The Dynamic Inflammatory Tissue Microenvironment: Signality and Disease Therapy by Biomaterials

Abstract

Tissue regeneration is an active multiplex process involving the dynamic inflammatory microenvironment. Under a normal physiological framework, inflammation is necessary for the systematic immunity including tissue repair and regeneration as well as returning to homeostasis. Inflammatory cellular response and metabolic mechanisms play key roles in the well-orchestrated tissue regeneration. If this response is dysregulated, it becomes chronic, which in turn causes progressive fibrosis, improper repair, and autoimmune disorders, ultimately leading to organ failure and death. Therefore, understanding of the complex inflammatory multiple player responses and their cellular metabolisms facilitates the latest insights and brings novel therapeutic methods for early diseases and modern health challenges. This review discusses the recent advances in molecular interactions of immune cells, controlled shift of pro- to anti-inflammation, reparative inflammatory metabolisms in tissue regeneration, controlling of an unfavorable microenvironment, dysregulated inflammatory diseases, and emerging therapeutic strategies including the use of biomaterials, which expand therapeutic views and briefly denote important gaps that are still prevailing.

Figure 1

(a) Schematic illustration of the tissue microenvironment at the site of injury. Tissue injury is sensed by the resident macrophages via the released DAMPs and neutrophils that are primary infiltrating cells recruited to the damage site, which in turn recruit monocytes and macrophages. The inflammatory microenvironment is formed by the released inflammatory cytokines, growth factors, and proteases in the earlier stage. It is then shifted to the anti-inflammatory microenvironment that exploits tissue repair and homeostasis in the later stage. (b) Illustrating how the physiochemical properties of biomaterials regulate the tissue immune system. Biomaterials aid in the regulation of inflammatory cells towards the regeneration/repair phase. They are involved in the polarization of M1 inflammatory macrophages to M2 anti-inflammatory/profibrotic/proregenerative macrophages, which is a critical process for tissue regeneration. They also play a crucial role in converting T-cells into T-regulatory cells. Reprinted with permission from [21] Copyright © Elsevier 2017.

Figure 2

Regulatory functions of HIF-1α and HIF-2α in M1 and M2 macrophages. HIF-1α modulates the glycolytic pathway of M1 macrophages and inflammatory cytokine production. HIF-2α regulates the alternatively activated M2 macrophages through activating arginase and oxidative phosphorylation.

Figure 3

Overview of the principal metabolic regulation of TCA, glycolysis, electron transport chain, and fatty acid synthesis in macrophages involved in switching macrophage phenotypes. Glycolysis is primarily involved in the activation of M1 that further secretes proinflammatory cytokines. The TCA cycle mainly supports the stimulation of M2 macrophages, consequently inducing secretion of prorepair cytokines. The important metabolites or enzymes involved in the phenotype switching are highlighted in orange color. Reprinted with permission from [134] Copyright © 2020 Springer Nature.

Figure 4

(a, b) Stages in the development of atherosclerotic lesions. Reprinted with permission from [195] Copyright © 2021 Springer Nature.

Figure 5

(a) Schematic illustration of the therapeutic mechanism by PEG-b-PPS micelles for reducing ROS and proinflammatory cytokines in the atherosclerotic process. Reprinted with permission from [203] Copyright 2018 Elsevier Ltd. (b) Schematic diagram of FTIAN as a thrombus-specific theranostic agent that is able to image thrombus and exert potent antithrombotic activity. Reprinted with permission from [204] Copyright © 2021 American Chemical Society.

Figure 6

siRNA nanoparticles target epithelial cells or macrophages in the intestinal lumen. Reprinted with permission from [210] Copyright © Dove Press 2016.