Kongari, Abhinav Paul; (2024) Micron-scale electromagnetic tweezers for intracellular force application. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There has been significant recent progress in understanding how mechanical forces are generated and sensed by biological molecules such as motors and cytoskeletal filaments, but it is primarily based on studies involving purified proteins or extracts. The way different types of motor and non-motor molecules interact and generate forces within living cells is poorly understood due to limitations in methods allowing intracellular force probing. Magnetic tweezers offer a non-contact and non-invasive method to apply mechanical force. However, their use is currently limited due to the size of magnets and gradients that they generate, as well as the large size of particles required to apply sufficient force. This work investigates the use of two-pole electromagnetic tweezers, designed and optimised to the physical limit to controllably apply micron-scale sharp gradients of the magnetic field, thereby resulting in the highly specific application of forces to magnetic particles in at least two different directions inside a single cell. I theoretically optimised the shape of electromagnetic tweezer tips using a customised computational toolbox and established a fabrication pipeline to electrochemically etch tips to the desired geometry reliably. A feedback control toolbox was then set up to remove the hysteresis and provide a controllable on/off circuit for controllable force application. This optimised design generated significantly steeper magnetic field gradients, reducing the size of required magnetic nanoparticles, thus offering improved granularity and precision in intracellular force application. The capacity of the tips to apply bi-directional forces was further demonstrated via in vitro experiments using DNA tethers. Finally, the setup was used to manipulate magnetic nanoparticles in different directions independently within live mammalian cells. The findings from this thesis contribute to the field by pushing the limits of current force-application tools within living cells, creating opportunities for deeper investigation into the intricacies of cellular biomechanics.

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