Journal of Biomaterials and Nanobiotechnology, 2011, 2, 250-257
doi:10.4236/jbnb.2011.23032 Published Online July 2011 (
Copyright © 2011 SciRes. JBNB
Preparation, Characterization and Drug-Release
Behaviors of Crosslinked Chitosan/Attapulgite
Hybrid Microspheres by a Facile Spray-Drying
Qin Wang1, Jie Wu2, Wenbo Wang1, A iqin Wang1,2*
1Center of Eco-material and Green Chemistry, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou,
China; 2Key Laboratory for Attapulgite Science and Applied Technology of Jiangsu Province, Huaiyin Institute of Technology,
Huaian, China.
Email: *
Received February 28th, 2011; revised March 20th 2011; accepted April 20th, 2011.
A series of chitosan/attapulgite (CTS/APT) hybrid microspheres were prepared by a facile spray-drying technique. The
developed hybrid microspheres were characterized by Fourier transform infrared spectra (FTIR), X-ray powder dif-
fraction (XRD), scanning electron microscopy (SEM) and the zeta potential. The encapsulation efficiency and in vitro
controlled release properties of the microspheres for drug were evaluated using diclofenac sodium (DS) as a model
drug. Results indicated that the introduction of APT into crosslinked CTS microspheres can achieve narrow size distri-
bution and make them more uniform. The isoelectric point of the microspheres increased from 8.14 to 9.18 with in-
creasing the content of APT to 10 wt%. DS loaded in hybrid microspheres is hardly released in simulated gastric fluid,
but quickly released in simulated intestinal fluid. The electrostatic interaction between hybrid microspheres and DS can
improve the encapsulation efficiency and controlled release behavior of CTS/APT microspheres, and the release
mechanism fits Fickian diffusion.
Keywords: Microsphere, Chitosan, Attapulgite, Spray Drying, Controlled Release
1. Introduction
During recent decades, microspheres have been widely
used in pharmaceutical applications due to their numer-
ous advantages such as higher bioavailability, prolonging
drug release, high dispersibility and fast permeability as
well as providing an optimal microenvironment for ef-
fective drug delivery [1]. Microspheres are mainly pro-
duced by different technological procedures like emul-
sion-crosslinking [2], ionic gelation [3], sieve method [4]
and spray-drying technique [5,6], etc. Among them, the
spray-drying technique is a one-step constructive process,
which provides greater control over particle size, particle
morphology and powder density and avoids tedious
processes. Hence, spray-drying becomes the most facile
and preferred technique for the fabrication of micro-
spheres, and it has been used widely in medical industry
due to the low cost and available equipment [7].
Chitosan (CTS) is one of the most extensively studied
polysaccharides and has shown great potential as a drug
carrier [8-10]. CTS microspheres obtained by spray-
drying technique draw considerable attention for both
oral and systemic applications in the drug delivery sys-
tem. These drug-loading microspheres not only have a de-
sirable size range in favor of respiration and absorption,
but also can provide a high loading efficiency [6,11].
However, the burst effect of drug loaded in pure CTS mi-
crospheres is undesirable in neutral or basic conditions,
which limited the application of CTS-based drug carriers
Recently, polymer with layered silicate or poly-
mer/layered silicate composites have received significant
attentions from both the academic and industrial area.
The introduction of clay minerals into organic matrix not
only solved the burst problem of the loaded drugs, but
also enhanced the stability of the delivery system in
simulated gastric fluid [15-17]. Attapulgite (APT) is a
Preparation, Characterization and Drug-Release Behaviors of Crosslinked Chitosan/Attapulgite
Hybrid Microspheres by a Facile Spray-Drying Technique
Copyright © 2011 SciRes. JBNB
type of naturally occurred nano-scale fibrous silicate clay,
consisting of two double chains of the pyroxene-type
(SiO3)2 like amphibole (Si4O11)6 running parallel to the
fibre axis, and used in drug delivery system [18]. To date,
the application of polymer/clay microspheres prepared
by a spray-drying technique drug as a delivery system
has not been reported. So, it is expected that the network
structure and drug-delivery properties of the microspheres
could be improved by the introduction of nanoscale APT
into crosslinked CTS microspheres.
