Medizinische und biologische Physik

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http://hdl.handle.net/2003/38057

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Milli, micro, nano: Venturing to small scales in proton beam therapy physics for radiobiological research
(2023) Behrends, Carina; Bäumer, Christian; Lühr, Armin
In der Strahlentherapie ist es fundamental den Strahlenschaden im Hinblick auf die Tumorkontrolle und auf Normalgewebskomplikationen zu steuern. Somit müssen Therapieansätze einen Kompromiss zwischen der applizierbaren Dosis für den klonogenen Zelltod der Tumorzellen und möglichen Nebenwirkungen finden. Mithilfe von strahlenbiologischen Experimenten können weitere Erkenntnisse über die schädigende Strahlenwirkung gewonnen werden. Diese Arbeit stellt drei unterschiedliche und unabhängige Forschungsansätze in der Physik der Protonentherapie von der Größenordnung Millimeter bis zu Nanometer vor, um strahlenbiologische Experimente und damit den langfristigen Therapieerfolg zu verbessern. Im ersten Projekt wird eine Methode zur Optimierung der Feldformung bei der Behandlungsmodalität von gescannten Protonennadelstrahlen in Kombination mit kollimierenden Aperturen präsentiert. Eine optimierte Positionierung des Spots relativ zur Aperturkante erzeugt dabei eine kleinere laterale Penumbra. In einem zweiten Projekt wird ein Versuchsaufbau entwickelt und optimiert, um Protonen, die ursprünglich auf klinische Energien beschleunigt wurden, so effizient wie möglich mit einer beliebigen Energie bis hinunter zu wenigen MeV bereitzustellen. Mit einem optimalen Setup können niederenergetische Protonen mit maximaler Effizienz für strahlenbiologische Experimente bereitgestellt werden. Das dritte Projekt untersucht den strahlensensitiven Effekt von Platinnanopartikeln (PtNPs) in der Protonentherapie, der potentiell eine erhöhte Tumorkontrolle bei der Behandlung bewirken kann. Es wird experimentell nachgewiesen, dass der strahlensensitive Effekt von PtNPs in der Protonentherapie nicht in einer erhöhten Energiedeposition der Protonen auf makroskopischer Skala begründet liegt. Insgesamt liefern die in dieser Arbeit untersuchten Projekte individuelle Beiträge zur Physik in der strahlenbiologischen Forschung und damit zur Verbesserung der Strahlenwirkung in der Protonentherapie.
Establishing a new model system for phase state measurments: The "swimming neuron" Paramecium
(2022) Paeger, Anne; Schneider, Matthias F.; Westerhausen, Christoph
The origin of cellular excitability has not yet been clearly elucidated. It has been proposed that the nonlinear stimulus-response curve of excitable cells, manifesting in all-or-none pulses (action potentials), is based on a phase transition in the cell membrane and is not a purely molecule-based phenomenon. Indeed, typical traces of transitions have already been found in a small number of studies with excitable cells. Further investigations are needed to show whether these findings are of a general nature. In this work, state diagrams of the cell membrane of intact, motile specimens of the ”swimming neuron” Paramecium are measured. Therefore, individual cells were trapped in a microfluidic channel and investigated by fluorescence spectroscopy. The thermo-optical state diagrams exhibited reversible sigmoidal and break-like regimes, which are clear indications for a transition in the cell cortical membranes. This transition had a width of ∼ 10 − 15°C and a midpoint that was located ∼ 4°C below the growth temperature. It can be shifted due to changes in growth temperature or by the addition of an anesthetic (hexanol). These results suggested that the cortical membrane(s) of Paramecia reside in a phase transition regime under physiological growth conditions.
On the optical detection of the physical state of excitable membranes
(2022) Fedosejevs, Sara Carina; Schneider, Matthias F.; Mussel, Matan
Phase transitions in biological systems are controversially discussed. As the origin of nonlinearities, they have been suggested responsible for cellular functions including nerve pulse propagation. In pure lipid interfaces characteristic functions, such as permeability, are modulated during a transition. These relations could have drastic implications for cells because their membranes are lipid-based. However, evidence for these transitions in cellular membranes of excitable cells - which are involved in the transmission of nerve pulses - has not been provided so far. Within this thesis thermodynamic phase states in lipid-based interfaces are characterized based on the use of a fluorescent dye (Atto488-DPPE) as local state reporter. Optical state diagrams of artificial, lipid interfaces are recorded, and state dependent kinetics investigated. Upon the straightforward application of this method to single, neuronal cells, a nonlinearity in the optical response is detected within the cellular membrane and identified as phase transition. The transition is extraordinary sharp (1°C) and sensitive to pH variations in the extracellular buffer. The existence of distinct physical phase states in cellular membranes and their highly nonlinear characteristic provides strong evidence that the membrane state is indeed crucial for excitability and conduction of nerve pulses. The results further underline that the membrane state has the potential to modify cell functionality in general as it is subject to modulation by physiologically important parameters such as pH.
Optical action potential
(2021) Fabiunke, Simon; Schneider, Matthias F.; Bagatolli, Luis
Voltage sensitive dyes have been used as an alternative route to detect membrane potentials. This replaces electrophysiological equipment and allows to study action potentials with optical tools. Changes in fluorescence emission are most commonly translated into changes in transmembrane potentials. In this thesis, it is demonstrated that the emission energy of the fluorescent dye Di-4-ANEPPDHQ is a state variable. Incorporation of the dye in artificial lipid membranes, where ion transport is obsolete, changes of the emission spectrum as a function of lateral pressure and temperature were detected, as well as in the presence of lateral propagating pulses. It is found that despite the complete absence of transmembrane ion movement, the spectrum shifted about 20 nm at the main transition, which falsifies the Nernst-potential as the origin of the changes in emission. To underline the relevance for action potentials in living systems, the same dye is incorporated into an excitable plant cell to investigate action potentials. There, a very similar blue shift of the emission spectrum is found as in the monolayer pulse experiments. In summary, these experiments show that Di-4-ANEPPDHQ (presumably all dyes), should be seen as a phase state reporter. This is entirely consistent with the interpretation of the nervous impulse as a propagating state change as has been proposed by others. This interpretation allows to map the state and state changes optically not only of nerves, but even of the entire brain.
