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ABSTRACT: Solute diffusion in hydrogels is important in many biotechnology fields. Solute behavior
in hydrogels has been explained in terms of reduction in hydrogel free volume, enhanced hydrodynamic
drag on the solute, increased path length due to obstruction, and a combination of hydrodynamic drag
and obstruction effects. In this article the various mathematical models derived to explain and predict
solute diffusion in hydrogels are reviewed and tested against literature data. These models can be divided
into those applicable to hydrogels composed of flexible polymer chains (i.e., homogeneous hydrogels) and
those composed of rigid polymer chains (i.e., heterogeneous hydrogels). For homogeneous hydrogels it
was determined that a scaling hydrodynamic model provided the best explanation for solute diffusion,
while for heterogeneous hydrogels obstruction models were more consistent with the experimental data.
Both the scaling hydrodynamic model and the most appropriate obstruction model contain undefined
parameters which must be clarified in order for these models to gain widespread acceptance.
Introduction
The diffusion of solutes in hydrogels has application
in a wide variety of fields. Hydrogels are used in
separation processes such as chromatography,1 for the
encapsulation of cells for both biomedical and fermentation purposes,2 in biosensors,3,4 and as biomaterials for
the delivery of bioactive agents to the body4-6 and
prosthetic applications.3,4 The one feature of hydrogels
that all these applications capitalize upon is the ability
of the hydrogel to restrict the diffusive movement of a
solute. It is therefore important to have an understanding of the parameters governing solute diffusion within
hydrogels as well as the means by which they affect
diffusion. For this reason, a number of mathematical
expressions have been developed in an effort to model
solute diffusion in hydrogels. It is the purpose of this
article to examine the most prevalent models and
compare them to data taken from the literature, to
assess their predictive abilities. Such an examination
was undertaken a number of years ago by Muhr and
Blanshard;7 however, a number of models have since
been proposed.
Before introducing the different models, it would be
beneficial to review the properties of hydrogels. Hydrogels are cross-linked hydrophilic polymers swollen
in water or an aqueous environment. Their threedimensional structure is often described as a mesh, with
the spaces between the polymer chains filled with water.
The cross-links can be formed by covalent or ionic bonds,
van der Waals forces, hydrogen bonds, or physical
entanglements.3,4 The cross-link sites form microregions of local polymer precipitation from solution. The
overall structure of hydrogels therefore ranges from
homogeneous, where the polymer chains have a high
degree of mobility, to heterogeneous, in which there is
a great deal of inter-polymer interaction and the polymer chains are virtually immobile at the molecular
level.7 Examples of homogeneous hydrogels include
poly(ethylene oxide), poly(acrylamide), and poly(vinyl
alcohol). Examples of heterogeneous hydrogels include
calcium alginate, agarose, and -carrageenan.3,7
Solute transport within hydrogels occurs primarily
within the water-filled regions in the space delineated
D0 V exp -
v*
vf
(1)
vf ) (1 - )vf,w + vf,p
(2)
vf (1 - )vf,w
(3)
Dg
Ba*
) P0 exp D0
vf,w 1 -
))
(4)
) (
M
hc-M
h *c
Dg
) k1
exp -k2rs2
*
D0
1
Mn - M
hc
(5)
) (
Dg
M
hc-M
h *c
) k1
D0
M
hn-M
h *c
exp -k2rs2
(1 - )
(6)
) ( ( ))
rs
Dg
) 1exp -Y
D0
1-
(7)
ln
()
( )
Dg
) ln() - k2rs2
D0
1-
(8)
8384 Amsden
Hydrodynamic Theory. Hydrodynamic descriptions of solute transport through gels are based on the
Stokes-Einstein equation for solute diffusivity. In the
Stokes-Einstein derivation, the solute molecule is assumed to be a hard sphere which is large compared to
the solvent in which it moves.21 The solute is considered
to move at a constant velocity in a continuum composed
of the solvent and is resisted by frictional drag. The
diffusivity at infinite dilution, Do, is expressed as21
Do )
kBT
f
(9)
De
) 1 - R11/2 - R2 ...
