Systematic approach to characterize the dynamics of protein adsorption on the surface of biomaterials using proteomics

Colloids and Surfaces B: Biointerfaces 188 (2020) 110756

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Systematic approach to characterize the dynamics of protein adsorption on the surface of biomaterials using proteomics

T

Jinku Kim Department of Bio and Chemical Engineering, Hongik University, 2639 Sejong-ro, Jochiwon-eup, Sejong, 30016, Republic of Korea

A R T I C LE I N FO

A B S T R A C T

Keywords: Protein adsorption Biocompatibility Biomaterials Proteomics Biological response

Protein adsorption on biomaterial surfaces has been investigated in the development of protein-repellent implantable devices. While the study of the adsorption of a single protein have produced valuable insights of the role of specific proteins in the biological responses to biomaterials, a systematic high throughput screening method is needed to gain more comprehensive understanding of such a complex process, mainly because biomaterials are exposed to protein mixtures when implanted in the human body. To further advance our knowledge of the dynamics of protein adsorption/desorption at interfaces between proteins and solid surfaces, proteomic technologies have been explored to determine relationships between adsorbed proteins on the surfaces and subsequent biological responses. In this review, we will briefly describe the protein adsorption process and proteomics technologies and focus on subsequent biological responses to biomaterials such as blood/biomaterial interactions, biocompatibility, and cell behavior, to obtain more comprehensive understanding of the process for the development of improved biomaterials. We also highlight a number of challenges of contemporary proteomics technologies and future perspectives to advance our knowledge of protein adsorption/desorption dynamics on the surfaces of biomaterials.

1. Introduction It is known that protein adsorption on a biomaterial surface plays a crucial role in determining its biological responses such as biocompatibility and cellular interactions [1–3]. For example, biomaterials used in cardiovascular devices such as coronary artery stents have been utilized for decades, however, those stents have been problematic due to blood clot formation and restenosis, both of which are influenced by protein adsorption [4,5]. This special case shows that better understanding the relationship between protein adsorption and biological responses of materials would be a pre-requisite in the development and the final performance of biomaterials [6–8]. In addition, the study of competitive adsorption of proteins on the surface is also important, primarily because biomaterials are exposed to mixtures of proteins (e.g., blood plasma) with different affinities for surfaces [9,10]. However, current methodologies used in the study of protein adsorption (e.g. radiolabeling [5,11], optical ellipsometry [12], surface plasmon resonance (SPR) [13,14], optical waveguide lightmode spectroscopy (OWLS) [15], fluorescence spectroscopy (e.g., total internal reflection fluorescence or TIRF) [16,17], FTIR/ATR [18,19]) analyze the adsorption of a single protein, or averaged properties of mixtures of proteins on the surface. Now, with advances in the technology, it is possible to determine the identities and concentrations of hundreds of

proteins in a complex biological sample simultaneously using proteomics [20]. Proteomics was originally introduced to study protein expression in cells and it is a collection of techniques that allow the simultaneous study of multiple proteins in complex mixtures, through protein separations and high-throughput identification [21–24]. Proteomics has proven to be useful in the study of protein adsorption onto biomaterial surfaces [25,26]. Previously, the adsorption of a few proteins such as albumin, immunoglobulin-γ (IgG) and fibrinogen were extensively studied [27,28]. However, it is known that there are other proteins in the adsorbed layer. For example, laminin, nidogen, and keratin adsorbed onto various biomaterials such as PMMA, may affect proliferation of epithelial cells to the material [29]. The proteomics technology for the analysis of protein adsorption on biomaterial surfaces has been increasingly applied for more comprehensive understanding of biological responses on the surfaces of biomaterials. Since the beginning of 21st century, increasing number of studies are investigating the adsorption of multiple proteins simultaneously on the surfaces of biomaterials using proteomics. The purpose of this review is to provide a brief overview of proteomic approaches for comprehensive understanding of the dynamics of protein adsorption on biomaterial surfaces. First, we will briefly describe protein adsorption process and proteomics technologies, and focus on biological responses to biomaterials such as blood/biomaterial interactions, biocompatibility, and

E-mail address: [email protected]. https://doi.org/10.1016/j.colsurfb.2019.110756 Received 6 October 2019; Received in revised form 3 December 2019; Accepted 23 December 2019 Available online 24 December 2019 0927-7765/ © 2019 Elsevier B.V. All rights reserved.

