Immunomodulatory biomaterials against bacterial infections: Progress, challenges, and future perspectives

Abstract

Bacterial infectious diseases are one of the leading causes of death worldwide. Even with the use of multiple antibiotic treatment strategies, 4.95 million people died from drug-resistant bacterial infections in 2019. By 2050, the number of deaths will reach 10 million annually. The increasing mortality may be partly due to bacterial heterogeneity in the infection microenvironment, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants. In addition, the complexity of the immune microenvironment at different stages of infection makes biomaterials with direct antimicrobial activity unsatisfactory for the long-term treatment of chronic bacterial infections. The increasing mortality may be partly attributed to the biomaterials failing to modulate the active antimicrobial action of immune cells. Therefore, there is an urgent need for effective alternatives to treat bacterial infections. Accordingly, the development of immunomodulatory antimicrobial biomaterials has recently received considerable interest; however, a comprehensive review of their research progress is lacking. In this review, we focus mainly on the research progress and future perspectives of immunomodulatory antimicrobial biomaterials used at different stages of infection. First, we describe the characteristics of the immune microenvironment in the acute and chronic phases of bacterial infections. Then, we highlight the immunomodulatory strategies for antimicrobial biomaterials at different stages of infection and their corresponding advantages and disadvantages. Moreover, we discuss biomaterial-mediated bacterial vaccines' potential applications and challenges for activating innate and adaptive immune memory. This review will serve as a reference for future studies to develop next-generation immunomodulatory biomaterials and accelerate their translation into clinical practice.

Graphical abstract

Figure 1

Illustrations show changes in the immune microenvironment during the acute and chronic phases of bacterial infection (A) The release of multiple toxins from bacteria in the acute phase of infection and the activation of innate immune cells lead to an increase in pro-inflammatory cytokines in the immune microenvironment. (B) In the chronic phase of infection, bacteria evade recognition and killing by immune cells through altered survival patterns, which also promote proliferation of multiple immunosuppressive cells, exhaustion of immune cells, and increased release of anti-inflammatory cytokines.

Figure 2

Dynamics of innate and adaptive immunity against bacterial infections over time

Figure 3

During the acute phase of infection, immunomodulatory antimicrobial biomaterials modulate the immune microenvironment (A) Biomaterials promote early neutrophil recruitment, and activation and phagocytosis of bacteria through the release of pro-inflammatory agents or their own physicochemical properties. Biomaterials also stimulate neutrophils to release ROS, RNS, and NETs to rapidly kill bacteria. (B) Biomaterials promote M2 polarization of macrophages through direct bactericidal action and release of anti-inflammatory agents that accelerate the healing of infected tissue while removing bacteria.

Figure 4

During the chronic phase of infection, immunomodulatory antimicrobial biomaterials modulate the immune microenvironment (A) Biomaterials promote M1 macrophage polarization and reduce infection recurrence through direct lysis of biofilms and intracellular bacteria and release of pro-inflammatory agents. (B) Biomaterials enhance the killing of intracellular bacteria and biofilms through direct bactericidal activity and by releasing immunomodulatory substances that reduce the number of immunosuppressive cells and restore the function of exhausted cells.

Figure 5

Immunomodulatory antimicrobial biomaterials induce the formation of innate and adaptive immune memory (A) Biomaterials enhance the long-term bactericidal capacity of macrophages by releasing trained immunity inducers that promote metabolic reprogramming. (B) Biomaterials enhance the function of antigen-presenting cells and induce the production of adaptive immune memory by exogenously introducing bacterial antigens or releasing antigens by in situ lysis of bacteria from infected tissues.