Post on 23-Dec-2015
Photocured Films of Hyaluronic Acid Functionalized with Cyclodextrin
Scott A. Zawko1, Shalu Suri2, Prinon Hossain2, Quan Truong2, Christine E.
Schmidt1,2
1Department of Chemical Engineering
2Department of Biomedical Engineering
The University of Texas at Austin, Austin, TX
Hydrogel material that binds drug molecules
Matrix: Hyaluronic Acid
Functionalities: Cyclodextrin
Goal:
Drug Gel Uptake Release
Composite Hydrogel Material
High molecular weight
High water content
High porosity
Biocompatible
Biodegradable
Hyaluronic Acid Host-Guest Inclusion
Complexes
Increase solubilization
Decrease crystallization
Increase stability
Cyclodextrin
OOHO
OH
HOOC
O
OHO
NHCOCH3
OH
n
O
O
HO
HO
OH
O
OOH
HO
OH
O
OOH
HO
OH
O
OOH
HO
HO
O
OOH
OH
HO
OOHO
OH
OH
O
OHO
OHHO
O
OH
OHHO
O
7MW = 5x105 – 2x106
I.D. ~ 6 Å
+Ka ~ 105 M-1
Adamantane
Cyclodextrin’s Structure
HO
OHHO
Hydrophilic Exterior
Hydrophobic Interior
O
O
HO
HO
OH
O
OOH
HO
OH
O
OOH
HO
OH
O
OOH
HO
HO
O
OOH
OH
HO
OOHO
OH
OH
O
OHO
OHHO
-cyclodextrin (n=7)
-cyclodextrin (n=6)
0
1
2
3
4
5
6
7
8
0 5 10 15
O
HO
CH3
CH3C
O
CH2OH
+
O
HO
CH3
CH3C
O
CH2OH
Ka ~ 103 M-1
Hydrocortisone
Cyclodextrin’s Structure
Cyclodextrin (mM)
Hydrocortisone Solubility (mM)
Photoinitiator
UV Light
Methacryloyl Cyclodextrin
Methacryloyl Hyaluronic Acid
+
Photocrosslinked Hydrogels
+Triethylamine
GMHAOOHO
OH
HOOC
O
OHO
NHCOCH3
OH
Leach, J.B. et al. (2003) Biotechnol Bioeng
OO
O
+Triethylamine
GMHAOOHO
OH
HOOC
O
OHO
NHCOCH3
OH
Leach, J.B. et al. (2003) Biotechnol Bioeng
OO
O
Methacryloyl Hyaluronic Acid (GMHA)
Molar Excess
Degree of Substitution
6x 0.05 10x 0.07 20x 0.11
Methacryloyl Hyaluronic Acid (GMHA)
Molar Excess
Degree of Substitution
6x 0.05 10x 0.07 20x 0.11
Molar Excess
Water / Acetone
Degree of Substitution
20x 100 / 0 0.11 20x 70 / 30 0.23 20x 50 / 50 0.32
+Triethylamine
GMHAOOHO
OH
HOOC
O
OHO
NHCOCH3
OH
Leach, J.B. et al. (2003) Biotechnol Bioeng
OO
O
O
OH
OHHO
OO
OR
ORRO
On n
Methacrylic Anhydride
NaOH, pH 8
C
OR = H or
n = 6, -cyclodextrinn = 7, -cyclodextrin
Methacryloyl Cyclodextrin
Possible steric hindrance
O
HO
CH3
CH3C
O
CH2OH
O
OO
O
O
O
No unpolymerizable CD
Low average DS
Comparable DS
Methacryloyl Cyclodextrin
1
2 3
4
5
6
MACD
DS = 3.2
1
2
34
5
MACD
DS = 3.6
0
2
4
6
8
10
12
0 5 10 15
[Cyclodextrin] (mM)
[Hyd
roco
rtis
on
e]
(mM
)
MACD: 1400 M-1
CD: 5380 M-10])[1( Lslope
slopeKa
Quantitation of MACD-Hydrocortisone Binding
CD (mM):
Hydrocortisone
0 1 3 5
Hyaluronic Acid Films
Hyaluronic Acid Gels
Swelling of Hyaluronic Acid – Cyclodextrin Hydrogels
I2959, UV Light
+
Cyclodextrin Hyaluronic Acid
2% w/v0.5% w/v
1.0% w/v
1.5% w/v
CD / HA Hydrogel
20% CD / 80% HA
33% CD / 67% HA
43% CD / 57% HA
0
10
20
30
40
50
Swelling Ratio
(PBS)
Cyclodextrin (%w/w)
HA 20 4333
CD / HACD / HA
Hydrocortisone Release (g)
Time (h)
43% CD
33% CD
20% CD
43% CD
20% CD
0
10
20
30
40
50
60
70
0 10 20 30 40
HA
Hyaluronic Acid-Cyclodextrin Hydrogels:
Hydrocortisone Uptake and Release
Hydrocortisone Uptake ReleaseGel
Hyaluronic Acid-Cyclodextrin Hydrogels:
0.00
0.05
0.10
0.15
0.20
0.25
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
Cyclodextrin (mol)
Hydrocortisone Release (mol)
1 HC : 8 MACD
1 HC : 21 MACD
Hydrocortisone Uptake and Release
Hydrocortisone Uptake ReleaseGel
0
10
20
30
40
50
60
70
80
HA 43% CD 43% CD
Adamantane
Hyaluronic Acid-Cyclodextrin Hydrogels:
Hydrocortisone Uptake and Release
Hydrocortisone Release (mol)
Pre-incubation with Adamantane Carboxylic Acid
COO-
Hyaluronic Acid Films
Hyaluronic Acid Gels
Methacryloyl Hyaluronic Acid Films
GMHA +
Photoinitiator
Air Dry
UV
Water / Acetone
Degree of Substitution Films
100 / 0 0.11 N 70 / 30 0.23 Y 50 / 50 0.32 Y
Optimization of Photoinitiator
0
1
2
3
4
5
6
0.0 2.5 5.0 7.5 10.0
0
10
20
30
40
50
60
70
80
Swelling Ratio (PBS)
% Linear Expansion
% Photoinitiator (w/w)
1 min UV
Optimization of UV Exposure
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0 1 2 3 4 5 6
0
5
10
15
20
25
30
35
40
45
Swelling Ratio (PBS)
% Linear Expansion
UV Exposure (min)
5% PI
Autoclave Sterilization of HA Films
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0
10
20
30
40
50
60
Swelling Ratio (PBS)
% Linear Expansion
Sterilization
None Fast Slow
30 minutes at 121 C and 15 psi
Resistance to Cell Adhesion
Human Dermal Fibroblasts
HA Film TCPS
500 m
Methacryloyl Hyaluronic Acid Films
Transparent
Free Standing
Highly Dense
Low Swelling
Biodegradable
Non-cell adhesive
Patternable
Applications
Post-surgical adhesion barriers
Coatings
Properties
300 nm
100 m
Matrix: Hyaluronic Acid
Functionalities: Cyclodextrin
Goal:
Drug Gel Uptake Release
Hydrogel material that binds drug molecules
http://www.bme.utexas.edu/faculty/schmidt
AcknowledgementsFunding Agencies
NSF BES – 021744
NSF BES – 0500969