title: Microsphere size influences the foreign body reaction.
abstract: Biodegradable poly-(DL-lactide-co-glycolide) (PLGA) microspheres (MSP) are attractive candidate vehicles for site-specific 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 influence of MSP size on the FBR. To this end we injected monodisperse MSP of defined size (small 5.8 µm, coefficient 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 infiltration, implant encapsulation, vascularisation and extracellular matrix deposition. Although PLGA MSP of all different sizes demonstrated excellent in vitro and in vivo biocompatibility, significant 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 influx and collagen deposition were increased in small MSP implants compared to large MSP. We conclude that the MSP size influences the FBR and thus might influence 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 efficacy of microsphere-based therapies in vivo.
authors.affiliation: University Medical Hospital Groningen, Dept. of Pathology & Medical Biology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.j.zandstra@umcg.nl.
authors.forename: J
authors.initials: J
authors.lastname: Zandstra
authors.forename: C
authors.initials: C
authors.lastname: Hiemstra
authors.forename: A H
authors.initials: AH
authors.lastname: Petersen
authors.forename: J
authors.initials: J
authors.lastname: Zuidema
authors.forename: M M
authors.initials: MM
authors.lastname: van Beuge
authors.forename: S
authors.initials: S
authors.lastname: Rodriguez
authors.forename: A A
authors.initials: AA
authors.lastname: Lathuile
authors.forename: G J
authors.initials: GJ
authors.lastname: Veldhuis
authors.forename: R
authors.initials: R
authors.lastname: Steendam
authors.forename: R A
authors.initials: RA
authors.lastname: Bank
authors.forename: E R
authors.initials: ER
authors.lastname: Popa
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005549:Foreign-Body Reaction / Q000209:etiology*; D006801:Humans; D019344:Lactic Acid / Q000009:adverse effects* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D008863:Microspheres; D011100:Polyglycolic Acid / Q000009:adverse effects* / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D001672:Biocompatible Materials; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid