1. 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
Presented at AICHE 11/16/06 in San Francisco
Session: Biomaterials for Drug Delivery I

2. Hydrogel material that binds drug molecules
Goal:
Hydrogel material that binds drug molecules
Drug
Gel
Uptake
Release
Matrix: Hyaluronic Acid
Functionalities: Cyclodextrin

3. Composite Hydrogel Material
Hyaluronic Acid
Host-Guest Inclusion Complexes
Increase solubilization
Decrease crystallization
Increase stability
Cyclodextrin
High molecular weight
High water content
High porosity
Biocompatible
Biodegradable O H n 7
MW = 5x105 – 2x106

4. Cyclodextrin’s StructureHO OH
b-cyclodextrin (n=7)
a-cyclodextrin (n=6)
Hydrophobic Interior
Hydrophilic Exterior
aCD diameter ~ A
bCD diameter ~ A
Uekama 2004
I.D. ~ 6 Å +
Ka ~ 105 M-1
Adamantane

5. Hydrocortisone Solubility (mM)
Cyclodextrin’s Structure
Hydrocortisone Solubility (mM)
b-Cyclodextrin (mM) +
Ka ~ 103 M-1
Hydrocortisone
aCD Ka with hydrocortisone is ~10.
Two orders of magnitude less than bCD.

6. Photocrosslinked Hydrogels
Photoinitiator
UV Light
Methacryloyl Cyclodextrin
Methacryloyl Hyaluronic Acid + +
Triethylamine
GMHA
Leach, J.B. et al. (2003) Biotechnol Bioeng

7. Methacryloyl Hyaluronic Acid (GMHA)+
Triethylamine
GMHA
Leach, J.B. et al. (2003) Biotechnol Bioeng

8. Methacryloyl Hyaluronic Acid (GMHA)+
Triethylamine
GMHA
Leach, J.B. et al. (2003) Biotechnol Bioeng

9. Methacryloyl Cyclodextrin
Possible steric hindrance

10. Methacryloyl Cyclodextrin1 2 3 4 5 6
MAbCD
DS = 3.2
MAaCD
DS = 3.6
No unpolymerizable CD
Low average DS
Comparable DS
Comparable DS
Eliminated DS 0

11. Quantitation of MAbCD-Hydrocortisone Binding
CD (mM):
Hydrocortisone 1 3 5
MAbCD: 1400 M-1
bCD: 5380 M-1

12. Hyaluronic Acid Gels
Hyaluronic Acid Films

13. Swelling of Hyaluronic Acid – Cyclodextrin Hydrogels
I2959, UV Light +
Cyclodextrin
Hyaluronic Acid
CD / HA Hydrogel
0.5% w/v
1.0% w/v
1.5% w/v
2% w/v
20% CD / 80% HA
33% CD / 67% HA
43% CD / 57% HA
Swelling Ratio
(PBS)
Cyclodextrin (%w/w) HA 20 43 33
bCD / HA
aCD / HA

14. Hyaluronic Acid-Cyclodextrin Hydrogels:
Hydrocortisone Uptake and Release
Hydrocortisone
Uptake
Release
Gel
Hydrocortisone Release (mg)
Time (h)
43% bCD
33% bCD
20% bCD
43% aCD
20% aCD HA

15. Hyaluronic Acid-Cyclodextrin Hydrogels:
Hydrocortisone Uptake and Release
Hydrocortisone
Uptake
Release
Gel
Cyclodextrin (mmol)
Hydrocortisone Release (mmol)
1 HC : 8 MAbCD
1 HC : 21 MAaCD

16. Hyaluronic Acid-Cyclodextrin Hydrogels:
Hydrocortisone Uptake and Release
Pre-incubation with Adamantane Carboxylic Acid HA
43% bCD
43% bCD Adamantane
Hydrocortisone Release (mmol)
Adamantane Carboxylic Acid abolishes 76% of the increase in uptake.

17. Hyaluronic Acid Gels
Hyaluronic Acid Films

18. Methacryloyl Hyaluronic Acid FilmsUV
Air Dry
GMHA +
Photoinitiator

19. Optimization of Photoinitiator % Photoinitiator (w/w)
1 min UV
Swelling Ratio (PBS)
% Linear Expansion
% Photoinitiator (w/w)

20. Optimization of UV Exposure
5% PI
Swelling Ratio (PBS)
% Linear Expansion
Photodegradation
Optimum: 1 min and 5% PI
60% WC and 28% Expansion
UV Exposure (min)

21. Autoclave Sterilization of HA Films
30 minutes at 121 C and 15 psi
Swelling Ratio (PBS)
% Linear Expansion
Dessicated, photocrosslinked GMHA films (5% w/v photoinitiator and 1 min UV exposure) were placed in autoclavable pouches and steam heat sterilized in a Market Forge Sterilmatic Sterilizer (Model STM-E Type C). The autoclave cycle was 8 minute warmup, 30 minutes at 121 C and 15 psi, followed by 25 minute cooldown to 80 C at which point the pouches were removed and dessicated until use. Films were sterilized at both liquids setting (slow steam exhaust) and solids setting (fast steam exhaust).
Slow exhaust for liquids to prevent to prevent contents from boiling over.
Fast exhaust is for solids and glassware.
None
Fast
Slow
Sterilization

22. Resistance to Cell Adhesion
Human Dermal Fibroblasts
500 mm
HA Film
TCPS

23. Methacryloyl Hyaluronic Acid Films
Properties
300 nm
Transparent
Free Standing
Highly Dense
Low Swelling
Biodegradable
Non-cell adhesive
Patternable
100 mm
Applications
Post-surgical adhesion barriers
Coatings

24. Hydrogel material that binds drug molecules
Goal:
Hydrogel material that binds drug molecules
Drug
Gel
Uptake
Release
Matrix: Hyaluronic Acid
Functionalities: Cyclodextrin

25. Acknowledgements Funding Agencies
NSF BES –
NSF BES –