Biomedical Engineering Reference
In-Depth Information
the foreign material due to its influence on the adsorption of proteins onto the material's surface;
a process that occurs almost instantaneously (Franz et al., 2011). The general rule is that the more
hydrophobic a material, the faster it will be recognized and removed from the body due to increased
hydrophobic interactions with phagocytic cells as well as various proteins (including, but not lim-
ited to, opsonins) (Carstensen et al., 1992). Since some stimuli-responsive materials undergo exten-
sive remodeling following exposure to their stimulus, the surface chemistry of these materials has
the potential to change drastically. This concept also applies to biodegradable materials, whose
surface chemistry can change as a function of time. Thus, additional studies are warranted to elicit
any changes that occur after stimulus-induced activation (or degradation in the case of biodegrad-
able materials) in order to assess deviations from the initial surface chemistry, and any effects these
changes have on the material's biocompatibility.
One of the best-studied methods of altering the surface chemistry to favor biocompatibility
is through the addition of PEG to the surface of the material (known as PEGylation). PEG is a
hydrophilic molecule that serves as a steric boundary, effectively preventing the adsorption of
proteins onto the surface of the material and imparting “stealth” characteristics (Muller et al.,
1992; Owens and Peppas, 2006). The incorporation of PEG into polymer formulations to form
PEG copolymers can be a particularly advantageous technique to increase the biocompatibil-
ity of stimuli-responsive and biodegradable polymers. As these PEG copolymers degrade or
undergo activation
,
the copolymer continues to display PEG molecules at its surface, thereby
allowing the PEG molecules to continue preventing protein adsorption (Owens and Peppas,
2006). Another strategy that has been suggested is the precoating of the material with a hydro-
philic protein such as human serum albumin (HSA). This approach was found to reduce the
extent of neutrophil activation caused by foreign material-neutrophil interactions (Nimeri et al.,
2002). In this approach, the selection of an appropriate protein for precoating is crucial as pre-
coating with some proteins has been shown to exacerbate neutrophil activation. This phenom-
enon has been demonstrated for formulations that used fibrinogen or immunoglobulin G as the
precoating protein (Nimeri et al., 2002). Since this technique involves coating only the surface
of the material with the protein, it is unlikely to have significant beneficial effects on the biocom-
patibility of the poststimulus material. However, it remains an established method for increasing
the biocompatibility of the prestimulus material.
4.6 REPRESENTATIVE METHODS OF BIOCOMPATIBILITY ASSESSMENT
FOR STIMULI-RESPONSIVE NANOMATERIALS
Stimuli-responsive materials pose several distinct challenges to biocompatibility testing due to their
inherent design to undergo drastic changes in response to a particular stimulus. Therefore, it is essen-
tial that both the pre- and poststimulus materials be evaluated for biocompatibility; as the biocompat-
ibility profile of the prestimulus material gives little to no indication as to the biocompatibility of that
material following stimulus exposure. As such, the regimen of tests conducted should be based on the
unique properties of the material in question as well as the intended application. When applicable,
the stimulus itself should also be evaluated for biocompatibility. Furthermore, this is not intended to
be an exhaustive list of all the methods used to establish biocompatibility. Instead, the intent here is
to highlight some of the established methods used to evaluate various critical aspects of biocompat-
ibility testing. As the field of stimuli-responsive materials advances and more complex materials are
created, additional parameters will need to be evaluated in order to obtain a complete biocompatibil-
ity profile. Additional information and testing guidelines (such as appropriate cell line selection) can
be found in the International Organization for Standardization's (ISO) 10993 document.
•
Blood compatibility
: Blood compatibility is a critical parameter, as most nanocarriers are
designed to selectively accumulate at their site of action through passive targeting. Passive
targeting requires that the nanocarriers remain in circulation, and therefore in contact with
