Center for Advanced Preclinical Imaging - Invitation to Hands-On Workshop
Luděk Šefc, Pavla Francová, Věra Kolářová, Karla Palma
Center for Advanced Preclinical Imaging (CAPI), 1st Medical Faculty, Charles University, Prague, Czech Republic
Center for Advanced Preclinical Imaging (CAPI), First Faculty of Medicine, Charles University (Prague) – member of Czech-BioImaging (a national research infrastructure for biological and medical imaging), invites you to a Hands-On Workshop on preclinical in-vivo imaging of small laboratory animals.
CAPI is equipped with following preclinical imaging modalities:
Magnetic Particle Imaging (MPI) – MPI scanner (Bruker)
Optical Imaging (OI) – Xtreme In Vivo (Bruker)
Magnetic Resonance (MRI) – ICON (Bruker)
CT-PET/SPECT imaging – Albira (Bruker)
Ultrasound – Photoacoustic imaging (US – PA) – Vevo LAZR X (VisialSonics)
High resolution spectral X-ray scanner (Advacam)
The workshop will be focused on the following topics:
a) Animal-handling, anesthesia, contrast agent application, animal monitoring system
b) multimodal imaging
c) comparing X-radiography using different detection systems (CCD, flat panel and WidePix detectors)
The workshop will be held within CAPI in Prague, i.e. Salmovská 3, 120 00 Praha 2, Czech Republic, http://www.capi.lf1.cuni.cz
on Monday 4. 6. 2018 from 14.00 to 18.00.
Mechanistic modelling of subcellular and cellular radiation effects with PARTRAC
Werner Friedland, Pavel Kundrát
Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany
PARTRAC  is a biophysical simulation tool for modelling radiation effects on subcellular and cellular scales. Starting from cross section databases, it simulates the stochastic nature of individual energy deposition and transport events for photons, electrons, protons and light ions over a wide energy range occurring naturally or in medical and technical applications. Subsequently, the formation of reactive species, their diffusion and mutual reactions are modelled. Induction of damage to cellular DNA is simulated taking into account both direct energy deposits and attacks of reactive species. To this end, multi-scale models of DNA and chromatin structures are implemented, ranging from the double-helix wrapped around histones, over formation of chromatin fibres, loops and domains, to chromosomes in territories of the spherical or ellipsoidal nucleus. In the next module, DNA damage response through non-homologous end-joining of double-strand breaks is followed, explicitly considering both temporal and spatial aspects by modelling enzymatic processing and mobility of DNA termini. Correct rejoining, misrejoining and the formation of chromosome aberrations are distinguished including specific structural abnormalities like dicentrics. Work in progress aims at extending PARTRAC to the endpoint of cell killing. The processes represented, methods used, and benchmarking against data will be discussed. Recent results will be presented on ion-induced DNA damage  and induction of dicentrics after ion microbeam irradiation . Future development of PARTRAC will be discussed, too.
 Friedland, Dingfelder, Kundrát, Jacob (2011) Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC. Mutation Research 711:28-40.
 Friedland et al. (2017) Comprehensive track-structure based evaluation of DNA damage by light ions from radiotherapy-relevant energies down to stopping. Scientific Reports 7:45161.
 Friedland et al. (2018) Modelling studies on dicentrics induction after sub-micrometer focused ion beam grid irradiation. Radiation Protection Dosimetry, submitted.
The use of Monte Carlo simulations to optimise new detector designs
Susanna Guatelli, David Bolst, James Vohradsky, Linh Tran, Jeremy Davis, Anatoly Rozenfeld
Centre For Medical Radiation Physics, University of Wollongong, Wollongong, Australia
Monte Carlo simulations, modelling particle interactions with matter, are a very useful tool to design and improve novel radiation detectors. Geant4 (www.geant4.org
) is a free, open-source Monte Carlo Toolkit, with applications spanning from High Energy Physics to medical physics and space science. It is used at the Centre For Medical Radiation Physics (CMRP), University of Wollongong, to improve the design of new silicon detectors for radiotherapy Quality Assurance and radiation protection. Geant4 is also used to characterise the response of the novel detectors in radiation fields of interest, supporting the experimental characterisation of the devices.
