Project Summary
Implantation of biomaterials and devices often leads to the development of a foreign body response (FBR), a chronic
inflammatory condition that can ultimately lead to implant failure, which may cause harm to or death of the patient.
The molecular mechanisms underlying the FBR remain poorly understood. Improved understanding of the molecular
mechanisms underlying the generation of FBR is the most important step for the development of novel and effective
therapeutic strategies that eliminate or reduce the FBR. Macrophages are central to development and progression of
the FBR. They participate in the expression of inflammatory proteins, formation of destructive foreign body giant
cells (FBGCs), remodeling of the extracellular matrix, and encapsulation of the implant. Emerging data support a
critical role for a mechanical signal, e.g., matrix stiffness, in macrophage activation. MicroRNAs (miRs) are
endogenous, small, non-coding RNAs that have emerged as powerful regulators of gene expression in numerous
cellular processes including macrophage activation, cell fusion, inflammation, and fibrosis. The function of specific
miRs in regulation of FBR to biomaterials is uncertain; specifically, it remains an open question whether matrix
stiffness regulates miR expression to drive FBR. These gaps pose a significant barrier to progress in the FBR field.
In recent, exciting preliminary data, we obtained evidence that miR-146a may be a negative regulator of FBR to
biomaterials. Specifically, we found that: 1) miR-146a expression levels decreased in the implant-adhered tissues in
a subcutaneous (s.c) implantation model, which correlated with increased macrophage accumulation, FBGC
formation, and collagen accumulation; 2) miR-146a deletion in mice exacerbated FBR processes in a s.c
implantation model; 3) the severity of the in vivo macrophage accumulation at the tissue-implant interface was
dependent on the stiffness of the implant; 4) genetic ablation of miR-146a augmented macrophage adhesion and
spreading on stiff matrix, FBGC formation, and inflammation in macrophages, and 5) genetic ablation of TRPV4, an
ion channel in the transient receptor potential vanilloid family, inhibited development of implant-adhered tissue
stiffness under FBR as determined by Atomic Force Microscopy. Further preliminary data suggested an association
between matrix stiffness, miR-146a activity, and TRPV4, under FBR conditions. The objective of this proposal is to
define the role of miR-146a in the FBR, and to elucidate the underlying molecular mechanisms. Based on our
preliminary data, our central hypothesis is that miR-146a modulates the FBR to biomaterials by regulating
macrophage activation and fibrogenesis in a manner dependent on implant-induced change in tissue stiffness. We
will test our hypothesis through molecular gain- or loss-of-function studies. We expect that the results of this study
may provide invaluable information and insight regarding the molecular mechanisms mediating the FBR to
biomaterials, which may lead to the development of a novel and effective microRNA-based therapeutic strategy for
the amelioration of the poorly understood FBR to biomaterials.
