀDA and
element percentage of dried hydrogels, it was confirmed that ArgꢀUPEA/F127ꢀDA hydrogels were used for comparison.
most of the ArgꢀUPEAs were successfully introduced into the First, the equilibrium swelling ratios of ArgꢀUPEA/Pluronicꢀ
hydrogels. The measured N contents in Table 1 were slightly DA/alginate hybrid hydrogels in DI water were always slightly
lower than the theoretical value (in the parentheses). The higher than that of the corresponding hydrogels in PBS
theoretical value was estimated according to the molecular solution, but no significant difference in equilibrium swelling
structure of polymer repeating unit and hydrogel composition ratio between PBS and DI media was observed for the pure
(
before crosslinking).
F127ꢀDA hydrogel. This result suggested that the electrolytes
in PBS might interfere with the interaction between water
molecules and charged groups in the hybrid hydrogels. Second,
Equilibrated Swelling Ratio & Swelling Kinetics of Hydrogels
The swelling behavior of the hybrid hydrogels was the equilibrated swelling ratio of all ArgꢀUPEA/Pluronicꢀ
systematically examined in terms of equilibrated swelling ratio DA/alginate and ArgꢀUPEA/PluronicꢀDA hybrid hydrogels
and swelling kinetics and
as a function of hydrogel were higher than that of pure PluronicꢀDA hydrogel (1,144 ±
compositions (the weight feed ratio of ArgꢀUPEA to F127ꢀDA) 17% and 1,150 ± 40 % in DI water and PBS, respectively),
and y parameter of ArgꢀUPEA.
while the ArgꢀUPEA/PluronicꢀDA/alginate hybrid hydrogel
showed a little bit smaller equilibrated swelling ratio than that
Table 1, ArgꢀUPEA/F127ꢀDA Hybrid Hydrogels and Their of the corresponding ArgꢀUPEA/PluronicꢀDA hydrogel. These
Physicochemical Properties
Sample
results implied that the incorporation of ArgꢀUPEA segment
did enhance equilibrated swelling ratio of the hydrogels and the
introduction of alginate may slightly reduce the equilibrated
swelling ratio of the hybrid hydrogels. One of the possible
reasons could be due to the electrostatic interaction between the
ArgꢀUPEA and alginate. Third, the equilibrated swelling ratios
of the hybrid hydrogels generally increase with an increase in
the weight feed ratio of ArgꢀUPEA to F127ꢀDA either in DI
water or PBS solution. For example, in DI water and at room
temperature, the hydrogel of 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate
Compressive
Modulus* (kPa)
6.23±0.45
N (%)
2
ꢀUArgꢀ2ꢀS/ F127ꢀ
DA/alginate (1:4, w/w)
ꢀUArgꢀ2ꢀS/ F127ꢀ
DA/alginate (2:3, w/w)
ꢀUArgꢀ4ꢀS/ F127ꢀ
DA/alginate (1:4, w/w)
ꢀUArgꢀ4ꢀS/ F127ꢀ
DA/alginate (2:3, w/w)
2.49
(2.60)
4.62
(4.84)
2.36
(2.51)
4.53
(4.68)
2
4.02±0.36
5.68±0.34
3.54±0.47
2
2
(
1/4, w/w) had an equilibrated swelling ratio of 1711±90%,
while the hydrogel of 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate (2/3, w/w)
had an increased equilibrated swelling ratio of 1889±70%.
Fourth, the equilibrated swelling ratios of the hybrid hydrogels
increase with an increase of the y value of the ArgꢀUPEA either
in DI water or PBS solution at a constant weight ratio of Argꢀ
UPEA to F127ꢀDA. For example, at the feed weight ratio of 1
to 4, in DI water and at room temperature, from 2ꢀUArgꢀ2ꢀ
S/F127ꢀDA/alginate (1/4, w/w) to 2ꢀUArgꢀ4ꢀS/F127ꢀ
DA/alginate (1/4, w/w), the equilibrated swelling ratio
increased from 1711±90% to 1843±50%.
*
Compressive modulus was measured in DI water at room
temperature.
