Investigating the Role of Macrophage miR-146a in Foreign Body Response to Biomaterials

Abstract

Annually, more than 70 million biomedical devices including pacemakers, dental implants, breast implants, and orthopedic prosthetics, are implanted globally, contributing to a total expenditure exceeding US100 billion. Implantation of biomaterials leads to a variety of cellular and tissue responses, including a chronic inflammatory condition known as foreign body response (FBR), resulting in the formation of a fibrous capsule surrounding the implant which isolates the implant from the host tissue. This causes loss of function of the implant, harm to the patient and sometimes even causes death of the patient. The central role of macrophages in driving FBR, undergoing fusion to give rise to destructive foreign body giant cell (FBGC), is well known, yet the precise molecular mechanism is still undefined. To address this gap in knowledge and recognize crucial molecular targets, we conducted a microRNA (miR) analysis and examined the regulatory role of macrophage-derived miR-146a in regulating FBR. Our research findings include: (a) severity of FBR is inversely related to macrophage-derived miR-146a level; (b) macrophage specific miR-146a regulate expression of genes associated with fibrosis, inflammation and mechanosensation; (c) implant-stiffness induced FBGC formation, collagen deposition, myofibroblast differentiation and F-actin generation is governed by miR-146a in murine implant models; (d) miR-146a drives cellular traction force generation, which is crucial for FBGC formation. These findings indicate the macrophage miR-146 is the central regulator of FBR in response to chemical and physical stimuli. This insight can help us in designing promising therapeutic interventions, as manipulating miR-146a expression or function at the site of the biomaterial implant, could delay or completely stop FBR. Emerging data supports biophysical cues influence macrophage function and FBR intensity, yet researchers still use conventional 2D cell culture methods which are unable to replicate the three-dimensional nature of cells and tissues. To address this concern, we successfully developed a alginate-collagen 3D microcapsules, that can closely mimic three-dimensional interactions present in cells/tissues. Using this model, we also determined the role of transient receptor potential vanilloid 4 (TRPV4) on FBGC formation, F-actin generation and change in genetic expression leading to a more fibrotic and inflammatory outcome. To sum it up, this research has helped us in identifying a novel target miR-146a, which can be used as a selective therapeutic strategy to address FBR.