Exploring the Overlooked Roles and Mechanisms of Fibroblasts in the Foreign Body Response

Abstract

Significance: Foreign body response (FBR), wherein a fibrotic capsule forms around an implanted structure, is a common surgical complication that often leads to pain, discomfort, and eventual revision surgeries. Although believed to have some mechanistic overlap with normal wound healing, much remains to be discovered about the specific mechanism by which this occurs. Recent Advances: Current understanding of FBR has focused on the roles of the immune system and the biomaterial, both major contributors to FBR. However, another key player, the fibroblast, is often overlooked. This review summarizes key contributors of FBR, focusing on the roles of fibroblasts. As much remains to be discovered about fibroblasts' specific roles in FBR, we draw on current knowledge of fibroblast subpopulations and functions during wound healing. We also provide an overview on candidate biomaterials and signaling pathways involved in FBR. Critical Issues and Future Directions: While the global implantable medical devices market is considerable and continues to appreciate in value, FBR remains one of the most common surgical implant complications. In parallel with the continued development of candidate biomaterials, further exploration of potential fibroblast subpopulations at a transcriptional level would provide key insights into further understanding the underlying mechanisms by which fibrous encapsulation occurs, and unveil novel directions for antifibrotic and regenerative therapies in the future.

Keywords: fibroblast; fibrosis; foreign body response; implant.

Michael T. Longaker, MD, MBA, FACS

Figure 1.

Capsular contracture as an example of foreign body response. Capsular contracture is the clinical term for fibrous encapsulation that occurs among patients who receive breast reconstruction or augmentation surgery. In this study, normal breast tissue (left) is compared with capsular contracture (right), using H&E staining. H&E, Hematoxylin and Eosin. Boxes indicate the areas from which magnified x400 images were captured. Taken with permission from “Extracellular matrix (ECM) structure in tissue from patients with capsular contracture” (panel A) by Kuo et al.

Figure 2.

Stages of wound healing. Wounds undergo a series of stages before scar formation. 1. Hemostasis: the coagulation cascade controls bleeding and platelets clot off the injury site. 2. Inflammation: macrophages and neutrophils remove bacteria and debris, while also stimulating processes during the proliferative phase. 3. Proliferation: endothelial cells reform capillaries and repair vasculature, while fibroblasts at the wound site secrete collagen and contribute to ECM formation. 4. Remodeling: the ECM matrix is gradually replaced by one that is more organized and structured, resulting in the observed scar. ECM, extracellular matrix. Adapted from “Wound Healing,” by BioRender.com (2022). Retrieved from http://app.biorender.com/biorender-templates

Figure 3.

Stages of foreign body response. 1. Provisional ECM formation: Plasma proteins released due to damaged vasculature get adsorbed by the foreign body, forming a provisional matrix around the implant. 2. Acute inflammation: Acting as a source of bioactive agent, the provisional matrix attracts immune cells, including neutrophils and macrophages to the implant site. These attempt to phagocytose the foreign body. 3. Chronic inflammation: Due to the continued attempt by macrophages to phagocytose the implant, these cells undergo additional differentiation, forming FBGC, which continue to attempt to degrade the implant in a process known as frustrated phagocytosis. 4. Fibrous encapsulation: fibroblasts attracted to the implant site by immune cell signaling deposit a collagen-rich ECM that surrounds the implant. FBGC, foreign body giant cell.

Figure 4.

Examples of biomaterial modification used to modulate foreign body response. Changes to stiffness, topography, coating, and material have all been shown to alter implant foreign body response.

Figure 5.

Comparison between foreign body response formation around PEG and PSer hydrogels as an example of the effect of biomaterial on fibrotic capsule formation. A visible reduction in the thickness and density of the fibrotic capsule is seen with the use of PSer hydrogels (bottom two rows) when compared with PEG hydrogels (top two rows). PEG, poly(ethyleneglycol); PSer, poly-dl-serine. Taken with permission from “Explantation and staining images of PEG and PSer hydrogels after subcutaneously implanted in mice for 1 week (a) and 2 weeks (b)” (panel B) by Zhang et al.