Development and technical validation of an ultrasound nebulizer to deliver intraperitoneal pressurized aerosols in a rat colon cancer peritoneal metastases model.

BACKGROUND/AIM: To develop and validate a nebulizer device for anti-cancer research on pressurized intraperitoneal aerosol supply in a preclinical peritoneal metastases (PM) rat model. MATERIAL AND METHODS: For aerosol generation, an ultrasonic nebulizer (USN) was modified. Aerosol analyses were performed ex-vivo by laser diffraction spectrometry (LDS). Intraperitoneal (IP) 99mtechnetium sodium pertechnetate (99mTc) aerosol distribution and deposition were quantified by in-vivo single photon emission computed tomography (SPECT/CT) and compared to liquid IP instillation of equivalent volume/doses of 99mTc with and without capnoperitoneum. PM was induced by IP injection of HCT116-Luc2 human colon cancer cells in immunosuppressed RNU rats. Tumor growth was monitored by bioluminescence imaging (BLI), 18F-FDG positron emission tomography (PET) and tissues examination at necropsy. RESULTS: The USN was able to establish a stable and reproducible capnoperitoneum at a pressure of 8 to 10 mmHg. LDS showed that the USN provides a polydisperse and monomodal aerosol with a volume-weighted diameter of 2.6 µm. At a CO2 flow rate of 2 L/min with an IP residence time of 3.9 s, the highest drug deposition efficiency was found to be 15 wt.-%. In comparison to liquid instillation, nebulization showed the most homogeneous IP spatial drug deposition. Compared to BLI, 18F-FDG-PET was more sensitive to detect smaller PM nodules measuring only 1-2 mm in diameter. BLI, 18F-FDG PET and necropsy analyses showed relevant PM in all animals. CONCLUSIONS: The USN together with the PM rat model are suitable for robust and species-specific preclinical pharmacological studies regarding intraperitoneal delivery of pressurized aerosolized drugs and cancer research.

Development of a rat capnoperitoneum phantom to study drug aerosol deposition in the context of anticancer research on peritoneal carcinomatosis.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a promising approach with a high optimization potential for the treatment of peritoneal carcinomatosis. To study the efficacy of PIPAC and drugs, first rodent cancer models were developed. But inefficient drug aerosol supply and knowledge gaps concerning spatial drug distribution can limit the results based on such models. To study drug aerosol supply/deposition, computed tomography scans of a rat capnoperitoneum were used to deduce a virtual and a physical phantom of the rat capnoperitoneum (RCP). RCP qualification was performed for a specific PIPAC method, where the capnoperitoneum is continuously purged by the drug aerosol. In this context, also in-silico analyses by computational fluid dynamic modelling were conducted on the virtual RCP. The physical RCP was used for ex-vivo granulometric analyses concerning drug deposition. Results of RCP qualification show that aerosol deposition in a continuous purged rat capnoperitoneum depends strongly on the position of the inlet and outlet port. Moreover, it could be shown that the droplet size and charge condition of the drug aerosol define the deposition efficiency. In summary, the developed virtual and physical RCP enables detailed in-silico and ex-vivo analyses on drug supply/deposition in rodents.

Experimental Model to Test Electrostatic Precipitation Technology in the COVID-19 Era: A Pilot Study.

