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

安全有效刺激大鼠颈脊髓的先进材料

• 批准号: 9035746
• 负责人: Jason Brant Carmel
• 金额: $ 27.85万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035746
• 关键词: Address; Animal Model; Animals; Basic Science; Blood - brain barrier anatomy; Brain; Cervical; Cervical spinal cord structure; Cervical spine; Chronic; Clinical; Clinical Data; Corticospinal Tracts; Devices; Dorsal; Dura Mater; Eating; Electric Stimulation; Electrodes; Environment; Exhibits; Food; Food Handling; Forelimb; Future; Generations; Head Movements; Heating; High temperature of physical object; Human; Impairment; Implant; Inflammation; Injury; Laboratories; Lead; Leg; Lesion; Lumbar spinal cord structure; Measures; Methods; Mission; Modeling; Motor; Motor Cortex; Movement; Muscle; Myelin; Neurologic; Neurostimulation procedures of spinal cord tissue; Paralysed; Pattern; Polymers; Public Health; Publishing; Rattus; Reaction; Recovery of Function; Research; Shapes; Silicone Elastomers; Spinal; Spinal Cord; Spinal cord injury; Staining method; Stains; Structure; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Training; Vertebral column; aqueous; arm movement; astrogliosis; awake; base; central nervous system injury; design; dexterity; disability; efficacy testing; electric impedance; epidural space; flexibility; hand rehabilitation; implantation; improved; inflammatory marker; injured; injury and repair; innovation; macrophage; materials science; migration; motor control; motor function recovery; motor recovery; parylene C; pre-clinical; prototype; public health relevance; relating to nervous system; research study; response; safety testing; spinal cord and brain injury; spinal cord repair; tool; translational study

 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.

 描述（由申请人提供）：腰部脊髓的刺激使得大鼠和现在瘫痪的人能够再次移动他们的腿，当我们试图确定其机制时，这种用脊髓硬膜外刺激的复活也可以应用于手部功能的恢复。在这种疗法中，我们受到对大鼠颈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，颈髓会随着头部运动而旋转和弯曲，因此阵列必须柔软。然而，电极阵列也需要坚硬，以便将其放置在薄薄的硬膜外间隙中。目前为腰椎脊髓设计的阵列是由相对坚硬的聚对二甲苯-C制成的，这使得它们可能会损伤椎间盘。我们开发了一种由软化聚合物制成的阵列，该阵列在干燥时在室温下坚硬，然后在植入潮湿和温暖的身体环境时变得像硅橡胶一样柔软。软化在高温下，这些阵列的电极采用光刻技术，因此可以实现高精度，我们认为软化脊柱刺激器在刺激脊柱回路方面比聚对二甲苯-C 阵列更安全、更有效。 为了测试阵列的安全性，我们将训练老鼠进行对前爪损伤敏感的食物操作任务。我们将给一半的老鼠植入软化聚合物阵列，另一半植入聚对二甲苯-C 阵列。我们将在植入后测量老鼠的前爪灵活性。初步研究表明，将阵列植入颈脊髓背侧的硬膜外腔后，大鼠的脊髓中没有炎症和损伤的组织学标记。阵列呈现出底层脊髓的形状，炎症组织标记表明脊髓没有损伤。为了测试阵列的功效，我们将测量电极阻抗和引起损伤所需的刺激强度。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，我们将测试配对大脑的能力。和脊髓刺激以促进运动恢复我们预计软化聚合物阵列将保持紧密的神经界面并抵抗损伤，因为它们具有柔韧性，这将导致脊髓回路更有效的长期激活和比聚对二甲苯更好的功能恢复。因此，我们打算填补刺激颈髓的技术空白。 这个工具可以极大地促进我们对恢复瘫痪患者运动能力的重要疗法的理解。