Innovative techniques to devise 3D-printed anatomical brain phantoms for morpho-functional medical imaging

Introduction. The Ph.D. thesis addresses the development of innovative techniques to create 3D-printed anatomical brain phantoms, which can be used for quantitative technical assessments on morpho-functional imaging devices, providing simulation accuracy not obtainable with currently available phantoms. 3D printing (3DP) technology is paving the way for advanced anatomical modelling in biomedical applications. Despite the potential already expressed by 3DP in this field, it is still little used for the realization of anthropomorphic phantoms of human organs with complex internal structures. Making an anthropomorphic phantom is very different from making a simple anatomical model and 3DP is still far from being plug-and-print. Hence, the need to develop ad-hoc techniques providing innovative solutions for the realization of anatomical phantoms with unique characteristics, and greater ease-of-use. Aim. The thesis explores the entire workflow (brain MRI images segmentation, 3D modelling and materialization) developed to prototype a new complex anthropomorphic brain phantom, which can simulate three brain compartments simultaneously: grey matter (GM), white matter (WM) and striatum (caudate nucleus and putamen, known to show a high uptake in nuclear medicine studies). The three separate chambers of the phantom will be filled with tissue-appropriate solutions characterized by different concentrations of radioisotope for PET/SPECT, para-/ferro-magnetic metals for MRI, and iodine for CT imaging. Methods. First, to design a 3D model of the brain phantom, it is necessary to segment MRI images and to extract an error-less STL (Standard Tessellation Language) description. Then, it is possible to materialize the prototype and test its functionality. - Image segmentation. Segmentation is one of the most critical steps in modelling. To this end, after demonstrating the proof-of-concept, a multi-parametric segmentation approach based on brain relaxometry was proposed. It includes a pre-processing step to estimate relaxation parameter maps (R1 = longitudinal relaxation rate, R2 = transverse relaxation rate, PD = proton density) from the signal intensities provided by MRI sequences of routine clinical protocols (3D-GrE T1-weighted, FLAIR and fast-T2-weighted sequences with ≤ 3 mm slice thickness). In the past, maps of R1, R2, and PD were obtained from Conventional Spin Echo (CSE) sequences, which are no longer suitable for clinical practice due to long acquisition times. Rehabilitating the multi-parametric segmentation based on relaxometry, the estimation of pseudo-relaxation maps allowed developing an innovative method for the simultaneous automatic segmentation of most of the brain structures (GM, WM, cerebrospinal fluid, thalamus, caudate nucleus, putamen, pallidus, nigra, red nucleus and dentate). This method allows the segmentation of higher resolution brain images for future brain phantom enhancements. - STL extraction. After segmentation, the 3D model of phantom is described in STL format, which represents the shapes through the approximation in manifold mesh (i.e., collection of triangles, which is continuous, without holes and with a positive – not zero – volume). For this purpose, we developed an automatic procedure to extract a single voxelized surface, tracing the anatomical interface between the phantom's compartments directly on the segmented images. Two tubes were designed for each compartment (one for filling and the other to facilitate the escape of air). The procedure automatically checks the continuity of the surface, ensuring that the 3D model could be exported in STL format, without errors, using a common image-to-STL conversion software. Threaded junctions were added to the phantom (for the hermetic closure) using a mesh processing software. The phantom's 3D model resulted correct and ready for 3DP. Prototyping. Finally, the most suitable 3DP technology is identified for the materialization. We investigated the material extrusion technology, named Fused Deposition Modeling (FDM), and the material jetting technology, named PolyJet. FDM resulted the best candidate for our purposes. It allowed materializing the phantom's hollow compartments in a single print, without having to print them in several parts to be reassembled later. FDM soluble internal support structures were completely removable after the materialization, unlike PolyJet supports. A critical aspect, which required a considerable effort to optimize the printing parameters, was the submillimetre thickness of the phantom walls, necessary to avoid distorting the imaging simulation. However, 3D printer manufacturers recommend maintaining a uniform wall thickness of at least 1 mm. The optimization of printing path made it possible to obtain strong, but not completely waterproof walls, approximately 0.5 mm thick. A sophisticated technique, based on the use of a polyvinyl-acetate solution, was developed to waterproof the internal and external phantom walls (necessary requirement for filling). A filling system was also designed to minimize the residual air bubbles, which could result in unwanted hypo-intensity (dark) areas in phantom-based imaging simulation. Discussions and conclusions. The phantom prototype was scanned trough CT and PET/CT to evaluate the realism of the brain simulation. None of the state-of-the-art brain phantoms allow such anatomical rendering of three brain compartments. Some represent only GM and WM, others only the striatum. Moreover, they typically have a poor anatomical yield, showing a reduced depth of the sulci and a not very faithful reproduction of the cerebral convolutions. The ability to simulate the three brain compartments simultaneously with greater accuracy, as well as the possibility of carrying out multimodality studies (PET/CT, PET/MRI), which represent the frontier of diagnostic imaging, give this device cutting-edge prospective characteristics. The effort to further customize 3DP technology for these applications is expected to increase significantly in the coming years

