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

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

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

Cyclodextrin’s Structure HO OH b-cyclodextrin (n=7) a-cyclodextrin (n=6) Hydrophobic Interior Hydrophilic Exterior aCD diameter ~ 4.7-5.3 A bCD diameter ~ 6.0-6.5 A Uekama 2004 I.D. ~ 6 Å + Ka ~ 105 M-1 Adamantane

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.

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

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

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

Methacryloyl Cyclodextrin Possible steric hindrance

Methacryloyl Cyclodextrin 1 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

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

Hyaluronic Acid Gels Hyaluronic Acid Films

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

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

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

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.

Hyaluronic Acid Gels Hyaluronic Acid Films

Methacryloyl Hyaluronic Acid Films UV Air Dry GMHA + Photoinitiator

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

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)

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

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

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

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

Acknowledgements Funding Agencies NSF BES – 021744 NSF BES – 0500969 http://www.bme.utexas.edu/faculty/schmidt