Do
(10)
in which
R1 rsxrf
(11)
[(
) ]
3LcNA
De
) exp r 1/2
Do
Mf ln(Lc/2rf) s
(12)
Dg
) exp(-kcrs0.75)
Do
(13)
[ ()
De
rs2
) 1+
Do
k
2 -1
1/2
1 rs
3 k
(14)
k ) 0.31rf2-1.17
(15)
Dg
1-2
)
Do
1+
(16)
p(rs) )
a* f(a) da
(17)
p(rs) ) 1 -
rs
(18)
random unit steps and that the unit step does not take
place if the solute encounters a polymer chain. The
cross-linked polymer is assumed to exist as a random
network of straight, long fibers of negligible width, and
the solute is considered to be a hard sphere. The unit
step is taken to be the root-mean-square average
diameter of spherical spaces residing between the fiber
network. From such an analysis, they expressed the
ratio of the diffusion coefficient in the gel to that in
infinite dilution in water as
(rs + rf)
Dg
x
) exp Do
rf
(19)
Dg
) e-R + R2eRE1(2R)
Do
(20)
where
R)
( )
rs + rf
rf
(21)
Dg
) exp[-0.84R1.09]
Do
(22)
obtained in one field are applicable in another. Recently, models developed to describe transport properties in random arrays of overlapping fibers have been
reviewed and compared to the results of a Brownian
motion simulation.33 The results indicate that, of these
models, that of Tsai and Strieder34 adapted for the
diffusive process as
Dg
2 -1
) 1+ R
Do
3
(23)
provided the best agreement to Brownian motion simulation data for cylinder volume fractions less than 0.40.
In eq 23, R is as described in eq 21. In the derivation
of this equation, the volume fraction of the fiber network
excluded to the solute, , was given by Ogstons
expression,31
) 1 - exp(-R)
(24)
( ( ))
Dg
rs + rf
) exp Do
4 rj + rf
(25)
) ks-1/2
(26)
Dg
)
Do
exp[-0.84R1.09]
[ ()
rs2
1+
k
1/2
1 rs
+
3 k
(27)
8386 Amsden
Dg
) exp(-a)
Do
(28)
( )
rf
) 0.174 ln 59.6
rs
(29)
Dg
) exp(-0.174ln(59.6rf/rs))
Do
(30)
Dg
2 -1
) 1 + R exp(-0.174ln(59.6rf/rs))
Do
3
(31)
Figure 1. Clague and Phillips simulation results of hydrodynamic effects on spherical solute diffusion through a random
network of cylindrical fibers.39 (A) Effect of fiber volume
fraction, fiber radius, and solute radius. In the legend, )
rf/rs. The lines represent the regression results of eq 28 with
a ) . (B) Relationship between fitted values of and rf/rs.
The line represents the regression result given by eq 29.
Figure 2. Application of the Cukier hydrodynamic-scaling model23 to literature data showing the effect of polymer volume fraction
on solute diffusivity within various homogeneous hydrogels: (A) polyacrylamide gels; (B) poly(vinyl alcohol) gels;42 (C) poly(ethylene oxide) (PEO) and poly(hydroxyethyl methacrylate) gels (HEMA); (D) dextran (Dex) and hydroxypropyl methylcellulose
(HPMC) gels. The lines represent regression results.
Table 1. Summary of Diffusion Models and the Hydrogels for Which They are Suited
model
expression
Dg
hydrodynamic
D0
Dg
Do
(1 - ))
[ ()
[
]
]
hydrodynamic
Dg
obstruction
obstruction
obstruction
) 1+
obstruction
combined
Dg
Do
[ (
exp[-0.84R1.09]
[ ()
)]
rs )
kBT
6Do
hydrogel class
homogeneous
Cukier23
homogeneous
Phillips et al.24
heterogeneous
Ogston et al.31
heterogeneous
Johansson et al.30
heterogeneous
heterogeneous
Amsden35
heterogeneous
Johnson et al.38
heterogeneous
heterogeneous
combined
ref
Lustig and Peppas16
(32)
8388 Amsden
solute(s)a
polymer
method
poly(acrylamide)
poly(acrylamide)
poly(vinyl alcohol)
sucrose, urea
RNase, BSA
TPL, R-LA, LYS, vit B12
Homogeneous
0.046-0.238
0.021-0.138
0.043-0.189
poly(ethylene oxide)
poly(ethylene oxide)
poly(hydroxyethyl
methacrylide)
hydroxypropylmethyl
cellulose
dextran
caffeine
LYS, vit B12, CHY, OVA
PPA
calcium alginate
calcium alginate
calcium alginate
agarose
-carageenan
ref
White and Dorion40
Tong and Anderson41
Matsuyama et al.42
0.092-0.317
0.062, 0.084
0.19-0.60
Graham et al.43
Merrill et al.44
Kou et al.45
AM
0.000-0.131
PFSGE-NMRc
0.048-0.227
Hennink et al.20
Heterogeneous
0.003
0.012
Sellen58
Tanaka et al.46
Amsden35
Kong et al.47
0.005-0.050
0.010-0.050
0.005, 0.010
Johansson et al.9
a Solute abbreviations: AM, adinazolam mesylate; BSA, bovine serum albumin; CHY, chymotrypsinogen; FBG, fibrinogen; IgG,
immunoglobulin G; R-LA, R-lactalbumin; -LG, -lactoglobulin; LYS, lysozyme; MYO, myoglobin; OVA, ovalbumin; PEG, poly(ethylene
glycol); PEP, pepsin; PPA, Phenylpropanolamine; RNase, ribonuclease; vit B12, vitamin B12. b FRAP: fluorescence recovery after
photobleaching. c PFSGE-NMR: pulsed field gradient spin-echo nuclear magnetic resonance.
