Biomedical Engineering Reference
In-Depth Information
Fig. 2 Schematic overview
of the different factors
influencing cytotoxicity.
(A-F) Examples of the
different factors: A: [
26
,
29
,
31
,
32
,
34
,
100
,
152
]; B: [
36
];
C: [
28
,
39
]; D: [
39
]; E: [
11
,
153
]; F: [
30
,
36
,
108
,
27
]
systemic
secondary
direct/indirect
general
cell division
organ sp.
cell-type sp.
acute
delayed progr.
Accumulation
pathway (B)
specificity (A)
appearance (C)
(Sub)Toxicity
exposure (D)
short
repeated
chronic
stability (F)
solubility (E)
activation/inactivation
by cells/medium
stable/unstable
hydro-/lipophyllic
volatile
insoluble/particles
This uptake and transport may be rate-limited and will take some time, resulting in
a delay of the time-point of effect induction and thus of effect appearance. Several
factors may affect toxicity and its appearance: (i) The critical effective compound
may be a constituent released by an implant itself. (ii) It may be a constituent
altered by metabolization. (iii) It may be a compound whose formation is induced
or catalysed by the released constituent—for example, reactive oxygen species
(ROS) may be formed by an indirect reaction. (iv) The effects found in vitro may
be strongly modified by other components that are present, which by themselves
within a wide concentration range affect the cells differently or not at all [
33
,
37
].
(v) In cell cultures containing several cell types, the toxicant may be produced by
one type but affect the other cell type(s). Examples are the bioactivation of
cyclophosphamide and isophenphos by liver cells resulting in a toxic product for
nerve cells [
36
]. (vi) The effects are not necessarily observed during treatment but
may appear several days after exposition (delayed or progressive effects). The
existence of delayed or progressive effects can be proven by removing the toxicant
after a short treatment period, replacing the culture medium with a fresh one
without the toxicant. A strong indication for the presence of delayed effects is
present if the effect of the initial treatment prevails several days later. Examples of
compounds that induce such delayed effects are cisplatin [
28
] and single wall
carbon nanotubes [
39
].
2.2 What is Measured in the ISO 10993-5 (2009)
Standard Test for Cytotoxicity?
The ISO 10993-5 in vitro cytotoxicity test guideline does not define one single
standard test method but it describes testing schemes that require decisions at
given time-points. Three categories of tests are proposed for assessing the cyto-
toxicity of potentially released materials: (1) extract tests, (2) direct-contact tests
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