Medical Imaging of Microrobots: Toward In Vivo Applications

Medical microrobots (MRs) have been demonstrated for a variety of non-invasive biomedical applications, such as tissue engineering, drug delivery, and assisted fertilization, among others. However, most of these demonstrations have been carried out in in vitro settings and under optical microscopy, being significantly different from the clinical practice. Thus, medical imaging techniques are required for localizing and tracking such tiny therapeutic machines when used in medical-relevant applications. This review aims at analyzing the state of the art of microrobots imaging by critically discussing the potentialities and limitations of the techniques employed in this field. Moreover, the physics and the working principle behind each analyzed imaging strategy, the spatiotemporal resolution, and the penetration depth are thoroughly discussed. The paper deals with the suitability of each imaging technique for tracking single or swarms of MRs and discusses the scenarios where contrast or imaging agent's inclusion is required, either to absorb, emit, or reflect a determined physical signal detected by an external system. Finally, the review highlights the existing challenges and perspective solutions which could be promising for future in vivo applications

Magnetic resonance imaging and navigation of ferromagnetic thermoseeds to deliver thermal ablation therapy

Minimally invasive therapies aim to deliver effective treatment whilst reducing off-target burden, limiting side effects, and shortening patient recovery times. Remote navigation of untethered devices is one method that can be used to deliver targeted treatment to deep and otherwise inaccessible locations within the body. Minimally invasive image-guided ablation (MINIMA) is a novel thermal ablation therapy for the treatment of solid tumours, whereby an untethered ferromagnetic thermoseed is navigated through tissue to a target site within the body, using the magnetic field gradients generated by a magnetic resonance imaging (MRI) system. Once at the tumour, the thermoseed is heated remotely using an alternating magnetic field, to induce cell death in the surrounding cancer tissue. The thermoseed is then navigated through the tumour, heating at pre-defined locations until the entire volume has been ablated. The aim of this PhD project is to develop MINIMA through a series of proof-of-concept studies and to assess the efficacy of the three key project components: imaging, navigation, and heating. First, an MR imaging sequence was implemented to track the thermoseeds during navigation and subsequently assessed for precision and accuracy. Secondly, movement of the thermoseeds through a viscous fluid was characterised, by measuring the effect of different navigation parameters. This was followed by navigation experiments performed in ex vivo tissue. To assess thermoseed heating, a series of in vitro experiments were conducted in air, water, and ex vivo liver tissue, before moving onto in vivo experiments in the rat brain and a murine subcutaneous tumour model. These final experiments allowed the extent of cell death induced by thermoseed heating to be determined, in both healthy and diseased tissue respectively

Scalable strategies for tumour targeting of magnetic carriers and seeds

With the evolving landscape of medical oncology, focus has shifted away from nonspecific cytotoxic treatment strategies toward therapeutic paradigms more characteristic of targeted therapies. These therapies rely on delivery vehicles such as nano-carriers or micro robotic devices to boosts the concentration of therapeutics in a specific targeted site inside the body. The use of externally applied magnetic field is suggested to be a predominant approach for remote localisation of magnetically responsive carriers and devices to the target region that could not be otherwise reached. However, the fast decline of the magnetic fields and gradients with increasing distances from the source is posing a major challenge for its clinical application. The aim of this thesis was to investigate potential magnetic delivery strategies which can circumvent some of the typical limitations of this technique. Two different approaches were explored to this end. The first approach was to characterise the ability of a conventional permanent magnet on targeting individual nano-carriers and develop novel magnetic designs which improve the targeting efficiency. The second approach was evaluating the feasibility of a magnetic resonance imaging system to move a millimetre-sized magnetic particle within the body. Phantom and in vivo magnetic targeting experiments illustrated the significant increase in effective targeting depth when our novel magnetic design was used for targeting nano-carriers compared with conventional magnets. In the later part of the thesis, the proof of concept and characterisation experiments showed that a 3 mm magnetic particle can be moved in ex vivo brain tissue using a magnetic resonance imaging system using clinically relevant gradient strengths. The magnetic systems introduced in this thesis provide the potential to target nano-carriers and millimetre-sized thermoseeds to tumours located at deep regions of human body through vasculature and soft tissue respectively

Minimally invasive therapies for the brain using magnetic particles

Delivering a therapy with precision, while reducing off target effects is key to the success of any novel therapeutic intervention. This is of most relevance in the brain, where the preservation of surrounding healthy tissue is crucial in reducing the risk of cognitive impairment and improving patient prognosis. Our scientific understanding of the brain would also benefit from minimally invasive investigations of specific cell types so that they may be observed in their most natural physiological environment. Magnetic particles based techniques have the potential to deliver cellular precision in a minimally invasive manner. When inside the body, Magnetic particles can be actuated remotely using externally applied magnetic fields while their position can be detected non-invasively using MRI. The magnetic forces applied to the particles however, rapidly decline with increasing distance from the magnetic source. It is therefore critical to understand the amount of force needed for a particular application. The properties of the magnetic particle such as the size, shape and magnetic content, as well as the properties of the applied magnetic field, can then be tailored to that application. The aim of this thesis was to develop magnetic particle based techniques for precise manipulation of cells in the brain. Two different approaches were explored, utilising the versatile nature of magnetic actuation for two different applications. The first approach uses magnetic nanoparticles to mechanically stimulate a specific cell type. Magnetic particles conjugated with the antibody ACSA-1 would selectively bind to astrocytes to evoke the controlled release of ATP and induce a calcium flux which are used for communication with neighbouring cells. This approach allows for the investigation into the role of astrocytes in localised brain regions using a naturally occurring actuation process (mechanical force) without effecting their natural environment. The second approach uses a millimetre sized magnetic particle which can be navigated through the brain and ablate localised regions of cells using a magnetic resonance imaging system. The magnetic particle causes a distinct contrast in MRI images, allowing for precise detection of its location so that it may be iteratively guided along a pre-determined path to avoid eloquent brain regions. Once at the desired location, an alternating magnetic field can be applied causing the magnetic particle to heat and deliver controllable, well defined regions of cell death. The forces needed for cell stimulation are orders of magnitude less than the forces needed to guide particles through the brain. Chapters 4 and 5 use external magnets to deliver forces in the piconewton range. While stimulation was demonstrated in small animals, scaling up this technique to human proportions remains a challenge. Chapters 6 and 7 use a preclinical MRI system to generate forces in the millinewton range, allowing the particle to be moved several centimetres through the brain within a typical surgical timescale. When inside the scanner, an alternating magnetic field causes the particle to heat rapidly, enabling the potential for multiple ablations within a single surgery. For clinical translation of this technique, MRI scanners would require a dedicated propulsion gradient set and heating coil