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force microscopy), QCM-D (Quartz Crystal Microbalance Dissipation) and TOF-SIMS (Time of flight secondary ion mass spectroscopy) analyses [41]. They demonstrated that earlier adsorbed proteins on a surface can be displaced by subsequently adsorbed proteins, which have higher surface affinity, larger molecular weight and conformationally flexible, and that this dynamic process is consistent with the ‘transient complex’ model [39]. Another recent study explored in situ ATR-FTIR and 2D−COS (Two-dimensional correlation spectroscopy) to measure real time adsorption amount of BSA (Bovine serum albumin) and the secondary structure of the adsorbed protein on aluminosilicate surface to elucidate in situ assessment of kinetic, conformational, and equilibrium adsorption on biomaterial surfaces [18]. While those studies gave more insights of competitive adsorption process on biomaterial surfaces over past decades, most of them used a single or a few proteins instead of using a complex biological protein mixture such as serum or plasma. The structural properties of adsorbed proteins may be crucial to the dynamics of competitive protein adsorption. When proteins arrive at the surface, interactions between adsorbed proteins and the surface occur over time and adsorbed proteins may undergo molecular relaxation or spreading process on the surface, resulting in a higher affinity to the surface [42]. Thus dynamics of the Vroman effect may be altered by the “spreading”(or relaxation) effects stemming from the conformational changes of adsorbed proteins [43]. If the “spreading” effect is present in the first arriving protein, then initially adsorbed protein on the surface may not be displaced with later arriving protein due to the “spreading” effect even if there are differences in transport rates and binding affinities between the two proteins. The spreading effect depends on residence time and the amount of free surface area of adsorbed proteins. For example, Cheng et al. revealed that that the available free surface area for the adsorbed fibronectin is greater at low solution concentration, resulting in more significant conformational changes, compared with high solution concentration, at which rapid filling of vacant sites on the surface hinders conformational change of adsorbed protein [44]. In addition, they also revealed that surface chemistry can play a role on the spreading effect of the adsorbed protein by measuring the occupied area of the protein on different surfaces using FTIR/ATR technique. However, their finding were observed by using a single protein adsorption, instead of using a protein mixture. In some cases such that the relaxation of initially adsorbed proteins occurs rapidly, then the Vroman effect could be eliminated. Therefore, the spreading effect of adsorbed proteins may not be ignored in the study of competitive protein adsorption and the Vroman effect. With the significant advances in experimental technologies including proteomics, we may be able to shed light on better understanding of competitive protein adsorption processes [45].

cell behavior. Finally, we will highlight a number of challenges of current methodologies and possible future experimental work to adequately assess the dynamics of competitive protein adsorption on the surfaces of biomaterials. 2. Protein adsorption If a material comes into contact with a living system, adsorbed proteins can be seen at the surface within one second, and a monolayer of proteins can be observed within minutes, almost without regard for surface chemistry [30,31]. There are three major driving forces that determine the rate of protein adsorption on the surface of a biomaterial, namely the protein concentration difference between the liquid phase and the surface, the intrinsic affinity of the protein for the surface, and the sized of the protein (i.e., its molecular weight). The intrinsic surface activity of a protein stems from the unique amino acid sequence and three-dimensional structure of a protein. Protein desorption, on the other hand, is slow compared to the time course of a typical experiment, if desorption occurs into buffer that does not contain proteins. However, cooperative interactions between proteins can lead to rapid desorption of weakly-bound proteins. Therefore, Langmuir equilibrium behavior is rarely observed, while full monolayer adsorption is almost always observed [32]. It is known that the interactions between proteins and an interface are often noncovalent (e.g. hydrogen-bonding, electrostatic and hydrophobic interactions) [9]. Examples of covalent adsorption are not common, but exist, such as protein complement C3 reaction with some hemodialyzer membranes. In this case, a thioester in the complement C3 protein forms a covalent bond with nucleophilic groups on the surface [30]. Protein adsorption can occur spontaneously only if the Gibbs free energy of the system decreases [33]:

(ΔG )ads = (ΔH )ads − (TΔS )ads < 0

(1)

where, H, S, and T are the enthalpy, entropy, and absolute temperature, respectively. The heat of adsorption has been measured for several proteins on a number of surfaces [30]. In general, the driving force for the adsorption of proteins is found to be due to entropic factors. The entropic changes that drive protein adsorption stem from changes in the water bound to the surface and to hydrophobic portions of the protein, as well as changes in the conformation of an adsorbed protein at the surface that maximize interactions between the surface and hydrophobic amino acids [33]. Protein adsorption on biomaterials can be non-specific or specific due to the differences in the surface chemistry, surface topography and competitive adsorption of proteins due to the Vroman effect [34]. In the case of single protein adsorption on a surface, a protein adsorbs to the surface and it reaches the maximum surface concentration. However, in a protein mixture solution such as serum, it is known that the first proteins adsorbed to the surface can be displaced by later arriving proteins, which have lower concentration and higher affinity to the surface. This phenomenon is now commonly referred to as “the Vroman effect” [35,36]. Advances in experimental and theoretical analyses have gained more insights on the dynamic aspects of protein adsorption onto biomaterials [2]. However, due to the complexity of dynamic adsorption process including the Vroman effect, it is far from comprehensive understanding and there are no existing models or experimental techniques available to fully explain the mechanism [37,38]. Nevertheless, this competitive displacement process may be explained by the formation of a “biomolecular transition complex” proposed by Huetz et al. by using iodine radiorabeling method [39]. Hirsh used AFM images of adsorbed protein layer that is consistent with transient complex formation, however they didn’t identify the adsorbed protein composition [40]. Furthermore, a more recent study showed that the dynamic competitive exchange process (i.e., the Vroman effect) can be observed through turning multi-layer protein aggregates by using AFM (Atomic

3. Proteomics Although proteomics has been used to study protein adsorption on biomaterial surfaces since the beginning of 21st century, its application to characterize the dynamics of protein adsorption/desorption on the surfaces of biomaterials has just begun. Proteomics can be defined as the large-scale analysis of proteins, usually by biochemical methods [22]. The classical method for separating proteins for proteomic analysis has been one or two-dimensional polyacrylamide gels, ever since the first appearance of the technique in the mid-1970’s [46]. Since then, numerous technologies have been introduced in the field of proteomics that impact both protein separation and protein identification. In this section, instead of reviewing the various proteomic technologies, which have been reviewed by others [47,48], we will describe the methods utilized in most studies mentioned in this review, which are illustrated in Fig. 1. These methods can be divided into two categories; (1) protein separation methods, and (2) mass spectrometric protein identification. In addition, the development of new technologies for proteomics and their application for the analysis of protein adsorption on the surface 2

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Fig. 1. A schematic showing the sequence of proteomic analysis using gel-based or gel-free proteomics. Proteins are derived from cells or tissue and solubilized. The crude protein mixture is then applied to a gel strip that separates the proteins in the first dimension based on their isoelectric points. After this step, the strip is applied to an SDS-PAGE gel where proteins are denatured and separated in the second dimension based on their size. The gels are then fixed and the proteins are visualized by staining the gels. After staining, the spots of interest are excised and in-gel digested with trypsin. Instead of using a PAGE gel, the gel-free approach requires insolution digestion of the extracted proteins and the resulting peptide mixture in separated by 1D or 2D LC prior to mass spectrometry. The peptide mixture of each protein is then subjected to mass spectrometer and the mass spectra for peptides were acquired. Finally, the proteins are identified by peptide molecular weight analysis or amino acid sequencing by MS/MS, in both cases using protein database searching programs.

usually made of polyacrylamide. The protein mixture, which often contains tens of thousands of proteins, are separated by isoelectric focusing (IEF), based on their net charge, in the presence of a strong electric field. The proteins are then separated in the second dimension based on their molecular mass, using SDS-PAGE (polyacrylamide gel) electrophoresis, a molecular sieving method. The combination of these two distinct techniques can resolve more than 10,000 proteins in one single gel [59,61]. Proteins separated on the gel are stained using a variety of stains including Coomassie blue, silver stains, or fluorescent dyes, or proteins can be quantified by radiographic techniques [62]. One of the remarkable breakthroughs for 2-DE was the development of immobilized pH gradients (IPG), based on the use of Immobiline reagents [63,64]. This technique made it possible to generate reproducible, high-resolution protein separations. Another exciting development for 2-DE is differential gel eletrophoresis (DIGE), which makes it possible to analyze several protein samples on only one gel, adding different fluorescent tags onto proteins in different samples [64]. Other developments and improvements have been introduced over the years, including the automation of the whole protein separation process from gel running to spot picking [65,66]. It is probable that 2-DE will remain the core technology of proteomics into the distant future, despite a number of shortcomings, including the current limitation of resolving all of the expressed proteins derived from mammalian cells or tissue [66].

will also be briefly described.

3.1. Protein preparation and separation method The very first step for proteomics is obtaining and separating proteins from complex mixtures containing as many as several thousands of proteins from a whole cell line, tissue or organism [49]. Currently, no single method of protein sample preparation can be universally applied due to the diverse nature of the proteins, even though new developments and improvements have been introduced over the years [50]. As alternative methods for protein separations, for example, the use of chip-based techniques [51,52], the direct analysis of protein complexes using mass spectrometry [53], the use of affinity tags [54,55] and large-scale yeast two-hybrid techniques [56] have been developed in the past years. However, two-dimensional polyacrylamide gel electrophoresis (2-DE) has been used for protein separation in the majority of proteomic projects [23,24]. Two-dimensional electrophoresis emerged as a high resolution technique for separating complex mixtures of proteins [57]. The technique has been used to identify serum and plasma proteins, with increasing sensitivity and reliability over time [58,59]. Currently, there are more than one thousand plasma proteins that are detectable by combining 2D electrophoresis with mass spectrometry [24]. The combination of gel electrophoresis and mass spectrometry has enabled the large-scale analysis of proteins, referred to as proteomics. Although the method has been significantly improved in the past decades since it was introduced, it is far from a perfect technique due to slow, labor-intensive processes that are not readily automated. Even still, the technique has tremendous power to separate thousands of proteins simultaneously, in spite of problems with reproducibility. Furthermore, subsequent high-sensitivity visualization of proteins on 2D gels has made the technique more attractive [60]. While 2-DE remains the most effective method to resolve complex protein mixture, one dimensional electrophoresis (1-DE; i.e. standard SDSPAGE) is still a reliable method for many proteomics projects due to the simplicity and reproducibility of the technique [49]. In SDS-PAGE, proteins are separated based on their molecular mass. The most common application of SDS-PAGE is the characterization of proteins after some initial purification of the proteins from a complex mixture, which is necessary due to its limited resolving power. If a protein mixture is more complex, then 2-DE can be used. In 2-DE, protein mixtures derived from cells or tissues are applied to gel strips that are

3.2. Mass spectrometric protein identification Once proteins are separated, visualized and/or quantified, they must be identified. Protein spots are excised from the gels and proteins are digested into fragments by a specific protease such as trypsin. The fragments are analyzed by mass spectroscopy, in which proteins are identified by comparing the measured mass of the peptide fragments with the predicted mass of fragments of proteins found in genetic or protein databases, which are available on the Internet (Table 1) [49]. The basic function of a mass spectrometer is to produce ions from neutral samples, to bring them into the gas phase, to separate the ions according to their mass-to-charge (m/z) ratio, and to detect those ions. Two remarkable ionization methods were introduced in the late 1980’s, electrospray ionization (ESI) [67,68] and matrix-assisted laser desorption/ionization (MALDI) [69,70], which have resulted in some of the most significant breakthroughs in the development of proteomics. John 3

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Table 1 World Wide Web tools for mass spectrometric protein identification. Site name

URL (http://…)

Information available

Resource

ProFound ExPasy MASCOT PepFrag Protein Prospector FASTA SEQUEST DAVID

www.prowl.rockefeller.edu www.expasy.ch www.matrixscience.com www.proteometrics.com prospector.ucsf.edu fasta.bioch.virginia.edu fields.scripps.edu/sequest david.abcc.ncifcrf.gov

peptide mass mapping and sequencing peptide mass mapping and sequencing peptide mass mapping and sequencing peptide mass mapping and sequencing peptide mass mapping and sequencing protein and nucleotide database searching uninterpreted MS/MS searching genetic/protein database searching

Rockefeller University, New York, NY Swiss Institute of Bioinformatics Matrix Science Ltd. Proteometrics Ltd. Univ. of California, San Francisco Univ. of Virginia, Charlottesville, VA The Scripps Research Institute National Cancer Institute (NCI)

MudPIT, ICAT or iTRAQ as mentioned below, MS-based proteomics has become a crucial tool to better understand the dynamic interactions between biomaterials and biological systems.

Fenn [71] and Koichi Tanaka [72] were awarded the Nobel Prize in chemistry in 2002 for their contribution in the development of some of these techniques. There are two main approaches to mass spectrometric protein identification. In the so-called ‘peptide-mass mapping’ approach [73], the most commonly used mass spectrometer for this approach is called MALDI-TOF (matrix-assisted laser desorption/ionization time of flight). In this approach, the sample is mixed with the matrix (small, UV absorbing aromatic compound), placed on a plate and dried in the air to evaporate solvent, resulting in matrix crystals mixed with sample. The sample is inserted into the mass spectrometer and energy from a CO2 laser launches the sample molecules in the sample into the gas phase, ionizing a few chemical groups on the sample molecule. The mass to charge (m/z) is measured in a time-of-flight mass analyzer, using the relationship between the kinetic energy of the ion (E), its mass (m) and its velocity (ν), E = ½ mν2. This method has gained popularity for identifying proteins, mainly due to the simplicity of operation and analysis. It is also readily automated. Another advantage of this method is a tolerance to small amounts of impurities, such as phosphates, Tris, urea, non-ionic detergents and some alkali metal salts [69]. Another popular mass spectrometric method utilizes electrospray ionization (ESI). In this method, a liquid sample in a narrow capillary tube is electrosprayed into the mass spectrometer [68]. The potential difference between the tip of a fine needle and the inlet of mass spectrometer generates a fine spray of charged droplets. The size of the droplets is decreased as the solvent evaporates, generating desolvated ions. Nanoelectrospray allows flow rates as low as 10 nL/min [74], and a capillary nano-HPLC connected to a nanoelectrospray source has been developed to allow the separation of complex mixtures of peptides prior to introduction into the mass spectrometer [75]. One type of mass spectrometer that uses ESI is the ion trap mass spectrometer, which acts as a tandem mass spectrometer. In this method, individual peptide ions can be isolated and accumulated in the trap after scanning the entire mass range to determine the presence of peptides in the sample. In the second step, the selected ion is fragmented via the introduction of an inert gas. Collision between ions circulating in the trap and the inert gas injects enough energy into the molecule to break the peptide backbone, usually between CO and NH bonds, producing a MS/MS spectra for the selected peptide ion [76]. Derhami et al. were the first to use ‘mass spectrometry (MS)-based proteomics’ to study protein adsorption on biomedical materials, in the sense that mass spectrometry was used to identify proteins from the 2D gel. They used 2-DE to separate proteins that eluted from titanium dioxide and tissue culture polystyrene surfaces, after incubation with bovine or human sera for 5 days [25]. To identify proteins on the 2D gels, they used trypsin digestion and MALDI-TOF mass spectrometry, which is more efficient than sequencing by Edman degradation [73]. Eluting human serum proteins from tissue culture polystyrene with a surface area of about 8 cm2, they observed ≈5 protein spots on the 2D gels. Since then, MS-based proteomics has been as a conventional method to identify and quantify protein mixture separated from 2DE to characterize protein adsorption on the surface of biomaterials. Furthermore, with the development of non-gel based proteomics such as

3.3. Advanced technologies without gel electrophoresis Although 2-DE gives a high-resolution protein separation, it is still extremely difficult to perform, time-consuming and fails to detect some of the most interesting proteins in a biological sample. For example, hydrophobic membrane proteins that are often considered as attractive drug targets [21], simply do not dissolve in the solvents used for isoelectric focusing. Neither do proteins with high molecular mass, which often play a crucial role in a cell. Some approaches to overcome these problems have been made, such as using a series of solubilization buffers [77]. Because of these problems, advanced non-gel proteomic technologies have been developed as alternatives to gel electrophoresisbased proteomics. One of them is so called “shotgun” proteomic approach such as multi-dimensional protein identification technology, or MUDPIT, suggested by Yates’ group [53,78] (Fig. 2). In this approach, complex protein mixtures from yeast cells were digested and loaded onto a multidimensional microcapillary column packed with strong cation exchange (SCX) and reverse-phase (RP) materials. The column was placed in-line with the mass spectrometer and an automated series of reverse-phase gradients were performed with increasing concentrations of salt. The proteins were eventually identified by correlating the generated tandem mass spectra with theoretical mass spectra using a computerized analysis. Using these techniques, they identified about 1500 proteins from the total yeast proteome, including more than 100 membrane-associated proteins which were not identified by typical 2DE method. They concluded that more comprehensive high-throughput proteomic analyses are possible with this technique. Another important approach for non-gel based proteomics is called the isotope coded affinity tags (ICAT) method suggested by Aebersold’s group [54,79] (Fig. 2). In this approach, the proteins from different cell states were reacted with two different ICAT reagents, either isotopically light or heavy, and the two samples were combined and digested. The labeled proteins with ICAT labels were isolated by affinity chromatography and were sequentially loaded onto a reverse-phase column or capillary electrophoresis equipped with a nanospray, which were connected to a mass spectrometer. The proteins in the mixture were then identified by a database searching program. By comparing the mass signal intensity ratio of two different peptides whose mass differ by the isotope label mass, they concluded that it is possible to carry out quantitative proteomic analysis using these techniques. However, it is certain that both techniques still have pitfalls, for example, due to differences in the quality of ion exchange at low solvent concentrations and the inherent poor quantitative nature of mass spectrometry. Nevertheless, due to the potentials provided by the non-gel based approaches, the use of these advanced techniques for the quantitative analysis of adsorbed proteins interacting with biomaterials has just begun, especially for understanding the nanoparticle-protein interactions [80]. For example, a study utilized the ICAT-based method to identify the adsorbed proteins to aluminum, nickel and diamond 4

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Fig. 2. Schematic showing the sequence of proteomic analysis using multi-dimensional protein identification technology (MUDFIT) [78]and isotope coded affinity tags (ICAT) [54] methods.

an appropriate host response in a specific application’ [8]. Others have defined biocompatibility as the ability of a material to interact with cells and liquids of the biological system to cause exactly the reaction, which the analogous body tissue would bring about [87]. Many investigations have focused on improving biocompatibility simply by reducing non-desirable biological responses, which can be obtained by reducing the amount of protein adsorption [88,89]. In order to achieve a reaction that an analogous body tissue would bring about, knowledge of the interaction between the surface of a biomaterial and a biological system is of crucial importance. This review will focus on understanding biological interactions of protein adsorption with materials via proteomics.

nanoparticles following their exposure to human serum [81]. They were able to identify 69 unique proteins and quantify the relative affinities of the proteins adsorbed to the various nanoparticles, however they did not analyze other factors such as particle size or surface charge, which are known to affect crucial in vivo fate of the biomaterials such as immunogenicity [82]. Another study investigated the interactions of adsorbed human blood plasma proteins with polystyrene nanoparticles with different surface chemistries and size by using 18Olabeling and LC–MS/MS-based quantitative proteomics analysis, which is similar to the ICAT method [83]. This quantitative proteomic technology enabled to simplify the isolation of adsorbed proteins from the nanoparticles and improve reproducibility, compared to the gel-based methods. The results revealed that the temporal formation of the stable protein corona around the nanoparticles was a fast process and reached the equilibrium within 5 min. Thus, such powerful non-gel based techniques may help to advance our understanding of the interactions of adsorbed proteins on biomaterials surfaces, which provides insights into the biocompatibility and in vivo fate of the biomaterials, compared to the conventional methods [84]. Besides novel proteomics technologies mentioned above, isobaric tags for relative and absolute quantification (iTRAQ), surface-enhanced laser desorption/ionization (SELDI) have been developed for more accurate and quantifiable protein analysis. An isobaric labeling methods such as iTRAQ have been used for quantitative proteomics by tandem mass spectrometry to determine the amount of proteins from different sources (e.g., isotope labeled molecules) in a single experiment [85]. Surface-enhanced laser desorption/ ionization (SELDI) is a soft ionization method in mass spectrometry (MS) to analyze protein mixtures and it is a variation of matrix-assisted laser desorption/ionization (MALDI) [86].

4.1. Blood plasma adsorption on biomaterials In general, when a biomaterial comes into contact with a biological system, the first event to take place at the surface of a biomaterial is protein adsorption, which initiates a variety of subsequent biological responses that are responsible for the eventual failure of a biomaterial, as shown in Fig. 3. A comprehensive understanding of these complex processes has not been achieved, yet more compressive information of these processes is a pre-requisite for improving the biocompatibility of biomaterials. Extensive investigations have been carried out over the past few decades on the dynamics of plasma protein adsorption at the surfaces of biomaterials after a biomaterial is exposed to blood [36,90]. The application of proteomics for the study of protein adsorption from blood, plasma, or serum may greatly enhance our knowledge of such a dynamic process.

4. Biological responses to biomaterials In the bench-to-bedside process for the development of biomaterials, safety and efficacy must be evaluated. In order to ensure the safety of a biomaterial, the complex process by which a biomaterial must be validated to be biocompatible, begins with a series of standard in vitro assays and progresses to a stringent set of standardized in vivo tests [4]. There is a noteworthy challenge from in vitro assays and a strong need to develop high throughput in vitro screening systems in the development of biomaterials. By consensus agreement, a biomaterial is biocompatible when that material does not cause any harm. The consensus definition of biocompatibility of materials is, ‘The ability of a material to perform with

Fig. 3. Schematic illustration of blood/biomaterial interactions at a surface [91]. 5