An electrophoretic study of fetal mouse brain proteins after in vivo exposure to phenytoin and disulfiram

Although there have been two-dimensional electrophoretic studies on fetal brain tissue (for instance, Yoshida and Takahashi, 1980), the emphasis in most of this work has been on developmental changes in protein expression, and not on the effects that drugs have on fetal brain protein complement. Klose and co-workers (1977) did an early study using two-dimensional gel electrophoresis to determine the effects of various teratogens on whole embryos. No protein changes were found and that line of research was not continued. In this study two-dimensional gel electrophoresis is extensively used, in the belief that the usefulness of this technique to experimental teratology has not been fully evaluated. It is reasonable to suppose that a central nervous system teratogen administered during critical periods of susceptibility will led to perturbations of orderly brain development, and that these perturbations will be reflected as changes to the protein complement. The total brain protein complement of mice that have been exposed to drugs in utero will therefore be analysed, in the hope that any inductions or deletions of proteins as a result of drug exposure may provide a clue to the molecular events underlying drug injury to the fetus

Smart Sensors for Healthcare and Medical Applications

This book focuses on new sensing technologies, measurement techniques, and their applications in medicine and healthcare. Specifically, the book briefly describes the potential of smart sensors in the aforementioned applications, collecting 24 articles selected and published in the Special Issue “Smart Sensors for Healthcare and Medical Applications”. We proposed this topic, being aware of the pivotal role that smart sensors can play in the improvement of healthcare services in both acute and chronic conditions as well as in prevention for a healthy life and active aging. The articles selected in this book cover a variety of topics related to the design, validation, and application of smart sensors to healthcare

The development of a near infrared spectroscopy system and its application for non invasive monitoring of cerebral blood and tissue oxygenation in the newborn infants

This project had two main objectives. The first of these was to design and construct a spectroscopic instrument to monitor small changes in optical transmission across an infant's head at several near infrared wavelengths resulting from changes in the cerebral oxygenation status. The overall attenuation of light by brain tissue is very high and is dominated by the scattering properties of the tissue. Hence a major requirement of the instrument was the ability to measure spectral changes at very low light levels. Once the instrument was available, the second objective was to convert the measured changes in optical transmission into changes in the concentration of the naturally occurring chromophores oxyhaemoglobin, deoxyhaemoglobin and oxidised and reduced cytochrome c oxidase. An important aspect of the work was that the chromophore concentration measurements should be quantified in non-arbitrary units. Medical Physics is, by its nature, highly interdisciplinary and this is reflected in the introductory chapter which briefly covers the clinical problems, the medical science background and the technical aspects of monitoring the cerebral oxygenation status of newborn infants. The second and third chapters examine those constituents of brain tissue which absorb and scatter light and how the complication of multiple scattering can be dealt with in performing quantitative spectroscopy. The fourth and fifth chapters describe the technical details of the instrument design and construction from the initial step of setting its design specifications to the final testing of its performance. The sixth chapter examines the absorption characteristics of the main chromophores of interest namely oxyhaemoglobin, deoxyhaemoglobin and the cytochrome enzymes of the respiratory chain within the brain cells. A discussion on the interpretation of the redox state of the respiratory enzymes in terms of the metabolic state of the brain is also included. The final chapter describes the data analysis methods, the measurement of optical pathlengths in scattering media and introduces a non-linear modification to the Beer-Lambert law which improves the accuracy of the spectroscopic measurements in highly scattering media

Advanced Applications of Rapid Prototyping Technology in Modern Engineering

Rapid prototyping (RP) technology has been widely known and appreciated due to its flexible and customized manufacturing capabilities. The widely studied RP techniques include stereolithography apparatus (SLA), selective laser sintering (SLS), three-dimensional printing (3DP), fused deposition modeling (FDM), 3D plotting, solid ground curing (SGC), multiphase jet solidification (MJS), laminated object manufacturing (LOM). Different techniques are associated with different materials and/or processing principles and thus are devoted to specific applications. RP technology has no longer been only for prototype building rather has been extended for real industrial manufacturing solutions. Today, the RP technology has contributed to almost all engineering areas that include mechanical, materials, industrial, aerospace, electrical and most recently biomedical engineering. This book aims to present the advanced development of RP technologies in various engineering areas as the solutions to the real world engineering problems