The talk will be dedicated to the description of a Geant4-based study aimed to improve the design of Silicon-On-Insulator (SOI) microdosimeters for Quality Assurance in proton, carbon ion and Boron Neutron Capture therapies. Since the 90’s, the CMRP is developing SOI microdosimeters as alternative to conventional tissue equivalent proportional counters (TEPCs), which have several limitations such as high voltage operation, large size of assembly which reduces spatial resolution and an inability to measure an array of cells.
In particular, Geant4 has been used to develop a methodology to convert microdosimetry measurements in silicon to tissue and to optimize the dimensions of the silicon sensitive volumes of the device. It has also been used to predict the detector response when irradiated in proton (e.g. MGH, Boston, US and IThemba Labs, Cape Town, South Africa) and carbon ion therapy (e.g. HIMAC, NIRS, Chiba, Japan) facilities. The use of Geant4 in microdosimetry has been validated with respect to experimental measurements.
Additive Manufacturing in Medicine
Radovan Hudak, Jozef Zivcak
Department of Biomedical Engineering and Measurement, Technical University of Kosice, Košice, Slovakia
Nowadays, additive manufacturing otherwise known as three-dimensional (3D) printing is fully implemented into the production of hard tissue replacements. Department of Biomedical Engineering and Measurement together with CEIT Biomedical Engineering company designed and produced more then 35 implants made of titanium alloy using additive technologies, which were subsequently implanted by Slovak and foreign surgeons. 3D printing of PEEK, bioceramic and magnesium alloys implants is recently tested to offer alternative materials to titanium for cranioplasties or biodegradable impalnts. 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. Compared with non-biological printing, 3D bioprinting involves additional complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical challenges related to the sensitivities of living cells and the construction of tissues. The 3D bioplotter (Envisiontec, Germany) was used to prepare tubular structures made of biodegradable PLA + PHB polymer for substitutes of human urethra. Tubular structures were tested from geometrical point of view to assure required precision, repeatability and possibility to print porous structures for application of epithelial and muscle cells and their growth. Several studies on PEEK spinal implants manufactured by 3D printing were accomplished, where mechanical testing, simulations and testing of biocompatibility were implemented. Presented research covers selected case studies of patient specific implants made by additive manufacturing and research in medical 3D printing and 3D bioprinting.
Track structure simulations with Geant4-DNA
IN2P3, CNRS, GRADIGNAN, France
The Geant4-DNA (http://geant4-dna.org
) extension to the Geant4 (http://geant4.org
) general purpose Monte Carlo toolkit aims to provide an open access platform capable of simulating ionising radiation induced early biological damage at the sub-cellular scale. This extension is entirely included in Geant4 and can be used to simulate step-by-step physical interactions of particles (electrons, protons, alpha particles including their charge states, and a few ions) down to very low energies in liquid water and select biological materials, thanks to a variety of physics models. In this lecture, we will present the functionalities of Geant4-DNA for the simulation of track structures. Example applications will be shown using our freely accessible Geant4 Virtual Machine.
Electronic devices can motivate patients during rehabilitation
Ákos Jobbágy1, Gábor Fazekas2, István Valálik3
1 Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary
2 National Institute for Medical Rehabilitation, Budapest, Hungary
3 Szent János Hospital, Budapest, Hungary
Physical therapy or physiotherapy aims to remediate impairments and to improve functioning. The main phases of physiotherapy are: functional assessment, setting up the therapeutic plan and physical intervention. The rehabilitation is more effective if the patient is motivated. The following electronic devices were developed at the Department of Measurement and Information Systems, Budapest University of Technology and Economics to aid rehabilitation: passive marker based analyzer of movement (PAM), a smart Nine-Hole Peg Tester and an input position and rotation sensor to Huple®, a special hemisphere-like tool for the habilitation of children with birth injuries.
PAM is a 2D analyzer, able to determine the x-y coordinates of passive markers moving basically in a plane. Finger tapping, tremor of the face, hand- and arm tremor and balance were tested. The recordings make possible the objective evaluation of patients’ actual state, an important feedback for their therapy.
