Unfortunately, these peripheral nerves are extremely small. For instance, the carotid sinus nerve, a potential target for treating hypertension and diabetes, is only 300–400 µm in diameter. In the mouse – a preclinical model used for basic research in bioelectronic medicine – the carotid sinus nerve is only 50 µm.

What's needed is a miniature electrical stimulation device that can reliably interface with small visceral nerves, can withstand motion without dislodging and is easy to implant via rapid keyhole surgery. A research team headed up at Boston University has developed just such a nerve interface – a micro-scale, electrode-laden nanoclip that can connect to nerves as small as 50 µm in diameter (J. Neural Eng. 14 036006).

"The nanoclip is a self-closing device – it can be pushed onto a nerve with minimal manipulation of the nerve, in a keyhole surgery," explained researcher Timothy Gardner." Many other designs require the use of sutures or forceps that are challenging to implement in a keyhole surgery. Reducing nerve manipulation and nerve cuff size will also allow applications in small, fragile nerves in preclinical rodent studies."

Nanoclip fabrication

Gardner and colleagues addressed the miniaturization challenge by using direct-write 3D laser printing with 200 nm resolution to fabricate a compact, flexible nanoclip from a commercial UV-curable polymer. Another innovation was the use of carbon nanotube fibres (CNTfs) as robust, flexible electrodes.

Fabrication is a multi-step process in which the nanoclip base is printed, the CNTf electrodes are placed into alignment slots, and then the upper half of the nanoclip is fabricated. Printing took approximately 30 minutes per device (though next-generation printing processes should reduce this to 30 s or less) and the total manufacturing time was about 90 minutes. The researchers note that this fabrication approach can create nanoclips of almost arbitrarily complex geometries, incorporating different types and numbers of electrodes.

The team investigated several designs for interfacing the nanoclip to the nerve, and settled on a double-trapdoor geometry with a semi-cylindrical interior channel. During implantation, the device advances towards the nerve until the doors deform and the nerve enters the central channel. Once the nerve clears the doors, they return to their original configuration and lock the nerve inside.

In vivo evaluation

To assess the safety of the implanted nanoclip, the researchers attached non-electrically-functional nanoclips (without CNTfs) to the tracheal syringeal (TS) nerves of four male zebra finches. They quantified neural damage by recording birdsong daily and monitoring any changes from the baseline song. For comparison, they also assessed the song of three birds with nerve damage from nerve crush, and a control bird.

Analysing the birdsong features revealed disruption of the song immediately after surgery. In the following weeks, the song recovered to baseline in most cases. "We have recently learned more about the devices and surgery," Gardner told medicalphysicsweb. "Our current data show that the nanoclips can be as minimally invasive as a sham surgery – with no detectable acute effect on song."

To confirm that the implanted nanoclips stayed attached, the researchers sacrificed the birds and visually inspected the nerve. All nanoclips remained latched over the nerve, with minimal evidence of local inflammation. Future tests of the nanoclip's safety will include histological study of biomarkers of axon structure, myelination and surrounding inflammation or fibrosis, in control and implanted animals

Nerve stimulation

Gardner and colleagues also examined the nanoclip's ability to stimulate and monitor nerve activity. They implanted two electrically functional nanoclips on the right TS nerve of a zebra finch – one for stimulation and one for recording. Subjecting the nerve to currents just below (13 µA) and just above (17 µA) the stimulation threshold, revealed a voltage deflection on the recording electrode for above-threshold stimulation only. This peak, which occurred about 1 ms after the current onset, demonstrates the physiological response of the nerve.

The researchers have several further developments lined up for the nanoclip. They plan to design a way to reliably insulate the CNTf electrodes located outside the clip, possibly by coating the CNTfs with parylene and selectively ablating the coating within the nanoclip. A prototype of such a device exhibited both stimulation and recording of evoked action potentials.

"The nanoclip described in this paper was partially hand assembled, with carbon nanotube threads manually placed over the nanoclip base," Gardner added. "We are now working to improve the preparation of electrode contacts on the nanotube threads and to integrate distinct electrode types not made of nanotube threads. The goal is to make devices for recording and stimulation that can be manufactured in a more automated manner, with precise specifications."

Working towards the development of bioelectronic medicines. Credit: GSK

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