Front Lines of Thoracic Surgery

Front Lines of Thoracic Surgery collects up-to-date contributions on some of the most debated topics in today's clinical practice of cardiac, aortic, and general thoracic surgery,and anesthesia as viewed by authors personally involved in their evolution. The strong and genuine enthusiasm of the authors was clearly perceptible in all their contributions and I'm sure that will further stimulate the reader to understand their messages. Moreover, the strict adhesion of the authors' original observations and findings to the evidence base proves that facts are the best guarantee of scientific value. This is not a standard textbook where the whole discipline is organically presented, but authors' contributions are simply listed in their pertaining subclasses of Thoracic Surgery. I'm sure that this original and very promising editorial format which has and free availability at its core further increases this book's value and it will be of interest to healthcare professionals and scientists dedicated to this field

Imaging Sensors and Applications

In past decades, various sensor technologies have been used in all areas of our lives, thus improving our quality of life. In particular, imaging sensors have been widely applied in the development of various imaging approaches such as optical imaging, ultrasound imaging, X-ray imaging, and nuclear imaging, and contributed to achieve high sensitivity, miniaturization, and real-time imaging. These advanced image sensing technologies play an important role not only in the medical field but also in the industrial field. This Special Issue covers broad topics on imaging sensors and applications. The scope range of imaging sensors can be extended to novel imaging sensors and diverse imaging systems, including hardware and software advancements. Additionally, biomedical and nondestructive sensing applications are welcome

Multicentre evaluation of MRI variability in the quantification of infarct size in experimental focal cerebral ischaemia

Ischaemic stroke is a leading cause of death and disability in the developed world. Despite that considerable advances in experimental research enabled understanding of the pathophysiology of the disease and identified hundreds of potential neuroprotective drugs for treatment, no such drug has shown efficacy in humans. The failure in the translation from bench to bedside has been partially attributed to the poor quality and rigour of animal studies. Recently, it has been suggested that multicentre animal studies imitating the design of randomised clinical trials could improve the translation of experimental research. Magnetic resonance imaging (MRI) could be pivotal in such studies due to its non-invasive nature and its high sensitivity to ischaemic lesions, but its accuracy and concordance across centres has not yet been evaluated. This thesis focussed on the use of MRI for the assessment of late infarct size, the primary outcome used in stroke models. Initially, a systematic review revealed that a plethora of imaging protocols and data analysis methods are used for this purpose. Using meta-analysis techniques, it was determined that T2-weighted imaging (T2WI) was best correlated with gold standard histology for the measurement of infarctbased treatment effects. Then, geometric accuracy in six different preclinical MRI scanners was assessed using structural phantoms and automated data analysis tools developed in-house. It was found that geometric accuracy varies between scanners, particularly when centre-specific T2WI protocols are used instead of a standardised protocol, though longitudinal stability over six months is high. Finally, a simulation study suggested that the measured geometric errors and the different protocols are sufficient to render infarct volumes and related group comparisons across centres incomparable. The variability increases when both factors are taken into account and when infarct volume is expressed as a relative estimate. Data in this study were analysed using a custom-made semi-automated tool that was faster and more reliable in repeated analyses than manual analysis. Findings of this thesis support the implementation of standardised methods for the assessment and optimisation of geometric accuracy in MRI scanners, as well as image acquisition and analysis of in vivo data for the measurement of infarct size in multicentre animal studies. Tools and techniques developed as part of the thesis show great promise in the analysis of phantom and in vivo data and could be a step towards this endeavour

Models and analysis of vocal emissions for biomedical applications: 5th International Workshop: December 13-15, 2007, Firenze, Italy

The MAVEBA Workshop proceedings, held on a biannual basis, collect the scientific papers presented both as oral and poster contributions, during the conference. The main subjects are: development of theoretical and mechanical models as an aid to the study of main phonatory dysfunctions, as well as the biomedical engineering methods for the analysis of voice signals and images, as a support to clinical diagnosis and classification of vocal pathologies. The Workshop has the sponsorship of: Ente Cassa Risparmio di Firenze, COST Action 2103, Biomedical Signal Processing and Control Journal (Elsevier Eds.), IEEE Biomedical Engineering Soc. Special Issues of International Journals have been, and will be, published, collecting selected papers from the conference