Implanted biomaterials and drug delivery vehicles have been reported to induce sequential events of immunologic reactions in response to injury caused by implantation procedures and result in acute inflammation marked by a dense infiltration of inflammation -mediating cells at the materials -tissue interface. Poly (lactide-co-gllycolide) (PLGA) is a member of a group of poly (α-hydroxy acid) that is among the few synthetic polymers approved for human clinical use by FDA. Consequently, it has been extensively used and tested for scaffold materials as a bioerodible material due to good biocompatibility, relatively good mechanical property, lower toxicity and controllable biodegradability. PLGA degrades by nonspecific hydrolytic scission of their ester bonds into their original monomer, lactic acid and glycolic acid. During these processes, there is very minimal systemic toxicity, however, in some cases, their acidic degradation products can decrease the pH in the surrounding tissue that result in local inflammatory reaction and potentially poor tissue development. Currently, biomaterials are endowed with biocompatibility through three different methods which are: coating with hy<font><font>drop</font></font>hilic molecules, modifying surface characteristics using physiochemical methods and impregnating bioactive substances. In our laboratory, the natural/ synthetic nano-hybrid scaffolds have been investigated such as small intestine submucosa (SIS), demineralized bone particles (DBP), DBP gel, fibrin, keratin, hyaluronic acid, collagen gel, silk and a 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer (PMEH) with PLGA to reduce cellular inflammatory response. In this lecture, we introduced synthetic/natural nanohybrid as DBP/PLGA and SIS/PLGA scaffold in terms of scaffold design for the reduction of host response and the augmentation of tissue formation. This information will be supporting the basic strategy for the scaffold design with better improved biocompatibility.