title: Protein adsorption in three dimensions.
abstract: Recent experimental and theoretical work clarifying the physical chemistry of blood-protein adsorption from aqueous-buffer solution to various kinds of surfaces is reviewed and interpreted within the context of biomaterial applications, especially toward development of cardiovascular biomaterials. The importance of this subject in biomaterials surface science is emphasized by reducing the "protein-adsorption problem" to three core questions that require quantitative answer. An overview of the protein-adsorption literature identifies some of the sources of inconsistency among many investigators participating in more than five decades of focused research. A tutorial on the fundamental biophysical chemistry of protein adsorption sets the stage for a detailed discussion of the kinetics and thermodynamics of protein adsorption, including adsorption competition between two proteins for the same adsorbent immersed in a binary-protein mixture. Both kinetics and steady-state adsorption can be rationalized using a single interpretive paradigm asserting that protein molecules partition from solution into a three-dimensional (3D) interphase separating bulk solution from the physical-adsorbent surface. Adsorbed protein collects in one-or-more adsorbed layers, depending on protein size, solution concentration, and adsorbent surface energy (water wettability). The adsorption process begins with the hydration of an adsorbent surface brought into contact with an aqueous-protein solution. Surface hydration reactions instantaneously form a thin, pseudo-2D interface between the adsorbent and protein solution. Protein molecules rapidly diffuse into this newly formed interface, creating a truly 3D interphase that inflates with arriving proteins and fills to capacity within milliseconds at mg/mL bulk-solution concentrations C(B). This inflated interphase subsequently undergoes time-dependent (minutes-to-hours) decrease in volume V(I) by expulsion of either-or-both interphase water and initially adsorbed protein. Interphase protein concentration C(I) increases as V(I) decreases, resulting in slow reduction in interfacial energetics. Steady state is governed by a net partition coefficient P=(C(I)/C(B)). In the process of occupying space within the interphase, adsorbing protein molecules must displace an equivalent volume of interphase water. Interphase water is itself associated with surface-bound water through a network of transient hydrogen bonds. Displacement of interphase water thus requires an amount of energy that depends on the adsorbent surface chemistry/energy. This "adsorption-dehydration" step is the significant free energy cost of adsorption that controls the maximum amount of protein that can be adsorbed at steady state to a unit adsorbent surface area (the adsorbent capacity). As adsorbent hydrophilicity increases, adsorbent capacity monotonically decreases because the energetic cost of surface dehydration increases, ultimately leading to no protein adsorption near an adsorbent water wettability (surface energy) characterized by a water contact angle θ→65(°). Consequently, protein does not adsorb (accumulate at interphase concentrations greater than bulk solution) to more hydrophilic adsorbents exhibiting θ<65(°). For adsorbents bearing strong Lewis acid/base chemistry such as ion-exchange resins, protein/surface interactions can be highly favorable, causing protein to adsorb in multilayers in a relatively thick interphase. A straightforward, three-component free energy relationship captures salient features of protein adsorption to all surfaces predicting that the overall free energy of protein adsorption ΔG(ads)(o) is a relatively small multiple of thermal energy for any surface chemistry (except perhaps for bioengineered surfaces bearing specific ligands for adsorbing protein) because a surface chemistry that interacts chemically with proteins must also interact with water through hydrogen bonding. In this way, water moderates protein adsorption to any surface by competing with adsorbing protein molecules. This Leading Opinion ends by proposing several changes to the protein-adsorption paradigm that might advance answers to the three core questions that frame the "protein-adsorption problem" that is so fundamental to biomaterials surface science.
