Department of Forensic Medicine, School of Basic Medicine and Biological Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China.
Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou 215123, China; Department of Orthopedics, Suzhou BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Suzhou, China.
Acta Biomater. 2022 Dec;154:259-274. doi: 10.1016/j.actbio.2022.11.021. Epub 2022 Nov 17.
Traumatic brain injury (TBI) remains the major cause of disability and mortality worldwide due to the persistent neuroinflammation and neuronal death induced by TBI. Among them, pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Inhibition of neuroinflammation and pyroptosis is considered a possible strategy for the treatment of TBI. In our previous study, exogenous hydrogen sulfide(HS) exerted a neuroprotective effect after TBI. Here, we developed a surface-fill HS-releasing silk fibroin (SF) hydrogel (HS@SF hydrogel) to achieve small-dose local administration and avoid volatile and toxic side effects. We used a controlled cortical impact (CCI) to establish a mild TBI model in mice to examine the effect of HS@SF hydrogel on TBI-induced pyroptosis. We found that HS@SF hydrogel inhibited the expression of HS synthase in neurons after TBI and significantly inhibited TBI-induced neuronal pyroptosis. In addition, immunofluorescence staining results showed that the necroptosis protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1) partially colocalized with the pyroptosis protein Gasdermin D (GSDMD) in the same cells. HS@SF hydrogel can also inhibit the expression of the necroptosis protein. Moreover, HS@SF hydrogel also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of HS@SF hydrogel was further confirmed by wire-grip test, open field test, Morris water maze, beam balance test, radial arm maze, tail suspension, and forced swimming test. Lastly, we also measured spared tissue volume, reactive astrocytes and activated microglia to demonstrate HS@SF hydrogel impacts on long-term prognosis in TBI. Our study provides a new theoretical basis for the treatment of HS after TBI and the clinical application of HS@SF hydrogel. STATEMENT OF SIGNIFICANCE: Silk fibroin (SF) hydrogel controls the release of hydrogen sulfide (HS) to inhibit neuronal pyroptosis and neuroinflammation in injured brain tissue. In this study, we synthesized a surface-fill HS-releasing silk fibroin hydrogel, which could slowly release HS to reshape the homeostasis of endogenous HS in injured neurons and inhibit neuronal pyroptosis in a mouse model of traumatic brain injury. Meanwhile, HS@SF hydrogel could alleviate brain edema and the degree of neurodegeneration, improve motor dysfunction, anxious behavior and memory impairment caused by TBI, reduce tissue loss and ameliorate neuroinflammation. Our study provides a new theoretical basis for the treatment of HS after TBI and the clinical application of HS@SF hydrogel.
创伤性脑损伤（TBI）仍然是全球残疾和死亡的主要原因，这是由于 TBI 引起的持续神经炎症和神经元死亡。其中，细胞焦亡是一种由炎症信号触发的特定类型的程序性细胞死亡（PCD），在 TBI 后的病理过程中起着重要作用。抑制神经炎症和细胞焦亡被认为是治疗 TBI 的一种可能策略。在我们之前的研究中，外源性硫化氢（HS）在 TBI 后发挥了神经保护作用。在这里，我们开发了一种表面填充 HS 释放丝素（SF）水凝胶（HS@SF 水凝胶），以实现小剂量局部给药并避免挥发性和毒性副作用。我们使用皮质控制冲击（CCI）在小鼠中建立轻度 TBI 模型，以检查 HS@SF 水凝胶对 TBI 诱导的细胞焦亡的影响。我们发现，HS@SF 水凝胶抑制了 TBI 后神经元中 HS 合酶的表达，并显著抑制了 TBI 诱导的神经元细胞焦亡。此外，免疫荧光染色结果表明，坏死蛋白受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）与细胞焦亡蛋白 Gasdermin D（GSDMD）在同一细胞中部分共定位。HS@SF 水凝胶还可以抑制坏死蛋白的表达。此外，HS@SF 水凝胶还可减轻 TBI 急性期的脑水肿和神经退行性程度。HS@SF 水凝胶的神经保护作用通过线夹试验、旷场试验、Morris 水迷宫、平衡棒试验、放射臂迷宫、悬尾和强迫游泳试验进一步得到证实。最后，我们还测量了剩余组织体积、反应性星形胶质细胞和激活的小胶质细胞，以证明 HS@SF 水凝胶对 TBI 的长期预后的影响。我们的研究为 TBI 后 HS 的治疗和 HS@SF 水凝胶的临床应用提供了新的理论依据。
丝素（SF）水凝胶控制硫化氢（HS）的释放，以抑制损伤脑组织中神经元的细胞焦亡和神经炎症。在这项研究中，我们合成了一种表面填充 HS 释放丝素水凝胶，它可以缓慢释放 HS，重塑损伤神经元内内源性 HS 的内稳态，并抑制创伤性脑损伤小鼠模型中的神经元细胞焦亡。同时，HS@SF 水凝胶可减轻脑水肿和神经退行性程度，改善 TBI 引起的运动功能障碍、焦虑行为和记忆障碍，减少组织损失，改善神经炎症。我们的研究为 TBI 后 HS 的治疗和 HS@SF 水凝胶的临床应用提供了新的理论依据。
