Chen Hu, Wang Wanshun, Yang Yiming, Zhang Beichen, Li Zefeng, Chen Lingling, Tu Qiang, Zhang Tao, Lin Dingkun, Yi Honglei, Xia Hong, Lu Yao
The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China; Department of Orthopedics, General Hospital of Southern Theatre Command of PLA, Southern Medical University, Guangzhou, Guangdong, 510010, China.
The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510405, China; Department of Orthopedic Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
Biomaterials. 2025 May;316:122995. doi: 10.1016/j.biomaterials.2024.122995. Epub 2024 Dec 5.
Utilizing drug-loaded hydrogels to restore nerve conductivity emerges as a promising strategy in the treatment of spinal cord injury (SCI). However, many of these hydrogels fail to deliver drugs on demand according to the dynamic SCI pathological features, resulting in poor functional recovery. Inspired by the post-SCI microenvironments, here we report a time-sequential and controllable drug delivery strategy using an injectable hydrogel responsive to reactive oxygen species (ROS) and matrix metalloproteinases (MMPs). This strategy includes two steps: first, the hydrogel responds to ROS and releases nanodrugs to scavenge ROS, thereby mitigating inflammation and protecting neurons from oxidative stress in the initial SCI stages; second, the accumulation of MMPs triggers the release of vascular endothelial growth factor from nanodrugs to promote angiogenesis and neural stem cell differentiation in the late stage of SCI. In two clinically relevant SCI models, a single injection of the hydrogel led to an efficient structural and functional recovery of SCI 6 weeks after the intervention. We observed less inflammation, fibrosis, and cavities but more angiogenesis and neurons in the hydrogel-treated injured spinal cord region compared with the untreated animals. The hydrogel exhibits mechanical strength and conductivity comparable to natural spinal cord, facilitating its further clinical translation.
利用载药水凝胶恢复神经传导性成为治疗脊髓损伤（SCI）的一种有前景的策略。然而，许多这类水凝胶无法根据SCI动态病理特征按需给药，导致功能恢复不佳。受SCI后微环境的启发，我们在此报告一种利用对活性氧（ROS）和基质金属蛋白酶（MMPs）有响应的可注射水凝胶的时序可控药物递送策略。该策略包括两个步骤：首先，水凝胶对ROS作出响应并释放纳米药物以清除ROS，从而在SCI初始阶段减轻炎症并保护神经元免受氧化应激；其次，MMPs的积累触发纳米药物中血管内皮生长因子的释放，以促进SCI后期的血管生成和神经干细胞分化。在两种临床相关的SCI模型中，单次注射水凝胶可使干预后6周的SCI实现有效的结构和功能恢复。与未治疗的动物相比，我们观察到在水凝胶治疗的脊髓损伤区域炎症、纤维化和空洞较少，但血管生成和神经元较多。该水凝胶表现出与天然脊髓相当的机械强度和传导性，有助于其进一步临床转化。
