Characteristics in-vitro and in-vivo

1.3 Characteristics in-vitro and in-vivo

1.3.1 Irradiation damage of neutron activated microspheres
Glass is relatively resistant to irradiation damage, as is shown by the long irradiations
that are necessary to produce rhenium loaded glass microspheres [16]. The γ-heating,
neutrons and other radiation conditions in a nuclear reactor result in considerable
irradiation damage to polymers. Literature concerning γ-irradiations for sterilisation of
the product can be found to gain an impression of the damage caused by irradiation of
polymeric microspheres, which must be irradiated in a nuclear reactor to produce
radioactive pharmaceuticals. We investigated the changes in morphology of the
surface of holmium loaded microspheres after irradiation [29]. Non-irradiated 165Ho-
PLLA-microspheres show a smooth, spherical appearance, whilst irradiated spheres
show minor surface changes of small free PLLA fragments. These fragments
represent, under the irradiation conditions used, a negligible part of total particle
volume. However, changes in molecular weight of PLLA were substantial [29] and
this was also confirmed in other studies using γ-sterilisation [47,48]. Two major
mechanisms of degradation (Fig. 2) take place in a polymer as it is subjected to
radiation: (1) chain scission occurs as a random rupturing of bonds, resulting in
reduction of the molecular weight or, (2) cross-linking which results in the formation
of three-dimensional networks. These mechanisms usually occur simultaneously. The
cause of the decrease in molecular weight of polymers is mainly radiation chain
scission owing to radical formation [49]. In γ-irradiation of PLLA chain scission
occurs predominantly in the amorphous phase of the polymer [31,47]. High crystalline
polymers are more radiation resistant. The reduction in molecular weight is also
dependent on the environment. Oxygen, water, additives and device dimensions are
major factors influencing the degradation [29,49,50]. In most polymers such as PLLA,
dl-PLA [51], poly(lactic-co-glycolic acid) (PLGA) [52,53,54] or polyglycolic acid
(PGA) [55] the mechanisms of degradation are comparable.

Table 4. Factors affecting the hydrolytic degradation behaviour of biodegradable
polyesters [57]
- Water permeability and solubility (hydrophilicity/hydrophobicity)
- Chemical composition
- Mechanism of hydrolysis (noncatalytic, autocatalytic, enzymatic)
- Additives (acidic, basic, monomers, solvents, drug)
- Morphology (crystalline, amorphous)
- Device dimensions (size, shape, surface to volume ratio)
- Porosity
- Glass transition temperature (glassy, rubbery)
- Molecular weight and molecular weight distribution
- Physico-chemical factors (ion exchange, ionic strength, pH)
- Sterilization
- Site of implantation

Anderson and Shive reported in detail the biocompatibility and tissue/material
interactions of biodegradable microspheres [57]. Injection of microspheres, either
subcutaneously or intramuscularly, results in the implantation of a high surface
area/low volume of material into a given tissue volume. Depending upon the packing
and volume of microspheres within an implant site, days to weeks may be required for
cellular infiltration from the surface of the microsphere volume, to its centre. The
infiltration of inflammatory cells and in particular, monocytes, macrophages and
fibroblasts, results in each microsphere having its attendant tissue/material interaction.
The volume of microspheres also elicits a response, which is generally seen early as a
granulation tissue response leading to a fibrous site. Given biocompatible
biodegradable microspheres, the response during the first two weeks is generally
similar, regardless of the degradation rate of the biodegradable polymer. A minimal
inflammatory reaction is observed. The second phase of the tissue response is initiated
by the predominance of monocytes and macrophages. This response occurs after 50-
60 days with poly(DL-lactide-co-glycolide) particles, and after more than 350 days
with PLLA [58]. The last phase is the breakdown of spheres in particles smaller than 5
μm, small enough to initiate a tissue response which is predominated by macrophages.