Drug-free wireless neural inhibition via an injectable microwave rod implant

Introduction: Chronic neuropathic pain affects around 8% of the population and is one of the leading causes of disability worldwide. Patients are often prescribed drugs for pain management, which can lose efficacy over time and can cause side effects ranging from cardiovascular events to addiction. The pathology of chronic pain is complex and heterogenous, making it difficult to treat. Neuromodulation presents an opportunity for robust and effective treatment of chronic pain by modulating the nerve signals directly. The most common neuromodulation method is electrical stimulation, including vagus nerve stimulation (VNS) and spinal cord stimulation (SCS). These methods involve the implantation of an electrode on the nervous system to deliver electrical impulses and interrupt aberrant firing patterns. The electrode, however, must be tethered to a subcutaneously implanted stimulator. In addition to hardware discomfort, maintenance and repair of the subcutaneous stimulator increases the cost and surgical risk associated with these devices.
Microwaves can penetrate >50 mm into tissue noninvasively and have been shown to reversibly inhibit neural activity via a primarily nonthermal mechanism. We have developed a microwave rod (MWR) implant that can wirelessly couple with external microwaves and produce a localized enhanced electric field to directly inhibit nerve conduction. The electric field has submillimeter spatial precision, breaking the microwave diffraction limit. The implant is miniature and easily injectable, making it minimally invasive. Furthermore, it enables neural inhibition at powers below the defined threshold for safe microwave exposure, making it a safe and effective treatment for chronic pain.

Materials and

Methods: To theoretically verify the resonance effect of the MWR, it was simulated under microwave in bulk water using COMSOL. The MWR was fabricated from pure titanium wire with a diameter of 0.5 mm, cut to a length of 7.55 mm or 8.07 mm and polished into a pointed or blunt tip. Rat primary cortical neurons were cultured in vitro and dyed with Oregon green dye for calcium imaging. To confirm microwave inhibition in mammalian neurons, 2.05 GHz microwave at 2.0 W/cm2 was applied directly to the cells for 10 s, pulsed at 10 Hz with 10 ms pulse width (i.e. 10s PW). To demonstrate its enhanced inhibition, the 7.55 mm blunt MWR was placed on top of the neurons and irradiated at its resonant frequency of 2.1 GHz at 0.2 W/cm2 for 10s PW. Next, we demonstrated blocking of nerve conduction using the MWR on a crayfish ventral nerve cord, which is a robust and simple model of nerve conduction. Action potentials (APs) were recorded at two points on an axon descending from the ventral nerve cord, one proximal to the nerve and one distal. The tip of the 8.07 pointed MWR was positioned near the axon in between the two recording sites to investigate whether the MWR could block conduction of the action potentials from the proximal to the distal recording sites. The MWR was irradiated with 2.1 GHz microwave at 1.3 W/cm2 for 10 s continuous (i.e. 10s CW). Pulsed microwave was not used to avoid electrical artifacts.

Results, Conclusions, and Discussions: The simulation of the MWR confirmed that it produces localized electric fields at both ends. The electric field at the tip was amplified ~36 times and had spatial precision ~620 μm (Figure a, b). When primary cortical neurons were irradiated with direct 2.05 GHz 10s PW microwave at 2.0 W/cm2, neuronal activity was decreased by 52.3% (Figure c, d). The inhibition lasted up to 20 s after microwave treatment, after which the neurons recovered their baseline activity. When a 7.55 mm blunt MWR was placed over the neurons and irradiated with 2.1 GHz 10 s PW, the same level of inhibition (51.4%) was achieved at 0.2 W/cm2 (Figure e, f). This means that the MWR enables inhibition at 10 times lower power. This is essential for minimizing the therapeutic microwave dosage to ensure safety.
The crayfish ventral nerve cord is used to study nerve conduction because it has robust firing. Additionally, it is easy to distinguish APs from different axons based on their amplitude, smaller axons having smaller APs. When an 8.07 mm pointed rod was placed next to the crayfish axon (Figure g, h) and irradiated with 1.3 W/cm2 10 s CW microwave, there was a noticeable decrease in the firing rate of the smaller axon at the distal site (Figure i). At the proximal site, there was no apparent change in the number or amplitudes of APs (Figure j, k). At the distal site, however, there was a large decrease in smaller amplitude APs while larger APs were unaffected (Figure l, m). The AP amplitude distribution recovered after microwave treatment. These results indicate that, while microwave alone does not inhibit nerve firing, the MWR amplifies the field enough to reversibly block nerve conduction. This is important to avoid off-target effects of the microwave. Furthermore, the MWR selectively blocked the smaller axons. This result is significant because in humans, pain signals are carried by smaller nerves – unmyelinated C fibers. This demonstrates an exciting potential for the MWR to inhibit pain signals without affecting the signals carried by larger nerves.

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