ref
White and Dorion40
Tanaka et al.46
Matsuyama et al.42
White and Dorion40
Graham et al.43
Gao and Fagerness28
Kou et al.45
Colton et al.61
18.1
6.4
6.54
6.97
6.3
4.30
5.51
3.79
37
23
25
37
37
23
37
37
PEG 326
PEG 678
PEG 1118
PEG 1822
PEG 2834
PEG 3978
4.9
3.5
2.8
2.2
1.8
1.5
25
25
25
25
25
25
ribonuclease
myoglobin
lysozyme
R-lactalbumin
chymotrypsinogen
pepsin
ovalbumin
bovine serum albumin
-lactoglobulin A
immunoglobulin G
fibrinogen
C12E8 micelle
C12E10 micelle
0.131
0.113
0.112
0.106
0.095
0.090
0.073
0.060
0.042
0.040
0.020
0.08
0.069
20
20
20
20
20
20
20
20
20
20
20
21
21
solute
r s,
kc
(SE
1.9
1.12
0.11
PAAM
urea
PAAM
BSA
Dextran LYS
0.09
0.025
36.3
19.1
0.45
0.57
0.020
0.020
36.3
56.3
8.7
0.58 0.034
0.66 0.027
0.619 0.050
PVA
BSA
IgG
vit B12
PEO
LYS
19.1 0.398 0.013
caffeine 5.25 0.883 0.020
PHEMA PPA
HPMC AM
6.0
5.4
1.10
1.16
0.06
0.009
R2
data ref
Table 5. Regression Results of the Application of the Lustig and Peppas16 Free Volume Model to Solute Diffusion in
Homogeneous Hydrogels (eq 7)a
polymer
PAAM
PAAM
Dextran
PVA
PEO
PHEMA
HPMC
a
solute
r s,
k1
(SE
k2
(SE
R2
urea
sucrose
RNase
BSA
LYS
BSA
IgG
vit B12
LYS
caffeine
PPA
AM
1.9
4.75
16.3
36.3
19.1
36.3
56.3
8.7
19.1
5.25
6.0
5.4
0.070
0.066
0.143
0.071
0.082
0.061
0.026
0.176
0.158
0.260
0.175
0.391
0.491
0.050
0.605
1.486
1.02
0.087
0.073
0.977
0.005
1.36
1.10
0.862
0.728
0.263
0.043
0.019
0.031
0.017
0.016
0.026
0.022
0.129
0.059
0.193
0.337
0.014
0.097
0.115
0.120
0.004
0.024
0.246
0.002
0.53
0.298
0.419
0.0080
0.0005
0.0976
0.3550
0.945
0.403
0.986
0.0126
0.0130
0.0081
3.07
0.076
0.970
0.998
0.924
0.783
0.726
0.984
0.978
0.925
0.996
0.904
0.878
0.970
data ref
White and Dorion40
Tong and Anderson41
Hennink et al.20
Matsuyama et al.42
Graham et al.43
Kou et al.45
Gao and Fagerness28
SE ) standard error (95% confidence interval). 2 ) sum of squares of the residuals. R2 ) correlation coefficient.
solute
urea
rs ()
1.9
k2
(SE
R2
data ref
0.774 0.039
()
ln
( )
Dg
) -k2rs2
Do
1-
(33)
Dg
k2rs2 2 k2rs2 3
...
) 1 - k2rs2 Do
2
6
(34)
8390 Amsden
Figure 3. Application of free volume theory models to literature data showing the effect of polymer volume fraction on solute
diffusivity within various homogeneous hydrogels: (A) polyacrylamide gels; (B) poly(vinyl alcohol) gels;42 (C) poly(ethylene oxide)
(PEO) and poly(hydroxyethyl methacrylate) gels (HEMA); (D) dextran (Dex) and hydroxypropyl methylcellulose (HPMC) gels.