BACKGROUND: In the COVID-19 crisis, laparoscopic surgery is in focus as a relevant source of bioaerosol release. The efficacy of electrostatic aerosol precipitation (EAP) and continuous aerosol evacuation (CAE) to eliminate bioaerosols during laparoscopic surgery was verified. STUDY DESIGN: Ex-vivo laparoscopic cholecystectomies (LCs) were simulated ± EAP or CAE in Pelvitrainer equipped with swine gallbladders. Release of bioaerosols was initiated by performing high-frequency electrosurgery with a monopolar electro hook (MP-HOOK) force at 40 watts (MP-HOOK40) and 60 watts (MP-HOOK60), as well as by ultrasonic cutting (USC). Particle number concentrations (PNC) of arising aerosols were analyzed with a condensation particle counter (CPC). Aerosol samples were taken within the Pelvitrainer close to the source, outside the Pelvitrainer at the working trocar, and in the breathing zone of the surgeon. RESULTS: Within the Pelvitrainer, MP-HOOK40 (6.4 × 105 cm-3) and MP-HOOK60 (7.3 × 105 cm-3) showed significantly higher median PNCs compared to USC (4.4 × 105 cm-3) (p = 0.001). EAP led to a significant decrease of the median PNCs in all 3 groups. A high linear correlation with Pearson correlation coefficients of 0.852, 0.825, and 0.759 were observed by comparing MP-HOOK40 (± EAP), MP-HOOK60 (± EAP), and USC (± EAP), respectively. During ex-vivo LC and CAE, significant bioaerosol contaminations of the operating room occurred. Ex-vivo LC with EAP led to a considerable reduction of the bioaerosol concentration. CONCLUSIONS: EAP was found to be efficient for intraoperative bioaerosol elimination and reducing the risk of bioaerosol exposure for surgical staff.

Surface Modification of Biodegradable Polymers towards Better Biocompatibility and Lower Thrombogenicity.

PURPOSE: Drug-eluting stents (DES) based on permanent polymeric coating matrices have been introduced to overcome the in stent restenosis associated with bare metal stents (BMS). A further step was the development of DES with biodegradable polymeric coatings to address the risk of thrombosis associated with first-generation DES. In this study we evaluate the biocompatibility of biodegradable polymer materials for their potential use as coating matrices for DES or as materials for fully bioabsorbable vascular stents. MATERIALS AND METHODS: Five different polymers, poly(L-lactide) PLLA, poly(D,L-lactide) PDLLA, poly(L-lactide-co-glycolide) P(LLA-co-GA), poly(D,L-lactide-co-glycolide) P(DLLA-co-GA) and poly(L-lactide-co-ε-caprolactone), P(LLA-co-CL) were examined in vitro without and with surface modification. The surface modification of polymers was performed by means of wet-chemical (NaOH and ethylenediamine (EDA)) and plasma-chemical (O2 and NH3) processes. The biocompatibility studies were performed on three different cell types: immortalized mouse fibroblasts (cell line L929), human coronary artery endothelial cells (HCAEC) and human umbilical vein endothelial cells (HUVEC). The biocompatibility was examined quantitatively using in vitro cytotoxicity assay. Cells were investigated immunocytochemically for expression of specific markers, and morphology was visualized using confocal laser scanning (CLSM) and scanning electron (SEM) microscopy. Additionally, polymer surfaces were examined for their thrombogenicity using an established hemocompatibility test. RESULTS: Both endothelial cell types exhibited poor viability and adhesion on all five unmodified polymer surfaces. The biocompatibility of the polymers could be influenced positively by surface modifications. In particular, a reproducible effect was observed for NH3-plasma treatment, which enhanced the cell viability, adhesion and morphology on all five polymeric surfaces. CONCLUSION: Surface modification of polymers can provide a useful approach to enhance their biocompatibility. For clinical application, attempts should be made to stabilize the plasma modification and use it for coupling of biomolecules to accelerate the re-endothelialization of stent surfaces in vivo.

Collaborative network of predictive markers complicates formation of prognostic groups in patients with advanced lung cancer.

