Biocompatibility of poly (DL-lactide-co-glycolide) microspheres implanted into the brain.
The delivery of therapeutic molecules to the brain has been limited in part due to the presence of the blood-brain barrier. One potential solution is the implantation of biodegradable polymers with sustained release of drugs. Poly (DL-lactide-co-glycolide) (PLG) is a bioerodible polymer with a long and successful history of use as a suture material. More recently, PLG has been investigated for localized and sustained delivery of molecules into both peripheral sites and the brain. Despite its well-defined safety profile for parenteral applications, little information exists concerning the safety of PLG when implanted into the brain. To further characterize the biocompatibility of PLG in the brain, we examined the gliotic response following implants of PLG into the brains of rats. As a control, each animal received an injection of the suspension medium into the contralateral hemisphere. Following implantation, PLG was well tolerated. GFAP-positive astrocytes were observed throughout the cerebral cortex and striatum on both the implanted and control sides, with the reaction being greatest within the heavily myelinated fiber tracts of the corpus callosum. Quantitative analyses revealed that this reaction occurred within 1 h postsurgery, reached its peak at 1 week following surgery, and then decreased markedly by 1 month postsurgery. A minimal gliotic reaction was still present 1 year postsurgery but was localized to the needle tract. No differences in GFAP reactivity were seen between the polymer-implanted and control sides at any time point. Histological analysis determined that the majority of the PLG disappeared between 1 and 4 weeks. A set of parallel studies in which PLG samples were retrieved from the brain at various time points corroborated these findings and determined that the majority of PLG degraded within 2 weeks following implantation. Together, these results demonstrate that PLG is well tolerated following implantation into the CNS and that the astrocytic response to PLG is largely a consequence of the mechanical trauma that occurs during surgery. The biocompatibility of PLG implanted into the CNS provides further support for its use in a wide range of new therapeutic applications for sustained and localized drug delivery to the brain.
Emerich
D F
DF
Department of Pharmacology, Alkermes, Inc., Cambridge, MA 02139, USA.
Tracy
M A
MA
Ward
K L
KL
Figueiredo
M
M
Qian
R
R
Henschel
C
C
Bartus
R T
RT
D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage*; D001921:Brain / Q000601:surgery*; D003342:Corpus Striatum / Q000601:surgery; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D005904:Glial Fibrillary Acidic Protein / Q000302:isolation & purification; D007276:Injections, Intraventricular; D019344:Lactic Acid / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D008863:Microspheres; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D005904:Glial Fibrillary Acidic Protein; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid