Biomaterial strategies for regulating the neuroinflammatory response

Abstract

Injury and disease in the central nervous system (CNS) can result in a dysregulated inflammatory environment that inhibits the repair of functional tissue. Biomaterials present a promising approach to tackle this complex inhibitory environment and modulate the mechanisms involved in neuroinflammation to halt the progression of secondary injury and promote the repair of functional tissue. In this review, we will cover recent advances in biomaterial strategies, including nanoparticles, hydrogels, implantable scaffolds, and neural probe coatings, that have been used to modulate the innate immune response to injury and disease within the CNS. The stages of inflammation following CNS injury and the main inflammatory contributors involved in common neurodegenerative diseases will be discussed, as understanding the inflammatory response to injury and disease is critical for identifying therapeutic targets and designing effective biomaterial-based treatment strategies. Biomaterials and novel composites will then be discussed with an emphasis on strategies that deliver immunomodulatory agents or utilize cell-material interactions to modulate inflammation and promote functional tissue repair. We will explore the application of these biomaterial-based strategies in the context of nanoparticle- and hydrogel-mediated delivery of small molecule drugs and therapeutic proteins to inflamed nervous tissue, implantation of hydrogels and scaffolds to modulate immune cell behavior and guide axon elongation, and neural probe coatings to mitigate glial scarring and enhance signaling at the tissue-device interface. Finally, we will present a future outlook on the growing role of biomaterial-based strategies for immunomodulation in regenerative medicine and neuroengineering applications in the CNS.

Fig. 1. Composition of central nervous system parenchymal tissue during homeostasis. (A) Peripheral immune cells such as lymphocytes, neutrophils, dendritic cells, and border-associated macrophages (Mφ) reside in the dura mater, contributing to immune surveillance. Astrocytes wrap around neurovasculature, contributing to the integrity and selectivity of the BBB. Astrocytes also facilitate metabolite transport to neighboring glia and neurons. During homeostasis, microglia remain in a branched state, surveying the environment for pathogens, DAMPs, and protein aggregates. Oligodendrocytes myelinate axons and facilitate metabolite transport alongside astrocytes. (B) Different cell types present in CNS tissue. (C) The extracellular matrix in the CNS primarily consists of hyaluronic acid, fibronectin, laminin, and proteoglycans.

Fig. 2. The stages of the inflammatory response to injury in the central nervous system. The inflammatory response in the CNS can be broken down into the acute inflammatory phase, which lasts hours to days, the sub-acute inflammatory phase, which lasts days to weeks, and chronic inflammatory stage, which lasts months to years. (A) The CNS tissue environment after injury includes an abundance of neurons, glia, and other immune cells as well as a variety of pro- and anti-inflammatory molecules that change throughout the various stages of inflammation. (B) Relative abundance of various immune cells during the stages of inflammation. (C) Relative abundance of pro- and anti-inflammatory cytokines, growth factors, and other biomolecules during the stages of inflammation. Abbreviations: M1 (classically activated macrophages/microglia), M2 (alternatively activated macrophages/microglia), A1 (activated astrocytes), Glu (glutamate), iNOS (inducible nitric oxide synthase), DAMPs (damage-associated molecular patterns), MMPs (matrix metalloproteinases), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α), IL-1β (interleukin-1β), IL-4 (interleukin-4), IL-10 (interleukin-10), IL-33 (interleukin-33), transforming growth factor-β (TGF-β), CSPGs (chondroitin sulfate proteoglycans).

Fig. 3. Nanoparticle-based delivery vehicles and their transport mechanisms through CNS tissue. Nanoparticle delivery vehicles such as exosomes, dendrimers, and polymeric nanoparticles enhance drug delivery across the blood-brain barrier. Nanoparticles may enter the CNS through gaps in the disrupted BBB or via “facilitated transport” pathways, such as carrier-, adsorptive-, and receptor-mediated transcytosis.

Fig. 4. Examples of recent advances in hydrogels to modulate CNS inflammation. (A) A photo-crosslinked gelatin hydrogel modified with cationic charged poly(amindoamine) dendrimers simultaneously scavenged HMGB1 and released IL-10 to reduce expression of TNF-α and IL-1β in spinal cord tissue. (B) A hyaluronic acid-methylcellulose (HAMC) hydrogel modified with brain derived growth factor (BDNF) and the immunomodulatory peptide KAFAK reduced expression of TNF-α, IL-1β, and IL-6 and increased expression of IL-10 in spinal cord tissue. (C) A HAMC hydrogel loaded with poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the co-delivery of erythropoietin and cyclosporine reduced lesion volume after stroke injury.

Fig. 5. Examples of recent advances in implantable scaffolds to modulate CNS inflammation. (A) An aligned collagen scaffold loaded with neural stem cells (NSCs) decreased the expression of pro-inflammatory cytokines including IL-1β and IL-6. (B) A collagen/heparin scaffold for the repair of brain tissue after TBI promoted synaptic formations as indicated by staining of microtubule associated protein 2 (MAP-2) and synaptophysin (Syn). (C) An aligned gelatin scaffold containing glial cell line-derived neurotrophic factor (GDNF)-loaded polydopamine nanoparticles polarized macrophage and microglia to M2 phenotypes after SCI as indicated by CD206 and F40/F80 staining.

Fig. 6. Different types of coatings for improving neural probe integration. Electrode shanks may be coated with (A) graphene monolayers to support neuronal attachment, (B) hydrogels with tunable mechanical properties and conjugated ligands for mimicking CNS parenchymal tissue, (C) carbon nanotubes for lower electrode impedance and increased charge transfer, and (D) conductive polymers, such as PEDOT, to enhance communication across the tissue–electrode interface.

Alycia N. Galindo

David A. Frey Rubio

Marian H. Hettiaratchi