The Nine-Hole Peg Test requires the tested person to pick nine pegs up from the holder and place them in the holes in the board in arbitrary order and then remove the pegs. The smart Nine-Hole Peg Tester features light emitting diodes, thus guided tests with different difficulties can be performed. Patients can use the smart device without supervision. Certain patients enjoyed the guided tests and were keen on improving their results. This increased the efficiency of their rehabilitation.
Gézengúz Foundation for Children with Birth Injuries uses the patented hemisphere-like tool, Huple®, to improve the balance ability of children with disability. Attaching an integrated 3D orientation sensor, x-IMU to Huple® allows the objective assessment of the actual movement control of the child sitting in it. An interface was developed to Huple® thus children can control simple PC games by tilting the hemisphere. As a result, they are motivated, they playfully improve their balancing ability.
Technologies to capture real world use of assistive devices
Centre for Health Sciences Research, University of Salford, Salford, United Kingdom
There is a bewildering range of devices now available to assist functional movement for those with physical impairments. Many of the devices on the market have limited evidence of efficacy, making the selection of the appropriate device for a given patient difficult. The clinical studies of efficacy which have been published, generally focus on parameters which can easily be measured in the lab or clinic, sometimes combined with self-report or interview feedback from the user. Very few studies report objective data on how, where and when the devices are actually used in everyday life. The lecture will first discuss why capturing data on real world usage of assistive devices is of potentially significant value to researchers, manufacturers and clinicians. A number of case studies will then be presented, focusing on real world monitoring of prostheses, walking aids and wheelchairs. Finally, a discussion of how such approaches could be used to better evidence the effectiveness of assistive devices, as well as some of the challenges such technologies raise, will be presented.
Introduction to equation-based modeling and simulation with Modelica and OpenModelica with focus on physiology modeling using Physiolibrary
Jiří Kofránek1, Filip Ježek2, Jan Šilar1
1 Institute of Pathophysiology, Charles University, 1st Faculty of Medicine, Prague, Czech Republic
2 Department of Cybernetics, Czech Technical University, Faculty of Electrical Engineering, Prague, Czech Republic
The development of models of human physiology was facilitated by a new generation of simulation environments using Modelica language. Fundamental innovation of Modelica language is the possibility to describe individual parts of the model as a system of equations directly describing the behavior of that part and not the algorithm of solving of these equations (see http://physiome.cz/modelica.pdf
This tutorial gives an introduction to the Modelica language, the OpenModelica environment, and an overview of modeling and simulation in a number of application areas.
The tutorial will show acausal approach of modeling physiological system using Physiolibrary, an open-source library for biomedical modeling, which allows presenting complex models composed from different domains in comprehensible and maintainable form. Together with participants, models will be constructed of cardiovascular system, chemical reactions, body thermal transfer, osmotic phenomenon and integrative approach. Attendees should bring their own computers to participate in the hands-on sections of the tutorial.
Based on participants previous knowledge, tutorial may be extended to introduction of model-based dynamic optimization with OpenModelica including goal functions, constraints, convergence and other advanced features of OpenModelica. Bring your laptop for exercises.
First part of tutorial will introduce acausal and object oriented Modelica language using an open-source tool OpenModelica (www.openmodelica.org
) and a commercial tool Dymola. Attendees can install the open-source OpenModelica tool in advance before the tutorial.
The second part of the tutorial will consist of hands-on sections that will demonstrate building selected models of 1) cardiovascular system dynamics – using hydraulic domain. 2) common biochemical reactions – using chemical domain. 3) body thermal transfers with blood flow using thermal domain 4) liquid volume of the penetrating solution in intracellular space, extracellular space, interstitial space, blood plasma or cerebrospinal fluid using osmotic domain 5) integrative approach which connects these domains together.
Advanced Implantable Cardiac Devices Settings and Patient Troubleshooting
Institute of Nursing, Silesian University, Faculty of Public Policies, Opava, Czech Republic
To the implantable cardiac devices belong now the pacemakers, implantable defibrillators and subcutaneous defibrillators. The aim of this tutorial is to show the possibilities of the recent programmable features within these devices and their using in practice. The troubleshooting part of the tutorial provides the overview of most common issues to solve in the clinical practice, like supporting/elimination of own patient rhythm, individual need of pacing, environment and electromagnetic disturbance. The technical standardization requirement will also be covered.