BACKGROUND: Evaluation of cancer therapies is mainly based on prolonging remission status and effect of survival. Various serological, clinical or histological markers are used to estimate the patient's prognosis, and to tailor specific therapies for patients with poor prognosis. However, it is still a challenge to combine all this information into a comprehensive risk prediction. PATIENTS AND METHODS: In 58 patients with advanced non small cell lung cancer we recorded 38 parameters (15 from clinic, 10 from histology, 13 from serology) to analyze their impact on survival. We both used univariate as well as multivariate approaches and decision tree analysis. RESULTS: Univariate analysis showed that ECOG status, stage, and the presence of cerebral or bone metastasis had a significant impact on survival, as well as the serum markers CA15-3, TPA, Cyfra. In a multivariate approach only ECOG and stage had a significant impact on survival. Considering correlation coefficients of >0.3 as an indicator of a functional relationship, we found several relations among the clinical (9), histological (8) or the serological parameters (13). Survival was related to 9 parameters by significant direct and cross-relation coefficients. The use of already few variables with its different possible options led to many different patterns in the cohort, almost all being specific for individual patients, and thereby underlining their heterogeneity. Decision tree analysis revealed that by including either stage and kind of therapy or stage and expression of YB-1 allows to identify sub-groups with distinct prognosis. CONCLUSION: Clinical, serological and histological markers, all provide prognostic information. Because they are all linked in a collaborative network, the formation of homogenous prognostic groups by use of single markers is limited. Alternative statistical approaches with focus on decision trees may allow use of various information to assess individual patients into distinct risk groups.

Bacterial colonization of psoriasis plaques. Is it relevant?

Bacterial colonization was investigated retrospectively in patients with plaque psoriasis (n=98 inpatient treatments, n=73 patients). At least one pathogen was found in 46% of all cases. Staphylococcus aureus was the most frequent bacterium. Bacterial colonization of psoriasis plaques could be relevant in individual cases.

Position controlled self-catalyzed growth of GaAs nanowires by molecular beam epitaxy.

GaAs nanowires are grown by molecular beam epitaxy using a self-catalyzed, Ga-assisted growth technique. Position control is achieved by nano-patterning a SiO(2) layer with arrays of holes with a hole diameter of 85 nm and a hole pitch varying between 200 nm and 2 µm. Gallium droplets form preferentially at the etched holes acting as catalyst for the nanowire growth. The nanowires have hexagonal cross-sections with {110} side facets and crystallize predominantly in zincblende. The interdistance dependence of the nanowire growth rate indicates a change of the III/V ratio towards As-rich conditions for large hole distances inhibiting NW growth.

Ferromagnetic GaAs/GaMnAs core-shell nanowires grown by molecular beam epitaxy.

GaAs/GaMnAs core-shell nanowires were grown by molecular beam epitaxy. The core GaAs nanowires were synthesized under typical nanowire growth conditions using gold as catalyst. For the GaMnAs shell the temperature was drastically reduced to achieve low-temperature growth conditions known to be crucial for high-quality GaMnAs. The GaMnAs shell grows epitaxially on the side facets of the core GaAs nanowires. A ferromagnetic transition temperature of 20 K is obtained. Magnetic anisotropy studies indicate a magnetic easy axis parallel to the nanowire axis.

Influence of nonhomogeneous distribution of topically applied UV filters on sun protection factors.

The aim of the present study is the development of a method to determine quantitatively in vivo the influence of homogeneity of the distribution of sunscreen containing UV filters on the sun protection factor (SPF). The SPF of a sunscreen applied either topically or inside an optical cell (pure or in a solvent) fixed above the skin is determined in vivo. In both cases, in vivo measurements using the erythema formation are carried out. Identical optical parameters of the skin are realized in both experiments. In addition, both in vitro (using tape stripping) and in vivo microscopic measurements are performed to analyze the homogeneity of distribution of the topically applied substances. An SPF of 8 is measured in the experiment applying the UV filters topically, whereas this value increases by a factor of 10 if the same amount of filter substances is distributed homogeneously in solution inside the optical cell. Tape strips removed from skin treated with the sunscreen reflect the inhomogeneous distribution of the topically applied substances on the skin. The direct correlation of homogeneity of distribution with the SPF opens up the possibility to increase the SPF by optimizing the formulation.