Semi-IPN Chitosan/PEG Microspheres and Films for Biomedical Applications: Characterization and Sustained Release Optimization Ismail Dogan Gunbas, † Umran Aydemir Sezer, ‡,# Sultan Gü lce I ̇ z, ∇ I ̇ smet Deliloğ lu Gü rhan, ∇ and Nesrin Hasirci* ,†,‡,§,∥,⊥ † Department of Polymer Science and Technology, ‡ Graduate Department of Biomedical Engineering, Faculty of Arts and Sciences, § Department of Micro and Nanotechnology, ∥ Department of Chemistry, Faculty of Arts and Sciences, and ⊥ BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, 06800 Ankara, Turkey # Department of Chemical Engineering and Applied Chemistry, Faculty of Engineering, Atilim University, 06836 Ankara, Turkey ∇ Department of Bioengineering, Ege University, 35100, I ̇ zmir, Turkey ABSTRACT: Micro drug carriers are one of the efficient methods for local or systemic cancer treatment. In this study, the aim was to prepare a novel semi-interpenetrated (semi-IPN) micro system by using biocompatible chitosan (CH) and polyethylene glycol (PEG). Various combinations of the systems were prepared and loaded with a model chemotherapeutic drug, methotrexate (MTX), and the effects of composition on the properties and the release behavior of microspheres were examined. Also, the mechanical and thermal properties were examined on film forms of similar compositions. Increase in cross-linking caused a decrease in particle size of CH from 144 to 91 μm, while the addition of PEG caused an increase up to 163 μm. Elastic modulus values of the films first increased and then decreased parallel to PEG content. In vitro studies showed faster MTX release from semi-IPN CH-PEG microspheres as compared to pure CH ones. Promising results were obtained in the development of biodegradable drug vehicles. 1. INTRODUCTION In recent years, biomaterials for tissue engineering or drug delivery have been studied extensively by many researchers to develop and modify polymeric materials meeting the needs of biomedical applications. In this regard, many synthetic and natural polymers have been synthesized and modified. Among these materials, biodegradable polymers have received special attention due to the nonrequirement of secondary surgery for implant removal. Moreover, the ability to control and alter the physical properties of degradable polymers such as degradation rate, permeability, and mechanical strength is an integral part of biopolymer design, which influences drug release, cellular growth, and function for successful biomedical applications. 1−3 Drug delivery systems have been widely used in cancer treatment to avoid the side effects, low cure rate of cancer drugs in the tissues, and the lack of selectivity. Thus, it is an obstacle to target to cancer tissue merely by means of the available conventional methods applied in drug delivery systems. Among these, microsphere and film systems are one of the targeted therapies for cancer treatment. The use of microsphere systems as drug delivery vehicles has certain advantages, such as enhanced effectiveness and reduced toxicity of the incorporated agents to nontargeted cells and tissues. Biodegradable micro- spheres can be utilized to direct drugs to organs by lodging them into the environment of the end organ. 4 Polymeric films are also used as drug carriers for local applications where the handling and mechanical properties are important. Especially for hard tissue applications, where the treatment is at a load bearing bone area, the mechanical strength of the implant becomes important. Thermal behavior is another essential parameter to get information about the thermal stability of the structures, which are especially important for optimization of sterilization and storage conditions. The drug carriers should possess certain essential qualities, including controlled and sustained release and high intratumoral concentration for a sufficient time without damaging the surrounding tissue cells. Chitosan (CH) is a widely used polymer in biomedical applications due to its properties of biodegradation, nontoxicity, biocompatibility, mucoadhesion, and its ability to open the intercellular tight junction of the lung epithelium. 5−7 In addition, CH is also able to improve drug absorption by means of protecting the drug against enzymatic degradation. 8 Chemical cross-linking is a highly versatile method to create and modify chitosan structures, where properties, such as mechanical, thermal, and chemical stabilities, can be improved. Tripolyphosphate, 9 glutaraldeyhde, 10 genipin, 11 and tartaric acid 12 are used as cross-linkers for chitosan-based materials. Polyethylene glycol (PEG) has been approved by the FDA for a wide range of biomedical materials. As a biocompatible, nontoxic, protein-resistant, nonimmunogenic material with good water solubility, PEG has been used frequently in tissue engineering, organ protection, and pharmaceutical applica- tions, 13 and is often blended or compounded with other polymers and utilized in the field of controlled drug release. 14 In the ever growing category of biodegradable polymers developed for biomedical applications, CH and PEG have emerged as promising biodegradable materials due to their highly controllable chemical and physical properties. The addition of PEG to CH improves mechanical properties, such Received: June 13, 2012 Revised: August 16, 2012 Accepted: August 22, 2012 Published: September 4, 2012 Article pubs.acs.org/IECR © 2012 American Chemical Society 11946 dx.doi.org/10.1021/ie3015523 | Ind. Eng. Chem. Res. 2012, 51, 11946−11954