title: The brain tissue response to biodegradable poly(methylidene malonate 2.1.2)-based microspheres in the rat.
abstract: The aim of this study was to follow the in vivo biodegradation as well as to appreciate the brain tissue response to poly(methylidene malonate 2.1.2) (PMM 2.1.2)-based microspheres implanted into the rat brain. Ninety-three adult Sprague-Dawley female rats were engaged in the study in which 54 underwent stereotactic implantation of blank gamma-sterilized PMM 2.1.2-based microspheres, prepared by an emulsion-extraction method. Twelve rats were implanted with the same 5-fluorouracil (5-FU)-loaded microspheres. Seventeen controls received the suspension medium alone (carboxymethylcellulose aqueous solution). The animals were sacrificed on post-operative days 1, 2, 8 and months 1, 2, 3, 6, 9, 12, 15 and 18. The brains were dissected, frozen, cut in a freezing microtome, and the slides were processed for immunohistological evaluation and scanning electron microscopy. During the first few days, the moderate inflammatory response to blank or loaded PMM 2.1.2 microspheres was largely a consequence of the mechanical trauma that occurs during surgery. The macrophagous-microglial reaction was similar to the one typically found following any damage in the CNS. There were also no differences in GFAP reactivity between the implanted animals and the controls. Blank microspheres began to degrade between 3 and 6 months, while 5-FU microspheres degraded between 8 days and 1 month. The polymer degradation generated in both cases a pronounced inflammatory and immunological reaction, leading to an important cell loss, a cerebral atrophy and to the death of several animals. PMM 2.1.2 was thus shown to be inadequate for intracerebral drug delivery.
authors.affiliation: Inserm U646 (Ingénierie de la vectorisation particulaire), 10 rue André Bocquel, 49 100 Angers, France. elvire.fournier@serono.com
authors.forename: Elvire
authors.initials: E
authors.lastname: Fournier
authors.forename: Catherine
authors.initials: C
authors.lastname: Passirani
authors.forename: Nathalie
authors.initials: N
authors.lastname: Colin
authors.forename: Serge
authors.initials: S
authors.lastname: Sagodira
authors.forename: Philippe
authors.initials: P
authors.lastname: Menei
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benoit
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Montero-Menei
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology*; D001673:Biodegradation, Environmental; D001921:Brain / Q000187:drug effects* / Q000601:surgery / Q000648:ultrastructure; D001923:Brain Chemistry / Q000187:drug effects; D004343:Drug Implants / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000032:analysis; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D007150:Immunohistochemistry; D008314:Malonates / Q000737:chemistry / Q000494:pharmacology*; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D015394:Molecular Structure; D011095:Polyethylenes / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D001672:Biocompatible Materials; D004343:Drug Implants; D005904:Glial Fibrillary Acidic Protein; D008314:Malonates; D011095:Polyethylenes; C091414:poly(methylidene malonate) 2.1.2; D005472:Fluorouracil