Biomaterial-Driven Immunomodulation: Cell Biology-Based Strategies to Mitigate Severe Inflammation and Sepsis

Abstract

Inflammation is an essential component of a wide variety of disease processes and oftentimes can increase the deleterious effects of a disease. Finding ways to modulate this essential immune process is the basis for many therapeutics under development and is a burgeoning area of research for both basic and translational immunology. In addition to developing therapeutics for cellular and molecular targets, the use of biomaterials to modify innate and adaptive immune responses is an area that has recently sparked significant interest. In particular, immunomodulatory activity can be engineered into biomaterials to elicit heightened or dampened immune responses for use in vaccines, immune tolerance, or anti-inflammatory applications. Importantly, the inherent physicochemical properties of the biomaterials play a significant role in determining the observed effects. Properties including composition, molecular weight, size, surface charge, and others affect interactions with immune cells (i.e., nano-bio interactions) and allow for differential biological responses such as activation or inhibition of inflammatory signaling pathways, surface molecule expression, and antigen presentation to be encoded. Numerous opportunities to open new avenues of research to understand the ways in which immune cells interact with and integrate information from their environment may provide critical solutions needed to treat a variety of disorders and diseases where immune dysregulation is a key inciting event. However, to elicit predictable immune responses there is a great need for a thorough understanding of how the biomaterial properties can be tuned to harness a designed immunological outcome. This review aims to systematically describe the biological effects of nanoparticle properties-separate from additional small molecule or biologic delivery-on modulating innate immune cell responses in the context of severe inflammation and sepsis. We propose that nanoparticles represent a potential polypharmacological strategy to simultaneously modify multiple aspects of dysregulated immune responses where single target therapies have fallen short for these applications. This review intends to serve as a resource for immunology labs and other associated fields that would like to apply the growing field of rationally designed biomaterials into their work.

Keywords: biomaterials; inflammation; innate immunity; macrophage; microparticles; nanoparticles; neutrophil; sepsis.

Figure 1

Inflammation is a highly complex, multistep process where nanoparticles can be engineered to intervene to tune the response at multiple points. During the initial generation of PAMPs and DAMPs, biomimetic nanoparticles have been used to sequester PAMPs and DAMPs from immune cell recognition (1). Innate immune cells that have taken up nanoparticles can be functionally reprogrammed from a pro-inflammatory phenotype (i.e., TNF-α, IL-1β, and IL-6 secreting) to an anti-inflammatory phenotype (2). The vascular endothelium also plays a key role in promoting inflammation and nanoparticles can be used to downregulate attachment of circulating immune cells and subsequent exudation (3). Nano-bio interactions can also alter direct homing to inflamed tissue sites by either eliminating chemokine production at the site (4) or redirecting inflammatory cells away from the inflamed site to the liver and spleen for elimination (5).

Figure 2

Macrophage mimicking nanoparticles (MΦ-NP) sequester bacteria derived endotoxin and subsequent inflammatory cytokines to limit inflammation associated damage (A). This results in a dose-dependent ability of the MΦ-NP to reduce free LPS (B) and pro-inflammatory cytokines such as IL-6 and TNF-α (C) in vitro. LPS-induced endotoxemia (D) and E. coli bacteremia (E) show a survival benefit specific to the biomimetic MΦ-NP, where *P < 0.05. Adapted from (54). Copyright (2017) National Academy of Science.

Figure 3

Selectivity experiments and TEM characterization of nanoparticles for targeted sequestration of venom proteins. Polymer composition was optimized to enable specificity toward venom yet avoid serum protein binding. Strategy for assessing selectivity of nanoparticles to venom (A). Selectivity assessment via SDS-PAGE visualization (B) of (1/1′) ladder; (2) purified PLA₂ from Naja mossambica venom; (3) serum control; (4) nanoparticle in serum only; (5) nanoparticle incubated in serum and PLA₂ from N. mossambica venom; (6) purified PLA₂ from honey-bee venom; (7) nanoparticle incubated in ovine plasma and PLA₂ from honey-bee venom. Unstained TEM image of nanoparticle for sequestration of venom (C). Reprinted with permission from (74). Copyright (2016) American Chemical Society.

Figure 4

Immunomodulatory effects of nanoparticles. Nanoparticle-dependent inflammatory cytokine suppression of innate immune cells when stimulated with LPS (top). Dynamic transcription factor activity of bone marrow-derived macrophages treated with particles followed by LPS stimulation and improved survival in lethal LPS-induced endotoxemia model. PVA, neutral charge. PEMA, negative charge. Adapted from (93). Copyright (2019) Elsevier.

Figure 5

Non-invasive strategy to alter immune cell responses to enhance spinal cord injury (SCI) recovery with in vivo biodistribution and analysis of nanoparticles. Experimental timeline for the study (A). In vivo images from spinal cord and spleen at 1 day post-injection (B). Fluorescence quantification of imaging in (B), where ***P < 0.001 and ****P < 0.0001 (C). Immunomodulation of macrophages as assessed with RT-qPCR data for pro-inflammatory and anti-inflammatory genes at multiple timepoints post-SCI and immunodetection of M2 macrophages (yellow color) within bridge following SCI (^aP < 0.05, ^bP < 0.01, ^cP < 0.001, and ^dP < 0.0001 compared to the PBS group, and ^#P < 0.05 and ^##P < 0.01 relative to the SCI only group) (D). Functional recovery of locomotor activity from SCI, where *P < 0.05, **P < 0.01, and ***P < 0.001 compared the the PBS group, and ^∧P < 0.05 relative to the SCI only group (E). Adapted from (95). Copyright (2019) National Academy of Sciences.