Since its inception just over a half century ago, the field of biomaterials has seen a consistent growth with a steady introduction of new ideas and productive branches. This review describes where we have been, the state of the art today, and where we might be in 10 or 20 years. Herein, we highlight some of the latest advancements in biomaterials that aim to control biological responses and ultimately heal. This new generation of biomaterials includes surface modification of materials to overcome nonspecific protein adsorption in vivo, precision immobilization of signaling groups on surfaces, development of synthetic materials with controlled properties for drug and cell carriers, biologically inspired materials that mimic natural processes, and design of sophisticated three-dimensional (3-D) architectures to produce well-defined patterns for diagnostics, e.g., biological microelectromechanical systems (bioMEMs), and tissue engineering.

BIOMATERIALS: Where We Have Been and Where We Are Going

Effect of wettability and surface functional groups on protein adsorption and cell adhesion using well-defined mixed self-assembled monolayers.

Biomedical surface science: Foundations to frontiers

Integrin-mediated cell adhesion to proteins adsorbed onto synthetic surfaces anchors cells and triggers signals that direct cell function. In the case of fibronectin (Fn), adsorption onto substrates of varying properties alters its conformation/structure and its ability to support cell adhesion. In the present study, self-assembled monolayers (SAMs) of alkanethiols on gold were used as model surfaces to investigate the effects of surface chemistry on Fn adsorption, integrin binding, and cell adhesion. SAMs presenting terminal CH(3), OH, COOH, and NH(2) functionalities modulated adsorbed Fn conformation as determined through differences in the binding affinities of monoclonal antibodies raised against the central cell-binding domain (OH > COOH = NH(2) > CH(3)). Binding of alpha(5)beta(1) integrin to adsorbed Fn was controlled by SAM surface chemistry in a manner consistent with antibody binding (OH > COOH = NH(2) > CH(3)), whereas alpha(V) integrin binding followed the trend: COOH >> OH = NH(2) = CH(3), demonstrating alpha(5)beta(1) integrin specificity for Fn adsorbed onto the NH(2) and OH SAMs. Cell adhesion strength to Fn-coated SAMs correlated with alpha(5)beta(1) integrin binding (OH > COOH = NH(2) > CH(3)), and experiments with function-perturbing antibodies demonstrated that this receptor provides the dominant adhesion mechanism in this cell model. This work establishes an experimental framework to analyze adhesive mechanisms controlling cell-surface interactions and provides a general strategy of surface-directed control of adsorbed protein activity to manipulate cell function in biomaterial and biotechnological applications.

Surface chemistry modulates fibronectin conformation and directs integrin binding and specificity to control cell adhesion

Implantable medical devices are increasingly important in the practice of modern medicine. Unfortunately, almost all medical devices suffer to a different extent from adverse reactions, including inflammation, fibrosis, thrombosis and infection. To improve the safety and function of many types of medical implants, a major need exists for development of materials that evoked desired tissue responses. Because implant-associated protein adsorption and conformational changes thereafter have been shown to promote immune reactions, rigorous research efforts have been emphasized on the engineering of surface property (physical and chemical characteristics) to reduce protein adsorption and cell interactions and subsequently improve implant biocompatibility. This brief review is aimed to summarize the past efforts and our recent knowledge about the influence of surface functionality on protein:cell:biomaterial interactions. It is our belief that detailed understandings of bioactivity of surface functionality provide an easy, economic, and specific approach for the future rational design of implantable medical devices with desired tissue reactivity and, hopefully, wound healing capability.

Surface chemistry influences implant biocompatibility.

The effect of specific chemical functionalities on the growth of bovine aortic endothelial cells (BAEC) was investigated using a set of well-characterized, chemically functionalized surfaces prepared by self-assembly of alkanethiolate monolayers on gold surfaces using the molecules X(CH2)15SH with X = −CH3, −CH2OH, −CO2CH3, and −CO2H. Cells seeded on a substrate in serum-containing culture medium interact with the adsorbed protein layer rather than the substrate. Therefore, the role of two serum proteins, albumin (Alb) (a nonadhesive or blocking protein) and fibronectin (Fn) (an adhesive protein), in cell growth was evaluated by measuring the amount of each protein bound and the tightness of binding (determined by resistance to SDS solubilization) on the self-assembled monolayers (SAMs). BAEC growth varied significantly with surface functionality. Cell growth increased in the following order:  −CH2OH < −CO2CH3 < −CH3 ≪ −CO2H, illustrating the effect of specific surface groups. Cell growth on all monolayer...

