Nanoparticles, especially from carbon, have great potential in biomedicine. However, prior to clinical use, biocompatibility and biodistribution of these nanoobjects have to be assessed. Currently, particle detection is mostly based on surface‐bound labels, inevitably altering materials' properties by surface modification. Further obstacles include bleaching, dissociation of labels from the surface, weak emission of fluorophores due to insufficient tissue opacity or hampered light penetration or the need for specific excitation wavelengths. These characteristics greatly constrain employment of such nanoparticles to address complex analytical questions. To overcome these drawbacks, the use of intrinsic structural features of nanoobjects is highly desirable: the particle surface remains unchanged and the nanoobject exhibits its innate behavior. Thus, for sensitive detection and quantification, labels should be incorporated in the nanoparticle core, thereby avoiding cleavage and warranting unchanged surface characteristics. The incorporation of clinically approved radionuclide 32P into the lattice of nanodiamond particles using highly defined ion implantation is described here. The properties, uptake, and biodistribution are studied in vivo, in the developing hen's egg model (hen's egg test on chorioallantoic membrane assay). It is found that 32P labeling of diamond nanoparticles allows their reliable localization and sensitive quantification in a cost efficient, highly reliable, and safe way using available autoradiographic devices and analytical methods.

Intrinsically 32P-Labeled Diamond Nanoparticles for In Vivo Imaging and Quantification of Their Biodistribution in Chicken Embryos

While quantum theory has been tested to an incredible degree on microscopic scales, quantum effects are seldom observed in our everyday macroscopic world. The curious results of applying quantum mechanics to macroscopic objects are perhaps best illustrated by Erwin Schrodinger's famous thought experiment, where a cat can be put into a superposition state of being both dead and alive. Obviously, these quantum predictions are in stark contradiction to our common experience. Even with plenty of theoretical explanations put forward to explain this discrepancy, a large number of questions about the frontier between the quantum and the classical world remain unanswered.

To distinguish between classical and quantum behavior, two fundamental concepts inherent to classical physics have been established over the years: The world view of local realism limits the power of classical experiments to establish correlations over space, while the world view of macroscopic realism (or macrorealism) restricts temporal correlations. Necessary conditions for both world views have been formulated in the form of Bell and Leggett-Garg inequalities, and Bell inequalities have been shown to be violated by quantum mechanics through increasingly conclusive experiments. Furthermore, many challenging steps towards convincing violations of macrorealism have been taken in a number of recent experiments.

In the first part of this thesis, conditions for macrorealism are analyzed in detail. Two necessary conditions for macrorealism, the original Leggett-Garg inequality and the recently proposed no-signaling in time condition, are presented. It is then shown that a combination of no-signaling in time conditions is not only necessary but also sufficient for the existence of a macrorealistic description. Finally, an operational formulation of no-signaling in time, in terms of positive-operator valued measurements and Hamiltonians, is derived.

In the next part, we argue that these results lead to a suitable definition of classical behavior. In particular, we provide a formalism to judge the classicality of measurements and time evolutions. We then proceed to apply it to a number of exemplary measurement operators and Hamiltonians. Finally, we argue for the importance of spontaneously realized Hamiltonians in our intuition of classical behavior.

Next, differences between local realism and macrorealism are analyzed. For this purpose, the probability polytopes for spatially and temporally separated experiments are compared, and a fundamental difference in the power of quantum mechanics to build both types of correlations is discovered. This result shows that Fine's theorem, which states that a set of Bell inequalities is necessary and sufficient for local realism, is not transferable to macrorealism. Thus, (Leggett-Garg) inequalities are in principle not well-suited for tests of macrorealism, as they can never form a necessary and sufficient condition, and unnecessarily restrict the violating parameter space. No-signaling in time is both better suited and more strongly motivated from the underlying physical theory.

In the final part of this thesis, a concrete experimental setup for implementing quantum experiments with macroscopic objects is proposed. It consists of a superconducting micro-sphere in the Meisner state, which is levitated by magnetic fields. Through its expelled magnetic field, the sphere's center-of-mass motion couples to a superconducting quantum circuit. Properly tuned, ground state cooling can be realized, since the sphere's motion is extremely well isolated from the surrounding environment. This setup therefore is a promising candidate for the observation of quantum effects in macroscopic systems.

