Neutrophil Extracellular Traps: Inflammation and Biomaterial Preconditioning for Tissue Engineering

Tissue injury initiates a tissue repair program, characterized by acute inflammation and recruitment of immune cells, dominated by neutrophils. Neutrophils prevent infection in the injured tissue through multiple effector functions, including the production of reactive oxygen species, the release of granules, the phagocytosis of invaders, and the extrusion of neutrophil extracellular traps (NETs). However, these canonical protective mechanisms can also have detrimental effects both in the context of infection and in response to sterile injuries. Of particular interest to biomaterials and tissue engineering is the release of NETs, which are extracellular structures composed of decondensed chromatin and various toxic nuclear and granular components. These structures and their dysregulated release can cause collateral tissue damage, uncontrolled inflammation, and fibrosis and prevent the neutrophil from exerting its prohealing functions. This review discusses our knowledge of NETs, including their composition and morphology, signaling pathways, inhibitors, and contribution to inflammatory pathologies, as well as their role in the resolution of inflammation. In addition, we summarize what is known about the release of NETs as a preconditioning event in the response to biomaterials and highlight future considerations to target the neutrophil response and enhance biomaterial-guided tissue repair and regeneration. Impact statement Neutrophil extracellular trap (NET) release is an active process programmed into the neutrophil's molecular machinery to prevent infection. However, the release of NETs on biomaterials appears to be a significant preconditioning event that influences the potential for tissue healing with largely detrimental consequences. Given their contribution to inflammatory pathologies, this review highlights the role of NETs in the response to biomaterials. Together, the studies discussed in this review suggest that biomaterials should be designed to regulate NET release to avoid maladaptive immune responses and improve the therapeutic potential of tissue-engineered biomaterials and their applications in the clinical setting.