Biomedical Engineering Reference
In-Depth Information
fibrosis, vascularization, and other tissue alterations. In some scor-
ing schemes, the reaction for the control material is subtracted from
the reaction of the test material. The resultant score is correlated to
a scale and defined as slight to severe irritant.
When addressing local effects following implantation, these
data may be obtained from other studies where the primary
endpoint is not a local effect. For example, during ocular device
functional, efficacy or toxicity studies, these implant sites are also
evaluated, providing, local effects data at these intervals. In these
cases where the local effects can be evaluated, specific studies
to examine only local effects are then not needed. Therefore, it is
prudent to consider practical design of ocular implantation studies
so irritation and other endpoints are possible in the same study.
The testing guideline in ISO 10993 has both subacute and sub-
chronic toxicity in the same general biological effect category
[
1
,
8
]. Subacute and subchronic differ in duration of exposure.
Subacute systemic toxicity is defined as adverse effects occurring
after multiple or continuous exposure between 24 h and 28 days.
Subchronic systemic toxicity is defined as adverse effects occurring
after the repeated or continuous administration of a test sample
for up to 90 days or not exceeding 10 % of the animals lifespan.
The rationale for selection of either a subacute or subchronic test
should be based on the biomaterial comprising the device, clinical
duration of use for the medical device, the nature of exposure,
and the overall testing strategy. The method of exposure is usually
by implantation subcutaneously to provide the exposure dose. For
ocular medical devices, this type of study is usually only needed if a
risk assessment shows that the biomaterial of the device has not
been adequately characterized for leachables systemically.
For subacute/subchronic studies where the device is implanted,
rats are most often used for these studies and parts of the device are
implanted subcutaneously. The subcutaneous tissue along each side
of the back is used most often as it can more readily accommodate
larger pieces of a device. Selection of a “dose” should be based on
the clinical dose of the device. This is best determined on a weight
basis. Using the device weight and patient weight (70 kg as a
standard weight for adults), a clinical dose is calculated (mg or g of
device/kg body weight). To improve the sensitivity of the assay, a
safety factor is assigned to the animal dose, 100
2.8 Subchronic
Toxicity
if possible. The
size of the device will dictate the safety factor that is possible. As a
general guideline, samples for subcutaneous implantation should be
no more than approximately 1.5-2 cm across and 2-3 mm thick
with rounded edges. To achieve a given dose, multiple specimens,
up to three per side, can be placed in each animal. The duration of
these studies range from 4 weeks to 3 months. The parameters
evaluated throughout the course of the study include clinical obser-
vations, body weight measurements,
implant site observations,
