Scaffolds to control inflammation and facilitate dental pulp regeneration

Abstract

In dentistry, the maintenance of a vital dental pulp is of paramount importance because teeth devitalized by root canal treatment may become more brittle and prone to structural failure over time. Advanced carious lesions can irreversibly damage the dental pulp by propagating a sustained inflammatory response throughout the tissue. Although the inflammatory response initially drives tissue repair, sustained inflammation has an enormously destructive effect on the vital pulp, eventually leading to total necrosis of the tissue and necessitating its removal. The implications of tooth devitalization have driven significant interest in the development of bioactive materials that facilitate the regeneration of damaged pulp tissues by harnessing the capacity of the dental pulp for self-repair. In considering the process by which pulpitis drives tissue destruction, it is clear that an important step in supporting the regeneration of pulpal tissues is the attenuation of inflammation. Macrophages, key mediators of the immune response, may play a critical role in the resolution of pulpitis because of their ability to switch to a proresolution phenotype. This process can be driven by the resolvins, a family of molecules derived from fatty acids that show great promise as therapeutic agents. In this review, we outline the importance of preserving the capacity of the dental pulp to self-repair through the rapid attenuation of inflammation. Potential treatment modalities, such as shifting macrophages to a proresolving phenotype with resolvins are described, and a range of materials known to support the regeneration of dental pulp are presented.

Keywords: Biomaterials; dental pulp; endodontics; inflammation; pulp regeneration; resolvins; tissue engineering.

Figure 1

Normal pulp contrasted with diseased pulp. In the normal pulp, odontoblasts are supported and renewed by a population of multipotent mesenchymal progenitor cells. This pool of cells can be drawn upon to regenerate pulp tissues and odontoblasts that are damaged by the formation of carious lesions or trauma. In the diseased pulp, bacterial biofilms form on the surface of the tooth, destroying the matrix of the enamel. When bacteria reach the fluid filled dentinal tubules, they rapidly spread through the dentin, enlarging the lesion and bringing the pulp in contact with LPS. LPS activated immune cells, for example macrophages, produce a number of inflammatory cytokines, causing widespread destruction of the pulpal tissues and impairing the recruitment and differentiation of the mesenchymal progenitor cells. Inflammation is therefore a significant barrier to dental pulp regeneration.

Figure 2

Macrophage polarization. Macrophages can switch between M₁ pro-inflammatory and M₂ pro-resolving phenotypes given appropriate stimuli. Bacterial LPS drives polarization into an M₁ phenotype and results in the production of a variety of pro-inflammatory cytokines, ultimately leading to pulp tissue damage. By contrast, various anti-inflammatory molecules such as Il-4, Il-13 and specialized pro-resolving lipid mediators such as the resolvins stimulate M₂ phenotype polarization. M₂ macrophages produce anti-inflammatory cytokines and a variety of growth factors, which in turn support tissue repair.

Figure 3

A: The chemical structure of a multidomain peptide (MDP), K₂(SL)₆K₂, which forms a facial amphiphile in water. The termini of the peptide consist of lysine residues, which are positively charged at physiological pH. B: Two MDPs align to form a ‘hydrophobic sandwich’ in order to minimize contact of the hydrophobic leucine side chains with the surrounding aqueous environment. C: Multiple hydrophobic sandwiches assemble to form nano-fibers, driven by the formation of hydrogen bonds between adjacent peptide backbones. Figures 3B and 3C created with PyMOL Molecular Graphics System, Version 1.6 Schrödinger, LLC.