Zhang Wen, Liu Yang, Wu Yu, Wang Zhicun, Liu Xiyu, Hu Qinsheng, Yang Li, Hu Cheng, Wang Yunbing
National Engineering Research Center for Biomaterials& College of Biomedical Engineering, Sichuan University, China.
Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, China.
Biomaterials. 2025 Aug;319:123217. doi: 10.1016/j.biomaterials.2025.123217. Epub 2025 Feb 25.
Millions of individuals worldwide suffer from ischemic stroke (IS). The focal hypo-perfused brain brings about hostile pathological environment, which further restricts endogenous neurogenesis post-stroke. In this work, we report an ROS-triggered hyaluronic acid (HA) and platelet lysates (pls) composite biomimetic hydrogel soft scaffold (pls gel) encapsulating matrix metalloproteinase (MMPs)-responsive triglycerol monostearate nanoparticles loaded with docosahexaenoic acid (TGMS@DHA, TD). Pls gel was chosen to be the hydrogel matrix to mimic brain extracellular matrix (ECM) to provide physical support for cell infiltration and accelerate angiogenesis as a growth factors (GFs) box. The borate ester bonded hydrogel could respond to reactive oxygen species and relieve oxidative stress. The loaded TD nanoparticles could be enzymatically cleaved by overexpressed MMPs in cerebral infarcted site, which could improve the adverse effects triggered by overexpressed MMPs. DHA with rich unsaturated bonds was proven that not only inhibit neuroinflammatory and oxidative stress, but also take part in promote neurogenesis. In brief, the ROS-triggered hydrogel scaffold pls gel@TD created an optimized microenvironment to manipulate the survival and differentiation of neural stem cells and promote endogenous regenerative repair processes. The in vitro results exhibited the biomimetic soft scaffold eliminated oxygen-glucose deprivation-derived free radical, saved mitochondrial dysfunction, reduced neuronal apoptosis, and promoted neovascularization. In the mice focal IS model, the biomimetic hydrogel scaffold regulated pathological environment in the ischemic site and induced migration and differentiation of endogenous neural stem cells, consequently relieved neuron ischemia injury. During the long-term observation, the hydrogel improved mice neurobehavioral functions. In conclusion, the hydrogel soft scaffold pls gel@TD was demonstrated to have promising therapeutic effects on remodeling pathological environment by transforming the hostile state into a pro-regenerative one in the infarct site, consequently promoting endogenous regenerative repair processes.
全球数以百万计的人患有缺血性中风（IS）。局部灌注不足的大脑会产生不利的病理环境，这进一步限制了中风后的内源性神经发生。在这项工作中，我们报道了一种由活性氧（ROS）触发的透明质酸（HA）和血小板裂解物（pls）复合仿生水凝胶软支架（pls凝胶），其包裹了负载二十二碳六烯酸的基质金属蛋白酶（MMPs）响应性单硬脂酸甘油酯纳米颗粒（TGMS@DHA，TD）。选择pls凝胶作为水凝胶基质来模拟脑细胞外基质（ECM），为细胞浸润提供物理支持，并作为生长因子（GFs）盒加速血管生成。硼酸酯键合水凝胶可对活性氧作出反应并减轻氧化应激。负载的TD纳米颗粒可被脑梗死部位过表达的MMPs酶解，这可以改善过表达的MMPs引发的不良反应。富含不饱和键的二十二碳六烯酸不仅被证明可以抑制神经炎症和氧化应激，还参与促进神经发生。简而言之，ROS触发的水凝胶支架pls凝胶@TD创造了一个优化的微环境，以调控神经干细胞的存活和分化，并促进内源性再生修复过程。体外结果表明，这种仿生软支架消除了氧-葡萄糖剥夺产生的自由基，挽救了线粒体功能障碍，减少了神经元凋亡，并促进了新血管形成。在小鼠局灶性IS模型中，这种仿生水凝胶支架调节了缺血部位的病理环境，诱导内源性神经干细胞迁移和分化，从而减轻神经元缺血损伤。在长期观察中，水凝胶改善了小鼠的神经行为功能。总之，水凝胶软支架pls凝胶@TD被证明在通过将梗死部位的不利状态转变为促再生状态来重塑病理环境方面具有有前景的治疗效果，从而促进内源性再生修复过程。