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fibrinogen adsorption on biomaterials has been intensively studied, due to the ability of the protein to promote platelet interactions with a material. For example, fibrinogen was found to be preferentially adsorbed over albumin, IgG and other proteins, such as lipoproteins and coagulation factors and the relationship between platelet reactivity and the degree of preferential fibrinogen adsorption was reported [122,123]. Platelet attachment did not occur if defibrinogenated or afibrinogenamic plasma were used, suggesting that there is close relationship between adsorbed fibrinogen and platelet adhesion [28]. It is known that adenosine diphosphate (ADP)-induced platelet aggregation requires fibrinogen and ADP-stimulated platelet receptors such as GPIIb/IIIa are directly involved in the mediation of platelet adhesion to fibrinogen, along with other plasma proteins such as fibronectin, vitronectin, and von Willebrand factor [124]. Transient fibrinogen adsorption has been observed and this process is known as the ‘Vroman effect’ [125]. A recent proteomic study revealed that neutrophil adhesion may be mediated by the orientation and conformation rather than the amount of adsorbed fibrinogen on pre-coated cobalt chromium alloy oxide surface, highlighting the importance of surface properties of biomaterials on protein adsorption [126]. Although fibrinogen has been emphasized in the study of the interactions between adsorbed plasma proteins and biological responses, there have been other investigations of the influence of albumin or IgG on platelet adhesion. For instance, the adsorption of albumin can also promote the platelet adhesion, which may contribute to leukocyte adhesion [127]. Another previous study demonstrated by proteomic analyses that other plasma proteins such as serum amyloid P may also play an important role in the eventual failure of biomaterials, since serum amyloid P could induce leukocyte and possibly platelet adhesion on the surface of biomaterials [26]. Much less is known about other plasma proteins including lipoproteins, transferrin and α1-antitrypsin, which are similarly abundant to fibrinogen, probably due to difficulties in obtaining the proteins in a pure form [10]. Regarding the effects of protein adsorption on the inflammatory response including the complement activation, a recent study demonstrated how protein adsorption in plasma influences the complement activation. The data revealed that there were strong relationships between the ratio of C4 to C4BP (C4 binding protein) and the generation of cytokines including IL-17, IFN-γ, and IL-6 [128]. Using proteomics, complement C3 was identified to medicate monocyte adhesion on poly (ethylene glycol) (PEG)-based hydrogels [129]. In addition, another comprehensive proteomic study identified over 300 proteins adsorbed on PEG-based hydrogels and the majority of them (245 proteins) were known to mediate inflammatory-related host responses [130].

Plasma protein adsorption on biomaterials has also been studied using two-dimensional electrophoresis. Ho et al. used two-dimensional electrophoresis to study the depletion of proteins from plasma at heparinized surfaces [92]. Later, Feng & Andrade used this depletion technique to characterize protein adsorption from plasma on low temperature isotropic carbon and silica powder [93]. The advantage of the depletion technique is that proteins do not need to be removed from the surface of the material for analysis. However, the depletion technique may not detect the adsorption of highly surface-active, low abundance plasma proteins. Later, Rosengren et al. used a similar method to study protein adsorption on particles of hydroxyapatite, alumina and zirconia, using 2D electrophoresis to analyze chromatographic fractions collected from the plasma, which was flowed over the particles [94,95]. Mueller and colleagues used two-dimensional electrophoresis to analyze adsorbed plasma proteins eluted from the surfaces of polystyrene microspheres, following a 5 min. incubation with plasma at 37 °C [96–104]. Subtle changes in surface chemistry had profound effects on protein adsorption at 5 min. For example, increasing the density of positive charges led to an increase in the adsorption of acidic proteins such as orsomucoid, leucine-rich α2-glycoprotein and α1-antitrypsin [103]. The addition of PEG to the microsphere surface decreased the total amount of the protein and the amount of fibrinogen on the surface, while the relative amount of immunoglobulins increased [104] (similar to the results obtained earlier by LeRoux et al. [105]). In addition, complement activation could be detected by the presence of a fragment of the α-chain of C3 on the 2D gel [97], building upon earlier work by Allemann et al. with poly(D,L-lactic acid) nanoparticles incubated with serum for up to 60 min. [106]. Stanislawski et al. used non-equilibrium pH gradient gel electrophoresis followed by SDS-PAGE to analyze proteins eluted from polyarylamide, polylactic acid, PET and polypropylene, finding that fibrinogen and Apo A-I adsorption were inversely correlated to the different surfaces [107]. Sun et al. incubated particles of titanium alloy, cobalt-chromium-molybdenum alloy, PMMA bone cement and high density polyethylene with serum for 18 h, observing albumin and α1-antitrypsin on the metals, and albumin, α1antitrypsin and Apo A-I on the polymers [108]. Later, Magnani et al. used 2D electrophoresis to characterize protein adsorption on glass beads modified with hyaluronic acid, finding that 8 M urea, 4 % CHAPS, 40 mM Tris and 65 mM DTE, pH 9.5 was able to remove 100 % of adsorbed proteins from the surfaces as judged by FTIR [109]. Most of aforementioned studies mentioned above used the gel matching method to identify protein spots on 2D gels by matching with the plasma master gels from the databases such as Swiss-2DPAGE [109], instead of using mass spectrometry. Without mass spectrometry, identification and quantification of the protein on the gel may be misrepresented due to low resolution and spot overlapping [110]. This is why mass spectrometry with or without gel electrophoresis is now essential and more powerful than the gel matching method for identification and quantification of protein mixture. While 2DE has been popular to analyze protein mixture of plasma or serum adsorbed on various biomaterials, one dimensional SDS-PAGE has also been used to study protein adsorption due to the simplicity and reproducibility of the technique [49]. Adsorbed proteins were typically eluted from surfaces with detergent before separation by SDS-PAGE [111]. In an innovative modification of this technique, adsorbed proteins were radioiodinated before elution and analysized by SDS-PAGE [112]. Four peaks on the SDS-PAGE gel could be assigned to fibrinogen, IgG, albumin and hemoglobin, although five major peaks could not be assigned. To overcome the problem of protein identification with SDSPAGE, Brash and colleagues used immunoblotting due to high sensitivity [113–121]. Among the plasma proteins, albumin, immunoglobulin γ (IgG) and fibrinogen are most widely studied, mainly due to their abundance in plasma (concentrations of albumin, IgG and fibrinogen are 500–800 μM, 50–120 μM and about 9 μM, respectively) [10]. In particular,

