Luyu Wang,Jinrui Li,Dan Zhang,Shanshan Ma,Junni Zhang,Feng Gao,Fangxia Guan,Minghao Yao
Recently, in situ formed injectable hydrogels have shown great potential in biomedical applications as therapeutic implants or carriers in tissue repair and regeneration. They can seal or fill the damaged tissue to function as cell/drug delivery vehicle perfectly through a minimally invasive surgical procedure. In this study, hyaluronic acid (HA) is functionalized with tyramine to produce an injectable hydrogel dual-enzymatically crosslinked by horseradish peroxidase (HRP) and galactose oxidase (GalOX). This new tyramine-modified HA (HT) hydrogel exhibited good injectability, favorable cytocompatibility to mice bone marrow mesenchymal stem cells (BMSCs), and low inflammatory response verified by cytotoxicity assay in vitro and an in situ subcutaneous injection study in vivo. In addition, the gelation time, swelling behavior, and degradation rate of the HT hydrogel could be adjusted through varying the concentrations of HT and GalOX in a certain range. These encouraging results suggest that such biocompatible HT hydrogels might have potential application in three-dimensional stem cell culture and tissue engineering.
Recently, an advanced stem cell and tissue engineering approach has been recognized as an emerging and fascinating strategy to promote neural repair in spinal cord injury (SCI). Hydrogels can be properly engineered to encapsulate cells, enhance cell viability and neural differentiation, and provide the advantage of flexible adaptation to irregular defects. In this study, a dual-enzymatically cross-linked gelatin hydrogel with hydrogen horseradish peroxidase (HRP) and galactose oxidase (GalOx) was proposed to combine human umbilical cord mesenchymal stem cells (hUC-MSCs) for facilitating nerve regeneration post-SCI. In vitro, hUC-MSCs in this 3D gelatin hydrogel displayed good viability, proliferation, and neuronal differentiation. To further evaluate the neural regeneration effect of hUC-MSCs loaded into gelatin hydrogels in vivo, a clinically-relevant and force-controlled contusion model of mouse spinal cords was established. We found that implantation of a hydrogel loaded with hUC-MSCs significantly promoted the motor function recovery evaluated by Basso Mouse Scale (BMS) and footprint tests. Further histological analysis showed that the hydrogel and hUC-MSC combined transplantation dramatically decreased inflammation, inhibited apoptosis and promoted neurogenesis. Overall, implantation of this dual-enzymatically cross-linked and MSC-laden 3D gelatin hydrogel is a promising therapeutic strategy for SCI treatment.
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