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Chapter 28
Poly(ethylene glycol) and Poly(carboxy betaine) Based Nonfouling Architectures: Review and Current Efforts Mojtaba Binazadeh,1,# Maryam Kabiri,1,# and Larry D. Unsworth*,1,2 1Department
of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta, T6G 2V4, Canada 2National Institute for Nanotechnology, National Research Council (Canada), Edmonton, Alberta, T6G 2M9, Canada #These authors have contributed equally to this work. *E-mail:
[email protected] Non-specific adsorption of proteins at the tissue-material interface occurs shortly after implantation and is thought to initiate several host responses (thrombosis, inflammation, wound healing) as well as modify critical therapeutic properties like the drug release profile. Furthermore, it has been shown that substrate surface properties can dramatically affect the adsorbed amount of proteins, as well as their final adsorbed conformation. To further understand how surface properties can affect protein adsorption, two drastically different types of polymers that represent characteristics crucial for the inhibition of non-specific protein adsorption are of interest, viz., the ‘gold-standard’ poly(ethylene glycol) (PEG) and the zwitterionic polybetaines. Unlike PEG whose hydration is due to hydrogen bonding between water molecules and polar ether bonds of the polymer backbone, zwitterionic polybetaines are distinguished by forming a very stable hydration shell as a result of a positive and a negative charge on the same monomer segment within the polymer chain. Current proposed mechanisms of non-specific adsorption and antifouling behaviour of polymeric surfaces are largely lacking a detailed understanding of the interactions at the molecular level. Therefore, work is continuing to utilize these two polymer systems for understanding protein adsorption
© 2012 American Chemical Society In Proteins at Interfaces III State of the Art 2012; Horbett, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.
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in differing ways. Through controlling secondary structures of peptides, it may be possible to systematically discuss how this affects adsorption to PEG modified surfaces, as well as the physicochemical properties. Moreover, through the use of poly (carboxybetaine methacrylamide) (PCBMA), it has been shown to be possible to control the hydration of the film, allowing for a systematic evaluation of the effect of hydration upon protein adsorption. It is thought that a clear study of molecular level events involved in the adsorption of proteins ultimately enables us to understand fundamental properties of proteins essential for further engineering of clinically relevant surfaces.
Non-specific adsorption of proteins at the tissue-material interface is known to influence a multiplicity of events related directly to the in vivo therapeutic efficacy of the tissue contacting biomaterial. Numerous studies have investigated the mechanisms of protein adsorption to surfaces in contact with physiological fluids, where the impetus for protein adsorption is thought to be a variety of forces present between surfaces and macromolecules within aqueous environments. Functional aspects of the therapeutic biomaterial reported to be influenced by non-specific protein adsorption, include the initiation of several host responses (thrombosis, inflammation, wound healing), the drug release profile, the biomaterial degradation, etc (1). It is well known that shortly after implantation, a layer of plasma proteins will cover the tissue contacting surface (2–6). Moreover, upon adsorption at the tissue-material interface these proteins may undergo a surface-induced conformational rearrangement. In addition to facilitating an increase in the protein-surface interaction, conformational changes in adsorbed proteins may lead to the exposure of occult domains that initiate adverse reactions such as the accumulation of inflammatory cells, foreign body response, and coagulation (7–11). It has been shown, for instance, that exposed protein domains may provide ligands that facilitate cell responses directly; for example, conformational changes in fibrinogen have been shown to expose several occult epitopes that interact with immune cells directly (12–14). Thus, significant effort has been expended in developing surfaces that either inhibit non-specific protein adsorption or minimize the conformational changes proteins undergo upon adsorption. Surface engineering for the express purpose of inhibiting non-specific protein adsorption, or subsequent protein denaturing, has shown that substrate surface properties can dramatically affect the adsorbed amount of proteins, as well as their final adsorbed conformation (15). That said, issues surrounding protein adsorption to surfaces have not been resolved and require further attention for the express purpose of developing cost effective, convenient, and versatile strategies for rendering surfaces resistant to non-specific protein adsorption (16). In order to investigate protein adsorption mechanisms different researchers have conducted experiments with a single- or multi-component protein solution, on a vast variety of surface architectures (17, 18). In fact too many surface architectures exist to 622 In Proteins at Interfaces III State of the Art 2012; Horbett, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.
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be covered herein. Suffice it to say that despite these efforts, controlling protein adsorption has met with limited success. It is thought that there are two main reasons this has been the case: i. the inherent amphiphilic properties of proteins provide multiple pathways by which proteins may interact with surfaces (19); and ii. it is not just the presence of the protein that can initiate a bioresponse, but also its conformation. Thus, designing surfaces for the express purpose of inhibiting or controlling non-specific adsorption events has been the focus of decades of research, and continues to be both an industrially relevant and a scientifically interesting area of activity. As a means of further understanding how surface properties can affect protein adsorption, two drastically different types of polymers are of interest, viz., the ‘gold-standard’ poly(ethylene glycol) (PEG) and the zwitterionic polybetaines. Through the discussion of these different polymers, coupled with designed experiments using controlled protein and surface properties, it is thought that a better understanding of molecular events crucial to dictating protein adsorption events may be gained.
Fundamental Forces Leading to Nonspecific Protein Adsorption There is a relatively low energy barrier between conformational states of various protein domains, which results in an overall native conformation that may be highly susceptible to structural changes induced by environmental disturbances: such as the introduction of a surface (e.g., air or bioimplant surface) (20). The interaction between a protein and a surface is thought to be the result of a balance between van der Waals, electrostatic, hydrophobic, and hydration forces (21). In aqueous solutions, London-van der Waals (dispersion) forces, which arise due to the interaction of two instantaneously induced dipoles, may constitute ~95% of all van der Waals types of interactions that exist between a protein and a surface found in aqueous media (22). Dispersion forces are considered long range and effective within distances