Technical note: Accuracy of MTF measurements with an edge phantom at megavoltage x-ray energies
(2019-10-03) Loot, Katharina; Block, Andreas
Purpose: Measurement of the modulation transfer function (MTF) is performed by evaluating the response of an imaging system to a predefined input. To obtain accurate results when using an edge phantom, the detector input signal must resemble an ideal step function. The MTF of megavoltage (MV) imagers used in radiotherapy has been measured with highly absorbing edge phantoms fabricated from thick metal blocks. This study investigates the influence of the edge phantom design on the accuracy of the resulting MTF. Methods: The MTF of an electronic portal imaging device (EPID) was measured at 6 MV beam quality with four edge phantoms made of lead with 1.3, 3.3, 5.0, and 10.0 cm thickness. Monte Carlo simulations were carried out for these and a selection of tungsten phantoms to determine the photon fluence at the imaging plane and quantify the systematic error in the MTF introduced by the edge phantom design. Results: The measured MTF depends on the design of the edge phantom. The detector input signal of a thin phantom is affected by secondary radiation from the phantom itself, causing an overestimation of the MTF. The amount of secondary radiation can be reduced by increasing the phantom thickness or introducing an air gap between the phantom and the detector. Both methods introduce geometric unsharpness, which can result in an underestimation of the true MTF. Edge phantoms made from 4.0 cm thick tungsten or 5.0 cm thick lead induce comparatively small systematic errors of below 3% or 5%, respectively. Conclusions: When MTF measurements are conducted at MV energies, even a highly absorbing edge phantom will introduce a systematic error of several percent. Direct comparison of MTFs obtained with different edge phantoms should therefore be treated with caution.
Nonlinear pulses at the interface and its relation to state and temperature
(2020-02-05) Kang, Kevin H.; Schneider, Matthias F.
Environmental temperature has a well-conserved effect on the pulse velocity and excitability of excitable biological systems. The consistency suggests that the cause originates from a fundamental principle. A physical (hydrodynamic) approach has proposed that the thermodynamic state of the hydrated interface (e.g., plasma membrane) determines the pulse behavior. This implies that the temperature effect happens because the environmental temperature affects the state of the interface in any given system. To test the hypothesis, we measured temperature-dependent phase diagrams of a lipid monolayer and studied the properties of nonlinear acoustic pulses excited along the membrane. We observed that the membrane in the fluid-gel transition regime exhibited lower compressibility (i.e., stiffer) overall with increasing temperature. Nonlinear pulses excited near the transition state propagated with greater velocity with increasing temperature, and these observations were consistent with the compressibility profiles. Excitability was suppressed significantly or ceased completely when the state departed too far from the transition regime either by cooling or by heating. The overall correlation between the pulses in the membrane and in living systems as a function of temperature supports the view that the thermodynamic state of the interface and phase transition are the key to understanding pulse propagation in excitable systems.
Measurement of the modulation transfer function with an edge phantom at megavoltage energies
(2020) Loot, Katharina; Block, Andreas; Spaan, Bernhard
The quality of a medical imaging system is determined by how well it transfers diagnostically important information. In terms of spatial resolution, the performance of a system can be objectively characterized by the modulation transfer function (MTF), which describes the transfer of image structures as a function of spatial frequency. MTF measurements at MV energies have previously been conducted with a wide variety of phantoms. The partly contradictory reports raise the question whether the MTF is influenced by the phantom design and, if so, what size of systematic error to expect. This thesis presents MTF measurements on a clinical MV portal imaging system used during radiation therapy. The influences of geometric unsharpness, absorption unsharpness and scatter on the measurement are investigated using Monte Carlo simulations. To quantify the impact of the phantom design on the MTF, a new method is developed that calculates the systematic error in an MTF measurement based on Monte Carlo simulations of the detector input signal. Several edge phantoms are presented which provide high measurement accuracy for a 6 MV photon beam. The results are applicable to all MV imaging devices operated with a comparable beam quality.
Similarities between action potentials and acoustic pulses in a van der Waals fluid
(2019-02-21) Mussel, Matan; Schneider, Matthias F.
An action potential is typically described as a purely electrical change that propagates along the membrane of excitable cells. However, recent experiments have demonstrated that non-linear acoustic pulses that propagate along lipid interfaces and traverse the melting transition, share many similar properties with action potentials. Despite the striking experimental similarities, a comprehensive theoretical study of acoustic pulses in lipid systems is still lacking. Here we demonstrate that an idealized description of an interface near phase transition captures many properties of acoustic pulses in lipid monolayers, as well as action potentials in living cells. The possibility that action potentials may better be described as acoustic pulses in soft interfaces near phase transition is illustrated by the following similar properties: correspondence of time and velocity scales, qualitative pulse shape, sigmoidal response to stimulation amplitude (an ‘all-or-none’ behavior), appearance in multiple observables (particularly, an adiabatic change of temperature), excitation by many types of stimulations, as well as annihilation upon collision. An implication of this work is that crucial functional information of the cell may be overlooked by focusing only on electrical measurements.

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