For dual chamber pacemakers, the timing of ventricular pacing, realized by AV delay parameter, is fundamental. It can be either fix or dynamic, incorporated the specific algo-rithms for AV delay extension. As the ventricular filling phase influences the patient hemo-dynamics, and an abundance of ventricular paced beats should be avoided, this parameter is critical.
For implantable defibrillators, the optimization of tachycardia detection process is of primary importance. False-positive shocks are quite often in the praxis. Therefore the trends of patient rhythm should be evaluated during ambulatory follow-ups and detection settings adjusted appropriately. Detection zones, sensing threshold, duration, morphological algo-rithms – all these parameters will be discussed in details. The similar situation is for subcuta-neous defibrillators, where however the settings have no so many options.
All implantable cardiac devices settings should be individualized. This educational course helps to better understanding of advanced settings.
Event related potentials: principles and practice
Dep. of Pathological Physiology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
The tutorial will introduce registration and analysis of the electrical activity of the brain associated with visual stimuli. In the first part, the principles of registration together with their clinical and experimental use (e.g. in brain computer interface) will be presented. In the second part, a live registration of sensory and cognitive potentials (ERPs) will be conducted among interested course participants. Registered data will be available on-line for a simple immediate ERP analysis. The tutorial should give an overview of ERP strengths and weaknesses for a future project build by the course participant.
Measurement and calculation of x-ray and neutron doses outside the treatment volume
Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, United States
Advances in radiotherapy have greatly improved our ability to deliver conformal tumor doses while minimizing the dose to adjacent organs at risk. However, there remains concern over stray radiation to normal tissues away from the treatment field as this radiation may induce second cancers, cardiac disease, and other late effects. This risk is becoming more relevant as patients live longer after treatment, providing an increased opportunity for late effects to manifest. In order to assess the potential risk to the patient, it is first necessary to know what radiation exposure the patient is subjected to. While the treatment planning system reports the dose in and near the treatment field, it does not provide reliable (if any) dosimetric information away from the field edge, and it does not provide any information on neutron doses. A serious challenge exists in that the assessment of stray x-ray and neutron doses can involve unique considerations. For example, when measuring the dose outside the treatment field, it is often important to consider the radiation energy spectrum, dose rate, and general shape of the dose distribution (particularly the percent depth dose), which are very different outside than inside the treatment field. Neutron dosimetry is also particularly challenging, and common errors in methodology can easily manifest as errors of several orders of magnitude. Calculation of the non-target dose (whether by Monte Carlo or analytical solutions) similarly requires unique consideration.
This presentation will highlight the recommendations from the recently published AAPM Task Group 158 report on non-target doses to provide guidance and strategies for physicists to measure and calculate x-ray and neutron doses away from the treatment field. This presentation will do this in the context of risks to the patient and clinical considerations.
Modelling radiation effects beyond single-cell level
Pavel Kundrát, Werner Friedland
Department of Radiation Sciences, Helmholtz Zentrum München, Neuherberg, Germany
Dedicated models of tissue responses to radiation depict the sigmoidal dose-effect relationship of tumor control and normal tissue complication probabilities (TCP and NTCP) in radiotherapy . Refining simple tools like the logistic or Poisson models, current descriptive and mechanistic approaches account for non-uniform dose distributions, hierarchical tissue organization, and effects of fractionation. Cellular automaton models represent individual cells and underlying processes such as cell growth and loss or angiogenesis in stochastic terms. Descriptive and mechanistic models of diverse levels of complexity exist also for long-term health risks, namely for radiation-induced cancer and cardiovascular diseases.
Another class of models [2-4] represent the fact that cells respond to any stressor, including ionizing radiation, not as independent entities but in a highly coordinated manner within tissues. The bystander phenomenon clearly illustrates this: Cells directly hit by ionizing radiation emit signals to which neighbor cells react and exhibit similar responses as the hit cells, including DNA damage or cell kill. Ionizing radiation modulates existing signaling processes and their outcomes, e.g. the anticarcinogenic process removing transformed cells upon signaling with normal cells.
