335 www.ecmjournal.org J Zandstra et al. Microsphere size and the foreign body reaction European Cells and Materials Vol. 28 2014 (pages 335-347) DOI: 10.22203/eCM.v028a23 ISSN 1473-2262 Abstract Biodegradable poly-(DL-lactide-co-glycolide) (PLGA) microspheres (MSP) are attractive candidate vehicles for site-specifc or systemic sustained release of therapeutic compounds. This release may be altered by the host’s foreign body reaction (FBR), which is dependent on the characteristics of the implant, e.g. chemistry, shape or size. In this study, we focused on the characterisation of the infuence of MSP size on the FBR. To this end we injected monodisperse MSP of defned size (small 5.8 µm, coeffcient of variance (CV) 14 % and large 29.8 µm, CV 4 %) and polydisperse MSP (average diameter 34.1 µm, CV 51 %) under the skin of rats. MSP implants were retrieved at day 7, 14 and 28 after transplantation. The FBR was studied in terms of macrophage infltration, implant encapsulation, vascularisation and extracellular matrix deposition. Although PLGA MSP of all different sizes demonstrated excellent in vitro and in vivo biocompatibility, signifcant differences were found in the characteristics of the FBR. Small MSP were phagocytosed, while large MSP were not. Large MSP occasionally elicited giant cell formation, which was not observed after implantation of small MSP. Cellular and macrophage infux and collagen deposition were increased in small MSP implants compared to large MSP. We conclude that the MSP size infuences the FBR and thus might infuence clinical outcome when using MSP as a drug delivery device. We propose that a rational choice of MSP size can aid in optimising the therapeutic effcacy of microsphere-based therapies in vivo. Keywords: Biocompatibility (in vivo), cytocompatibility (in vitro), collagens, tissue-material interactions, foreign body response. *Address for correspondence: Jurjen Zandstra, M.Sc University Medical Hospital Groningen Dept. of Pathology & Medical Biology Hanzeplein 1 9713 GZ Groningen, The Netherlands Telephone Number: +31-50-3615881 FAX Number: +31-50-3611911 E-mail: j.zandstra@umcg.nl Introduction Poly-(DL-lactide-co-glycolide) ( PLGA)-based microspheres (MSP) are attractive candidate vehicles for controlled delivery of therapeutic compounds. Several therapies based on PLGA MSP as a drug delivery system have been developed to treat for instance cancer (Enriquez et al., 2013; Okada, 1997), growth hormone defciency (Jones et al., 1997), or to regenerate bone (Lanao et al., 2013; Felix Lanao et al., 2013; Hoekstra et al., 2013). Site-specifc or systemic sustained release of therapeutic compounds by means of injectable drug delivery vehicles will, conceivably, receive increasing attention in the future, since it allows for optimal therapeutic effect at the site of interest, while minimising systemic loss and undesired side effects of the drug in the rest of the body. Synthetic, biodegradable polymers are attractive candidates for generating tuneable drug delivery vehicles, since both their chemical and their physical properties can be customised for the delivery of specifc drugs and for applications at specifc sites in the body (Lu et al., 2009). However, polymer drug vehicles will inevitably elicit an infammatory, or so-called foreign body reaction (FBR) in vivo, since they are recognised by the immune system as foreign to the body (Anderson, 2001; Onuki et al., 2008). This FBR typically consists of infltration of infammatory cells into the foreign body implant and encapsulation thereof, in an attempt to protect and isolate surrounding tissue from and to remove the intruding object. Moreover, vascularisation of the implant and deposition of extracellular matrix around and in the foreign implant are also characteristics of the FBR. The relationship between the physical and chemical properties of drug delivery vehicles or implant materials, including synthetic biodegradable polymers, and the extent and duration of the FBR are incompletely understood. Physical properties such as the size of the vehicle or implant, its surface topography and shape, may determine the extent of the FBR (Champion and Mitragotri, 2006). Several studies investigated the effect of MSP size on phagocytosis in vitro (Champion et al., 2008; Paul et al., 2013), on bone healing (Petrie Aronin et al., 2009), or on in vivo infammatory responses (Gelb et al., 1994; Kusaka et al., 2014). The same holds true for chemical properties of the material and also for the type of its degradation products. Microspheric particles are interesting vehicles for in vivo drug delivery due to their capacity to release drugs controllably with respect to duration and dosage. The obvious question arises in how far the diameter of MSP affects the magnitude of the FBR and, more specifcally, MICROSPHERE SIZE INFLUENCES THE FOREIGN BODY REACTION J. Zandstra 1, *, C. Hiemstra 2 , A.H. Petersen 1 , J. Zuidema 2 , M.M. van Beuge 1 , S. Rodriguez 3 , A.A.R. Lathuile 3 , G.J. Veldhuis 3 , R. Steendam 2 , R.A. Bank 1 and E.R. Popa 1 1 Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands 2 InnoCore Pharmaceuticals, Groningen, The Netherlands 3 Nanomi BV, Oldenzaal, The Netherlands