Dr. Martin Niklas
Next Generation Biophysical Hybrid Detectors
Particle therapy with protons and heavier ions such as helium, carbon or oxygen are revolutionizing radiotherapy towards precision oncology. Particles deposit their energy precisely in the tumor volume while sparing the surrounding normal tissue. Despite the rapid clinical success of particle therapy there is still a great lack in understanding the fundamental mechanisms linking physical energy deposition by the ions and the biological response on cellular, subcellular and molecular scale. Understanding this relationship is yet crucial for further implementation of ion therapy into oncological concepts.
A next generation biodosimetric tool was thus engineered employing the hybrid technology cell-fluorescent ion track hybrid detector (Cell-Fit-HD) [1-8]. It comprises a fluorescent nuclear track detector (FNTD, physical compartment); a device for individual particle detection as well as a substrate for viable cell-coating (biological compartment, Figure 1). Cell-Fit-HD provides full 3D visualization and direct spatial correlation of the physical energy deposition by single ions and the corresponding subcellular events in clinical ion beams.
Figure 1. (A) Two FNTDs. (B) FNTD read-out signal by confocal microscopy after perpendicular irradiation with carbon (C-12) ions. (C) Viable biological compartment (A549 cell layer) on the physical compartment (FNTD) labelled with Calcein AM. (D) Co-registration of read-out signal from physical and biological compartment. The red spots are single ion traversals. Cell nuclei are labelled with HOECHST (blue).
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Our mission is the further development of the hybrid detector to establish a novel biomedical imaging platform (in-vitro). It allows online-monitoring of individual tumor cells up to 96 h after clinical irradiation. We are able to precisely correlate cellular damage on sub-cellular and single cell level to the individual physical energy deposition in the cell nucleus. Based on these measurements, we can track cells, monitor their fate, and correlate it with named parameters to study the relationship of dose deposition and cell fate on the single cell level. Further we apply molecular tools to investigate physiological responses of single cells as a function of dose in real-time. This allows to study radiation biology with high temporal and contextual resolution. Our interdisciplinary project group is thus working at the interface of live sciences, medicine and physics.
Our key interests are:
- Online-Monitoring of DNA repair kinetics associated to single particle traversals up to 96 h (Figure 2)
Figure 2. Spatial correlation of radiation-induced foci induction in A549 cells with single ion traversals (C-12, physical dose= 1.5 Gy). A: Endogenous 53BP mCherry signal (~15 min post irradiation).B: Corresponding g-H2AX signal. C: Single ion traversals. D: Spatial correlation of single ion traversal (gray) with endogenous 53BP signal (red) in a nucleus (highlighted in A and B). E: Spatial correlation of single ion traversal (red) with g-H2AX signal (green) in the nucleus (highlighted in A and B). F: Spatial correlation of g-H2AX signal (green) with endogenous 53BP signal (red) in the nucleus (highlighted in A and B).
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- Access of physical beam parameters in individual subcellular compartments
- Correlation of individual cellular response to the ion's physical energy deposition
- Ascertain relative biological effectiveness (RBE) values to single cell dose deposition
- Studying the effects of pharmaceutical drugs on irradiation response
- Resolve the ion's energy deposition beyond diffraction limit (Figure 3)
Figure 3. Image acquired by STED microscopy to resolve individual ion trajectory beyond diffraction limit. In cooperation with Division of Optical Nanoscopy (DKFZ, Hell) and Research Group Ion Beam Therapy (DKFZ, Greilich)
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To succeed our goals we have collaborations with
- Research Group Ion Beam Therapy (Greilich) at German Cancer Research Center
- Landauer, Inc, USA
- University Hospital Heidelberg and Heidelberg Ion-Beam Therapy Center
- Leiden University Medical Center
Reference:
[1] Greilich et al., Radiat. Meas., 2013
[2] Niklas and Greilich et al., Radiat. Oncol., 2013
[3] Niklas et al., Phys. Med. Biol., 2013
[4] Niklas et al., Int. J. Radiat. Oncol., 2013
[5] Niklas, PhD Thesis, University of Heidelberg 2014
[6] Dokic et al., Front. Oncol., 2015
[7] Dokic and Mairani et al., Oncotarget, 2016
[8] Niklas et al. Phys. Med. Biol., 2016