Foreign body reaction: towards a macrophage-centered adverse outcome pathway for fibrotic encapsulation.

Abstract

The foreign body reaction (FBR), characterized by chronic inflammation and fibrotic capsule formation around implanted medical devices, remains a major cause in device-related complications. Current preclinical risk assessment relies on <i>in vivo</i> testing according to ISO 10993-6:2024, which are limited by species differences, incomplete mechanistic insight, and ethical concerns. Additionally, ISO/TS 10993-20:2006 outlines immunotoxicity knowledge regarding implant-induced effects such as FBR and specifies a collection of <i>in vitro</i> assays. The perspective presented here, aims to explore the applicability of the Adverse Outcome Pathway (AOP) framework to FBR in order to integrate evidence and methods into a structured mechanistic context and facilitate the application of <i>in vitro</i> tests in preclinical risk assessment of FBR. A targeted literature review was conducted to identify and organize biological mechanisms into a putative AOP, map available new approach methodologies, and highlight critical knowledge gaps and uncertainties. This initial framework may guide early screening for low-FBR materials and support mechanistically anchored, non-animal biocompatibility assessment strategies for medical devices.