Biomaterials: Protein–Surface Interactions

The study of protein–surface interactions represents one of the most important topics in the field of biomaterials, and as such, it has been a focus of intensive study for several decades. The reason for the great interest in this topic is the realization that protein– surface interactions are fundamentally responsible for the biocompatibility of medical devices, or the lack thereof. When a solid material (e.g., a catheter, stent, hip joint replacement, or tissue engineering substrate) comes in contact with a fluid that contains soluble proteins (e.g., blood, interstitial fluid, cell culture media), proteins rapidly adsorb onto the surface of the material, saturating the surface within a time frame of seconds to minutes. Therefore, when living cells (which are much larger than proteins and thus much more slowly moving) approach the biomaterial surface, they do not actually contact the molecular structure of the material surface itself, but rather they contact and interact with the molecular structure of the adsorbed protein layer. Cells, of course, cannot ‘‘see’’ the adsorbed protein layer, but rather they interrogate their surroundings by way of membrane-bound receptors that can bind to specific bioactive features presented by the adsorbed proteins. Then, through a series of orchestrated molecular mechanisms, these receptor–protein binding events are transduced through the cell membrane in a manner that stimulates specific intracellular processes that then determine a cell’s response. Accordingly, at the most fundamental level the key to controlling cellular response is to control the type of bioactive sites that are presented by the adsorbed layer of proteins. This, in turn, can be controlled by controlling the amounts and the types of proteins that are adsorbed and their orientation, conformation, and packing arrangement on the biomaterial surface. While this is conceptually simple to understand, the numerous types of soluble proteins contained in physiological fluids combined with their structural complexity has made, and continues to make, this an extremely challenging problem. Many excellent reviews and entire books have been written over the past couple of decades that address the multitude of issues related to the interaction of proteins with surfaces. Several of these reviews and books are referenced in the ‘‘Further Readings’’ section at the end of this article and the readers interested in this topic are encouraged to seek out these additional sources of information. Given the vast number of studies that have been conducted on this topic, it is of course impossible to provide a complete review of the literature in one article. Instead, the goal here is to provide an overview of the basic understanding that has been achieved over the years regarding how proteins interact with surfaces. This will be accomplished by first providing an overview of protein adsorption processes and then by addressing the special case of the design of surfaces to prevent protein adsorption. Following these topics, attention will be focused on highlighting several of the most interesting relatively recent techniques that have been developed and applied to further our understanding of the submolecular-level mechanisms involved in how surface chemistry influences the orientation, conformation, and organization of adsorbed proteins. The continued development of our understanding of these processes is critical if we are to get beyond the current era of surface design largely by trial and error, and move into an era where surfaces are proactively designed to directly control adsorbed protein bioactivity, and thereby control cellular response. This article will then close with a conclusion section that addresses future directions toward the continuing goal of the development of truly biocompatible materials for the design of medical devices for improved patient care.