In this work, APT was introduced into crosslinked
CTS microspheres to derive hybrid microspheres in order
to alleviate the burst problem of pure CTS microspheres
for DS in the gastrointestinal environment. The resultant
microsphere was characterized by Fourier transform in-
frared spectra (FTIR), X-ray powder diffraction (XRD)
and scanning electron microscopy (SEM). The encapsu-
lation efficiency and in vitro release behaviors were sys-
tematically evaluated using diclofenac sodium (DS) as a
model drug.
2. Materials and Methods
2.1. Materials
Chitosan (CTS, degree of deacetylation is 0.90, average
molecular weight is 90 × 104) was supplied by Zhejiang
Yuhuan Ocean Biology Co. (Zhejiang, China). Attapul-
gite (APT) was supplied by Mingguang Colloidal Co.
(Anhui, China). Diclofenac sodium (DS) was purchased
from Jiuzhou pharmaceutical factory (He’nan, China).
All the other reagents used were of analytical grade and
all solutions were prepared with distilled water.
2.2. Preparation of Crosslinked CTS/APT
Hybrid Microspheres
The CTS/APT hybrid microspheres were prepared by a
spray drying technique as follows. First, CTS (1.0 g) was
dissolved in 100 mL 1 w/w% acetic acid solution, and a
calculated amount of APT was dispersed into the solu-
tion with a continuous stirring at 200 rpm for 4 h to get a
homogenous dispersion. Second, a moderate amount of
crosslinking agent glutaraldehyde was added into the
above mixture and was further stirred at 1000 rpm for 30
min at room temperature. The resultant suspension was
then spray-dried (Mini Spray Dryer, Type SY1600, China)
through a 0.7 mm nozzle at a feed rate of 12 mL/min,
and the inlet temperature was controlled at 150˚C. Third,
the yellow hybrid microsphere power can be obtained,
and then dried to constant weight in an oven at 70˚C. A
series of crosslinked CTS/APT hybrid microspheres with
different composition were prepared as shown in Table
2.3. Preparation of DS-Loaded Hybrid
Microspheres and Determination of
Encapsulation Efficiency
0.2 g DS was dissolved in 100 mL distilled water and
then 1.0 g of hybrid microsphere was dispersed in the
above solution. After shaking for 12h in a thermostatic
shaker bath (THZ-98A) set at 150 rpm and 30˚C, DS-
loaded hybrid microspheres were isolated by centrifuga-
tion and then dried to constant weight in an oven at 70˚C.
To evaluate the amount of the DS entrapped inside the
hybrid microspheres, an indirect method was used [19].
Aliquots from the filtered solutions remaining after the
removal of the hybrid microspheres were assayed using a
UV-vis spectrophotometer (SPECORD 200, ANALYTIK
JENA AG) at 280 nm. The encapsulation efficiency of
DS entrapped was calculated according to the following
Encapsulation efficiency (%) = (w–cv) × 100/w (1)
where w is the mass of DS used for drug loading, g; c is
the concentration of DS in the filtrate (g mL1) and v is
the volume of the filtrate (mL).
2.4. In Vitro Drug Release
In vitro release experiments were carried out using an
intelligent dissolution apparatus by immersing 0.25 g of
the dried DS-loaded hybrid microspheres in 500 mL dis-
solution media. The dissolution media (pH 2.1 or pH 6.8)
were prepared by combining HCl, KH2PO4 and NaOH
solution according to the Chinese Pharmacopoeia 2005.
The mixture was stirred at 50 rpm and kept at 37 ± 1˚C.
At predetermined time intervals, 5 mL of the solution
was taken and the same amount of the fresh dissolution
media was added back to maintain a constant volume.
The collected 5 mL of solution was filtrated through a
membrane with a pore diameter of 0.45 μm. The filtrate
(3 mL) was diluted to 25 mL with the fresh dissolution
media. The concentration of DS was determined by a
UV-vis spectrophotometer at the wavelength 280 nm,
and then the cumulative release percentage of DS was
2.5. Characterization
FTIR spectra of CTS/APT hybrid microspheres were
recorded on a Thermo Nicolet NEXUS TM spectropho-
tometer using a KBr pellet. SEM observations were taken
using scanning electron microscopy (JSM-5600LV, JEOL,
Ltd.) after the samples were dispersed in ethanol and
coated by a gold film. Power XRD analyses were per-
formed using a diffractometer with Cu anode (PAN alyti-
cal X’pert PRO), running at 40 kV and 30 mA, scanning
from 3˚ to 40˚ at 3˚/min. The zeta potential was measured
Preparation, Characterization and Drug-Release Behaviors of Crosslinked Chitosan/Attapulgite
Hybrid Microspheres by a Facile Spray-Drying Technique
Copyright © 2011 SciRes. JBNB
by Zetasizer Nano ZS (Malvern Instruments Ltd., Wor-
cestershire, UK) after the samples (0.1 g) were dispersed
in 10 ml distilled water. Main particle size was deter-
mined using OMEC LS-pop (6) laser particle analyzer
(Omec technology Ltd., Zhuhai, China) after the samples
(0.1 g) were dispersed in 2 ml ethanol.