4.2. Effects of surface properties In light of the influences of surface properties of biomaterials on biological responses, it is known that stiffness of materials may be able to affect cell behavior on the surface [131,132]. A quantitative proteomic study found that material stiffness may be able to modulate proliferation of fibroblast in a competitive protein environment such as serum via adsorbed protein layer. Interestingly, the study found that fetuin A was responsible to influence fibroblast proliferation, not fibronectin, however unlike fetuin A, fetuin B may not influence cellular behavior of other cell types such as osteoblasts [132]. A more recent study confirmed these findings by demonstrating that material stiffness influences the compositions of adsorbed protein layers and the cells may be able to sense material stiffness through the adsorbed protein layer in competitive protein adsorption environment. The study also confirmed that fetuin A adsorbed on elastomeric microspheres, affected cell proliferation of fibroblasts using a quantitative proteomics along with QCM-D and surface plasmon resonance (SPR) [133]. However, if the study could provide more information of the dynamic nature of adsorption process (e.g., thermodynamics or kinetics) in competitive protein adsorption, it would benefit greatly to elucidate the 6

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extracellular matrix (ECM) proteins adsorbed on various biomaterials underscores that surface chemistry determines surface proteomic profiles and subsequent cellular behavior using epithelial cells [29]. The study also demonstrated that the biomaterials with the surface chemistry closer to natural tissues (e.g., aminated PMMA) can improve biological performance of the materials. In addition, other proteomic studies revealed that the surface coatings (i.e., poly(sodium styrene sulfonate) or polyNaSS) grafted on different substrates (titanium alloys or polyethylene terephthalate or PET) modulate selective protein adsorption and the subsequent cellular response, compared to unmodified surfaces [147,148]. Interestingly, the authors in the studies introduced GRAVY (the grand average of hydropathicity) scores and allipatic index, calculated from amino acid sequences of the proteins on 2D gels and correlated them with selective protein adsorption. Therefore, more precise control of surface properties of biomaterials may be needed to further reduce non-desirable protein adsorption on those surfaces, and subsequent unfavorable cellular responses. While most of these studies revealed the specific relationships of surface properties of given biomaterials with protein adsorption and subsequent biological responses using proteomics, there are few reports to further correlate the dynamic aspects of protein adsorption onto biomaterials (e.g., the Vroman effect) with surface properties of the biomaterials.

relationships between material stiffness and adsorption mechanisms. In addition, Kizhakkedathu group showed that protein adsorption on various biomaterial surfaces rely on the density of polymer brush coatings carrying different carbohydrate residues, by demonstrating that the protein adsorption decreased with increasing the brush grafting density (chains/nm2) [134–136]. Furthermore, a recent proteomic study demonstrated that the conformation of PEG coating on carbon nanotubes (mushroom to mushroom-brush transition), may affect more on plasma protein adsorption around the nanoparticles, compared to the surface charge. Thus the PEG conformation had deeper influence on the biological performance of the biomaterials such as blood circulation time or organ accumulation of the nanoparticles [137]. With regard to affinity for the surface, it is known that abundance of a protein in plasma is not closely related to its presence in an adsorbed protein layer at long times. Preferential adsorption of fibrinogen has been observed on various surfaces compared to albumin and IgG, which are more abundant than fibrinogen. For example, fibrinogen was preferred over albumin and IgG on PTFE, silicone rubber, and a segmented polyetherurethaneurea [138]. In general, the chemical nature of the surface determines the ‘surface selectivity’ for proteins adsorbed to the surface, since each protein has its unique amino acid sequences and three-dimensional structures. Selective protein adsorption was also found on bone substitute materials. A total of 138 serum proteins were identified on octacalcium phosphate (OCP) vs. 103 proteins were on hydroxyapatite (HA) and 48 proteins were from both materials via quantitative LC–MS/MS analysis. Among the proteins, two bone forming proteins (apolipoprotein E or Apo E and complement 3 or C3) were detected on both substrates, but at different capacities [139]. In general, hydrophobic interactions between non-polar protein groups and non-polar surface groups on hydrophobic polymeric surfaces in aqueous solution, induce protein adsorption to the surfaces [140]. Following conformational change to increase the number of interactions between non-polar groups, the binding affinity of a protein to the surface is found to be much greater on hydrophobic surfaces than on hydrophilic ones [141]. Hydrophobicity of a surface directly influences the conformational change of an adsorbed protein. For example, protein adsorption is more readily reversible on hydrophilic surfaces, compared to hydrophobic surfaces [142]. Due to this phenomenon, hydrophilic materials have been investigated to reduce or inhibit protein adsorption. Although hydrogels or hydrophilic surface coatings that absorb a large fraction of water due to their hydrophilicity, have been widely used as protein resistant/repellent materials [143,144], non-desirable biological responses (e.g., macrophage response, foreign body response) on hydrophilic surfaces have been reported in vitro as well as in vivo [89,118]. A recent study revealed that immunoglobulin (IgG) adsorption on polycaprolactone (PCL) produced thicker and more hydrophobic layers compared to thin and hydrophilic albumin coated PCL surfaces. In addition, IgG coated surfaces resulted in reducing metabolic activities of human primary endothelial cells as compared to albumin or fibrinogen coated surfaces [145]. However, they didn’t further scrutinize the relationships of the dynamics of competitive protein adsorption among the tested proteins with surface properties of the biomaterials, which may provide the information of the shape, conformation and the charge of the proteins during adsorption process and its effects on cellular responses. Despite the increased understanding of the relationships between physicochemical properties of biomaterials and biological responses, very little is known about the molecular mechanisms underlying the biological responses to surface properties of materials, especially surface chemistry. Proteomics has also been utilized for this purpose. For example, a recent investigation revealed that different in vivo outcomes (i.e., fibrous capsule thickness) between different chemical compositions of the sol-gel silica coatings on titanium alloys and numerous proteins associated with complement pathway, were identified using proteomic analysis (LC–MS/MS) of plasma proteins adsorbed on the titanium alloys [146]. Another comprehensive proteomic analysis of

