Spinal intradural electrodes:opportunities,challenges and translation to the clinic

Bruce Harland,Chien Yew Kow,Darren Svirskis

Damage to the spinal cord disrupts the electrically active nerve cells which normally transmit afferent and efferent signals,resulting in loss of motor,sensory,and autonomic functions.Potential treatments for spinal cord injury utilizing implanted spinal electrodes can be broadly classified into three different categories.The first of these approaches is “spinal stimulation” where electrodes,usually positioned above the level of injury,provide electrical stimulation to target and disrupt pain signals before they reach the brain.The second approach uses “activity-dependent neuro-technologies”,in which electrodes positioned below the level of injury initiate a complex spatiotemporal pattern of stimulation at the lumbar spinal cord to generate a walking gait in the limbs (Minev et al.,2015;Wagner et al.,2018).The third treatment approach has been coined “electroceuticals”,in which a pair of electrodes positioned close to and either side of a spinal cord injury site generate a low-frequency electric field to promote regrowth and direct axons to reconnect across the damaged region(Shapiro,2014).Most research studies or clinical applications utilizing these approaches use the epidural placement of the electrodes,in which the electrodes are placed in the epidural space (Figure 1).In contrast,our research group is developing an implant to deliver electroceutical treatments designed to be inserted underneath the dura mater,which is referred to as intradural or subdural positioning (Harland et al.,2022;Figure 1).We are currently using this implant to test different electrical field treatments in a preclinical model while looking ahead to how such a device may be translated to a clinical setting.Therefore,in this perspective,we will explore the advantages and challenges associated with intradural placement of electrodes in the spinal cord and discuss the current and future feasibility of clinical implantation of intradural electrodes and devices.

Figure 1｜ Position of epidural electrode and intradural electrode indicated relative to the generalized anatomy of the spinal cord and surrounding structures.

The spinal cord is surrounded by cerebrospinal fluid,which is enclosed within the dura mater and further embedded in bones,ligaments,and muscles.Intradural electrodes are positioned on the pial surface of the spinal cord,for a given injection of current the electric fields generated in the white matter are much greater than when electrodes are positioned away from the targettissue.To illustrate this point,epidural stimulation must first penetrate the dura mater and arachnoid membrane made up of collagen and elastin fibers (～1 mm thick).More problematic is the need for the stimulation signal to penetrate the subarachnoid space (～3 mm for the sagittal posterior surface of the human spinal cord) filled with highly conductive cerebrospinal fluid (CSF),which flows at a speed of 5–10 cm/s.Modeling suggests that for epidural electrodes,traversal of the motional CSF results in a dilution of signal strength and its dispersal over a 2.5 to 3 times wider surface area of the spinal cord compared with equivalent intradural placement of the electrode.In this model (Huang et al.,2014),the more focused stimulation profile of intradural placement facilitated around a five times greater penetration of the stimulation signal below the surface of the cord.Furthermore,it was estimated that fifty times more power was required to achieve the same voltage or field strength at the surface of the spinal cord using epidural electrode placement.Therefore,intradural electrodes have the advantages of being able to deliver a stronger stimulation,and target a more precise area,with deeper penetration,while using a fraction of power input.

Intradural placement also extends the opportunity of using electrodes to record neural activity from the spinal cord (Harland et al.,2022).By bringing the electrodes closer to the source,greater sensitivity is achieved to record signals.This opens up a number of potential applications.Current intraoperative neurophysiological monitoring is conducted from outside the dura to ensure cord function is maintained during surgeries such as spinal decompression,spinal tumor removal,or deformity correction surgery.Current techniques only allow for crude measurements to a portion of conductive paths,however,intradural placement of electrodes would allow much more robust and detailed monitoring to be conducted.For spinal cord injury,a suitable array and spatial density of electrodes could be deployed across the damaged cord to map the extent of injury and functionality.Such electrical biomarkers related to injury and recovery could be useful to augment our current understanding of both normal and abnormal neurophysiology.Such biomarkers would potentially accelerate the development of brain-spinal cord-computer interfaces (Jiang et al.,2022).

An intradural implant can also be used as a delivery platform for chemical treatments to be administered directly onto the spinal cord or cerebrospinal fluid circulation.Emergent drug delivery technologies could be used to control the release of beneficial medicines such as neurotrophic growth factors over periods of daysto-months,including the ability to trigger their release at optimal timings (Cheah et al.,2021).

The challenge then,is both the presence and the placement of electrodes or a device into the sensitive CSF-filled subarachnoid space.Potential adverse effects can be divided into those of early and late onset.Potential early complications include risks of CSF leak and potential cord compression which would necessitate invasive interventions.Late complications include inflammatory/immune reactions between the spinal cord and electrode interface.

Placement of electrodes into the intradural space requires either a durotomy or dural puncture,resulting in potential post-operative CSF leak if a watertight dural closure is not achieved.A CSF leakage may in turn lead to severe postural headache,intracranial hypotension resulting in intradural hematoma,and meningitis or even ventriculitis.A potential complicating factor in achieving a watertight dural closure in the case of intradural electrode placement is that the electrode lead traverses from intradural to epidural space.As such,it is likely that dural closure needs to be augmented with a dural substitute and/or dural sealant.That said,intrathecal catheters(which are connected to a subcutaneous pump)are commonly placed via a dural puncture in selected cases,demonstrating that having a catheter/lead traversing dura is possible without significantly increased adverse clinical outcomes.Nevertheless,the risk of CSF leak in cases of intradural electrode placement will need to be further evaluated and carefully weighed against its potential benefits.One group developing an intradural stimulator for neuropathic pain has incorporated methods to seal the dura into the device design,such as a dural cuff or compression plates positioned either side of the dura and sealed with resorbable gaskets (Nagel et al.,2019).