Quantum violation of classical physics in macroscopic systems

Purpose: Treatment of urethral strictures is a major challenge in urology. For investigation of different treatment
methods an animal model was developed by reproducible induction of urethral strictures in rabbits to mimic the human
clinical situation. By means of this model the potential of endoluminal LDR brachytherapy using β-irradiation as
prophylaxis of recurrent urethral strictures investigated.
Material and Methods: A circumferential urethral stricture was induced by energy deposition using laser light
application (wavelength λ=1470 nm, 10 W, 10 s, applied energy 100 J) in the posterior urethra of anaesthetized New
Zealand White male rabbits. The radial light emitting fiber was introduced by means of a children resectoscope (14F).
The grade of urethral stricture was evaluated in 18 rabbits using videourethroscopy and urethrography at day 28 after
stricture induction.
An innovative catheter was developed based on a β-irradiation emitting foil containing 32P, which was wrapped around
the application system. Two main groups (each n=18) were separated. The "internal urethrotomy group" received after
28days of stricture induction immediately after surgical urethrotomy of the stricture the radioactive catheter for one week
in a randomized, controlled and blinded manner. There were 3 subgroups with 6 animals each receiving 0 Gy, 15 Gy and
30 Gy. In contrast animals from the “De Nuovo group” received directly after the stricture induction (day 0) the
radioactive catheter also for the duration of one week divided into the same dose subgroups. In order to determine the
radiation tolerance of the urethral mucosa, additional animals without any stricture induction received a radioactive
catheter applying a total dose of 30 Gy (n=2) and 15 Gy (n=1). Cystourethrography and endoscopic examination of
urethra were performed on all operation days for monitoring treatment progress. Based on these investigation a
classification of the stricture size was performed and documented for correlation. At further 28 days after catheter
removal the animals were euthanasized and the urethra tissue was harvested. Histological examination of tissue with
assessment of radiation damage, fibrotic and inflammatory changes were performed. After deblinding histological
finding were correlated with the applied dose.
Results: All animals developed a stricture, while 15/18 (83,3%) showed a significant, high grade stricture with more
than 90% lumen narrowing. Histopathological examination including evaluation of urethral inflammation, fibrosis and
collagen content were investigated in additional 6 rabbits confirming the former findings. No rabbits died prematurely
during the study.
The experiments showed that the procedure of the application of radioactive catheter was safe without any problems in
contamination and protection handling. The combination of internal urethrotomy and LDR-brachytherapy results in a
stricture free rate of 66.7% in the 15-Gy group, compared with only 33.3% among animals from the 0- and 30-Gy
groups. Furthermore histological classification of inflammation and fibrosis of 0 Gy and 15 Gy showed similar extent.
Conclusion: This new method of laser induced urethral stricture was very efficient and showed a high reproducibility,
thus being useful for studying stenosis treatments. The experiments showed that application of local β-irradiation by
means of radioactive catheters modulated the stenosis development. This kind of LDR-brachytherapy shows potential for
prophylaxis of urethral stricture. As this was an animal pilot experiment a clinical dose response study is needed.

In-vivo laser induced urethral stricture animal model for investigating the potential of LDR-brachytherapy

Purpose Primary or recurrent urethral stenoses are common clinical problems. The aim of this feasibility study was development and application test of a novel radioactive catheter for potential use in low-dose-rate (LDR) brachytherapy to prevent urethral stenosis. Material and methods A beta radiation emitting phosphorous-32 (32P)-foil was developed and integrated in indwelling catheter, which is usually inserted after surgical intervention in the urethra. Activity and dose distribution were measured after neutron activation of the phosphorus-31 (31P)-foil component with scintillation techniques as well as radiochromic films, and compared to MC simulations. Practicability and radiation safety of this new applicator were tested on male rabbits, which, before catheter application, had undergone a new method of stricture induction by radial laser light irradiation. Results Measured dose distributions of catheters with 32P-foils were found to be in good agreement with MC simulations. Wash-out tests confirmed the radioactive catheter setup to be inside permitted limits of a sealed source. Strictures could be induced by laser light in all animals, surgically treated by slitting and irradiation with a 7-day dose of 15 Gy or 30 Gy, without adverse effects of radiation during a 4-week observation time. Conclusions This proof-of-concept study presents a safe and technically simple approach to LDR brachytherapy intending to prevent urethral stenosis. The prescribed irradiation dose can be administered in a reproducible and precise manner using a urethral catheter as a carrier of beta radiating foil. The study duration of 63 days was too short to make statistically significant stricture-related conclusions. This approach may be considered for similar problems in other hollow organs and in cases regarding superficial hyper-proliferation.

/pdf/development-and-pre-clinical-test-of-a-phosphorous-32-1al51m0v.pdf

Development and pre-clinical test of a phosphorous-32 containing polyetheretherketone foil aiming at urethral stricture prevention by low-dose-rate brachytherapy

Preclinical study investigating the potential of low-dose-rate brachytherapy with 32P stents for the prevention of restenosis of paranasal neo-ostia

For LDR-brachytherapy, a limited number of implant geometries and materials are available. To avoid wound healing related hyper-proliferation (stenosis, keloids) a novel radioactive foil system was developed based on beta emitting (32)P, which can be easily integrated in existing implants such as urethral catheters or bile duct stents. As substrate material for these foils PEEK (polyetherethercetone) was chosen because of its radiation hardness during neutron activation of (32)P. The activity was determined by liquid scintillation counting and gamma spectroscopy, dose distributions were measured with scintillation detectors and radiochromic films. The correlation between activity and dose was checked by Monte-Carlo-simulations (Geant4). Prototypes of the (32)P-implants have shown in wash-out tests the required tightness for sealed radioactive sources. In animal tests on urethra and bile duct, the uncomplicated and save application of (32)P-foils mounted on standard implants has been demonstrated, which is almost unchanged due to the simple radiation protection with plexiglass. This concept of radioactive implants with integrated (32)P-foils could extend essentially the application possibilities of LDR-brachytherapy.

32P-haltige Folien als Implantate für die LDR-Brachytherapie gutartiger Stenosen in der Urologie und Gastroenterologie

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32P-haltige Folien als Implantate für die LDR-Brachytherapie gutartiger Stenosen in der Urologie und Gastroenterologie