Design of therapeutic biomaterials to control inflammation

Abstract

Inflammation plays an important role in the response to danger signals arising from damage to our body and in restoring homeostasis. Dysregulated inflammatory responses occur in many diseases, including cancer, sepsis and autoimmunity. The efficacy of anti-inflammatory drugs, developed for the treatment of dysregulated inflammation, can be potentiated using biomaterials, by improving the bioavailability of drugs and by reducing side effects. In this Review, we first outline key elements and stages of the inflammatory environment and then discuss the design of biomaterials for different anti-inflammatory therapeutic strategies. Biomaterials can be engineered to scavenge danger signals, such as reactive oxygen and nitrogen species and cell-free DNA, in the early stages of inflammation. Materials can also be designed to prevent adhesive interactions of leukocytes and endothelial cells that initiate inflammatory responses. Furthermore, nanoscale platforms can deliver anti-inflammatory agents to inflammation sites. We conclude by discussing the challenges and opportunities for biomaterial innovations in addressing inflammation.

Keywords: Biomedical materials.

Fig. 1. Therapeutic biomaterials to control inflammation.

Biomaterials can be applied to control sterile inflammation in the early stage (scavenging strategy), middle stage (blockage strategy) and late stage (delivery strategy). cfNA, cell-free nucleic acid; DAMP, damage-associated molecular pattern; EPR, enhanced permeability and retention; RONS, reactive oxygen and nitrogen species.

Fig. 2. The inflammatory microenvironment.

The inflammatory microenvironment comprises invasive pathogens, damaged cells and vasculature, infiltrating immune cells, danger signals, such as pathogen-associated molecular patterns and endogenous tissue damage-associated molecular patterns, and a plethora of pro-inflammatory molecules, such as cytokines, chemokines, enzymes, leukotrienes and eicosanoids. In particular, reactive oxygen and nitrogen species (RONS) can activate Toll-like-receptor-mediated nuclear factor-κB (NF-κB) and interferon regulatory factor pathways during inflammation. Localized inflammation induces the activation of microvascular endothelial cells, causing changes in vascular permeability to promote leukocyte homing, such as neutrophil adhesion and transmigration, as well as activation of platelets and monocytes. Nanoparticles can accumulate in the inflammatory microenvironment owing to the enhanced permeability and retention (EPR) effect, transcytosis or nanomaterials-induced endothelial leakiness (NanoEL). COX2, cyclooxygenase 2; HMGB1, high-mobility group box 1; IL-1β, interleukin-1β; IL-6, interleukin-6; PGE₂, prostaglandin E₂; TNF, tumour necrosis factor.

Fig. 3. Scavenging strategies to modulate inflammation.

In the early stage of inflammation, pathogen-associated molecular patterns (PAMPs) and endogenous tissue damage-associated molecular patterns (DAMPs) are released from injured cells. Reactive oxygen and nitrogen species (RONS), cell-free nucleic acids (cfNAs) and PAMPs or DAMPs can induce an inflammatory response and the recruitment of immune cells. a | RONS scavengers, such as artificial selenoenzymes and catalytic nanomaterials. b | cfNA scavengers, such as nucleic-acid-binding polymers, fibres and particles, can reduce the level of RONS and cfNAs in PAMPs or DAMPs and attenuate inflammation development.

Fig. 4. Blockage strategies to modulate inflammation.

In the middle stage of inflammation, immune cells are recruited to the inflammatory site, generating excessive pro-inflammatory cytokines and inducing severe inflammation. a | Anionic biomaterials, such as linear polymers, dendritic polymers and nanomaterials, can block the interaction between L-selectins on leukocytes and L-selectin ligands on the endothelium, or P-selectin on the endothelium and P-selectin ligands on leukocytes, to inhibit the migration of immune cells to the inflammation sites. b | Toll-like receptor (TLR) antagonists can be applied to block the activation of TLRs on immune cells to prevent the activation of immune cells.

Fig. 5. Delivery strategies to modulate inflammation.

In the final stage of uncontrolled inflammation, an excess of immune cells produces an inflammatory response, which can result in a cytokine storm. Biomaterials can be applied as drug delivery platforms, in particular, as nanocarriers, to extracellularly or intracellularly deliver therapeutic agents to the inflammatory sites through the enhanced permeability and retention effect, transcytosis or nanomaterials-induced endothelial leakiness.

Fig. 6. Anti-inflammatory biomaterials design.

a | Inflammation is a highly dynamic process, exemplified here by the development of sepsis. Sepsis is characterized by an intricate interplay of pro-inflammatory and anti-inflammatory responses. An optimal anti-inflammatory therapy should, therefore, adapt to the progression of inflammation. b | Various parameters of biomaterials can be designed for scavenging, blockage and delivery strategies for inflammation modulation. Composition, size, shape, charge and mechanical compliance affect the behaviour of the biomaterial in vitro and in vivo, including tissue distribution, trafficking and cellular interactions. The mechanical compliance of biomaterials, whether as scaffold to interact with leukocytes or as a nanoparticulate injectable to interact with cells and tissues, is also relevant. Finally, biomaterials can play a passive or active role in inflammation-modulation strategies. DAMP, damage-associated molecular pattern; GSH, glutathione; IL-1β, interleukin-1β; IL-6, interleukin-6; mtDNA, mitochondrial DNA; NET, neutrophil extracellular trap; ΝF-κB, nuclear factor-κB; PAMP, pathogen-associated molecular pattern; RONS, reactive oxygen and nitrogen species; ROS, reactive oxygen species; TNF, tumour necrosis factor.