Wednesday, April 2, 2025
4/2/2025
Tunable Surface Coatings to Control Protein Dynamics and Attenuate the FBR - The foreign body response (FBR) induced by the implantation of synthetic biomaterials remains a formidable challenge. The FBR begins as an inflammatory process that is mediated by innate immune cells and culminates in the production of an avascular fibrous capsule. While the FBR has been extensively studied, a detailed understanding of the molecular mechanisms that underlie the FBR remains elusive. The current dogma assumes that the FBR is driven by proteins that adsorb and unfold irreversibly on biomaterial surfaces. However, using novel single-molecule methods, we have shown that adsorption and unfolding on surfaces is highly dynamic and reversible, and that proteins in contact with surfaces desorb rapidly in both the folded and unfolded states. This newfound understanding paints a different picture, which suggests that otherwise non-inflammatory proteins contribute to the production of soluble damage-associated molecular patterns (DAMPs) that accumulate in the fluid surrounding an implant. Our preliminary in vitro studies found a direct link between surface-induced transiently unfolded fibronectin and the activation of macrophages, whereas surfaces that stabilized folded fibronectin were less inflammatory. Our in vivo studies found that Toll-like receptor (TLR) 2 and 4, which recognize DAMPs, are the main drivers of the FBR. Accordingly, the overarching goal of this research is to investigate the mechanistic basis for the events that trigger and sustain the FBR by linking protein dynamics, DAMPs, myeloid cell activation, and the FBR. Using a highly multi-disciplinary approach, we will test the hypothesis that continuous production of soluble DAMPs due to rapid unfolding, slow re-folding, and desorption of proteins from the surface of an implant sustains the FBR, and that modulating such protein dynamics to stabilize the non-inflammatory folded state weakens the FBR. To test this hypothesis, the specific aims of this proposal are to: (1) determine the impact and nature of protein dynamics on DAMP production and their impact on myeloid cell activation (Aim 1), (2) identify universal brush chemistries that weaken myeloid cell activation by generally controlling protein-brush interactions (Aim 2), and (3) evaluate polymer brushes as coatings for implants to weaken the FBR in vivo and in human cells (Aim 3). To carry out the proposed research, our team will combine innovative single-molecule methods, protein engineering, tunable surface chemistries, and molecular dynamic simulations with machine learning to understand the protein- biomaterial interface and to identify novel surface chemistries that provide generalized control over protein dynamics in complex protein solutions. We will study the role of protein dynamics on neutrophils and macrophages and utilize mouse models with mutant TLRs to link the protein-biomaterial interface to DAMPs and to the FBR. Completion of this project will provide a mechanistic basis for the role of protein dynamics in the FBR and lead to the discovery of new surface chemistries with improved biocompatibility. Such outcomes will provide the framework to prevent the FBR and improve clinical translation of implantable biomaterials.
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