Biomedical Engineering Reference
In-Depth Information
entrapped within the cells (Fig.
4
) and H
2
DCF may be converted to a significant
extent into DCF in a cell-free environment under the influence of various drugs
like apocynin (100 lM) and chlorpromazine (10 lM) (A. Bruinink and U. Tobler,
unpublished results).
2.4 Cytotoxicity Parameters and Prognostic Value
for In Vivo Situations
Based on current data and tests, it must be stated that the prognostic value of in
vitro cytotoxicity tests for animals and humans is limited and depends on the kind
of released compounds and the in vitro model. In some cases a correlation is found
[
57
,
160
], but unfortunately in most cases not [
17
,
62
,
136
,
149
]. The general
limitations of current in vitro tests are that the in vivo situation is not mimicked.
In vitro, tests are performed under static conditions in terms of fluid flow, while in
vivo dynamic situations prevail resulting in a homeostatic condition in stead of an
equilibrium regarding compound release (including particles). The homeostatic
concentration is defined by the rate of compound release and its clearance. One
key issue defining the homeostatic concentration at the implant surface is the
microcirculation in the vicinity of the implant defining not only the clearance [
59
]
but also the component release [
67
]. A clearance can only be achieved in vitro
either by compound metabolism/degradation, by inactivation through binding to
proteins, or via medium exchange (e.g. medium replacement, presence of an
artificial fluid flow) [
27
,
59
]. However, a medium exchange is usually not per-
formed (unless the consumption of nutrients are makes it necessary) during the
short cell culture period for cytotoxicity evaluation.
The lack of correlation between in vitro tests and clinical experience is probably
not only related to the clearance but also to a variety of other factors:
1. Exposure period. One important factor is certainly the short exposure period in
the ISO 10993-5 tests, as discussed above. The biological reactions in vivo may
be induced by different pathways and continue beyond the evaluated exposure
period of 2-72 h.
2. Release kinetics. The release of toxic implant constituents may occur only
initially with a strong decline with time (burst release), or be nearly constant or
even increase [
65
]. The outcome of the in vitro ISO 10993-5 is in both cases the
same and does not distinguish between the different reactions. However, the
response of the body to these two types of materials may differ strongly. For
instance, Rosengren and co-workers inserted polyurethane discs with 0.5 or 1%
zinc diethyldithiocarbamate and nontoxic discs in the abdominal wall of rats for
1 day up to 6 weeks and investigated the foreign body response [
114
]. They
could show that the foreign body reaction disappeared with the reduction of
toxic compound release (in vivo, tissues may react with an inflammatory
response while in vitro cells may respond to toxic compounds with signs of
cytotoxicity). Thus an initial release of toxic constituent need not be dramatic
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