authors.affiliation: Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA. eav3@psu.edu
authors.forename: Erwin A
authors.initials: EA
authors.lastname: Vogler
mesh_terms: D000327:Adsorption; D000818:Animals; D006801:Humans; D007700:Kinetics; D011506:Proteins / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D011506:Proteins
references.citation: J Biomed Mater Res A. 2004 Mar 1;68(3):544-57
references.pmid: 14762935
references.citation: Adv Colloid Interface Sci. 1986 Sep;25(4):267-340
references.pmid: 3333131
references.citation: Adv Colloid Interface Sci. 1998 Feb;74:69-117
references.pmid: 9561719
references.citation: Biochem J. 1974 Oct;143(1):83-91
references.pmid: 4464859
references.citation: Biophys Chem. 1999 Sep 13;81(1):59-80
references.pmid: 10520251
references.citation: Trends Biotechnol. 1991 Jun;9(6):201-8
references.pmid: 1367245
references.citation: Langmuir. 2008 Mar 18;24(6):2553-63
references.pmid: 18229964
references.citation: Langmuir. 2008 Dec 16;24(24):14115-24
references.pmid: 19360943
references.citation: Biomaterials. 2006 Dec;27(34):5780-93
references.pmid: 16919724
references.citation: Biomaterials. 2008 Jul;29(21):3062-74
references.pmid: 18442850
references.citation: Mol Cell Proteomics. 2002 Nov;1(11):845-67
references.pmid: 12488461
references.citation: Anal Biochem. 2007 Feb 1;361(1):120-5
references.pmid: 17187752
references.citation: J Biomed Mater Res. 1998 Aug;41(2):304-11
references.pmid: 9638536
references.citation: Chem Rev. 2002 Aug;102(8):2651-70
references.pmid: 12175263
references.citation: Biomaterials. 2006 Jun;27(18):3404-12
references.pmid: 16504286
references.citation: Langmuir. 2011 Mar 15;27(6):2634-43
references.pmid: 21322572
references.citation: Thromb Haemost. 1984 Jul 29;51(3):326-30
references.pmid: 6495253
references.citation: J Biomed Mater Res. 1995 Aug;29(8):1017-28
references.pmid: 7593032
references.citation: Langmuir. 2004 Aug 31;20(18):7779-88
references.pmid: 15323531
references.citation: J Colloid Interface Sci. 1998 Nov 1;207(1):11-19
references.pmid: 9778385
references.citation: J Colloid Interface Sci. 1997 Feb 1;186(1):9-16
references.pmid: 9056289
references.citation: J Colloid Interface Sci. 2004 Oct 1;278(1):81-90
references.pmid: 15313640
references.citation: Biomaterials. 2007 Aug;28(22):3273-83
references.pmid: 17466368
references.citation: Langmuir. 2007 May 8;23(10):5591-600
references.pmid: 17425343
references.citation: Biophys Chem. 2001 Nov 28;93(2-3):141-57
references.pmid: 11804722
references.citation: J Biomater Sci Polym Ed. 1994;6(2):223
references.pmid: 7947485
references.citation: Anal Biochem. 1984 Jul;140(1):190-5
references.pmid: 6486405
references.citation: J Biomater Sci Polym Ed. 1991;3(1):95-107
references.pmid: 1786247
references.citation: J Colloid Interface Sci. 2002 Jan 1;245(1):81-5
references.pmid: 16290338
references.citation: Biomaterials. 2009 Nov;30(33):6495-513
references.pmid: 19751950
references.citation: J Mol Biol. 1987 Aug 5;196(3):641-56
references.pmid: 3681970
references.citation: J Biomed Mater Res. 1969 Mar;3(1):175-89
references.pmid: 5784963
references.citation: J Phys Chem. 1968 Aug;72(8):2862-6
references.pmid: 4873854
references.citation: Biomaterials. 2006 Dec;27(34):5801-12
references.pmid: 16928398
references.citation: Langmuir. 2010 Jun 1;26(11):8061-74
references.pmid: 20146434
references.citation: Biomaterials. 1985 Sep;6(5):338-45
references.pmid: 4052547
references.citation: Anal Chem. 2001 Dec 15;73(24):5796-804
references.pmid: 11791547
references.citation: Biomaterials. 2006 Jun;27(17):3187-94
references.pmid: 16494939
references.citation: Biomaterials. 2008 May;29(13):2033-48
references.pmid: 18289663
references.citation: Langmuir. 2010 Jul 20;26(14):11934-45
references.pmid: 20575543
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10167-72
references.pmid: 8816770
references.citation: Biomaterials. 2005 Jun;26(17):3445-53
references.pmid: 15621233
references.citation: Biomaterials. 2011 Oct;32(28):6670-5
references.pmid: 21684003
references.citation: Langmuir. 2005 Jun 21;21(13):5852-8
references.pmid: 15952833
references.citation: J Phys Chem B. 2005 Jul 21;109(28):13811-7
references.pmid: 16852729
references.citation: J Biomed Mater Res A. 2006 Sep 15;78(4):843-54
references.pmid: 16832826
references.citation: Biophys J. 1997 Feb;72(2 Pt 1):595-612
references.pmid: 9017189
references.citation: Biomaterials. 2009 Dec;30(36):6814-24
references.pmid: 19796805
references.citation: J Biomed Mater Res A. 2005 Nov 1;75(2):445-57
references.pmid: 16104049
