Differential effects of agarose and poly(lactic-co-glycolic acid) on dendritic cell maturation Mutsumi Yoshida, Julia E. Babensee Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive Atlanta, GA 30332 Received 3 November 2005; revised 26 January 2006; accepted 1 March 2006 Published online 2 August 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.30798 Abstract: Application of biomaterials in combination products in which the biomaterial is presented to the host with a biological component prompts the need for under- standing the biomaterial-associated adjuvant effect in the immune response against antigens associated with such a product. We have previously demonstrated that a polymer commonly used in tissue engineering and vaccine deliv- ery, poly(lactic-co-glycolic acid) (PLGA), exerts an adjuvant effect in vivo, which was supported by PLGA-induced dendritic cell (DC) maturation in vitro. In this study, the effects of agarose and PLGA on DC maturation were com- pared in vitro to establish differential biomaterial effects. Human monocyte-derived DCs were treated with agarose or PLGA microparticles or films, and their maturation effect was measured as expression of costimulatory and MHC class II molecules, allostimulatory capacity, and proinflammatory cytokine secretion. Direct comparison of DC maturation phe- notype indicated that PLGA was a stronger stimulus of DC maturation than agarose, and this maturation was not affected by microparticle phagocytosis. However, agarose- treated DCs showed higher activation of nuclear factor jB (NFjB) 24 h after the initial stimulation of DCs. Taken to- gether, these results demonstrate differential biomaterial effects on DC maturation, substantiating the maturation effect of PLGA, and provide screening methods for biomaterial adju- vant effect for applications in combination products. Ó 2006 Wiley Periodicals, Inc. J Biomed Mater Res 79A: 393–408, 2006 Key words: combination products; biomaterial; adjuvant; dendritic cells INTRODUCTION Advent of innovative combination products has raised new regulatory concerns previously not con- sidered. Some such combination products unite bio- materials with cells, DNA, or proteins, and include vaccine systems with nonviral polymeric carriers and tissue-engineered constructs in which cells are delivered with a biomaterial component. As the pur- pose of the biomaterial varies by application, identi- fying whether the biomaterial, due to its associated adjuvant effect, is intended or not to support the host immune response towards the product is essen- tial in designing and choosing a material that is most appropriate for a given application. In tissue engineering applications, immune responses are to be minimized to avoid graft rejection, while vaccine strategies aim to enhance the immune response to achieve protective immunity. Consequently, a bio- material with low or high adjuvant effect, respec- tively, would be ideal for such applications. Although the host inflammatory response associated with biomaterials has been studied in great depth (reviewed in Refs. 1–3), the adjuvant effect of biomate- rials in the context of tissue engineering and combina- tion products is not as well characterized. For example, poly(lactic-co-glycolic acid) (PLGA), a biomaterial com- monly studied in both tissue engineering and vaccine delivery applications, has been shown to act as an adju- vant; delivery of a model antigen with PLGA was shown to result in increased production of antibody against the model antigen, 4–7 with the physical form of the PLGA affecting its adjuvant effect. 8 Moreover, because adjuvants act through the matu- ration of antigen presenting cells such as dendritic cells (DCs), 9 as characterized by increase in costimula- tory and MHC molecule expression, cytokine secretion, and allostimulatory capacity, 10,11 the effect of PLGA on DC maturation has been studied with varying results, likely due to the differences in the DC culturing sys- tems used. 12–14 DCs are professional antigen present- ing cells central in the control of the immune response by connecting innate and adaptive immunity. 10,15 In Correspondence to: J. E. Babensee; e-mail: julia.babensee@ bme.gatech.edu Contract grant sponsor: National Institutes of Health; contract grant number: 1RO1EB004633-01A1 Contract grant sponsor: National Science Foundation; contract grant number: BES-0239152 Contract grant sponsor: Arthritis Foundation Ó 2006 Wiley Periodicals, Inc.