Furthermore, the effects of pH and temperature on the
equilibrium swelling ratios of the ArgꢀUPEA/Pluronicꢀ
DA/alginate hybrid hydrogels were examined as shown in
Figure 3. The preliminary results indicated that the swelling
ratios of the hybrid hydrogels were sensitive to the change of
pH (Figure 3a). For example, for the hybrid hydrogels at a feed
ratio of 1:4, the equilibrium swelling ratio of 2ꢀUArgꢀ2ꢀS/F127ꢀ
DA at an acidic pH (pH = 4) was much higher than that at a
basic condition (pH = 10). However, the introduction of
alginate slightly reduced this pH effect on the equilibrium
swelling ratios. Figure 3b showed that the swelling ratios of the
hybrid hydrogels were also sensitive to the change of
environmental temperature. Due to the temperature responsive
property of F127, all the hydrogels showed temperature
sensitivity: high temperature would cause the shrinking of
hydrogel and low temperature would cause the swelling of
hydrogel. The introduction ArgꢀUPEA and alginate slightly
Figure 2, Equilibrated swelling ratio of ArgꢀUPEA/Pluronicꢀ
DA/alginate hydrogels in PBS (pH=7.4) solution and DI water
at room temperature. a) Pure F127ꢀDA hydrogel (control); b) 2ꢀ
UꢀArgꢀ2ꢀS/F127ꢀDA (1/4, w/w); c) 2ꢀUArgꢀ2ꢀS/F127ꢀ
DA/alginate (1/4, w/w); d) 2ꢀUꢀArgꢀ4ꢀS/F127ꢀDA (1/4, w/w);
e) 2ꢀUArgꢀ4ꢀS/F127ꢀDA/alginate (1/4, w/w); f) 2ꢀUꢀArgꢀ2ꢀ
S/F127ꢀDA (2/3, w/w); g) 2ꢀUꢀArgꢀ2ꢀS/F127ꢀDA/alginate (2/3,
w/w); h) 2ꢀUꢀArgꢀ4ꢀS/F127ꢀDA (2/3, w/w); i) 2ꢀUꢀArgꢀ4ꢀ
S/F127ꢀDA/alginate (2/3, w/w)
For the swelling ratios at equilibrium, they were tested in
both deionized water (DI water) and 1X PBS solution. Figure 2
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reduced the temperature sensitivity of the hydrogel since the DA/alginate (2:3, w/w) hydrogel showed faster degradation
percentage of F127ꢀDA decreased slightly after the than the 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate (1:4, w/w), indicating
introduction, and the whole decreasing trends did not show that more percentage of 2ꢀUArgꢀ2ꢀS/alginate would cause
obvious changes.
faster degradation. The degradation curves for trypsin treated
The swelling kinetics of the ArgꢀUPEA/Pluronicꢀ hydrogels ended before 100% because the degraded hydrogel
DA/alginate hydrogel was studied over a period of 4 days in DI debris was very hard to collect at that time. With the
water at room temperature. For example, Figure 4 showed the uncrosslinked but electronic absorbed alginate, the possible
hydrogels of varied compositions (different types of Argꢀ physical structure of the hybrid hydrogels could be close to a
UPEAs or feed weight ratio of ArgꢀUPEA to F127ꢀDA) had a semiꢀIPN or double network. Some reports have discussed the
high swelling rate during the initial 3 hours. After the initial 3 enzymatic biodegradation of semiꢀIPN hydrogels and the
hours, the swelling rate levelled off, and finally reached their degradation behaviour/rate depends on the hydrogel type,
3
6ꢀ38
swelling equilibrium within about 12ꢀ18 hours. Compared with composition, enzyme type and concentration
. For the Argꢀ
the pure F127ꢀDA hydrogel and ArgꢀUPEA/PluronicꢀDA UPEA/PluronicꢀDA/alginate hybrid hydrogel platform, the
3
1
hydrogel , the corresponding ArgꢀUPEA/PluronicꢀDA/alginate biodegradation mechanism is complicated due to the
hydrogel did not show obvious swelling rate difference.
complicated structure and composition of this hybrid hydrogel
platform. The role of PluronicꢀDA in biodegradation is also
important since it’s the main component and forms the major
part of the hydrogel network. Therefore, further systematic
investigation is needed for the details of the enzymatic
degradation of this platform.
20
15
10
5
0
F127-DA
2-UArg-2-S/F127-DA/alginate (1:4, w/w)
2-UArg-2-S/F127-DA/alginate (2:3, w/w)
2-UArg-4-S/F127-DA /alginate(1:4, w/w)
2-UArg-4-S/F127-DA/alginate (2:3, w/w)
0
20
40
60
80
Swelling Time (h)
Figure 4,
Swelling kinetics of the ArgꢀUPEA/Pluronicꢀ
DA/alginate hydrogel
2-UArg-2-S/F127-DA/alginate/(1:4, w/w)/PBS
1
20
00
2-UArg-2-S/F127-DA/alginate/(1:4, w/w)/trypsin
2-UArg-2-S/F127-DA/alginate/(2:3, w/w)/PBS
-UArg-2-S/F127-DA/alginate/(2:3, w/w)/trypsin
2
1
8
0
0
6
Figure 3, Equilibrium swelling ratios of the hybrid hydrogels in
aqueous solution as a function of the pH value (a, at room
temperature) and temperature value (b, in DI water)
40
20
0
Biodegradation of Hydrogels
0
5
10
15
20
25
30
Time (d)
Figure 5 showed some biodegradation results of 2ꢀUArgꢀ2ꢀ
S/F127ꢀDA/alginate hydrogels.
In PBS buffer, without
enzyme, the hydrogels showed no obvious degradation within 1 Figure 5,
Biodegradation of the ArgꢀUPEA/Pluronicꢀ
month. Therefore, in PBS buffer, the biodegradation was slow DA/alginate hydrogel at 37 °C
and would not affect the drug release mechanism greatly.
Interior Morphology (SEM) of Arg-UPEA/F127-DA Hydrogels
However, the 0.1 mg/mL trypsin enzyme would help to degrade
the hydrogel completely for 2ꢀ3 weeks. 2ꢀUArgꢀ2ꢀS/F127ꢀ
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The crossꢀsectional interior morphology of the freeze dried culture. For the cells cultured on the hybrid hydrogel surface,
ArgꢀUPEA/F127ꢀDA/alginate hydrogel was examined by SEM there were no visible signs of cell rounding or membrane
to further understand the 3ꢀD structure of hybrid hydrogel. blebbing which would indicate cell death. The BAEC cells
Even though the interior structure/morphology of hydrogel after attached onto the pure F127ꢀDA hydrogel surface, however, did
freeze drying would be different from the real state of the show some morphology change and the BAEC cells did not
swelling hydrogel, it is still a very helpful index for obtaining completely attach and spread on the F127ꢀDA hydrogel surface.
first hand detail of the hydrogel 3ꢀD interior micro structure. As The light dots are air bubbles. Therefore, the cell culture results
shown in Figure 6a, compared with ArgꢀUPEA/F127ꢀDA indicated the 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate could support the
3
1
hydrogels , the ArgꢀUPEA/F127ꢀDA/alginate hydrogel has cell attachment and proliferation well, which would bring this
similar average pore size and cell wall thickness, but a little bit platform a great potential as a new type of scaffolds for drug
more nanofiber webs entangled with the hydrogel cells. Figure delivery applications.
6b showed an example of the interior morphology change of
ArgꢀUPEA/F127ꢀDA/alginate hybrid hydrogel after 30 days’
incubation at 37 °C in PBS buffer.
Figure 6, SEM images of freeze dried 2ꢀUArgꢀ2ꢀS/F127ꢀ
DA/alginate (1:4, w/w) hybrid hydrogel (a: 0 day incubation in
PBS; b: 30 days incubation in PBS). White scale bar is 30 µm.
