Toward Bioelectronic Medicine—Neuromodulation of Small Peripheral Nerves Using Flexible Neural Clip

Abstract Neural modulation technology and the capability to affect organ function have spawned the new field of bioelectronic medicine. Therapeutic interventions depend on wireless bioelectronic neural interfaces that can conformally and easily attach to small (few hundred micrometers) nerves located deep in the body without neural damage. Besides size, factors like flexibility and compliance to attach and adapt to visceral nerves associated moving organs are of paramount importance and have not been previously addressed. This study proposes a novel flexible neural clip (FNC) that can be used to interface with a variety of different peripheral nerves. To illustrate the flexibility of the design, this study stimulates the pelvic nerve, the vagus nerve, and branches of the sciatic nerve and evaluates the feasibility of the design in modulating the function of each of these nerves. It is found that this FNC allows fine‐tuning of physiological processes such as micturition, heart rate, and muscle contractions. Furthermore, this study also tests the ability of wirelessly powered FNC to enable remote modulation of visceral pelvic nerves located deep in the body. These results show that the FNC can be used with a range of different nerves, providing one of the critical pieces in the field of bioelectronics medicines.


Design of flexible neural clip (FNC) interface
A flexible and soft polyimide clip interface provides not only conformal contact with the nerve, but also gentle pressure on the nerve to keep the clip interface in place. The flexible neural clip (FNC) is created based on the design of a paper clip that provides easy and secure implantation. The flexible and biocompatible polyimide serves as a scaffold of the FNC for the functions. The key element of FNC interface is the dimension of clip (length, width, and thickness of clip-springs, clip-strip, and clip-cavities) (Figure 1d) considering Young`s modulus of the polyimide of 2.3G Pa. [1] The thickness of the device is largely tradeoff between flexibility and rigidity of the polyimide. To reliably perform clipping and conformal contact to a nerve, the total thickness of 16 µm was experimentally selected. Based on mechanical stress test of clip opening, the acceptable angle (α) between the clip-strip and the clip-spring was around 33~ 34° for reliable and repetitive opening function. The clip-strip width was taken the radius of nerves into account keeping the angle ( Figure S1a). As shown in Figure S1b, this unique design allows gentle pressure to a nerve enough to clip the nerve while still making good contact.

Preliminary test of pelvic nerve stimulation
The clip design allowed easy and reliable implantation with less damage and close contacts on the pelvic nerves. We performed repetitive stimulations using supra-threshold amplitudes to show the reproducibility of pelvic nerve stimulation using the FNC (Figure S4a; n = 8 trials). Repeatable voiding responses were obtained in all 8 trials during a single continuous recording session, with pressure changes ( Figure S4b). To examine how reliable our FNC work across different animals, we reused the same FNC for experiments carried out in two rats on different days. Similar to each of the two rats, applying higher stimulation amplitude caused greater peak change in intra-bladder pressures ( Figure S5a) and decreased the time taken to reach the peak pressure ( Figure S5b), indicating that the FNC can be reliably implanted without much lost in electrode performance and is mechanically robust for handling across different experiments.

Wireless Neural Clip Interface
Firstly, active version of FNC was fabricated in the same manner of the fabrication procedure where contact pads matched with the size of mini-PCB ( Figure S7a). Secondly, wireless components including diodes and capacitors were soldered on the PCB ( Figure S7b).
Thirdly, the FNC was aligned on the PCB, then, silver paste was applied for electrical connections. Finally, a coil and UV LED were soldered and the entire FNC was encapsulated in a silicone elastomer except the active electrodes of the FNC.

Wireless pelvic nerve stimulation
The prepared wireless FNC was tested in phosphate buffered saline (PBS) solution first before moving to in vivo experiments. The wireless FNC was implanted on a pelvic nerve. For consistent repetition of each trial, the wireless external coil was postioned and fixed at a proper place using a manipulator (Figure S8a). UV LED was intentionally soldered and extended outside of the wireless FNC to monitor the operation of the device and wireless stimulation ( Figure S8b). During the stimulation, we made the implantation site dry from body fluids. Stimulation parameters were applied with a frequency of 10 Hz, duration of 5-6 seconds, and phase width of 150, 300, and 500 µs, respectively. Intra-bladder pressure was measured in the same manner of previous test. There was at least 3 minutes interval before and after each stimulation.        A magnified photomicrograph of implanted FNC on a pelvic nerve.