Biocompatibility of Poly (DL-Lactide-co-Glycolide) Microspheres Implanted into the Brain

Abstract

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.

Effective GDNF brain delivery using microspheres—A promising strategy for Parkinson's disease

“…No evidence of damage was observed on the tissue that surrounds the implanted microparticles indicating that they were well tolerated. Consistent with previous reports, GFAP-positive reactive astrocytes were observed around the needle tract ( Figure 6A) [14,16,24]. This reaction was the same for the 3 groups of animals demonstrating that the astrocytic response is attributed to the mechanical trauma that occurs during surgery and not to the polymer.…”

“…First of all, microparticles are prepared with biodegradable polymers that do not require removal once the treatment is finished. Secondly, brain biocompatibility of particles prepared with poly (lactic-co-glycolic) acid (PLGA) polymers has already been well established [13][14][15][16] and therefore the appearance of host immune reaction against injected microparticles is very unlikely. Finally, the drug release profile of PLGA microspheres brings another important advantage.…”

Biomaterials for the central nervous system

“…Studies have shown that the CNS tissue response to PLGA drug carriers is a moderate and non-specific inflammatory reaction due to the mechanical trauma by implantation, irrespective of the drug carrier shape or the implantation site (Menei et al 1993;Lillehei et al 1996, Kou et al 1997Emerich et al 1999;Fournier et al 2003). Local injection of PLGA microspheres has been used to deliver anti-tumour agents such as mitoxantrone, hemopexin, platelet factor 4 fragment, 5-fluoro-uracil and carboplatin (Menei et al 1996;Chen, W. et al 1997;Benny et al 2005;Yemisci et al 2006) for treatment of brain tumours.…”

Drug transport to brain with targeted nanoparticles

“…48,51 Generally considered as biocompatible, 41 PLA or PLGA microspheres have also a good CNS biocompatibility. 52,53 No mortality was reported with albumin-coated nanoparticles in mice with up to a 2000 mg/kg dose. 44 However, PLA 60000 nanoparticles stabilized with sodium cholate were much more toxic with two of five deaths at a 220 mg/kg dose and five of five at a 440 mg/kg dose associated with marked clinical signs (dyspnea, reduced locomotor activity), alteration of hematological and biochemical parameters and lung hemorrhage.…”