Biomedical Engineering Reference
In-Depth Information
''elastic network'' resistance) plus the resistance of
the PEG molecule to release both bound and free
water from within the hydrated coil (called ''osmotic
repulsion'') ( Gombotz et al. , 1991; Antonsen and
Hoffman, 1992 ). The size of the adsorbing protein
and its resistance to unfolding may also be an
important factor determining the extent of adsorp-
tion on any surface ( Lim and Herron, 1992 ). The
thermodynamic principles governing the adsorption
of proteins onto surfaces involve a number of
enthalpic and entropic terms favoring or resisting
adsorption. These terms are summarized in Table
3.2.13-1. The major factors favoring adsorption will
be the entropic gain of released water and the
enthalpy loss due to cation-anion attractive
interactions between ionic protein groups and
surface groups. The major factors favoring resistance
to protein adsorption will be the retention of bound
water, plus, in the case of an immobilized hydrophilic
polymer, entropic and osmotic repulsion of the
polymer coils.
In spite of the evidence for a PEG molecular weight
effect, excellent protein resistance can be achieved
with very short chain PEGs (OEGs) and PEG-like
surfaces ( Lopez et al., 1992 ; Sheu et al., 1993 ).
Surface-assembled monolayers (SAMs) of
lipid-oligoEG molecules have been studied, and it
has been found that at least about 50% of the surface
should be covered before significant resistance to
protein adsorption is observed ( Prime and
Whitesides, 1993 ). This suggests that protein resis-
tance by OEG-coated surfaces may be related to
a ''cooperativity'' between the hydrated, short OEG
chains in the ''plane of the surface,'' wherein the
OEG chains interact together to bind water to the
surface, in a way that is similar to the hydrated coil
and its osmotic repulsion, as described above. It has
also been observed that a minimum of 3 EG units are
needed for highly effective protein repulsion
( Harder et al. , 1998 ). Based on all of these
observations, one may describe the mechanism as
being related to the conformation of the individual
oligoEG chains, along with their packing density in
the SAM. It has been proposed that helical or
amorphous oligoEG conformations lead to stronger
water-oligoEG interactions than an all-trans oligoEG
conformation ( Harder et al. , 1998 ).
Packing density of the nonfouling groups on the surface is
difficult to measure and often overlooked as an important
factor in preparing NFSs. Nevertheless, one may con-
clude that the one common factor connecting all NFSs is
their resistance to release of bound water molecules from
the surface. Water may be bound to surface groups by
both hydrophobic (structured water) and hydrophilic
(primarily via hydrogen bonds) interactions, and in the
latter case, the water may be H-bonded to neutral polar
groups, such as hydroxyl ( OH) or ether ( C O C )
groups, or it may be polarized by ionic groups, such as
COO or NH þ 3 . The overall conclusion from all of the
above observations is that resistance to protein adsorption
at biomaterial interfaces is directly related to resistance of
interfacial groups to the release of their bound waters of
hydration.
Based on these conclusions, it is obvious why the most
common approaches to reducing protein and cell binding
to biomaterial surfaces have been to make them more
hydrophilic. This has been accomplished most often by
chemical immobilization of a hydrophilic polymer (such
as PEG) on the biomaterial surface by one of the fol-
lowing methods: (a) using UV or ionizing radiation to
graft copolymerize a hydrophilic monomer onto surface
groups; (b) depositing such a polymer from the vapor of
a precursor monomer in a gas discharge process; or (c)
directly immobilizing a preformed hydrophilic polymer
on the surface using radiation or gas discharge processes.
Other approaches to make surfaces more hydrophilic
have included the physical adsorption of surfactants or
chemical derivatization of surface groups with neutral
polar groups such as hydroxyls, or with negatively
charged groups (especially since most proteins and cells
are negatively charged) such as carboxylic acids or their
salts, or sulfonates. Gas discharge has been used to co-
valently bind nonfouling surfactants such as Pluronic
Table 3.2.13-1 Thermodynamics of protein adsorption
Favoring adsorption
DH ads
()
VdW interactions (short-range)
()
Ion-ion interactions (long-range)
DS ads
(þ)
Desorption of many H 2 Os
(þ)
Unfolding of protein
Opposing adsorption
DH ads
(þ)
Dehydration (interface between surface
and protein)
(þ)
Unfolding of protein
(þ)
Chain compression (PEO)
DS ads
()
Adsorption of protein
()
Protein hydrophobic exposure
()
Chain compression (PEO)
()
Osmotic repulsion (PEO)
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