Optimization of the spatial distribution of a therapeutic pressurized aerosol (PIPAC): an ex-vivo study

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URI: http://hdl.handle.net/10900/99548
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-995488
http://dx.doi.org/10.15496/publikation-40929
Dokumentart: Dissertation
Date: 2020-04-09
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Königsrainer, Alfred (Prof. Dr. med.)
Day of Oral Examination: 2020-02-20
DDC Classifikation: 610 - Medicine and health
Keywords: Peritonealkarzinose , Aerosol , Chemotherapie , Arzneimittel
Other Keywords:
PIPAC
drug delivery system
inverted bovine urinary bladder
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Abstract:

For a long time, PM has been considered to be a terminal clinical condition. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative therapeutic approach with the target to become a curative treatment. The chemotherapeutic drugs are not delivered anymore into the abdominal cavity by conventional lavage, but administered by means of a pressurized, chemotherapeutic drug containing aerosol. The objective is to achieve a homogeneous drug distribution within the abdominal cavity. Through the gaseous propagation of the chemotherapeutic drugs, every region, regardless of its proximity or distance to the nozzle of the nebulizer in the laparoscopic setting, is covered sufficiently. This is not attainable with conventional lavage, where the low abdominal regions are treated sufficiently due to gravitational forces, while the upper regions are less covered, resulting in ineffective cancer treatment, as not all tumor nodules are caught. In the past, various in vivo, ex vivo and postmortem swine experiments have been made to describe and improve the distribution pattern of an injected aerosol and the penetration depth into the serosal tissue. However, theoretical considerations regarding homogenous drug distribution via aerosolized administration did not match with actual results. Drug propagation was found out to be heterogeneous. All presented models suffer from different limitations, such as difficult reproducibility of results, extensive costs, and high discrepancies between anatomical conditions and model setup. Therefore, in this dissertation, a new ex vivo preclinical model, the inverted bovine urinary bladder, has been introduced. Advantages of the inverted bovine urinary bladder include simple handling, cost effectiveness, effect evaluation of various substances both on the mucosa and the serosa, integration of the physico-chemical characteristics of the operational environment, and proximity to the abdominal anatomical conditions. Additionally, so far, no model is able to cover the transient behavior of spray propagation. Therefore, a first dynamic experimental model, the Thermographic Imaging, has been established to describe the aerosol propagation within a model box during the injection period in real time. The presented Thermographic Imaging model is able to characterize the spraying behavior of the inserted different nebulizers and the aerosol propagation behavior during injection phase, but due to technical restrictions is not applicable to the sedimentation process of the aerosol during the exposure period. A further focus of this dissertation is the implementation of a series of experiments, in which aerosols are created via two different nebulizers (Capnopen® and Prototype4) and and their distribution/penetration depth pattern is evaluated in these new established models. First, a visual-qualitative proof of drug distribution in all parts of the bladder was conducted, observing the effect of injected dye methylene blue and ICG. This was enhanced with penetration depth measurements of injected DAPI in three predefined regions within the urinary bladder. Obtained data revealed relevant differences not only between the three different regions, but also between the investigated two Capnopen® types. The Prototype4 achieved superior penetration depth in total and a more homogenous distribution. In a third step, cisplatin, one of the chemotherapeutic drugs used in PIPAC technology, was aerosolized and tissue concentration in the same three locations measured. Obtained data confirm the findings of DAPI penetration depth measurements. These series of experiments show impressively the need of optimizing both the technical, physical, and pharmacodynamic characteristics of the injected aerosol and the distribution pattern. The aerosol characteristics of the Prototype4 are superior in many ways. The combination of improved injection, more homogenous droplet size range, higher and more equally distributed penetration depth values and tissue concentration underlines the achieved aerosol improvement. The inverted bovine urinary bladder turns out to be a valid model for the evaluation of the distribution pattern and penetration depth in the serosal tissue. In the future, these obtained promising results from the preclinical models should be transferred to the clinical operational setting.

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