LAYERED, FLEXIBLE DRUG DELIVERY FILMS FOR THE PREVENTION OF FIBROTIC SCAR TISSUE FORMATION

Open wounds account for about 50% of military injuries and 10% of non‐fatal traffic injuries. Scar tissue formation in these wounds may be reduced or prevented if treated with a combination of molecules whose release is tuned to the healing phases. The goal of this research was to develop flexible, layered drug delivery films for sequential, localized release of anti‐inflammatory, anti‐oxidant, and anti‐fibrotic molecules to soft tissue. Films were composed of cellulose acetate phthalate (CAP) and Pluronic F‐127 (Pluronic). To impart flexibility, plasticizers, triethyl citrate (TEC) or tributyl citrate (TBC), were added. Mechanical analysis was performed on films as prepared and following phosphate‐buffered saline incubation to determine property changes after implantation. Tensile tests revealed higher plasticizer content increased film elongation but decreased elastic modulus and ultimate tensile strength. TEC films elongated twice as much as those with TBC. After incubation, properties increased because plasticizer leached from films. Micro computerized tomography and scanning electron microscopy determined how erosion and plasticizer leaching affected the film’s structures before and after incubation. Porosity increased as plasticizer content increased; however, plasticizer content did not significantly affect erosion rates. Next, effects of drugs with plasticizers on film erosion, release, and mechanical properties were investigated. Films were loaded with quercetin, an anti‐oxidant, or pirfenidone, an anti‐fibrotic, and plasticized with TEC or TBC. TEC‐plasticized films containing quercetin released drug at a slower rate than TBC films. Pirfenidone‐loaded films released drug at a faster rate than erosion occurred for both plasticizers. Increased pirfenidone loading resulted in significantly higher modulus and decreased elongation, an anti‐plasticizer effect. Increasing quercetin loading significantly increased elongation. Size, solubility, and structure differences between quercetin and pirfenidone affected drug interaction with the films and the consequent mechanical and release properties. Cell studies found TBC to be toxic even in low concentrations. Consequently, only TEC was further analyzed. Layered devices containing two drugs demonstrated sequential release regardless of drug order. Plasticizer concentration did not significantly affect the release profiles. Lastly, in vitro and in vivo 9‐layered device studies sequentially released drugs confirming the research objective: sequential, local release of anti‐inflammatory, anti‐oxidant, and anti‐fibrotic molecules from CAPPluronic films