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

 描述（由申请人提供）：腰椎脊髓的刺激允许大鼠和现在的瘫痪患者再次移动腿。这种用脊髓硬膜外刺激的复苏也可以应用于手功能的恢复。当我们试图确定这种疗法的机制时，我们受到对大鼠颈髓施加刺激的技术的限制，这是CNS损伤和修复的重要模型。颈部脊髓会随着头部的移动而旋转和弯曲，因此阵列必须柔软。然而，电极阵列还需要是刚性的，以便将其放置到薄的硬膜外腔中。目前设计用于腰椎脊髓的阵列由Parylene-C制成，Parylene-C相对较硬，使得它们可能损伤颈髓或与下面的硬脑膜失去接触。我们开发了一种由软化聚合物制成的阵列，该聚合物在干燥时在室温下是刚性的，然后在植入潮湿和温暖的身体环境中时变得像硅橡胶一样柔软。除了在高温下软化之外，阵列还具有通过光刻形成图案的电极，这允许高精度。我们假设软化脊髓刺激器在刺激脊髓回路方面比Parylene-C阵列更安全、更有效。到 为了测试阵列的安全性，我们将训练大鼠进行对前爪损伤敏感的食物操作任务。我们将在一半大鼠中植入软化聚合物阵列，另一半植入Parylene-C阵列。我们将在植入后测量前爪灵活性。将对大鼠进行灌注，并检查脊髓的炎症和损伤的组织学标志物。初步研究表明，将阵列植入颈髓背侧硬膜外腔后，大鼠的爪功能没有受损。这些阵列采用了下面脊髓的形状，炎症的组织标记表明脊髓没有损伤。为了测试阵列的功效，我们将在8周的每日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。我们还将测试植入阵列调节肌肉对运动皮层刺激的反应的能力，正如我们在初步结果中所证明的那样。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，软化聚合物阵列将保持紧密的神经界面，并将抵抗损害，因为它们是灵活的。这将导致比Parylene-C阵列更有效的脊髓回路的长期激活和更好的功能恢复。因此，我们打算填补技术上的空白， 一只清醒的老鼠这个工具可以大大加速我们对一种重要疗法的理解，以恢复瘫痪患者的运动。

 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.