Classes of materials used in medicine - Biomedical Engineering Desk Reference - page 299

polyols to polymer surfaces (Sheu et al., 1993), and it has
also been used to deposit an ''oligoEG-like'' coating from
vapors of triglyme or tetraglyme (Lopez et al., 1992).
More recently, a hydrophilic polymer containing phos-
phorylcholine zwitterionic groups along its backbone has
been extensively studied for its nonfouling properties
( Iwasaki et al., 1999 ). Coatings of many hydrogels in-
cluding poly(2-hydroxyethyl methacrylate) and poly-
acrylamide show reasonable nonfouling behavior. There
have also been a number of naturally occuring bio-
molecules such as albumin, casein, hyaluronic acid, and
mucin that have been coated on surfaces and have
exhibited resistance to nonspecific adsorption of pro-
teins. Naturally occurring ganglioside lipid surfactants
having saccharide head groups have been used to make
''stealth'' liposomes ( Lasic and Needham, 1995 ). One
paper even suggested that the protein resistance of
PEGylated surfaces is related to the ''partitioning'' of
albumin into the PEG layers, causing those surfaces to
''look like native albumin'' ( Vert and Domurado, 2000 ).
Recently, SAMs presenting an interesting series of
head-group molecules that can act as H-bond acceptors
but not as H-bond donors have been shown to yield sur-
faces with unexpected protein resistance ( Chapman
et al. , 2000; Ostuni et al. , 2001; Kane et al. , 2003 ). In-
terestingly, PEG also fits in this category of H-bond ac-
ceptors but not donors. However, this generalization does
not explain all NFSs, especially a report in which mannitol
groups with H-bond donor -OH groups were found to be
nonfouling ( Luk et al. , 2000 ). Another hypothesis pro-
poses that the functional groups that impart a nonfouling
property are kosmotropes, order-inducing molecules
(Kane et al., 2003). Perhaps because of the ordered water
surrounding these molecules, they cannot penetrate the
ordered water shell surrounding proteins so strong in-
termolecular interactions between surface group and
protein cannot occur. An interesting kosmotrope mole-
cule with good nonfouling ability described in this paper is
taurine, H 3 N þ (CH 2 ) 2 SO 3 . Table 3.2.13-2 summarizes
some of the different compositions that have been applied
as NFSs.
It is worthwhile to mention some computational
papers (supported by some experiments) that offer new
insights and ideas on NFSs ( Lim and Herron, 1992;
Pertsin et al. , 2002; Pertsin and Grunze, 2000 ). Also,
many new experimental methods have been applied to
study the mechanism of NFSs including neutron reflec-
tivity to measure the water density in the interfacial
region (Schwendel et al., 2003), scanning force micros-
copy (Feldman et al., 1999), and sum frequency gener-
ation ( Zolk et al. , 2000 ).
Finally, it should be noted that bacteria tend to adhere
and colonize almost any type of surface, perhaps even
many protein-resistant NFSs. However, the best NFSs
can provide acute resistance to bacteria and biofilm

Table 3.2.13-2 NFS compositions
Synthetic hydrophilic surfaces

PEG polymers and surfactants

Neutral polymers

Poly(2-hydroxyethyl methacrylate)
Polyacrylamide
Poly(N-vinyl-2-pyrrolidone)
Poly(N-isopropyl acrylamide) (below 31 C)

Anionic polymers

Phosphoryl choline polymers

Gas discharge-deposited coatings (especially from PEG-like
monomers)

Self-assembled n-alkyl molecules with oligo-PEG head groups

Self-assembled n-alkyl molecules with other polar head groups

Natural hydrophilic surfaces

Passivating proteins (e.g., albumin and casein)

Polysaccharides (e.g., hyaluronic acid)

Liposaccharides

Phospholipid bilayers

Glycoproteins (e.g., mucin)

build-up better than most surfaces (Johnston et al.,
1997). Resistance to bacterial adhesion remains an un-
solved problem in surface science. Also, it has been
pointed out that susceptibility of PEGs to oxidative
damage may reduce their utility as NFSs in real-world
situations ( Kane et al. , 2003 ).

Conclusions and perspectives

It is remarkable how many different surface composi-
tions appear to be nonfouling. Although it is difficult to
be sure about the existence of a unifying mechanism for
this action, it appears that the major factor favoring re-
sistance to protein adsorption will be the retention of
bound water by the surface molecules, plus, in the case of
an immobilized hydrophilic polymer, entropic and os-
motic repulsion by the polymer coils. Little is known
about how long a NFS will remain nonfouling in vivo.
Longevity and stability for nonfouling biomaterials re-
mains an uncharted frontier. Defects (e.g., pits, uncoated
areas) in NFSs may provide ''footholds'' for bacteria and
cells to begin colonization. Enhanced understanding of
how to optimize the surface density and composition of
NFSs will lead to improvements in quality and fewer
microdefects. Finally, it is important to note that a clean,
''nonfouled'' surface may not always be desirable. In the