The capability to directly interrogate intracellular structures inside a single cell for measurement and manipulation is important for understanding subcellular and suborganelle activities, diagnosing diseases, and developing new therapeutic approaches. Compared with measurements of single cells, physical measurement and manipulation of subcellular structures and organelles remain underexplored. To improve intracellular physical measurement and manipulation, we have developed a multipole magnetic tweezers system for micromanipulation involving submicrometer position control and piconewton force control of a submicrometer magnetic bead inside a single cell for measurement in different locations (spatial) and different time points (temporal). The bead was three-dimensionally positioned in the cell using a generalized predictive controller that addresses the control challenge caused by the low bandwidth of visual feedback from high-resolution confocal imaging. The average positioning error was quantified to be 0.4 μm, slightly larger than the Brownian motion–imposed constraint (0.31 μm). The system is also capable of applying a force up to 60 pN with a resolution of 4 pN for a period of time longer than 30 min. The measurement results revealed that significantly higher stiffness exists in the nucleus’ major axis than in the minor axis. This stiffness polarity is likely attributed to the aligned actin filament. We also showed that the nucleus stiffens upon the application of an intracellularly applied force, which can be attributed to the response of structural protein lamin A/C and the intracellular stress fiber actin filaments.

From single-pole magnetic tweezers to robotic magnetic-field generation systems, the development of magnetic micromanipulation systems, using electromagnets or permanent magnets, has enabled a multitude of applications for cellular and intracellular measurement and stimulation. Controlled by different configurations of magnetic-field generation systems, magnetic particles have been actuated by an external magnetic field to exert forces/torques and perform mechanical measurements on the cell membrane, cytoplasm, cytoskeleton, nucleus, intracellular motors, etc. The particles have also been controlled to generate aggregations to trigger cell signaling pathways and produce heat to cause cancer cell apoptosis for hyperthermia treatment. Magnetic micromanipulation has become an important tool in the repertoire of toolsets for cell measurement and stimulation and will continue to be used widely for further explorations of cellular/intracellular structures and their functions. Existing review papers in the literature focus on fabrication and position control of magnetic particles/structures (often termed micronanorobots) and the synthesis and functionalization of magnetic particles. Differently, this paper reviews the principles and systems of magnetic micromanipulation specifically for cellular and intracellular measurement and stimulation. Discoveries enabled by magnetic measurement and stimulation of cellular and intracellular structures are also summarized. This paper ends with discussions on future opportunities and challenges of magnetic micromanipulation in the exploration of cellular biophysics, mechanotransduction, and disease therapeutics.

Inspired by the collective intelligence in natural swarms, microrobotic agents have been controlled to form artificial swarms for targeted drug delivery, enhanced imaging, and hyperthermia. Different from these well-investigated tasks, this work aims to develop microrobotic swarms for embolization, which is a clinical technique used to block blood vessels for treating tumors, fistulas, and arteriovenous malformations. Magnetic particle swarms were formed for selective embolization to address the low selectivity of the present embolization technique that is prone to cause complications such as stroke and blindness. We established an analytical model that describes the relationships between fluid viscosity, flow rate, branching angle, magnetic field strength, and swarm integrity, based on which an actuation strategy was developed to maintain the swarm integrity inside a targeted region under fluidic flow conditions. Experiments in microfluidic channels, ex vivo tissues, and in vivo porcine kidneys validated the efficacy of the proposed strategy for selective embolization.