An overview of the above-mentioned models will be given, focusing on their mechanistic background and practical applications.
 Friedland, Kundrát (2014) Modeling of radiation effects in cells and tissues. In: Brahme (Ed.) Comprehensive Biomedical Physics, 9:105-142. Amsterdam: Elsevier.
 Kundrát, Friedland (2016) Enhanced release of primary signals may render intercellular signalling ineffective due to spatial aspects. Scientific Reports 6:33214.
 Kundrát, Friedland (2015) Mechanistic modelling of radiation-induced bystander effects. Radiation Protection Dosimetry 166:148-151.
 Kundrát et al (2012) Mechanistic modelling suggests that the size of preneoplastic lesions is limited by intercellular induction of apoptosis in oncogenically transformed cells. Carcinogenesis 33:253-259.
Biological Cells and Tissues in Electric Fields
Faculty of Electrical Engineering and Computing, University of Zagreb, Zagreb, Croatia
Today, biological cells and tissues are exposed to electric fields in order to induce certain biological effect - for instance, the electroporation of cell membranes. The exposure is, however, often unintentional coming from numberless electrical devices. In this tutorial we present basic methodology for modeling and understanding the electrical response of biological cell and tissue to harmonic and pulsed electric fields of various intensities and frequencies. The focus is on short-term electrical and thermal response of tissue to high intensity pulsed electric field used in electrochemotherapy and electro gene therapy. The methodology is based on basic concepts of electromagnetic theory.
Challenge of nanotechnology in radiotherapy and hadrontherapy
Technologies supporting diagnostics and therapy of diabetes with special attention to tele-homecare and the artificial pancreas
Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Warsaw, Poland
Diabetes is one of the most challenging medical problems worldwide. The tutorial will review technologies, which are used to support diagnostics, monitoring and treatment of diabetes. It will cover the state of the art and recent developments in: (1) the intermittent and continuous glucose monitoring, (2) the glycated hemoglobin A1c monitoring and interpretation, (3) the subcutaneous insulin infusion using the conventional portable pumps, patch pumps and implantable pumps, (4) the alternative routes of insulin delivery, (5) decision support systems in the intensive insulin therapy, (6) the tele-homecare support of the diabetes treatment applying eHelath and mHealth systems, and (7) the artificial pancreas systems, including electromechanical, biological, bioartificial and biochemical solutions.
MRI Physics for the non-specialist: understanding the basics to appreciate the current advances
School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, United Kingdom
MRI uses signals generated by nuclear magnetic resonance (NMR) of hydrogen nuclei (protons) in water. The signal frequency depends on the strength of the magnetic field, typically 1.5 tesla (NMR frequency 64 MHz) or 3.0 T (NMR frequency 128 MHz. Three spatial-encoding methods are employed, all of which use the concept of the magnetic field gradient. By sending electrical current (hundreds of amperes) through a gradient coil, an extra magnetic field is produced, the strength of which varies linearly with position inside the scanner bore. The scanner includes three independent gradient coils, generating magnetic field gradients along the principal axes X, Y and Z. In frequency-encoding, the NMR signal is recorded while a field gradient is applied. Since the magnetic field varies with position along the gradient direction, the NMR resonant frequency (also called the Larmor frequency) is a function of position, so the detected signal contains a range of frequencies; analysing the frequency content generates a one-dimensional projection of the water-distribution within the patient. The technique called phase-encoding is employed in the second in-plane dimension; here, the gradient is pulsed on and off prior to measurement of the signal, altering the phase of the NMR signal as a function of position. Finally, the slice itself is defined using selective-excitation, in which the excitation 90-degree radiofrequency pulse is specially-shaped and is applied in the presence of a field gradient perpendicular to the slice plane (e.g. along Z for a transaxial X-Y slice). In order to generate data for an NxN image, the pulse sequence is usually applied N times, varying the phase-encode gradient amplitude with each repetition. A two-dimensional Fourier transform of the raw data matrix (the “k-space” data) yields the MR image, which can be encoded with the disease-dependent NMR parameters (T1, T2, diffusion etc.) to aid diagnosis.