Polyanhydrides - Biodegradable Polymers - page 65

synthetic pathway, while aromatic monomers are eliminated without further meta-
bolic transformation [111] . Dang et al. studied surface erosion of Gliadel wafers
during in vivo degradation in rat brain as well as during in vitro degradation in
phosphate-buffered saline [2]. Morphological changes of the wafer during erosion
were studied and SEM was used to present a visual proof of the erosion process.
The wafer cross section before and after implantation in the brains of rats for
various time periods has been studied. Before implantation, the surface of a
BCNU-loaded polyanhydride wafer appeared very uniform with spray-dried micro-
spheres densely packed together on the outer surface. Two hours after the wafer
implantation, the porous structure extended approximately 20-30

m from the
surface into the interior of the wafer with outer thin layer of the wafer being eroded
in the beginning and rest remained intact. Cross section of the degrading wafer
followed dynamic process of water penetration from the surface to interior. One
day following implantation, the wafer surface became highly porous and porosity
decreased toward the region closer to the interior of the wafer. Higher magnifi ca-
tion of the erosion zone revealed that the eroded microspheres had a dense struc-
ture at the external surface, while the materials from the inner core had already
eroded and disappeared. As the advancing waterfront erodes deeper layers of the
wafer, the porosity of the wafer increases resulting in increased numbers of chan-
nels and pores for water to access the interior of the wafer. Five days after wafer
implantation, the entire cross section of the wafer displayed a uniformly high
porosity without any individual microspheres being present. It indicates that water
had penetrated through the whole wafer and degraded the interior as well as the
exterior of the wafer. These results indicated that SEM analysis and weight loss
studies were in a good correlation of in vitro- in vivo degradation behavior. Domb
et al. studied the metabolic disposition and elimination process of (P[CPP-SA]
20:80) by implantation in adult Sprague-Dawley rat brain using radiolabeled poly-
mers [112]. The results clearly showed that P(CPP-SA) 20:80 copolymer is exten-
sively hydrolyzed 7 days postimplantation and revealed that the anhydride bonds
in the copolymer are gradually degraded to give water-soluble SA monomer which
are extensively metabolized in the body and excreted mostly as carbon dioxide.
The elimination of the CPP component was slow due to its minimal solubility.
The main route of elimination of insoluble CPP is by macrophages and infl am-
matory cells after its disintegration into small fragments.

μ

3.7
Toxicological Aspects of Polyanhydrides

The toxicological aspect of polyanhydrides deals with the host response in terms
of cytotoxicity, allergic responses, irritation, infl ammation, and systemic and
chronic toxicity. Cytotoxicity tests are the fi rst in a sequential program of tests for
assessing the biocompatibility of a polymer for which, tissue culture methods are
used [111]. In a study, bovine aortic endothelial cells and bovine smooth muscle
cells were used to evaluate the in vitro biocompatibility of three polyanhydrides