Figure 7, Representative micrographs of Detroit 539 human
fibroblast and BAEC cells after 48 h culture on the hydrogel
Cell Attachment and Proliferation on Hydrogel Surface
Excellent biocompatibility of hydrogel is a prerequisite for surface, 10x, white scale bar is 200 µm. a) Detroit 539 human
its potential biomedical/clinical applications. Here the cellular fibroblast cells cultured on the surface of pure F127ꢀDA
interaction with ArgꢀUPEA/F127ꢀDA/alginate hybrid hydrogels hydrogel; b) Detroit 539 human fibroblast cells cultured on the
was studied to preliminarily evaluate the biocompatibility of surface of 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate (1/4, w/w) hydrogel;
hydrogels. The fibroblast and BAEC cells were cultured on the c) BAEC cells cultured on the surface of pure F127ꢀDA
surface of ArgꢀUPEA/F127ꢀDA hybrid hydrogels to investigate hydrogel; d) BAEC cells cultured on the surface of 2ꢀUArgꢀ2ꢀ
the cell attachment and proliferation performance. Figures 7a S/F127ꢀDA/alginate (1/4, w/w) hydrogel.
and 7b showed one example of the Detroit 539 human
fibroblast cells cultured for 48h on the surface of pure F127ꢀDA
hydrogel and 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate (1/4, w/w) hybrid
Controlled release of hydralazine, insulin and IL-12 via Arg-
UPEA/F127-DA/alginate Hybrid Hydrogels
hydrogel, respectively. Compared with the pure F127ꢀDA
hydrogel control, the hybrid hydrogel had better cell drugs, especially small molecule ionic drugs, is still a big
morphology and much higher amounts of the challenge for most of the hydrogel system. Combine the unique
As we discussed before, the sustained release of ionic
attached/proliferated fibroblast cells after 48 h, and the density properties of hydrogel and PEC, this platform is expected to be
and morphology of the attached/ proliferated fibroblast cells able to release a variety of ionic drugs in a sustained manner.
3
1
were in the same level as the 2ꢀUArgꢀ2ꢀS/F127ꢀDA hydrogel .
Hydralazine (Apresoline, Figure S1), as a model small
This result indicated that the introduction of alginate did not molecule ionic drug, was preloaded into the hydrogel samples
change the biocompatibility of the ArgꢀUPEA/F127ꢀDA (small pellet). The loading amount of hydralazine was set at 5
hydrogel. Figures 7c and 7d showed another example of the or 10 wt% of ArgꢀUPEA plus alginate. The drug content was
BAEC cells cultured for 48 h on the surface of pure F127ꢀDA analyzed by high performance liquid chromatography (HPLC).
hydrogel and 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate (1/4, w/w) hybrid The elution time of the hydralazine chlorine salt peak is around
hydrogel, respectively. Normally, endothelial cells are more 2.35ꢀ2.37 mins, which was consistent with the previous reports
3
9, 40
sensitive to the cell culture environment than the fibroblast
. The confirmation of the chemical structure of the released
cells. For the BAEC cell morphology, there is significant hydralazine was carried out by LCꢀMS method and the major
3
9, 40
morphology change between the F127ꢀDA hydrogel control diagnostic MS fragments were analyzed
. The result (Table
(
Figure 7c) and hybrid hydrogel surface (Figure 7d) after 48 h’s S1) showed that the released hydralazine chlorine salt did not
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have any change. A standard curve was made for the calibration
supporting information, Figure S4). The Figure 8a showed
(
some release data of hydralazine via ArgꢀUPEA/F127ꢀ
DA/alginate hydrogels in PBS buffer. The release data from
pure F127ꢀDA hydrogel and ArgꢀUPEA/F127ꢀDA showed that
all the drugs were released within 4ꢀ6 hours. The reasons could
be due to the large hydrogel pore size, small MW/size of
hydralazine salt and same charge property of hydralazine and
ArgꢀUPEA (electrical repulsion).
For ArgꢀUPEA/F127ꢀ
DA/alginate, around 20ꢀ25 wt% hydralazine would be released
within 4ꢀ6 hours, and then the release time would be within
weeks depending on the hydrogel formulation or temperature.
