Samantha Coffler

BackgroundMagnetic control of cell activity has applications from non-invasive neurostimulation to remote activation of cell-based therapies. To date, no magnetically gated channel has been identified, limiting magnetic approaches to strong alternating fields (kHz to MHz) or using co-factors such as nanoparticles.ObjectiveWe aimed to determine whether slowly varying magnetic fields can elicit a response in excitable cells without exogenous co-factors, characterize the intrinsic magnetic sensitivity and response time to stimulation, and identify the mechanism of action.MethodSpiking HEK cells were exposed to a magnetic field reaching 500 mT within 200 ms using a permanent magnet. Calcium imaging was used to quantify responses across >7,500 micropatterned independent cell clusters (150-300 cells each). Pharmacological blockers and co-culture with MIN6 beta-pancreatic cells were used to probe mechanism and functional output.ResultsThe response is rare, approximately 1 in 50 cell clusters, but is fast and reproducible, generating rapid, spike-like calcium transients within 200 ms of magnetic field stimulation consistent with electrically driven depolarization.However, with a magnetic field 10,000 times slower than in transcranial magnetic stimulation (TMS) and an induced electric field an order of magnitude lower than necessary for membrane depolarisation, we explored alternative biophysical mechanisms.Gadolinium and pharmacological inhibition of TRP channels attenuated the response, while Piezo channel inhibition had no effect, implicating mechanosensitive TRP channels in the magnetic response. When cells form gap junctions, the magnetically-induced calcium transient can propagate to neighboring cells, enabling tissue-level responses. Co-culture of spiking HEK cells with beta-pancreatic MIN6 cells showed that this co-culture responds to magnetic fields by increasing insulin production.ConclusionOur calculations suggest that induced electric fields, eddy currents, heating, and ROS-mediated pathways are quantitatively or kinetically unable to explain the observed response. Instead, our calculation suggests that this response depends on mechanoreception pathways activated by the magnetic torque of TRP-associated lipid rafts, a hypothesis supported by our data. Together, these results open a path towards the fast magnetic control of biological activity without needing synthetic co-factors. By better understanding this mechanism and enriching for magneto-sensitivity it may be possible to adapt this approach to the rapidly expanding tool kit for wireless cell activity regulation.

Objective: Several novel methods, including magnetogenetics and magnetoelectric stimulation, use high frequency alternating magnetic fields to precisely manipulate neural activity. To quantify the behavioral effects of such interventions in a freely moving mouse, we developed a dual-channel magnetic chamber, specifically designed for rate-sensitive magnetothermal-genetic stimulation, and adaptable for other uses of alternating magnetic fields. Approach: Through an optimized coil design, the system allows independent control of two spatially orthogonal uniform magnetic fields delivered at different frequencies within a 10 × 10 × 6 cm ³ chamber suitable for mouse studies. The two channels have nominal frequencies of 50 and 550 kHz with peak magnetic field strengths of 88 and 12.5 mT, achieved with resonant coil drives having peak voltages of 1.6 and 1.8 kV and currents of 1.0 and 0.26 kA, respectively. Additionally, a liquid cooling system enables magnetic field generation for second-level durations, and an observation port and camera allow video capture of the animal’s behavior within the chamber. Main Results: The system generates high-amplitude magnetic fields across two widely separated frequency channels with negligible interference (< 1%). Relatively uniform magnetic field distribution (±10% across 94% of the chamber volume) is maintained throughout the chamber, and temperature increase of the inner side of the coil enclosure during the operation is limited to < 0.35 °C/s to ensure in vivo safety. Using cobalt-doped and undoped iron oxide nanoparticles, we demonstrate channel-specific heating rates of 3.5 °C/s and 1.5 °C/s, respectively, validating frequency-selectivity. Both channels can run continuously for 4 seconds stably. Significance: We present a novel magnetic stimulation platform that combines high-frequency, high-power capability with two independently-controlled channels generating different frequencies, along with a real-time behavioral observation system for freely moving animals. The system supports frequency-multiplexed stimulation strategies for precise modulation of neural activity, making it a versatile tool for advancing magnetogenetics, neural circuit interrogation, and noninvasive stimulation approaches in neuroscience and bioengineering.

Magnetic control of cell activity has applications ranging from non-invasive neurostimulation to remote activation of cell-based therapies. Unlike other methods of regulating cell activity like heat and light, which are based on known receptors or proteins, no magnetically gated channel has been identified to date. As a result, effective approaches for magnetic control of cell activity are based on strong alternating magnetic fields able to induce electric fields or materials that convert magnetic energy into electrical, thermal, or mechanical energy to stimulate cells. In our investigations of magnetic cell responses, we found that a spiking HEK cell line with no other co-factors responds to a magnetic field that reaches a maximum of 500 mT within 200 ms using a permanent magnet. The response is rare, approximately 1 in 50 cells, but is fast and reproducible, generating an action potential within 200 ms of magnetic field stimulation. The magnetic field stimulation is over 10,000 times slower than the magnetic fields used in transcranial magnetic stimulation (TMS) and the induced electric field is more than an order of magnitude lower than necessary for neuromodulation, suggesting that induced electric currents do not drive the cell response. Instead, our calculation suggests that this response depends on mechanoreception pathways activated by the magnetic torque of TRP-associated lipid rafts. Despite the relatively rare response to magnetic stimulation, when cells form gap junctions, the magnetic stimulation can propagate to nearby cells, causing tissue-level responses. As an example, we co-cultured spiking HEK cells with beta-pancreatic MIN6 cells and found that this co-culture responds to magnetic fields by increasing insulin production. Together, these results point toward a method for the magnetic control of biological activity without the need for a material co-factor such as synthetic nanoparticles. By better understanding this mechanism and enriching for magneto-sensitivity it may be possible to adapt this approach to the rapidly expanding tool kit for wireless cell activity regulation.