Biomaterial characteristics and biofluid composition differentially modulate protein adsorption and macrophage...

Dysregulated macrophage responses to common surgical polymers contribute to implantable medical device failure. While biomaterial characteristics are known to influence macrophage behavior, the contribution of the local biological milieu and the adsorbed proteins remains poorly understood. Here, we investigate how biomaterial physicochemical properties and biofluid composition differentially modulate adsorbed proteomes and macrophage transcriptomes on common surgical polymers as well as explore the link between the latter two. We first quantify the stiffness, roughness, wettability and protein adsorption capacity of PDMS, PP, PTFE, HDPE and nylon, and characterize the protein composition of plasma, serum and surgical drain fluid obtained from breast reconstruction patients. Then, we expose these common surgical polymers to the three clinically-relevant biofluids and profile the resulting adsorbed proteomes with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In parallel, we culture THP-1 macrophages on the same preconditioned biomaterials and analyze their transcriptomes using RNA sequencing. We find that biofluid composition primarily establishes the adsorbed proteomes which the biomaterials subsequently refine into material-specific protein signatures. In contrast, biomaterial characteristics, except protein adsorption capacity, primarily determine macrophage transcriptomes, with stiffness, roughness and hydrophobicity being associated with inflammation, metabolic stress and tissue remodeling programs. Proteome-transcriptome integration reveals strong global concordance, alongside a subset of proteins - particularly lipoproteins and metabolism-associated proteins (e.g., zinc-alpha-2-macroglobulin and transthyretin) - that appears to disproportionally drive this relationship. Together, these findings support a model in which common surgical polymers regulate macrophage responses via both direct physicochemical cues and indirect protein-mediated mechanisms. STATEMENT OF SIGNIFICANCE: Implantable medical devices fail because protein adsorption onto their biomaterial surfaces initiates the foreign body response, culminating in inflammation and fibrotic encapsulation. How the composition of the adsorbed protein layer shapes macrophage behavior and subsequent inflammation remains largely unknown. Moreover, the relative contributions of biomaterial properties and the surrounding fluid has not been clearly defined. Integrating proteomics and transcriptomics, we demonstrate that biofluid composition establishes the structure of the adsorbed protein layer, whereas biomaterial properties refine it into protein signatures that are concordant with corresponding macrophage transcriptomes. Notably, lipid handling and metabolism-associated proteins emerge as potential predictors of inflammatory, metabolic stress and tissue-remodeling macrophage responses. These findings establish protein adsorption as a critical design consideration in engineering more biocompatible biomaterials.