Molecular characterization of macrophage response to model biomaterial surfaces in vitro

Abstract

Cellular response to various model biomaterials has important fundamental significance to numerous medical device and diagnostic applications. Biomaterial implants are plagued by failure, associated with a host "foreign body" inflammatory reaction, regardless of composition or physiological placement. Underlying the rejection process is a complex dynamic relationship between cells, biomaterials and milieu. In vivo, circulating monocytes arrive at a biomaterial surface, attach to it and differentiate to macrophages, the key mediators of the "foreign body" reaction. Macrophage presence signals a chain of events that may result in chronic inflammation, and ultimately implant failure. Understanding the mechanisms by which macrophages are able to adhere to and differentiate on implant surfaces is an important first step toward developing biocompatible implants. Macrophage response to a diverse group of model biomaterials surfaces was investigated. Gross cellular response was tracked over time, reporting adhesive behavior, proliferative rates, and morphological changes as a function of surface chemistry. Initial studies compared commonly employed cell culture substrates and select model biomaterials with clinical relevance. Subsequently, the study of surface chemistry's effect on cell adhesive behavior was extended to a large group of plasma-polymerized co-patterned surfaces of distinct chemistries. Molecular level response to biomaterials was tracked via the Rho GTPase cellular signaling cascade, one integrin-linked outside-in signaling cascade with the ability to affect cell adhesion, proliferation and spreading in response to environmental cues. Expression and activation of the Rho proteins was compared based on cell maturity (promonocyte to monocyte to macrophage lineages), cell derivation and by model surface chemistry. Finally, the molecular mechanism by which macrophage cells adhere to and proliferate on albumin selective fluorocarbon surfaces was investigated through integrin blocking studies. Collectively, these experiments represent an important step toward an improved understanding of the unique behaviors exhibited by macrophage cells as part of the natural response to unnatural materials present in the body.