Another potential complication of utilizing an intradural implant is spinal cord compression.In this regard,the size,shape,and malleability of the implant material used need to be carefully considered.Within the thecal sac’s limited space,an intradural implant behaves as a space-occupying lesion,and as such,should be minimized in size without compromising its functionality.In addition,the implant needs to be flexible and malleable,as it will need to both enter the thecal sac at an angle,as well as conforming to the contour of the spinal cord while being compatible with changes in patient position(verticalvs.horizontal).Elastomeric materials such as silicon can include stretchable connection lines and electrodes but must be made larger to maintain low impedance.Ultrathin polyimide plastics can be embedded with electrodes and tracts at the micrometer scale and can conform to the curvature of tissue surface such as the brain or spinal cord (Vomero et al.,2020),but have limited stretchability.While positioning implants in direct contact with the spinal surface has the potential to result in an immune reaction,this does not occur when silicon and polyimide implants of suitable dimensions were inserted along the thoracic spinal cord in rats (Minev et al.,2015;Harland et al.,2022).However,the degree of foreign body response as well as glial scarring of tissue around the electrodes needs to be investigated over months or years for a clinical device.This may result in increased impedance over time,leading to higher voltage requirements and malfunction or reduced effectiveness of the electrode.Significant arachnoiditis or adhesions can also lead to CSF dysregulation and syrinx formation,leading to neurological deficits.Revision for an adherent intradural lead carries significant risks of spinal cord injury.

Although the first neuropathic pain stimulators developed around 30 years ago were intradural,they were quickly standardized into epidural devices on the basis that less invasive surgery is required.These epidural stimulators significantly alleviate chronic pain in some patients,but in others fail to adequately treat pain over the longterm,and there is a split opinion about whether spinal stimulators should be recommended to patients (Traeger et al.,2023).It is unclear why these devices perform better in some patients than others and why they tend to lose effectiveness over time.One possible mode of failure is due to the weakening and spreading of the signal as it traverses the dura mater and CSF,which may be corrected by using an intradural version of the device (Huang et al.,2014).Advancement of epidural stimulators continues to occur,especially around the use of percutaneous leads,which allow a minimally invasive procedure,have greater flexibility and adjustability,and reduced the risk of lead migration and scar tissue formation.However,the widespread use of epidural spinal stimulators for pain has set the tone for the spinal cord,discouraging the development and use of intradural technologies,in contrast to the brain for which penetrating electrodes are being actively developed and clinically deployed for deep brain stimulation.Activity-dependent neurotechnologies were also originally developed as an intradural device,a flexible silicon substrate containing stretchable electrodes and wires interfaced with the thoracolumbar spinal cord in rats (Minev et al.,2015).For the clinical translation of this neuromodulation technique,an epidural paddle stimulator was used as the required stimulation,focus area,and depth on the surface of the cord was compatible with this device (Wagner et al.,2018).In contrast,for our intradural implant constructed of ultrathin polyimide,we want to be able to use very lowfrequency electrical stimulation approaching direct current (0.0011 Hz) to transmit a beneficial electric field across a spinal injury site.An intradural placement allows us to limit the current injection required through the electrodes,which helps to mitigate the risk of the faradaic reactions associated with this very low-frequency stimulation,and subsequently puts less stress on electrode materials and reduces biological adverse events.Intradural positioning also facilitates much greater penetration of the electric field below the surface of the cord,which is important for spinal cord healing applications.Our computational modeling suggests that with intradural placement,the electric field generated by our implant is even able to reach some regions on the ventral half of the spinal cord.

Intradural electrodes allow a stronger,more focused,and deeper penetrating electrical field while requiring much less current,at the expense of some additional risks.Those risks would be justified by an electroceutical treatment proven to regenerate tissue around and through an injury,or a pain treatment capable of consistently alleviating severe chronic pain.Moving into the future,it is likely that surgical techniques as well as the capabilities of implantable devices will continue to evolve,with intradural spinal cord implantations potentially becoming routine.

This work was supported by the CatWalk Spinal Cord Injury Trust and the Health Research Council of New Zealand (Project grant and HRC/Catwalk Partnership 19/895) (to DS).

Bruce Harland,Chien Yew Kow,Darren Svirskis*

School of Pharmacy,University of Auckland,Auckland,New Zealand (Harland B,Svirskis D)Department of Neurosurgery,Auckland City Hospital,Auckland,New Zealand (Kow CY)

*Correspondence to:Darren Svirskis,PhD,d.svirskis@auckland.ac.nz.

https://orcid.org/0000-0001-9435-1773(Darren Svirskis)

Date of submission:April 6,2023

Date of decision:May 27,2023

Date of acceptance:June 9,2023

Date of web publication:July 20,2023

https://doi.org/10.4103/1673-5374.380895

How to cite this article:Harland B,Kow CY,Svirskis D (2024) Spinal intradural electrodes:opportunities,challenges and translation to the clinic.Neural Regen Res 19(3):503-504.

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