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.

As all the physiological processes in our body are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the primary objective of this research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. This particular device was designed aimed at the treatment of periodontitis, a highly prevalent oral inflammatory disease that affects 90% of the world population. This condition is caused by bacterial biofilm on the teeth, resulting in a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The polymers used for the fabrication of this multilayered device consists of cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion property of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. After the initial characterization of the CAPP system, the device was specifically modified to achieve sequential release of drugs aimed at the treatment of periodontitis. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. To obtain different erosion times and achieve appropriate release profiles specific to the disease condition, the device was modified by increasing the number of layers or by inclusion of a slower eroding polymer layer. In all the cases, the device was able to release the four different drugs in the designed temporal sequence. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. Following extensive studies on the in vitro sequential drug release from these devices, the in vivo drug release profiles were investigated. The CAPP devices with different release rates and dosage formulations were implanted in a rat calvarial onlay model, and the in vivo drug release and erosion was compared with in vitro results. In vivo studies showed sequential release of drugs comparable to those measured in vitro, with some difference in drug release rates observed. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule.