SCIENCE TIMES E-dura: A Novel Neural Interface Device
S
pinal cord stimulators are bulky and stiff and conduct electric signals with low spatial resolution compared with the in vivo neural tissue with which they are designed to interact. Generally, neural interface devices resemble car engine parts more than human anatomic components. This structural disparity limits the degree to which such devices interact with the nervous system and prevents efficacious implementation of new technology capable of high-resolution monitoring and modulation of neurons. In addition, scar formation at the contact sites limits the efficacy of these implants over time. Thus, bioengineers are challenged to produce a neural interface device that conforms to the mechanical characteristics of living tissue. Electronic dura mater, or e-dura, as discussed recently in an article published in Science,1 demonstrates potential in achieving this goal (Figure 1). As the name implies, e-dura was designed to mechanically mimic the dura mater surrounding the spinal cord. It is composed of a highly elastic silicone substrate measuring 120 mm in thickness. Soft platinum-silicone electrodes and a microchannel fluid delivery system are embedded in this substrate. The device is designed to be placed in the subdural space, and it is capable of electric
stimulation or recording, as well as delivery of drugs. The designers tested the effect of intrathecal implantation of e-dura on a rat model. For comparison, a group of rats received a stiffer implant corresponding to the properties of most current neural implants, and another group underwent sham surgery. After implantation or sham surgery, the motor function of the animals was systematically assessed over the course of 6 weeks. The rats with stiff implants showed marked difficulty in ambulation, foot control, and balance, whereas the e-dura group performed similarly to the sham group. Thus, long-term implantation of e-dura did not result in deterioration of spinal cord function. Six weeks after implantation, the rat spinal cords were removed and examined macroscopically, microscopically, and by 3-dimensional reconstruction. The stiff implants caused significant deformation of the cord and a substantial inflammatory response indicated by accumulation of activated astrocytes and microglia. Conversely, cord sections from the e-dura group were similar to those from the sham group (Figure 2). These results indicate that the mechanical properties of the e-dura allow it to conform to and move with the spinal cord without producing compression or inciting a significant inflammatory response. To further illustrate this point, the designers constructed a spinal cord model using hydrogel surrounded by a thin silicone tube mimicking dura. When placed into the model, the stiff
implant produced compression of the synthetic cord, which worsened with bending. The e-dura did not cause any deformation of the cord at rest or with motion. This again demonstrates the ability of e-dura to integrate into the subdural space without disruption of normal surrounding tissues. Next, the capacity of e-dura to electrically stimulate and record neurons and to deliver drugs was tested. E-dura implanted over rat spinal cords was used to produce electrospinograms. The motor cortex of the brain was stimulated, and e-dura accurately recorded the descending motor commands carried by spinal neurons. Stimulation of the sciatic nerve demonstrated that the device also was capable of recording ascending sensory signals. Finally, the capacity of e-dura to stimulate neurons was investigated. Rats were rendered permanently paraplegic by contusion of the thoracic cord. E-dura was then placed over the cord below the level of injury. Continuous electric stimulation was delivered to the lateral aspect of the spinal cord at the L2 and S1 levels. Stimulation was restricted to these segments and differentially modulated between left and right sides of the cord. Additionally, serotonergic 5HT1A/7 and 5HT2 agonists were delivered to the cord via the fluid delivery channel of the device. The coadministration of electric and serotonergic chemical stimulation allowed rats to walk with their hind legs while supported in a harness (Figure 3). This achievement demonstrates the ability of e-dura to effectively interact with neural tissue.
Figure 1. Optical image of an implant, and scanning electron micrographs of the gold film and the platinum-silicone composite. From Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163. Reprinted with permission from AAAS.
NEUROSURGERY
VOLUME 76 | NUMBER 6 | JUNE 2015 | N9
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
Figure 2. Biointegration. A, hind-limb kinematics during ladder walking 6 weeks after implantation. Bar plots reporting mean percentage of missed steps, averaged per animal onto the rungs of the ladder (n ¼ 8 trials per rat, n ¼ 4 rats per group). B, 3-dimensional spinal cord reconstructions, including enhanced views, 6 weeks after implantation. Arrowheads indicate the entrance of the implant into the subdural space. Bar plots reporting mean values of spinal cord circularity index (4p · area/perimeter2). C, photographs showing microglia (Iba1) and astrocytes (glial fibrillary acidic protein [GFAP]) staining reflecting neuroinflammation. Scale bars: 30 mm. Heat maps and bar plots showing normalized astrocyte and microglia density. D, spinal cord model scanned using micro–computed tomography without and with a soft or stiff implant. E-dura implant is 120 mm thick. The red line indicates the stiff implant (25 mm thick), which is not visualized because of scanner resolution. Plot reporting local longitudinal strain as a function of global applied strain. Statistical test: Kruskal-Wallis 1-way analysis of variance (*P , .05; **P , .01; error bars: SEM). From Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163. Reprinted with permission from AAAS.
E-dura represents a step toward the engineering of more biocompatible implants. Although the human in vivo response remains unproven, this first-generation technology represents a redirection in industry-driven research efforts that may have implications for functional and spinal neurosurgery.
Figure 3. Recording without and with electrochemical stimulation during bipedal locomotion under robotic support after 3 weeks of rehabilitation. Stick diagram decompositions of hind-limb movements are shown, together with leg muscle activity and hind-limb oscillations. Modified from Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163. Reprinted with permission from AAAS.
N10 | VOLUME 76 | NUMBER 6 | JUNE 2015
Michael Wang, MD John Serak, MD University of Miami Miller School of Medicine Jackson Memorial Hospital Miami, Florida
REFERENCE 1. Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163.
