Cell-Inspired Biomaterials for Modulating Inflammation

Abstract

Inflammation is a crucial part of wound healing and pathogen clearance. However, it can also play a role in exacerbating chronic diseases and cancer progression when not regulated properly. A subset of current innate immune engineering research is focused on how molecules such as lipids, proteins, and nucleic acids native to a healthy inflammatory response can be harnessed in the context of biomaterial design to promote healing, decrease disease severity, and prolong survival. The engineered biomaterials in this review inhibit inflammation by releasing anti-inflammatory cytokines, sequestering proinflammatory cytokines, and promoting phenotype switching of macrophages in chronic inflammatory disease models. Conversely, other biomaterials discussed here promote inflammation by mimicking pathogen invasion to inhibit tumor growth in cancer models. The form that these biomaterials take spans a spectrum from nanoparticles to large-scale hydrogels to surface coatings on medical devices. Cell-inspired molecules have been incorporated in a variety of creative ways, including loaded into or onto the surface of biomaterials or used as the biomaterials themselves. Impact statement Chronic inflammatory diseases and cancers are widespread health care concerns. Treatment plans for these diseases can be complicated and the outcomes are often mixed due to off-target effects. Current research efforts in immune engineering and biomaterials are focused on utilizing the body's native immune response to return to homeostasis as a therapeutic approach. This review collects many of the most current findings in the field as a resource for future research.

Keywords: biomaterial; cancer; cell-inspired; inflammation; macrophage; nanoparticle.

FIG. 1.

Resolution of inflammation. (A) Tissue resident macrophages sense tissue damage and recruit neutrophils to the area of injury, which then signal for the infiltration of circulating monocytes. Resolution of inflammation is triggered by the apoptosis of neutrophils, leading to the secretion of “find-me” signals, presentation of phosphatidylserine, and engulfment by macrophages. This causes the phenotype shift in macrophage from proinflammatory (M1) to resolution-phase (M2). (B) M1 and M2 macrophages direct inflammation by adjusting cell marker expression, secreting pro- or anti-inflammatory cytokines, and modulating phagocytic and migratory abilities. Adapted from Ortega-Gómez et al. Color images are available online.

FIG. 2.

Anti-inflammatory cell membrane mimicking nanoparticles. (A) Nanoparticles can be produced through synthetic (liposomes and solid lipid nanoparticles) and cell-derived (cell membrane-coated nanoparticles and engineered EVs) means. They may contain anti-inflammatory lipids, drugs, and proteins. (B) In one example of a cell membrane inspired coating, stromal cell membrane supplemented with exogenous PS is used to mimic the surface of an apoptotic body on a PLGA nanoparticle. This particle contains membrane-associated proteins, phospholipids, and additional cell surface features in conjunction with synthetic PS. By mimicking an apoptotic body, the authors are able to reduce macrophage-associated inflammatory response. (C) The proportion of PS incorporated correlates with the degree of TNF-α production following LPS stimulation. In particles with a higher proportion of PS, TNF-α production is reduced. (D) Particles with 20% PS supplementation result in significant reductions in TNF-α, IL-1β, IL-6, and iNOS gene expression following LPS stimulation. (B-D) Adapted from Kraynak et al. EVs, extracellular vesicles; IL, interleukin; LPS, lipopolysaccharide; PLGA, poly(lactic-co-glycolic acid); PS, phosphatidylserine; TNF, tumor necrosis factor. Color images are available online.

FIG. 3.

Protein inspired biomaterials for inflammation modulation. (A) Nanoparticle or implant interfaces are functionalized with surface proteins conjugated to a solid or porous surface or soluble proteins eluted out of a matrix. These proteins can be used in conjunction with one another or with inflammation-modulating drugs. (B) IL-4 conjugated to the surface of a polycaprolactone vascular graft shows a decrease in the thickness of tissue surrounding the graft, decrease in total number of macrophages, increase in M2-polarized macrophages, and a decrease in M1-polarized macrophages. (B) Adapted from Tan et al. Color images are available online.

FIG. 4.

NA-based biomaterials. (A) NA nanoparticles comprised of oligonucleotides loaded inside liposomes or onto the surface of solid particles, nanostructures consisting of NAs formed into varying shapes, and hydrogels formed by NA units ligated together. (B) Schematic of immunomodulatory spherical NA with TLR agonist or TLR antagonist ODN coated on a gold or liposomal core. (C) Spherical NAs coated with CpG ODNs significantly induced NF-κB activation in macrophages (top left) and reduce tumor volume in vivo (top right) while spherical NAs coated with TLR antagonist ODNs suppressed the NF-κB activation induced by phosphorothioate CpG (bottom left) and reduced fibrosis score in the model of nonalcoholic steatohepatitis (bottom right). (B, C) Adapted from Radovic-Moreno et al. CpG, cytosine-guanine; ODN, oligodeoxynucleotide; OVA, ovalbumin; NA, nucleic acid; NF-κB, nuclear factor-kappaB; PBS, phosphate-buffered saline; ssDNA, single-stranded DNA; ssRNA, single-stranded RNA; TLR, toll-like receptor. Color images are available online.