2.6. Statistical Analysis
All the tests including measurements of drug content and
in vitro drug cumulative release properties were carried
out three times and the averages were reported. Statistical
data analysis was performed using the Student’s t-test
with p < 0.05 as the minimal level of significance.
3. Results and Discussion
3.1. Encapsulation Efficiency of Crosslinked
CTS/APT Hybrid Microspheres for DS and
Their Sizes
Table 1 lists composition of prepared formulations, en-
capsulation efficiency and mean particle size of the hy-
brid microspheres. It can be seen that the encapsulation
efficiency of the hybrid microspheres for DS is always
higher than 98%. This may be mainly attributed to elec-
trostatic interaction between the microsphere carriers and
the DS drug. In order to prove the electrostatic interac-
tion, the zeta potentials of the hybrid microspheres and
DS drug were determined at various pHs and are showed
in Figure 1. It is shown that the isoelectric points of
crosslinked CTS, CTS/APT-1 and CTS/APT-2 micro-
spheres are pHs 8.14, 9.18 and 8.28, respectively; while
the isoelectric point of DS is pH 4.03. This indicates that
the hybrid microspheres show positive charge, and DS
possesses negative charge in distilled water (pH 6.85).
Therefore, a strong electrostatic interaction between the
hybrid microspheres and DS leads to the higher encapsu-
lation efficiency of the hybrid microspheres for DS.
Drug carrier systems with particle size below 200 µm
can prolong the gastrointestinal transit time and control
the release of the encapsulated drug. But in fact, the op-
timal particle size for prolonging residence time of mi-
crospheres in the colon is between 4 and 15 µm [20].
From Table 1, it is observed that the mean particle sizes
of the hybrid microspheres DS loaded range from 3.70 ±
0.001 to 5.27 ± 0.007 µm (D50). This result suggests that
CTS/APT hybrid microspheres can prolong and control
the DS release in the colon. Moreover, microspheres in
that size range are also able to attach more efficiently to
the mucus layer and accumulate in the inflamed region
without the need for macrophage uptake [21].
The size distribution of the hybrid microspheres was
investigated and is presented in Figure 2. As can be seen,
the size distribution of crosslinked CTS microspheres
changes from 0.2 to 19.5 µm, but from 0.2 to 16.11 µm
for CTS/APT-1 hybrid microsphere and from 0.2 to
13.31 µm for CTS/APT-2 hybrid microsphere. This in-
dicates that the introduction of APT into crosslinked CTS
microsphere can achieve narrow size distribution and
make them more uniform. In addition, the particle size
distribution is also expressed in terms of SPAN factor
determined as:
SPAN = (D90 – D10)/D50 (2)
where D10, D50 and D90 are the diameter sizes and the
given percentage value is the percentage of particles
smaller than that size. A high SPAN value indicates a
wide size distribution and a high polydispersity [22].
According to Gottlieb and Schwartzbach’s report [23], a
relative SPAN less than 2.00 for spray-dried with D50
below 10 μm, is normally considered as a narrow distri-
bution in spray drying. It was seen from Table 1 that all
SPAN factor values are lower than 2.00, indicating that
CTS/APT hybrid microspheres have narrow size distri-
3.2. FTIR Spectra
To prove the interaction among crosslinked CTS, APT
and DS, the FTIR spectra of DS, APT, crosslinked CTS,
CTS/APT-1 and DS-loaded CTS/APT-1 hybrid micro-
spheres are shown in Figure 3. As can be seen from
Table 1. Composition of prepared formulations, encapsulation efficiency and mean particle sizes of the hybrid microspheres.
