Nerve regeneration following spinal cord injury using matrix metalloproteinase-sensitive, hyaluronic acid-based biomimetic hydrogel scaffold containing brain-derived neurotrophic factor

摘要

Spinal cord injury leads to the permanent loss of motor and sensory function in the body. To enhance spinal cord regeneration, we used a hyaluronic acid-based hydrogel as a three-dimensional biomimetic scaffold for peptides and growth factors. Three components were used to provide guidance cues: a matrix metalloproteinase peptide crosslinker, an IKVAV (Ile- Lys-Val-Ala-Val) peptide derived from laminin, and brain-derived neurotrophic factor (BDNF). Human mesenchymal stem cells (hMSCs) were cultured in hydrogels in vitro for 10 days to induce neuronal differentiation of hMSCs. Based on gene-expression data, the matrix metalloproteinase-sensitive peptide, IKVAV peptide, and BDNF were critical in the differentiation of hMSCs. Remodeling activity was found to be a key factor in guiding neural differentiation of stem cells. To test this approach in vivo, we used the spinal cord injured rat model and five different hydrogel compositions. Samples were injected into the intrathecal space, and animals were monitored for 6 weeks. Compared to all other groups, animals injected with BDNF-containing hydrogels showed the greatest improvement on locomotive tests (Basso-Beattie-Bresnahan score) during the initial stage after injury. These results suggest that hyaluronic acid-based hydrogels containing IKVAV and BDNF create microenvironments that foster differentiation of stem cells along the neural cell lineage, and they could be used to facilitate nerve regeneration after spinal cord injury.