references.citation: Langmuir. 2011 Jan 4;27(1):148-57
references.pmid: 21126036
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9037-41
references.pmid: 10908651
references.citation: Biomaterials. 2007 Oct;28(30):4355-69
references.pmid: 17644174
references.citation: J Mol Biol. 1996 Jul 26;260(4):588-603
references.pmid: 8759322
references.citation: Biomaterials. 1984 Nov;5(6):319-25
references.pmid: 6525391
references.citation: Annu Rev Biophys Bioeng. 1977;6:151-76
references.pmid: 326146
references.citation: Biomaterials. 2010 Feb;31(6):1068-79
references.pmid: 19892397
references.citation: J Biomed Mater Res. 1987 Aug;21(8):1023-8
references.pmid: 3654686
references.citation: J Biomater Sci Polym Ed. 1993;4(6):591-9
references.pmid: 8280673
references.citation: Biomaterials. 2006 Aug;27(24):4325-32
references.pmid: 16644008
references.citation: Biopolymers. 1996 Nov;39(5):619-26
references.pmid: 8875817
references.citation: J Mol Biol. 1999 Jul 2;290(1):253-66
references.pmid: 10388571
references.citation: Langmuir. 2008 Sep 2;24(17):9183-8
references.pmid: 18672918
references.citation: J Am Chem Soc. 2003 Oct 22;125(42):12782-6
references.pmid: 14558825
references.citation: J Exp Med. 1925 May 31;41(6):779-93
references.pmid: 19869026
references.citation: Nature. 1987 Aug 27-Sep 2;328(6133):834-6
references.pmid: 3627230
references.citation: Langmuir. 2009 Dec 15;25(24):14105-15
references.pmid: 19627073
references.citation: Langmuir. 2006 Jul 4;22(14):6181-8
references.pmid: 16800674
references.citation: Langmuir. 2010 Jun 1;26(11):8075-80
references.pmid: 20146432
references.citation: Acta Biomater. 2005 Sep;1(5):583-9
references.pmid: 16701838
references.citation: Colloids Surf B Biointerfaces. 2005 Jun 25;43(2):95-8
references.pmid: 15922578
references.citation: Langmuir. 2004 Jul 6;20(14):5870-8
references.pmid: 16459603
references.citation: Bull N Y Acad Med. 1972 Feb;48(2):302-10
references.pmid: 4500645
references.citation: J Biomater Sci Polym Ed. 1991;2(3):203-16
references.pmid: 1854685
references.citation: Nature. 1975 Mar 27;254(5498):304-8
references.pmid: 1118010
references.citation: Science. 1998 Sep 11;281(5383):1650-3
references.pmid: 9733506
references.citation: Biomaterials. 2009 Apr;30(10):1857-69
references.pmid: 19168215
references.citation: Anal Biochem. 1993 Nov 1;214(2):495-9
references.pmid: 8109739
references.citation: Anal Chem. 1997 Aug 15;69(16):3321-8
references.pmid: 9271071
references.citation: Arch Biochem Biophys. 1993 Jan;300(1):206-12
references.pmid: 8424654
references.citation: J Biomed Mater Res. 1993 Dec;27(12):1463-76
references.pmid: 8113233
references.citation: J Biomater Sci Polym Ed. 1999;10(10):1015-45
references.pmid: 10591130
references.citation: Chem Rev. 1999 Aug 11;99(8):2161-2200
references.pmid: 11849023
references.citation: J R Soc Interface. 2006 Apr 22;3(7):283-301
references.pmid: 16849238
references.citation: J Biomed Mater Res. 1984 Jul-Aug;18(6):685-93
references.pmid: 6544770
references.citation: Anal Biochem. 1995 Jan 1;224(1):221-6
references.pmid: 7710075
references.citation: Anal Chem. 2001 Apr 1;73(7):225A-229A
references.pmid: 11321335
references.citation: J Biomed Mater Res. 1993 Jul;27(7):837-50
references.pmid: 8360211
references.citation: Biomaterials. 1997 Mar;18(5):405-13
references.pmid: 9061181
references.citation: J Phys Chem B. 2008 Jan 24;112(3):1028-40
references.pmid: 18171041
references.citation: Biomaterials. 1986 Jan;7(1):9-16
references.pmid: 3955162
references.citation: Biomaterials. 2008 Jul;29(20):2941-53
references.pmid: 18440630
references.citation: Pharm Res. 2003 Apr;20(4):684-92
references.pmid: 12739779
references.citation: J Biomed Mater Res A. 2004 Mar 1;68(3):504-12
references.pmid: 14762930
references.citation: J Biol Chem. 1984 Jan 10;259(1):347-53
references.pmid: 6423628
references.citation: Langmuir. 2004 Jun 8;20(12):5071-8
references.pmid: 15984270
references.citation: J Biomed Mater Res. 1995 Aug;29(8):1005-16
references.pmid: 7593031
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5553-7
references.pmid: 7539920
references.citation: Biomaterials. 1998 Mar;19(4-5):397-406
references.pmid: 9677153
references.citation: Biomaterials. 2007 Jan;28(3):405-22
references.pmid: 17007920
references.citation: Biomaterials. 1986 Mar;7(2):89-96
references.pmid: 2423146
references.citation: Biomaterials. 2005 Jun;26(16):2965-73
references.pmid: 15603791
references.citation: Acta Biomater. 2009 Jun;5(5):1389-98
references.pmid: 19135420
references.citation: Biomaterials. 2011 Feb;32(4):969-78
references.pmid: 21035180