Mean particle size (µm)
Samples CTS (g) APT (g)
Efficiency (%)D10 D
50 D
Crosslinked CTS 4.0 0.0 3.0 98.97 ± 0.01 2.33 ± 0.057 5.27 ± 0.007 8.82 ± 0.156 1.23 ± 0.021
CTS/APT-1 4.0 0.4 3.0 99.04 ± 0.01 2.11 ± 0.035 4.56 ± 0.003 7.47 ± 0.092 1.18 ± 0.030
CTS/APT-2 4.0 0.8 3.0 99.05 ± 0.02 2.35 ± 0.007 4.77 ± 0.028 7.49 ± 0.085 1.09 ± 0.013
CTS/APT-3 4.0 0.4 2.0 98.35 ± 0.04 2.50 ± 0.001 4.92 ± 0.001 7.57 ± 0.014 1.03 ± 0.003
CTS/APT-4 4.0 0.4 4.0 98.87 ± 0.01 1.92 ± 0.007 3.70 ± 0.001 5.64 ± 0.007 1.00 ± 0.004
Preparation, Characterization and Drug-Release Behaviors of Crosslinked Chitosan/Attapulgite
Hybrid Microspheres by a Facile Spray-Drying Technique
Copyright © 2011 SciRes. JBNB
Figure 1. Values of zeta potential (mV) for crosslinked CTS,
CTS/APT-1, CTS/APT-2 and DS in different pH solutions.
Figure 2. Particle size distribution of hybrid microspheres
containing DS.
Figure 3 (b), the main absorption peaks of APT at 1027
and 982 cm–1 are ascribed to the stretching vibration of
Si–OH groups. In Figure 3 (c), the absorption peaks at
1655 cm–1 and 1560 cm–1 are observed and ascribed to
the formation of imine group after crosslinking CTS with
glutaraldehyde [24]. After incorporating APT into the
crosslinked CTS microsphere, the FTIR spectrum in
Figure 3 (d) has no change compared with that shown in
Figure 3 (c). This may be because the absorption peaks
of APT can be covered by the absorption peaks of
crosslinked CTS. The information obtained from (b), (d)
in Figure 3 indicates that APT may be dispersed into the
crosslinked CTS networks by physical mixing.
FTIR spectrum of DS shows a characteristic peak at
1576 cm–1 due to the aromatic stretching and the –COO
asymmetric stretching; the peaks observed at 1507 and
1453 cm–1 are due to N-H deformation and C-N stretch-
ing, respectively; and a sharp peak observed at 765 cm–1
is due to the C-Cl group attached to the aromatic moiety
(Figure 3 (a)). These peak positions are in accordance
with the previous report [25]. The FTIR spectrum in
Figure 3 (e) shows principal peaks of DS molecule at
1575, 1505, 1452 and 750 cm–1 when the DS molecule
were incorporated into the hybrid microspheres, which
indicates the successful entrapment of DS. In addition,
no extra peaks can be seen, indicating there is no chemi-
cal reaction of DS either with crosslinked CTS or with
3.3. XRD Analysis
To further study the interaction between the crosslinked
CTS and APT, the XRD patterns and typical diffraction
peaks of APT, crosslinked CTS, CTS/APT-1 and CTS/
APT-2 hybrid microspheres are shown in Figure 4. As
can be seen, the XRD pattern of APT in Figure 4 (a)
shows a reflection peak at about 2θ = 8.43˚ (basal spac-
ing d = 1.05 nm), and the XRD pattern of the crosslinked
CTS microspheres in Figure 4 (b) shows a reflection
peak at about 2θ = 19.17˚ (d = 0.46 nm). After 10 wt%
APT was incorporated, the typical diffraction peaks of
APT (Figure 4 (c)) are greatly weakened and shifted
from 8.43˚ to 8.39˚, and the typical diffraction peaks of
the crosslinked CTS shifted from 19.17˚ to 19.65˚. More-
over, these diffraction peaks in Figure 4 (d) are further
shifted to 8.38˚ and 19.74˚ as 20 wt% APT was intro-
duced. However, these basal spacing corresponding in
Figures 4 (a)-(d) has no change. The weaken and slight
shift of these diffraction peaks of crosslinked CTS and
APT may be only because of the electrostatic interaction
between crosslinked CTS and APT, instead of chemical
reaction of APT with crosslinked CTS. Moreover, the
invariant basal spacing of APT indicates that crosslinked
CTS may not be intercalated into the monolayer structure
of APT.
