A stimuli-responsive hydrogel that targets myeloid differentiation primary response 88 signaling in the foreign body response.
Journal Article
Overview
abstract
Myeloid differentiation primary response protein 88 (MyD88) is an intracellular signaling molecule that is a central mediator of inflammation. MyD88 mediates inflammation in the foreign body response (FBR), a complex immune reaction triggered by implanted biomaterials that leads to fibrous encapsulation. Inhibiting MyD88 offers a promising approach to combat the FBR. A stimuli-responsive therapeutic poly(ethylene glycol) (PEG) hydrogel was developed to release a small molecule inhibitor of MyD88 (T6167923) when cleaved by matrix metalloproteinase 12 (MMP-12). MMP-12, also known as macrophage elastase, is produced primarily by macrophages, the immune cells that are responsible for the FBR. The therapeutic hydrogel was designed by modifying T6167923 with a free thiol (T6167923(SH)) enabling its immobilization into a hydrogel via a PEG spacer to increase its solubility once released and with a peptide linker PLGLEEA known to be sensitive to MMP-12. The bioactivity of free T6167923(SH) in solution was first confirmed in murine macrophages in vitro, leading to a dose-dependent inhibition of NF-κB activation and pro-inflammatory cytokine (IL-6 and TNF-α) production. Once tethered and released from the hydrogel, the released inhibitor is linked to the PEG spacer and the amino acid sequence PLG (i.e., Inhibitor-PEG-PLG). As MyD88 inhibition occurs intracellularly, cell uptake of the inhibitor was confirmed but the efficacy decreased with increasing length of PEG. Thus, a small PEG12 linker was chosen to design the therapeutic hydrogel. MMP-12 diffusion through the hydrogel network was confirmed, which successfully cleaved the MMP-sensitive sequence enabling release of a payload. The therapeutic hydrogel was subcutaneously implanted in mice, leading to a 50% decrease in the inflammatory cell layer thickness relative to the non-therapeutic PEG hydrogel control at day 7. By day 28, the thicknesses of the inflammatory cell layer and the fibrous capsule were reduced by 74% and 61%, respectively, relative to hydrogel implants without tethered inhibitor. In summary, this study demonstrates a promising novel therapeutic hydrogel that is capable of attenuating inflammation when triggered by macrophage elastase.
