Intraspinal stimulation with a silicon-based 3D chronic microelectrode array for bladder voiding in cats

Abstract

Objective.Bladder dysfunction is a significant and largely unaddressed problem for people living with spinal cord injury (SCI). Intermittent catheterization does not provide volitional control of micturition and has numerous side effects. Targeted electrical microstimulation of the spinal cord has been previously explored for restoring such volitional control in the animal model of experimental SCI. Here, we continue the development of the intraspinal microstimulation array technology to evaluate its ability to provide more focused and reliable bladder control in the feline animal model.Approach.For the first time, a mechanically robust intraspinal multisite silicon array was built using novel microfabrication processes to provide custom-designed tip geometry and 3D electrode distribution. Long-term implantation was performed in eight spinally intact animals for a period up to 6 months, targeting the dorsal gray commissure area in the S2 sacral cord that is known to be involved in the coordination between the bladder detrusor and the external urethral sphincter.Main results.About one third of the electrode sites in the that area produced micturition-related responses. The effectiveness of stimulation was further evaluated in one of eight animals after spinal cord transection (SCT). We observed increased bladder responsiveness to stimulation starting at 1 month post-transection, possibly due to supraspinal disinhibition of the spinal circuitry and/or hypertrophy and hyperexcitability of the spinal bladder afferents.Significance. 3D intraspinal microstimulation arrays can be chronically implanted and provide a beneficial effect on the bladder voiding in the intact spinal cord and after SCT. However, further studies are required to assess longer-term reliability and safety of the developed intraspinal microstimulation array prior to eventual human translation.

Keywords: bladder dysfunction; microstimulation; silicon-based microelectrode array; spinal cord injury.

Figure 1.

Photograph of a probe with a 4 × 8 microelectrode configuration (lower half). Yellow pads are wire-bonding sites.

Figure 2.

(A) Photograph of a 64-channel array assembly with two planar probes and a three-rod holder for suspending three spacers between the probes; (B) photograph of the released array.

Figure 3.

Photograph of the spinal cord laminectomy with the barrel and wings of the inserter tool with a loaded array on the left and the stabilizing pad of the array cable on the right.

Figure 4.

Access resistance of 44 functional electrode sites (<200 kΩ) over the course of implantation in three animals (SP05, SP07, and SP09). The thick line indicates the average values.

Figure 5.

Urodynamic measurements of bladder responses to microstimulation illustrating: (A) stability over 166 d post-implantation, and (B) recovery of bladder control over 58 d after low-thoracic SCT. Abbreviations: dpi—day post-implantation; dpt—day post-transection. The pink bar indicates the duration of stimulation and the number inside the bar indicates the stimulated electrode site.

Figure 6.

Photograph of bladder voiding induced by stimulating a single electrode site.

Figure 7.

(A) Photomicrograph of eight shank tips in the spinal cord immunostained with NeuN and counterstained with Cresyl Violet. (B) Closeup of two shank tips in the area marked by a rectangle in A.

Figure 8.

Locations of the electrode sites in the rostral S₂ spinal segment that produced micturition-related responses: (A) increases in the bladder pressure and (B) decreases in the EUS pressure. The circle size indicates the amount of bladder pressure and EUS pressure change from the baseline level. The circle size scales are shown above the panels. Different circle colors indicate five individual animals (SP05—gray, SP06—red, SP09—green, SP10—blue, SP12—orange). The mediolateral and dorsoventral coordinates are provided in reference to the dorsal edge of the central canal. The blue lines in each panel represent the gray matter and the spinal cord boundaries and the location of the central canal.