Endothelial cell growth and protein adsorption on terminally functionalized, self-assembled monolayers of alkanethiolates on gold

The glow discharge plasma deposition (GDPD) of tetraethylene glycol dimethyl ether is introduced as a novel method for obtaining surfaces that are resistant to protein adsorption and cellular attachment. Analysis of films by x-ray photoelectron spectroscopy and several biological assays indicate the formation of a fouling-resistant, PEO-like surface on several substrata (e.g., glass, polytetrafluoroethylene, polyethylene). Adsorption of 125I-radiolabelled proteins (fibrinogen, albumin and IgG) from buffer and plasma was very low (typically less than 20 ng/cm2) when compared to the untreated substrata, which exhibited much higher levels of protein adsorption. Not all coated substrata adsorbed equal amounts of protein (e.g., coated glass samples typically adsorbed more protein than coated polyethylene or coated polytetrafluoroethylene samples), suggesting that the substratum used may affect the amount of protein adsorbed. Measurement of dynamic platelet adhesion, using epifluorescent video microscopy, and endothelial cell attachment further demonstrates the short-term nonadhesiveness of these surfaces.

Glow discharge plasma deposition of tetraethylene glycol dimethyl ether for fouling‐resistant biomaterial surfaces

Time of flight secondary ion mass spectrometry (ToF-SIMS) is a useful technique in the study of adsorbed protein films because of its high surface sensitivity and chemical selectivity. However, the protein mass spectra generated by ToF-SIMS are complex fragmentation patterns of a polymer consisting of 20 different monomers (i.e., amino acids). Principal component analysis (PCA) was implemented to classify several reference positive ion protein spectra according to protein and substrate type. Furthermore, the positive ion 74/102 and 120/130 SIMS intensity ratios, radiolabeled experiments, and PCA were used to track the relative surface concentrations of bovine serum albumin and bovine fibronectin in a binary adsorption experiment. In all cases, the combination of ToF-SIMS and PCA proved capable in classifying proteins by their type (in the case of pure protein spectra) and relative surface concentration (in the case of the binary protein spectra).

Characterization of adsorbed protein films by time of flight secondary ion mass spectrometry.

Static time-of-flight secondary ion mass spectrometry (ToF-SIMS), monochromatized x-ray photoelectron spectroscopy (XPS) and 125I radiolabeling have been used to characterize albumin films adsorbed onto titanium, gold, polytetrafluoroethylene and r.f. glow discharge-deposited tetrafluoroethylene (TFE) substrates. A comparison between albumin and fibronectin films also was made. The intensities of characteristic amino acid mass fragments (immonium ions) detected in the static ToF-SIMS experiments depended on the protein type, the substrate type and the adsorption conditions, demonstrating the sensitivity of static ToF-SIMS for probing the structure of adsorbed protein films. Based on the results from albumin and fibronectin, static ToF-SIMS can provide information about the identity of adsorbed proteins and their conformation, orientation, denaturation, etc. X-ray photoelectron spectroscopy can distinguish pure protein films, but the higher molecular specificity of static ToF-SIMS is more useful than XPS for examining complex protein films. The 125I radiolabeling experiments and the XPS atomic percentage of nitrogen were used to quantify the amount of adsorbed protein. Copyright © 2001 John Wiley & Sons, Ltd.

Caren D. Tidwell

Papers

Endothelial cell growth and protein adsorption on terminally functionalized, self-assembled monolayers of alkanethiolates on gold

Glow discharge plasma deposition of tetraethylene glycol dimethyl ether for fouling‐resistant biomaterial surfaces

Characterization of adsorbed protein films by time of flight secondary ion mass spectrometry.

Static time‐of‐flight secondary ion mass spectrometry and x‐ray photoelectron spectroscopy characterization of adsorbed albumin and fibronectin films