Macrophage and Fibroblast Interactions in Biomaterial‐Mediated Fibrosis

Abstract

Biomaterial‐mediated inflammation and fibrosis remain a prominent challenge in designing materials to support tissue repair and regeneration. Despite the many biomaterial technologies that have been designed to evade or suppress inflammation (i.e., delivery of anti‐inflammatory drugs, hydrophobic coatings, etc.), many materials are still subject to a foreign body response, resulting in encapsulation of dense, scar‐like extracellular matrix. The primary cells involved in biomaterial‐mediated fibrosis are macrophages, which modulate inflammation, and fibroblasts, which primarily lay down new extracellular matrix. While macrophages and fibroblasts are implicated in driving biomaterial‐mediated fibrosis, the signaling pathways and spatiotemporal crosstalk between these cell types remain loosely defined. In this review, the role of M1 and M2 macrophages (and soluble cues) involved in the fibrous encapsulation of biomaterials in vivo is investigated, with additional focus on fibroblast and macrophage crosstalk in vitro along with in vitro models to study the foreign body response. Lastly, several strategies that have been used to specifically modulate macrophage and fibroblast behavior in vitro and in vivo to control biomaterial‐mediated fibrosis are highlighted.

Modulation of Foreign Body Reaction against PDMS Implant by Grafting Topographically Different Poly(acrylic acid) Micropatterns

“…TGF‐β released from the macrophage is involved in pro‐fibrotic activities. TGF‐β is also involved in the proliferation and differentiation of fibroblasts . The grade shown in y ‐axis of Figure d was determined by setting highest and lowest TGF‐β level as 5 points and 0 point, respectively, following the methods in other previous studies .…”

“…TGF-β is also involved in the proliferation and differentiation of fibroblasts. [10,37] The grade shown in y-axis of Figure 7d was determined by setting highest and lowest TGF-β level as 5 points and 0 point, respectively, following the methods in other previous studies. [38,39] As shown in Figure 7d and Figure S2b, Supporting Information, Bare-PDMS showed the highest expression of TGF-β at 4 weeks and a slight decrease at 8 weeks of the fibrosis stage, while the TGFβ gradually decreased from 2 weeks to 8 weeks in the case of PAA-PDMS, PAA/Hole, and PAA/Stripe.…”

“…Many studies have focused on investigating the interaction between implanted biomaterials and the host response that causes capsular contracture via FBRs to improve the function and durability of PDMS‐based silicone implants . Although the mechanism of FBRs against PDMS implants has not yet been fully understood, it has been accepted that several cells including macrophages, fibroblasts, and myofibroblasts play a key role in encapsulating the implant with a dense collagenous avascular capsule . In particular, nonspecific protein adsorption and macrophage adhesion in the initial inflammatory process promote the overall FBRs.…”

“…[6][7][8] Although the mechanism of FBRs against PDMS implants has not yet been fully understood, it has been accepted that several cells including macrophages, fibroblasts, and myofibroblasts play a key role in encapsulating the implant with a dense collagenous avascular capsule. [9][10][11][12] In particular, nonspecific protein adsorption and macrophage adhesion in the initial inflammatory process promote the overall FBRs. Therefore, it has been considered important to suppress the FBRs by reducing the cell adhesion at the surface of the implant and controlling the cell behavior by modifying the characteristics of the implant such as surface chemistry and topography.…”

Humanin vitromodel of material-driven vascular regeneration reveals how cyclic stretch and shear stress differentially modulate inflammation and tissue formation

“…The phenotypic state of the macrophage is ambiguous, often displaying both pro-and antiinflammatory features simultaneously, and depends on the phase of tissue repair and the biochemical cues from the cellular environment it is exposed to. [19]- [21] In addition, while the exact (intra)cellular mechanisms remain elusive, it is increasingly acknowledged that macrophages are mechanosensitive and adjust their function in response to both physical and mechanical cues. [22]- [24] For example, it has been reported that lower strains (8%) permit macrophage polarization towards a reparative M2 profile in 3-dimensional (3D) electrospun scaffolds, whereas higher strains (12%) promote a more pro-inflammatory M1 profile, both in terms of cell phenotype and cytokine secretion.…”