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
S
pinal cord stimulators are bulky and stiff and conduct electric signals with low spatial resolution compared with the in vivo neural tissue with which they are designed to interact. Generally, neural interface devices resemble car engine parts more than human anatomic components. This structural disparity limits the degree to which such devices interact with the nervous system and prevents efficacious implementation of new technology capable of high-resolution monitoring and modulation of neurons. In addition, scar formation at the contact sites limits the efficacy of these implants over time. Thus, bioengineers are challenged to produce a neural interface device that conforms to the mechanical characteristics of living tissue. Electronic dura mater, or e-dura, as discussed recently in an article published in Science,1 demonstrates potential in achieving this goal (Figure 1). As the name implies, e-dura was designed to mechanically mimic the dura mater surrounding the spinal cord. It is composed of a highly elastic silicone substrate measuring 120 mm in thickness. Soft platinum-silicone electrodes and a microchannel fluid delivery system are embedded in this substrate. The device is designed to be placed in the subdural space, and it is capable of electric
stimulation or recording, as well as delivery of drugs. The designers tested the effect of intrathecal implantation of e-dura on a rat model. For comparison, a group of rats received a stiffer implant corresponding to the properties of most current neural implants, and another group underwent sham surgery. After implantation or sham surgery, the motor function of the animals was systematically assessed over the course of 6 weeks. The rats with stiff implants showed marked difficulty in ambulation, foot control, and balance, whereas the e-dura group performed similarly to the sham group. Thus, long-term implantation of e-dura did not result in deterioration of spinal cord function. Six weeks after implantation, the rat spinal cords were removed and examined macroscopically, microscopically, and by 3-dimensional reconstruction. The stiff implants caused significant deformation of the cord and a substantial inflammatory response indicated by accumulation of activated astrocytes and microglia. Conversely, cord sections from the e-dura group were similar to those from the sham group (Figure 2). These results indicate that the mechanical properties of the e-dura allow it to conform to and move with the spinal cord without producing compression or inciting a significant inflammatory response. To further illustrate this point, the designers constructed a spinal cord model using hydrogel surrounded by a thin silicone tube mimicking dura. When placed into the model, the stiff
implant produced compression of the synthetic cord, which worsened with bending. The e-dura did not cause any deformation of the cord at rest or with motion. This again demonstrates the ability of e-dura to integrate into the subdural space without disruption of normal surrounding tissues. Next, the capacity of e-dura to electrically stimulate and record neurons and to deliver drugs was tested. E-dura implanted over rat spinal cords was used to produce electrospinograms. The motor cortex of the brain was stimulated, and e-dura accurately recorded the descending motor commands carried by spinal neurons. Stimulation of the sciatic nerve demonstrated that the device also was capable of recording ascending sensory signals. Finally, the capacity of e-dura to stimulate neurons was investigated. Rats were rendered permanently paraplegic by contusion of the thoracic cord. E-dura was then placed over the cord below the level of injury. Continuous electric stimulation was delivered to the lateral aspect of the spinal cord at the L2 and S1 levels. Stimulation was restricted to these segments and differentially modulated between left and right sides of the cord. Additionally, serotonergic 5HT1A/7 and 5HT2 agonists were delivered to the cord via the fluid delivery channel of the device. The coadministration of electric and serotonergic chemical stimulation allowed rats to walk with their hind legs while supported in a harness (Figure 3). This achievement demonstrates the ability of e-dura to effectively interact with neural tissue.
Figure 1. Optical image of an implant, and scanning electron micrographs of the gold film and the platinum-silicone composite. From Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163. Reprinted with permission from AAAS.
NEUROSURGERY
VOLUME 76 | NUMBER 6 | JUNE 2015 | N9
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
Figure 2. Biointegration. A, hind-limb kinematics during ladder walking 6 weeks after implantation. Bar plots reporting mean percentage of missed steps, averaged per animal onto the rungs of the ladder (n ¼ 8 trials per rat, n ¼ 4 rats per group). B, 3-dimensional spinal cord reconstructions, including enhanced views, 6 weeks after implantation. Arrowheads indicate the entrance of the implant into the subdural space. Bar plots reporting mean values of spinal cord circularity index (4p · area/perimeter2). C, photographs showing microglia (Iba1) and astrocytes (glial fibrillary acidic protein [GFAP]) staining reflecting neuroinflammation. Scale bars: 30 mm. Heat maps and bar plots showing normalized astrocyte and microglia density. D, spinal cord model scanned using micro–computed tomography without and with a soft or stiff implant. E-dura implant is 120 mm thick. The red line indicates the stiff implant (25 mm thick), which is not visualized because of scanner resolution. Plot reporting local longitudinal strain as a function of global applied strain. Statistical test: Kruskal-Wallis 1-way analysis of variance (*P , .05; **P , .01; error bars: SEM). From Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163. Reprinted with permission from AAAS.
E-dura represents a step toward the engineering of more biocompatible implants. Although the human in vivo response remains unproven, this first-generation technology represents a redirection in industry-driven research efforts that may have implications for functional and spinal neurosurgery.
Figure 3. Recording without and with electrochemical stimulation during bipedal locomotion under robotic support after 3 weeks of rehabilitation. Stick diagram decompositions of hind-limb movements are shown, together with leg muscle activity and hind-limb oscillations. Modified from Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163. Reprinted with permission from AAAS.
N10 | VOLUME 76 | NUMBER 6 | JUNE 2015
Michael Wang, MD John Serak, MD University of Miami Miller School of Medicine Jackson Memorial Hospital Miami, Florida
REFERENCE 1. Minev IR, Musienko P, Hirsch A, et al. Electronic dura mater for long-term multimodal neural interfaces. Science. 2015;347(6218):159-163.
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