5. Towards dynamic insights of competitive protein adsorption on biomaterials using proteomics To date, proteomics has been predominantly used for identifying proteins from cell lysates or tissues. Herein, we briefly provide overview of the large-scale protein analysis strategy, proteomics to analyze protein adsorption on biomaterial surfaces, especially for investigating the relationships between plasma (or serum) protein adsorption and subsequent biological responses, which eventually determine the biological performance of biomaterials. As described in the text, a number of proteomic studies revealed that adsorbed proteins (e.g., fibrinogen) on biomaterials can promote adverse biological responses such as leukocyte adhesion and platelet adhesion [149]. However, they did not examine the underlying mechanisms why different materials produce selective proteomic outcomes. For example, platelet adhesion was observed only on PDMS surfaces, but not on tissue culture polystyrene [150,151], suggesting that the conformation of adsorbed proteins on the different surfaces may affect preferential platelet adhesion. Perhaps the least understood phenomena encountered with adsorbed proteins is their conformational changes on the surface. Therefore, if we examined the effects of the conformational changes of proteins adsorbed onto different surfaces on platelet adhesion, which have different degrees of hydrophilicity, then we may find underlying reasons why those proteins promote platelet adhesion only on PDMS and not on tissue culture polystyrene. In the near future, by using proteomics, the specificity of the adhesion of leukocytes and/or platelets to adsorbed proteins may be examined (e.g., by blocking respective receptors to the adsorbed proteins with antibodies). Furthermore, the dynamics of protein adsorption/ desorption on the surface of biomaterials have just begun to be investigated by proteomics. In fact, our group began to explore the possibility of using proteomics to study the kinetics of protein adsorption/ desorption on biomaterials, by identifying the proteins that displaced pre-adsorbed bovine serum albumin [45]. We demonstrated the possibility of measuring the extent of conformational change of single protein (i.e., albumin) using hydrogen/deuterium (H/D) exchange combined with mass spectrometry. In the future, such methods can be applied to multi-component systems, thus eventually determine the kinetics of changes of conformation and orientations of adsorbed proteins, with ‘state of the art’ proteomics technologies, such as structural proteomics [152], and/or quantitative proteomics, such as fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) [153,154]. There is no doubt that proteomics is a powerful technique to reveal 7

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the adsorbed protein layers in terms of species and abundance. However, this tool needs to be used in conjunction with other technologies to reveal the whole state of the adsorbed proteins. In fact, recently developed state-of-the-art surface analytical tools such as quartz crystal microbalance with dissipation (QCM-D), multi-parameter surface plasmon resonance (MP-SPR), two-dimensional correlation spectroscopy (2D-COS) along with atomic force microscopy (AFM) enable us to shed light on deeper understanding the interactions at the interfaces between protein adsorption on the biomaterial surfaces and subsequent biological responses [155]. The extraction methods, which elute adsorbed proteins from biomaterial surfaces before proteomic analysis may yield inaccurate results if tightly-bound proteins are not adequately removed from the surface [156,157]. Thus, appropriate choice of elution buffer would be crucial to remove all of the adsorbed proteins from the surface, to ensure that less tightly adsorbed proteins does not to be overrepresented on the proteomic analysis, although the degrees to which this occurs is yet to be determined. Despite the daunting challenges such as dynamic abundance range between plasma proteins (> 1010) for the characterization of “human plasma proteome profiling’’ [54], substantial progresses of the project have been made in the past decade and it is now possible to identify thousands of plasma proteins [158,159]. These dramatic achievements certainly help to customize proteomic analysis using patients’ own plasma to precisely predict the feasibility of a given biomaterial to be accepted or rejected depending on the pathological conditions (e.g., osteoporosis) of the host [160]. Furthermore, as biocompatibility of a biomaterial has evolved to integrate and promote biofunctionality [161], the newly developed proteomic technologies may allow us not only to determine the biocompatibility, but to assess the biofunctionality, which results in safe and favorable biological responses in the human body.

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Declaration of Competing Interest

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Acknowledgements

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This work was supported by 2017 Hongik University Research Fundand by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education ( < GN3 > NRF-2016R1D1A3B01008280 < /GN3 >).

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