Gene-Hydrogel Microenvironment Regulates Extracellular Matrix Metabolism Balance in Nucleus Pulposus.

Wei Chen,Dandan Zheng,Hongbo Zhang,Yuhui Zhang,Hélder A Santos,Wenguo Cui,Hongxing Shen,Lianfu Deng,Hao Chen

doi:10.1002/advs.201902099

Abstract

Gene therapy provides an ideal potential treatment for intervertebral disk degeneration by delivering synthetic microRNAs (miRNAs) to regulate the gene expression levels. However, it is very challenging to deliver miRNAs directly, which leads to inactivation, low transfection efficiency, and short half‐life. Here, Agomir is loaded in hydrogel to construct a gene‐hydrogel microenvironment for regulating the synthesis/catabolism balance of the tissue extracellular matrix (ECM) to treat degenerative diseases. Agomir is a cholesterol‐, methylation‐, and phosphorothioate‐modified miRNA, which can mimic the function of miRNA to regulate the expression of the target gene. Agomir874 that mimics miRNA874 is synthesized to down regulate the expression of matrix metalloproteinases (MMPs) in nucleus pulposus (NP). At the same time, a polyethylene glycol (PEG) hydrogel is synthesized through Ag‐S coordination of 4‐arm PEG‐SH and silver ion solution, which has injectable, self‐healing, antimicrobial, degradable, and superabsorbent properties and matches perfectly with the mechanism of intervertebral disk. By delivering Agomir‐loaded PEG‐hydrogel to a degenerative intervertebral disk, a gene‐hydrogel microenvironment is constructed in situ, which reduces the expression of MMPs, regulates the synthesis/catabolism balance of ECM in the NP of the intervertebral disk, and improves the tissue microenvironment regeneration.

Highlights

By delivering Agomir-loaded polyethylene glycol (PEG)-hydrogel to a degenerative intervertebral disk, a gene-hydrogel microenvironment is constructed in situ, which reduces the expression of matrix metalloproteinases (MMPs), regulates the synthesis/catabolism and phosphorothioate-modified miRNA fragment, which can mimic the function of miRNAs to regulate the expression of target genes.[10]
By delivering an Agomir, synthesized by special chemical modification based on the structure of miRNA whose expression is reduced in Intervertebral disk degeneration (IVDD), the gene-hydrogel microenvironment is constructed in situ by intervertebral space injection of Agomir loaded in PEG-hydrogel
We demonstrated that Agomir874 based on the structure of miRNA874 can down-regulate the expression of MMPs, thereby regulating the metabolism balance of extracellular matrix (ECM) in nucleus pulposus (NP) and slowing the process of IVDD for the first time

Summary

Introduction

By delivering an Agomir, synthesized by special chemical modification based on the structure of miRNA whose expression is reduced in IVDD, the gene-hydrogel microenvironment is constructed in situ by intervertebral space injection of Agomir loaded in PEG-hydrogel. B) The Agomir@PEG was injected into the intervertebral space to construct the gene-hydrogel microenvironment. Www.advancedscience.com observed, and the addition of Agomir 874 did not affect the antimicrobial activity of PEG-hydrogels (Figure 2b).

Results

Conclusion