In situ theranostic platform combining highly localized magnetic fluid hyperthermia, magnetic particle imaging, and thermometry in 3D.

Theranostic platforms, combining diagnostic and therapeutic approaches within one system, have garnered interest in augmenting invasive surgical, chemical, and ionizing interventions. Magnetic particle imaging (MPI) offers a quite recent alternative to established radiation-based diagnostic modalities with its versatile tracer material (superparamagnetic iron oxide nanoparticles, SPION). It also offers a bimodal theranostic framework that can combine tomographic imaging with therapeutic techniques using the very same SPION. Methods: We show the interleaved combination of MPI-based imaging, therapy (highly localized magnetic fluid hyperthermia (MFH)) and therapy safety control (MPI-based thermometry) within one theranostic platform in all three spatial dimensions using a commercial MPI system and a custom-made heating insert. The heating characteristics as well as theranostic applications of the platform were demonstrated by various phantom experiments using commercial SPION. Results: We have shown the feasibility of an MPI-MFH-based theranostic platform by demonstrating high spatial control of the therapeutic target, adequate MPI-based thermometry, and successful in situ interleaved MPI-MFH application. Conclusions: MPI-MFH-based theranostic platforms serve as valuable tools that enable the synergistic integration of diagnostic and therapeutic approaches. The transition into in vivo studies will be essential to further validate their potential, and it holds promising prospects for future advancements.

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice.

MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes.

Mapping remodeling of thalamocortical projections in the living reeler mouse brain by diffusion tractography.

A major challenge in neuroscience is to accurately decipher in vivo the entire brain circuitry (connectome) at a microscopic level. Currently, the only methodology providing a global noninvasive window into structural brain connectivity is diffusion tractography. The extent to which the reconstructed pathways reflect realistic neuronal networks depends, however, on data acquisition and postprocessing factors. Through a unique combination of approaches, we designed and evaluated herein a framework for reliable fiber tracking and mapping of the living mouse brain connectome. One important wiring scheme, connecting gray matter regions and passing fiber-crossing areas, was closely examined: the lemniscal thalamocortical (TC) pathway. We quantitatively validated the TC projections inferred from in vivo tractography with correlative histological axonal tracing in the same wild-type and reeler mutant mice. We demonstrated noninvasively that changes in patterning of the cortical sheet, such as highly disorganized cortical lamination in reeler, led to spectacular compensatory remodeling of the TC pathway.

Microcoil-based MR phase imaging and manganese enhanced microscopy of glial tumor neurospheres with direct optical correlation.

Susceptibility differences among tissues were recently used for highlighting complementary contrast in MRI different from the conventional T(1), T(2), or spin density contrasts. This method, based on the signal phase, previously showed improved image contrast of human or rodent neuroarchitecture in vivo, although direct MR phase imaging of cellular architecture was not available until recently. In this study, we present for the first time the ability of microcoil-based phase MRI to resolve the structure of human glioma neurospheres at significantly improved resolutions (10 × 10 µm(2)) with direct optical image correlation. The manganese chloride property to function as a T(1) contrast agent enabled a closer examination of cell physiology with MRI. Specifically the temporal changes of manganese chloride uptake, retention and release time within and from individual clusters were assessed. The optimal manganese chloride concentration for improved MR signal enhancement was determined while keeping the cellular viability unaffected. The presented results demonstrate the possibilities to reveal structural and functional observation of living glioblastoma human-derived cells. This was achieved through the combination of highly sensitive microcoils, high magnetic field, and methods designed to maximize contrast to noise ratio. The presented approach may provide a powerful multimodal tool that merges structural and functional information of submilimeter biological samples.

Volumetric analysis of MRI data monitoring the treatment of polycystic kidney disease in a mouse model.

OBJECT: The human condition autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of cysts in the kidneys that increase renal volume and lead to kidney failure. Mice studies are performed for treatment development monitored with imaging. The analysis of the imaging data is typically manual, which is costly and potentially biased. This paper presents a reliable and reproducible method for the automated segmentation of polycystic mouse kidneys. MATERIALS AND METHODS: Treated and untreated mice have been imaged longitudinally with high field anatomic MRI. The region of interest (ROI) of the kidneys in the images is identified and restored for artifacts. It is then analyzed statistically and geometric models are estimated for each kidney. The statistical and geometric information are provided to the graph cuts algorithm that delineates the kidneys. RESULTS: The accuracy of the analysis has been demonstrated by showing consistency with results obtained with previous methods as well as by comparing with manual segmentations. CONCLUSION: The method developed can accelerate and improve the accuracy of kidney volumetry in preclinical treatment trials for ADPKD.

Analysis of MR images of mice in preclinical treatment monitoring of polycystic kidney disease.

A common cause of kidney failure is autosomal dominant polycystic kidney disease (ADPKD). It is characterized by the growth of cysts in the kidneys and hence the growth of the entire kidneys with eventual failure in most cases by age 50. No preventive treatment for this condition is available. Preclinical drug treatment studies use an in vivo mouse model of the condition. The analysis of mice imaging data for such studies typically requires extensive manual interaction, which is subjective and not reproducible. In this work both untreated and treated mice have been imaged with a high field, 9.4T, MRI animal scanner and a reliable algorithm for the automated segmentation of the mouse kidneys has been developed. The algorithm first detects the region of interest (ROI) in the image surrounding the kidneys. A parameterized geometric shape for a kidney is registered to the ROI of each kidney. The registered shapes are incorporated as priors to the graph cuts algorithm used to extract the kidneys. The accuracy of the automated segmentation has been demonstrated by comparing it with a manual segmentation. The processing results are also consistent with the literature for previous techniques.