Advanced materials for safe and effective stimulation of the rat cervical spinal cord

 描述(申请人提供)：刺激腰椎脊髓使大鼠和现在瘫痪的人可以再次活动他们的腿。这种脊髓硬膜外刺激的复苏也可用于手功能的恢复。当我们试图确定这种疗法的机制时，我们受到了对大鼠颈脊髓施加刺激的技术的限制，颈髓是中枢神经系统损伤和修复的重要模型。颈髓随着头部的移动而旋转和弯曲，因此阵列必须灵活。然而，电极阵列也需要坚硬，以便将其放置到薄薄的硬膜外间隙中。目前为腰椎脊髓设计的阵列是由对二甲苯-C制成的，这种材料相对较硬，因此很可能会损伤颈髓或与下面的硬脑膜失去接触。我们已经开发出一种由软化聚合物制成的阵列，这种聚合物在室温下干燥时会变得僵硬，然后在植入潮湿和温暖的身体环境时就会变得像硅橡胶一样柔软。除了在高温下软化外，这些阵列还具有采用光刻技术图案化的电极，从而实现了高精度。我们假设，软化脊髓刺激器在刺激脊髓环路时将比Parene-C阵列更安全和更有效。至 测试阵列的安全性，我们将训练大鼠进行一项对前爪损伤敏感的食物操作任务。我们将给一半的大鼠植入软化聚合物阵列，一半植入对二甲苯-C阵列。我们将测量植入后的前爪灵巧度。大鼠将被灌流，并检查脊髓的炎症和损伤的组织学标志。初步研究表明，将该阵列植入大鼠颈脊髓背侧硬膜外间隙后，对大鼠足爪功能无损害。这些阵列的形状类似于下面的脊髓，炎症的组织标志物表明脊髓没有损伤。为了测试阵列的有效性，我们将在每天8周的刺激中测量电极阻抗和引起肌肉反应所需的刺激强度-脊髓阈值。我们还将测试植入的阵列调节肌肉对运动皮质刺激的反应的能力，正如我们在初步结果中所展示的那样。最后，我们将测试成对的脑和脊髓刺激促进皮质脊髓束损伤后运动功能恢复的能力。我们预计，软化的聚合物阵列将保持紧密的神经接口，并将抵抗损害，因为它们是灵活的。这将导致更有效的脊髓电路的长期激活和更好的功能恢复比对二甲苯-C阵列。因此，我们打算填补刺激颈髓的技术空白 清醒的、行为正常的老鼠。这一工具可以极大地促进我们对一种恢复瘫痪患者运动的重要疗法的理解。

 DESCRIPTION (provided by applicant): Stimulation of the lumbar spinal cord allows rats and now people with paralysis to move their legs again. Such reanimation with spinal epidural stimulation can also be applied for recovery of hand function. As we seek to determine the mechanisms of this therapy, we are limited by the technology to apply stimulation to the cervical spinal cord of the rat, an important model for CNS injury and repair. The cervical spinal cord rotates and bends with head movement, so arrays must be supple. However, the electrode array also needs to be stiff, in order to place it into the thin epidural space. Current arrays, designed for the lumbar spinal cord, are made of Parylene-C, which is relatively stiff, making them likely to injure the cervical cord or to lose contact with the underlying dura mater. We have developed an array made of a softening polymer that is stiff at room temperature when dry and then becomes as supple as silicone rubber when implanted into the wet and warm body environment. In addition to softening at high temperatures, the arrays have electrodes patterned with photolithography, which allows high precision. We hypothesize that softening spinal stimulators will be safer and more effective at exciting spinal circuits than Parylene-C arrays. To test the safety of the arrays we will train rats on a food manipulation task that is sensitive for forepaw impairment. We will implant half of rats with softening polymer arrays and half with Parylene-C arrays. We will measure forepaw dexterity after implantation. Rats will be perfused, and the spinal cords examined for histological markers of inflammation and injury. Preliminary studies show that after the arrays are implanted in the epidural space dorsal to the cervical spinal cord, rats have no impairment in paw function. The arrays take the shape of the underlying spinal cord, and tissue markers of inflammation indicate no damage to the spinal cord. To test the efficacy of the arrays, we will measure electrode impedance and the stimulation intensity necessary to cause a muscle response-the spinal threshold-over 8 weeks of daily stimulation. We will also test the ability of implanted arrays to modulate muscle responses to motor cortex stimulation, as we demonstrate in our preliminary results. Finally, we will test the ability of paired brain and spinal cord stimulation to promote recovery of motor function after injury to the corticospinal tract. We expect that the softening polymer arrays will maintain a tight neural interface and will resist damage because they are flexible. This will resul in more effective long-term activation of spinal circuits and better functional recovery than Parylene-C arrays. Thus, we intend to fill a gap in technology for stimulating the cervical cord of the awake, behaving rat. This tool could dramatically accelerate our understanding of an important therapy to restore movement in people with paralysis.