title: Drug Distribution in Microspheres Enhances Their Anti-Inflammatory Properties in the Gottingen Minipig.
abstract: The foreign body reaction (FBR), one of the body's defense mechanisms against foreign materials, results in loss of implant biocompatibility. A popular strategy to prevent FBR is the constant release of dexamethasone in the tissue surrounding the implant. However, FBR prevention has not been sufficiently studied in large animal models, which offer a better representation of the human subcutaneous tissue physiology. Accordingly, a long-term strategy to prevent FBR to subcutaneous implants in a large animal model is necessary to translate the existing research for clinical applications. Here, a poly(lactic-co-glycolic) (PLGA) microsphere/poly(vinyl alcohol) (PVA) hydrogel composite coating for one-month prevention of FBR in Gottingen minipigs was developed. A modified PLGA microsphere formulation process is presented, that utilizes coprecipitation of dexamethasone and PLGA. Traditional methods result in heterogeneous distribution of large drug crystals in the microsphere matrix, which in turn results in low drug loading since the drug crystal size is close to that of the microspheres. The modified microsphere preparation method showed homogeneous distribution of dexamethasone, which in turn gave rise to increased drug loading, low burst release, and minimal lag phase. Elimination of the lag phase was dictated from previous work that compared FBR between rats and minipigs. The ability of the coatings to improve implant biocompatibility was successfully tested in vivo via histological examination of explanted tissue from the area surrounding the implants. The biocompatible coatings presented here are suitable for miniaturized implantable devices, such as biosensors, that require constant communication with the local microenvironment.
authors.affiliation: Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Michail
authors.initials: M
authors.lastname: Kastellorizios
authors.affiliation: Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Namita
authors.initials: N
authors.lastname: Tipnis
authors.affiliation: Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Fotios
authors.initials: F
authors.lastname: Papadimitrakopoulos
authors.affiliation: Department of Pharmaceutical Sciences and ‡Department of Chemistry and Institute of Materials Science, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Burgess
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005549:Foreign-Body Reaction / Q000517:prevention & control*; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D008863:Microspheres; D023421:Models, Animal; D011100:Polyglycolic Acid / Q000737:chemistry*; D011142:Polyvinyl Alcohol / Q000737:chemistry; D019736:Prostheses and Implants; D051381:Rats; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000893:Anti-Inflammatory Agents; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003907:Dexamethasone; D011142:Polyvinyl Alcohol
keywords: PLGA microspheres; coprecipitation; dexamethasone; foreign body reaction; swine