3.4. Morphological Analysis
To show the influence of APT on the surface structure of
crosslinked CTS microspheres more directly, the surface
morphologies of crosslinked CTS/APT hybrid micro-
spheres with different amounts of APT were also ob-
served by SEM and are shown in Figure 5. As can be
seen, the hybrid microspheres with different amounts of
APT obtained by the spray-drying technique all exhibited
regular spherical shape. Comparing Figure 5 (a) with
Figure 5 (b) and Figure 5 (c), it can be observed that the
crosslinked CTS microsphere only shows a smooth sur-
face, whereas a coarse surface can be observed for the
Preparation, Characterization and Drug-Release Behaviors of Crosslinked Chitosan/Attapulgite
Hybrid Microspheres by a Facile Spray-Drying Technique
Copyright © 2011 SciRes. JBNB
Figure 3. FTIR spectra of (a) DS, (b) APT, (c) crosslinked CTS, (d) CTS/APT-1 and (e) DS-loaded CTS/APT-1.
Figure 4. XRD patterns of (a) APT, (b) crosslinked CTS, (c)
CTS/APT-1 and (d) CTS/APT-2.
crosslinked CTS/APT hybrid microsphere. With the fur-
ther magnification of the microspheres (Figure 5(a’)-
c’)), it is found that the virgulate crystals of APT are
uniformly dispersed in the microsphere, and the number
of the virgulate crystals increase with enhancing the con-
tent of APT. However, the sphericity of the microsphere
with higher APT content is worse than that of crosslinked
CTS microsphere.
3.5. DS Release Behaviors
The release behaviors of DS from the microspheres with
various composition were investigated and compared in
simulated gastric fluid and simulated intestinal fluid. The
cumulative release percentage of DS from the micro-
sphere formulations were plotted as a function of time
and are shown in Figure 6. Obviously, only little DS re-
leases from the matrices in simulated gastric fluid due to
the insolubility of DS in acidic medium. However, after
being transferred into simulated intestinal fluid, the re-
lease rate is initially higher due to the dissolution of sur-
face-adhered drug, and then the drug release rate was
slowed due to the diffusion process of DS from the in-
ternal network to external solution.
In addition, the release ratio of three microspheres
with various amounts of APT at pH 6.8 phosphate buffer
solution (PBS) is in the order of CTS/APT-2 > cross-
linked CTS > CTS/APT-1 at the same time. This may be
attributed to the follow facts: 1) as can be seen from
Figure 1, CTS/APT-1 hybrid microsphere has the high-
est positive Zeta potential at pH 6.8 PBS compared with
crosslinked CTS and CTS/APT-2 microspheres. This
indicates that crosslinked CTS/APT-1 hybrid micro-
sphere possesses more positive charges and can produce
stronger electrostatic interaction with negatively charged
DS in pH 6.8 PBS. Therefore, the release of DS from
Preparation, Characterization and Drug-Release Behaviors of Crosslinked Chitosan/Attapulgite
Hybrid Microspheres by a Facile Spray-Drying Technique
Copyright © 2011 SciRes. JBNB
Figure 5. SEM of (a) crosslinked CTS (×5000), (b) CTS/
APT-1 (×5000) and (c) CTS/APT-2 (×5000); (a’) crosslinked
CTS (×20000), (b’) CTS/APT-1 (×20000) and (c’) CTS/
APT-2 (×20000).
Figure 6. The cumulative release of DS from hybrid micro-
CTS/APT-1 hybrid microspheres is slow under the action
of strong electrostatic interaction; 2) there is also electro-
static interaction between crosslinked CTS/APT-2 hybrid
microspheres and DS. However, the higher content of
APT causes the more coarse surface compared with
crosslinked CTS and CTS/APT-1 microsphere (Figure 5),
and the coarse surface makes DS deposit on the surface
of the hybrid microsphere in the process of DS adsorp-
tion and microsphere washing. As a result, the marked
burst effect of DS from the surface of crosslinked CTS/
APT-2 hybrid microsphere is observed.
As can be also seen from Figure 6, the CTS/APT-3
hybrid microspheres shows the highest drug release ratio,
followed by CTS/APT-1 and CTS/APT-4 at the same
time (the concentration of glutaraldehyde is different).
CTS contains large amounts of chemically reactive -NH2
and -OH groups, and its free amino groups can react with
glutaraldehyde to form a crosslinked polymeric network.
But a lower glutaraldehyde concentration can only gen-
erate a looser network structure and allows faster diffu-
sion of the loaded drug into the dissolution media [26].
Therefore, the release rate of DS from the hybrid micro-
spheres decreases significantly with increasing the con-
centration of glutaraldehyde.
In order to further understand the release behavior of
DS from the hybrid microspheres in pH 6.8 PBS, in vitro
release data in Figure 6 were fitted to various models to
analyze the kinetics and mechanism of DS release from
the hybrid microspheres. For elucidating the kinetics of
DS release, the experimental data was analyzed using
zero-order Equation (3), first-order Equation (4) [27,28],
higuchi’s square root model Equation (5) [29], and the
Power law Equation (6) [30,31]. Where, Ft is the drug
release fraction at time “t”, k1-4 is the release constant of
respective equations, t is the release time, and n is the
characteristic diffusion exponent.
 (4)
kt (5)
kt (6)
The correlation coefficient (2
r) for Equation (6) is
between 0.988 and 0.97 for the microspheres released at
pH 6.8 PBS (Table 2). This is correspondingly higher
than the other kinetic equations, namely Zero-order,
First-order kinetics and Higuchi equation, suggesting that
the release mode of DS follows the Power law. In many
experimental situations, including the case of drug re-
lease from the microsphere system, the mechanism of DS
diffusion deviates from the Fickian equation and follows
a non-Fickian (anomalous) behavior. For a sphere, when
n < 0.43, this represents a Fickian diffusion mechanism.
When n > 0.86, this represents a Case II transport
mechanism. When n value is between 0.43 and 0.86, the
transport is a typical and both Fickian diffusion and Case
II transport contribute to the release, i.e. anomalous
transport. In these cases, the calculated values of n by
Power law for Equation (6) are shown in Table 2. The
results of n presented in Ta b le 2 are in the range of 0.160
~ 0.227. This demonstrates that the release mechanism
fits Fickian diffusion.
4. Conclusions
In this work, DS-loaded CTS/APT hybrid microspheres
with controlled release properties in the simulated intes-
tinal fluid were prepared by a facile spray-drying tech-
nique. The results from FTIR spectra and XRD patterns
showed that APT was dispersed into hybrid microspheres
by physical mixing and DS is stable in the matrices de-
veloped without undergoing any chemical changes. In
Preparation, Characterization and Drug-Release Behaviors of Crosslinked Chitosan/Attapulgite
Hybrid Microspheres by a Facile Spray-Drying Technique
Copyright © 2011 SciRes. JBNB
Table 2. The release mechanism of DS from hybrid microspheres.
Zero-order First-order Higuchi Power law
k1 2
r k2 2
r k3 2
r n k4 2
Release mechanism
Crosslinked CTS 0.033 0.884 0.083 0.933 0.1390.9600.227 0.447 0.988 Fickian diffusion
CTS/APT-1 0.029 0.878 0.073 0.920 0.1240.9490.203 0.456 0.978 Fickian diffusion
CTS/APT-2 0.026 0.893 0.068 0.944 0.1110.9610.162 0.531 0.988 Fickian diffusion
CTS/APT-3 0.026 0.871 0.113 0.948 0.1120.9480.143 0.603 0.983 Fickian diffusion
CTS/APT-4 0.031 0.869 0.062 0.916 0.1310.9490.260 0.358 0.97 Fickian diffusion
addition, the introduction of APT can not only enhance
the isoelectric points but also achieve narrow size distri-
bution of hybrid microspheres, which made the hybrid
microspheres exhibit slow and sustained drug release
profiles in the simulated intestinal fluid due to the
stronger electrostatic interaction and smaller average sizes.
Based on all experimental results, it can be concluded that
CTS/APT hybrid microspheres loaded with DS could be
suitable candidates for oral delivery of DS with con-
trolled release properties, opening a new therapeutic po-
tential for this carriers for local treatment of chronic in-
flammatory and degenerative joint diseases.
5. Acknowledgements
The authors would like to thank the “Special Research
Fund of Scholarship of Dean of CAS” and Jiangsu Pro-
vincial Science and Technology Office (No.BE2009098)
for financial support of this research.
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