The lines represent regression results.
Table 7. Regression Results for Application of Obstruction Models to Dg/Do versus Solute Radius Literature Data for
Heterogeneous Hydrogels
model
Johansson et al.30
polymer (ref)
alginate35
alginate46
alginate58
carageenan9 ( ) 0.005)
carageenan9 ( ) 0.010)
Amsdena,35
rf fit ()
(SE
R2
rf fit ()
(SE
R2
ks fit ()
(SE
R2
3.46
7.31
7.28
2.66
3.72
0.05
0.46
0.40
0.08
0.13
0.001
0.013
0.036
0.001
0.004
0.992
0.974
0.931
0.964
0.912
2.10
5.13
5.68
2.38
3.08
0.26
0.50
0.55
0.04
0.07
0.029
0.019
0.065
0.001
0.001
0.801
0.962
0.878
0.992
0.974
5.63
13.02
13.62
6.56
7.31
0.24
1.05
0.87
0.25
0.10
0.005
0.020
0.043
0.001
0.001
0.964
0.960
0.918
0.951
0.987
a Regression done using r ) 8.0 . SE ) standard error (95% confidence interval). 2 ) sum of squares of the residuals. R ) correlation
f
coefficient.
8392 Amsden
Figure 6. Implementation of obstruction models to literature data showing the relationship between solute radius and solute
diffusivity within heterogeneous hydrogels: (A) model of Tsai and Streider34 (eq 23) versus solute diffusion in calcium alginate
gels; (B) model of Tsai and Streider34 (eq 23) versus solute diffusion in -carageenan; (C) model of Amsden35 (eq 25) versus solute
diffusion in calcium alginate gels; (D) model of Amsden35 (eq 25) versus solute diffusion in -carageenan; (E) model of Johansson
et al.30 (eq 22) versus solute diffusion in calcium alginate gels; (F) model of Johansson et al.30 (eq 22) versus solute diffusion in
-carageenan.
Figure 7. Implementation of combined hydrodynamic and obstruction models to literature data of the relationship between
solute radius and solute diffusivity within heterogeneous hydrogels: (A) model of Johnson et al.38 (eq 27) versus solute diffusion
in calcium alginate gels; (B) model of Johnson et al.38 (eq 27) versus solute diffusion in -carageenan gels (data from Johansson
et al.9); (C) model of Clague and Phillips39 (eq 31) versus solute diffusion in calcium alginate gels; (D) model of Clague and Phillips39
(eq 31) versus solute diffusion in -carageenan gels (data from Johansson et al.9).
Table 8. Regression Results for Application of Combined Hydrodynamic and Obstruction Models to Dg/Do versus Solute
Radius Literature Data for Heterogeneous Hydrogels
modela
Johnson et al.38
polymer (ref)
alginate35
alginate46
alginate58
carageenan9 ( ) 0.005)
carageenan9 ( ) 0.010)
a
rf fit ()
(SE
5.44
13.95
14.87
8.00
9.56
0.50
1.81
2.35
0.66
0.39
0.018
0.033
0.121
0.002
0.002
rf fit ()
(SE
R2
0.872
0.937
0.774
0.912
0.956
4.09
11.15
13.72
7.21
8.73
0.58
2.15
2.20
0.69
0.60
0.032
0.055
0.120
0.002
0.004
0.780
0.893
0.774
0.891
0.904
SE ) standard error (95% confidence interval). 2 ) sum of squares of the residuals. R ) correlation coefficient.
8394 Amsden
Table 9. Regression Results for Application of Obstruction Models to Dg/Do versus Polymer Volume Fraction Literature
Data for Heterogeneous Hydrogels
modela
Johansson et
polymer (ref)
alginate35
agarose47
agarose47
agarose47
agarose47
al.30
Amsdenb,35
solute (radius, )
rf fit ()
(SE
R2
ks fit ()
(SE
R2
BSA (36.3)
MYO (18.9)
BSA (36.3)
C12E8 micelle (27.4)
C12E10 micelle (31.7)
3.48
6.02
7.9
6.26
6.24
0.05
0.23
0.50
0.50
0.31
0.018
0.005
0.033
0.023
0.010
0.951
0.960
0.753
0.284
0.876
5.73
11.63
12.45
10.19
9.72
0.11
1.39
0.31
0.36
0.64
0.018
0.030
0.003
0.003
0.009
0.940
0.776
0.978
0.939
0.908
a SE ) standard error (95% confidence interval). 2 ) sum of squares of the residuals. R ) correlation coefficient. b Regression done
using rf ) 8.0 .
MA980765F