For examples, higher percentage of ArgꢀUPEA /alginate (2ꢀ
UArgꢀ2ꢀS/F127ꢀDA/alginate (2/3, w/w) hydrogel) would cause
slower release of hydralazine than the 2ꢀUArgꢀ2ꢀS/F127ꢀ
DA/alginate (1/4, w/w) hydrogel due to the stronger
electrostatic density/interaction, while room temperature would
cause faster release of hydralazine than 37 °C due to the larger
pore size (larger equilibrated swelling ratio). Therefore, this
hybrid hydrogel platform could achieve the sustained release
and easy regulating the release profiles of small molecule ionic
drugs.
Due to the significantly different properties of insulin and
ILꢀ12, the release profiles of insulin and ILꢀ12 from Argꢀ
UPEA/F127ꢀDA/alginate hydrogels were different from the
hydralazine. Insulin has a MW around 5,800 Da and isoelectric
point about 5.3, while the mouse ILꢀ12 has a MW around 75
KDa and isoelectric point about 4.3. The loading amount of
insulin was set at 20 wt% of ArgꢀUPEA plus alginate and the
loading amount of ILꢀ12 was set at 5 µg per hydrogel pellet.
Figure 8b showed the insulin release profiles from hydrogels in
PBS buffer at 37 °C. The insulin content was analyzed by BCA
assay. Since the hydrogel show no biodegradation in PBS
buffer (without enzyme) for at least 1 month. The ArgꢀUPEA
component will not affect the BCA assay results much. The
release data from pure F127ꢀDA hydrogel showed that the
insulin release was completed around 1 day. For the 2ꢀUArgꢀ2ꢀ
S/F127ꢀDA (1/4, w/w) hydrogel, the insulin release was
completed around 7 days due to the strong electrostatic
interaction between ArgꢀUPEA and insulin and relative big size
of insulin. For ArgꢀUPEA/F127ꢀDA/alginate hydrogel, around
1
0ꢀ15% insulin would be released within 4ꢀ6 hours, then the
sustained release was obtained for around 2ꢀ3 weeks for 2ꢀ
UArgꢀ2ꢀS/F127ꢀDA/alginate (1/4, w/w) hydrogel. Figure 8c
showed some release data of ILꢀ12 from hydrogels in PBS
buffer at 37 °C. The ILꢀ12 was analyzed by ELISA assay.
Compared with insulin release profile, the ILꢀ12 release profile
showed slower release rate due to the much larger MW/size and
sustained release were observed for both 2ꢀUArgꢀ2ꢀS/F127ꢀDA
(
1/4, w/w) and 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate (1/4, w/w)
hydrogels. The 2ꢀUArgꢀ2ꢀS/F127ꢀDA/alginate (1/4, w/w) Figure 8, Controlled ionic drug release from hydrogels. a)
hydrogel showed slower release rate than the 2ꢀUArgꢀ2ꢀ Hydralazine chlorine salt; b) insulin; c) ILꢀ12
S/F127ꢀDA (1/4, w/w) hydrogel.
Acknowledgements
Cornell University Morgan Tissue Engineering Seed Grant
Program is greatly appreciated for the financial support. We
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DOI: 10.1039/C4TB00576G
also thank Prof. C. A. ReinhartꢀKing at Cornell University for 22. N. Bertrand, J. Wu, X. Xu, N. Kamaly and O. C. Farokhzad,
using her lab for some cell culture work.
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H. Pan, W. Chen, S.ꢀM. Chiao, B. S. Hsiao and B. Chu,
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Ithaca, NY, 14853, USA; Phone: (607) 255ꢀ1938; Fax: 607ꢀ255ꢀ1093;
Email: cc62@cornell.edu.
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DOI: 10.1039/C4TB00576G
Development of a biocompatible and biodegradable hybrid hydrogel
platform for sustained release of ionic drugs
a
b
c
a, c,*
Jun Wu,
† Xin Zhao, † Dequn Wu, Chih-Chang Chu
We have developed and characterized a new hydrogel platform for ionic drug delivery, incorporating cationic, anionic, and temperature responsive precursors.
In vitro biological assays show that these polymers have excellent biocompatibility, controllable biodegradability, and sustained ionic drug release capability.