AbstractThis study was performed to evaluate the basic biological response to deoxyribonucleic acid (DNA)‐based coatings for soft tissue implants. To that end, in vitro experiments were used to study their cytocompatibility, and in vivo subcutaneous implantation studies with transponders in a rat model were performed to evaluate their histocompatibility. The DNA‐based coatings were fabricated using the electrostatic self‐assembly technique using cationic poly‐D‐lysine or poly‐allylamine hydrochloride and anionic DNA. Noncoated substrates served as controls. In vitro, the behavior of primary rat dermal fibroblasts was assessed in terms of cell proliferation and morphology. Both types of multilayered DNA‐coatings significantly increased rat dermal fibroblast proliferation without altering the morphological appearance of the cells. The tissue response to multilayered DNA‐coatings was assessed using an in vivo rat model, in which transponders were inserted subcutaneously for 4 and 12 weeks. No macroscopic signs of inflammation or adverse tissue reactions were observed at implant retrieval. Histological analyses demonstrated a uniform tissue response to all types of implants. All implants were encapsulated in a fibrous tissue capsule without intervening inflammatory cells at the implant surface. Histomorphometrically, multilayered DNA‐coatings induced fibrous tissue capsules with similar quality and thickness compared to noncoated controls. In addition, all fibrous tissue capsules showed similar expression of α‐smooth muscle actin. This study demonstrates that multilayered DNA‐coatings are cytocompatible and histocompatible, and justifies further research on their functionalization with biologically active compounds to modulate tissue responses. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006