Optimization of intraperitoneal aerosolized drug delivery using computational fluid dynamics (CFD) modeling.

Intraperitoneal (IP) aerosolized anticancer drug delivery was recently introduced in the treatment of patients with peritoneal metastases. However, little is known on the effect of treatment parameters on the spatial distribution of the aerosol droplets in the peritoneal cavity. Here, computational fluid dynamics (CFD) modeling was used in conjunction with experimental validation in order to investigate the effect of droplet size, liquid flow rate and viscosity, and the addition of an electrostatic field on the homogeneity of IP aerosol. We found that spatial distribution is optimal with small droplet sizes (1-5 µm). Using the current clinically used technology (droplet size of 30 µm), the optimal spatial distribution of aerosol is obtained with a liquid flow rate of 0.6 mL s-1. Compared to saline, nebulization of higher viscosity liquids results in less homogeneous aerosol distribution. The addition of electrostatic precipitation significantly improves homogeneity of aerosol distribution, but no further improvement is obtained with voltages higher than 6.5 kV. The results of the current study will allow to choose treatment parameters and settings in order to optimize spatial distribution of IP aerosolized drug, with a potential to enhance its anticancer effect.

Exploring high pressure nebulization of Pluronic F127 hydrogels for intraperitoneal drug delivery.

Peritoneal metastasis is an advanced cancer type which can be treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Here, chemotherapeutics are nebulized under high pressure in the intraperitoneal (IP) cavity to obtain a better biodistribution and tumor penetration. To prevent the fast leakage of chemotherapeutics from the IP cavity, however, nebulization of controlled release formulations is of interest. In this study, the potential of the thermosensitive hydrogel Pluronic F127 to be applied by high pressure nebulization is evaluated. Therefore, aerosol formation is experimentally examined by laser diffraction and theoretically simulated by computational fluid dynamics (CFD) modelling. Furthermore, Pluronic F127 hydrogels are subjected to rheological characterization after which the release of fluorescent model nanoparticles from the hydrogels is determined. A delicate equilibrium is observed between controlled release properties and suitability for aerosolization, where denser hydrogels (20% and 25% w/v Pluronic F127) are able to sustain nanoparticle release up to 30 h, but cannot effectively be nebulized and vice versa. This is demonstrated by a growing aerosol droplet size and exponentially decreasing aerosol cone angle when Pluronic F127 concentration and viscosity increase. Novel nozzle designs or alternative controlled release formulations could move intraperitoneal drug delivery by high pressure nebulization forward.

Intraperitoneal aerosolized drug delivery: Technology, recent developments, and future outlook.

Current therapies for patients with peritoneal metastases (PM) are only moderately effective. Recently, a novel locoregional treatment method for PM was introduced, consisting of a combination of laparoscopy with intraperitoneal (IP) delivery of anticancer agents as an aerosol. This 'pressurized intraperitoneal aerosol chemotherapy' (PIPAC) may enhance tissue drug penetration by the elevated IP pressure during CO2 capnoperitoneum. Also, repeated PIPAC cycles allow to accurately stage peritoneal disease and verify histological response to treatment. This review provides an overview of the rationale, indications, and currently used technology for therapeutic IP nebulization, and discusses the basic mechanisms governing aerosol particle transport and peritoneal deposition. We discuss early clinical results in patients with advanced, irresectable PM and highlight the potential of electrostatic aerosol precipitation. Finally, we discuss promising novel approaches, including nebulization of nanoparticles and prolonged release formulations.

Electrostatic Intraperitoneal Aerosol Delivery of Nanoparticles: Proof of Concept and Preclinical Validation.

There is an increasing interest in intraperitoneal delivery of chemotherapy as an aerosol in patients with peritoneal metastasis. The currently used technology is hampered by inhomogenous drug delivery throughout the peritoneal cavity because of gravity, drag, and inertial impaction. Addition of an electrical force to aerosol particles, exerted by an electrostatic field, can improve spatial aerosol homogeneity and enhance tissue penetration. A computational fluid dynamics model shows that electrostatic precipitation (EP) results in a significantly improved aerosol distribution. Fluorescent nanoparticles (NPs) remain stable after nebulization in vitro, while EP significantly improves spatial homogeneity of NP distribution. Next, pressurized intraperitoneal chemotherapy with and without EP using NP albumin bound paclitaxel (Nab-PTX) in a novel rat model is examined. EP does not worsen the effects of CO2 insufflation and intraperitoneal Nab-PTX on mesothelial structural integrity or the severity of peritoneal inflammation. Importantly, EP significantly enhances tissue penetration of Nab-PTX in the anatomical regions not facing the nozzle of the nebulizer. Also, the addition of EP leads to more homogenous peritoneal tissue concentrations of Nab-PTX, in parallel with higher plasma concentrations. In conclusion, EP enhances spatial homogeneity and tissue uptake after intraperitoneal nebulization of anticancer NPs.

A hybrid computational aeroacoustic methodology for broadband noise prediction.

Current hybrid computational aeroacoustic methodologies for broadband noise prediction rely on large eddy simulation (LES) for noise source computation, and integral methods for noise propagation. In this paper, LES of a benchmark controlled-diffusion airfoil was conducted, utilizing the rotation rate based Smagorinsky model (RoSM). The RoSM is seen to provide flow results of equal or improved accuracy as compared to the dynamic Smagorinsky model, with 35% less computational cost, with computational benefits of the RoSM increasing with mesh size. Current integral methods for noise propagation, including Formulation 1A of Farassat, require numerical differentiation of highly turbulent input flow data coming from LES, introducing numerical inaccuracies. Here, Formulation 1 of Farassat is modified to entirely avoid the numerical differentiation of flow field data. The ability of the methodology for broadband noise prediction is demonstrated, with the prediction at high frequencies being considerably closer to experimental data than Formulation 1A. For low discrete frequency noise prediction, Formulation 1A is still recommended. The use of two innovative approaches in conjunction for broadband noise prediction is seen to be efficient and easy to implement, without compromising on accuracy.

A time-domain method for prediction of noise radiated from supersonic rotating sources in a moving medium.

This paper presents a time-domain method for noise prediction of supersonic rotating sources in a moving medium. The proposed approach can be interpreted as an extensive time-domain solution for the convected permeable Ffowcs Williams and Hawkings equation, which is capable of avoiding the Doppler singularity. The solution requires special treatment for construction of the emission surface. The derived formula can explicitly and efficiently account for subsonic uniform constant flow effects on radiated noise. Implementation of the methodology is realized through the Isom thickness noise case and high-speed impulsive noise prediction from helicopter rotors.

Fast computation of time-dependent acoustic fields.

A method for the fast evaluation of time-dependent acoustic fields from complex sources is presented. The technique is based on a fast integration method for the boundary integral arising in a Kirchhoff formulation and requires a small, and roughly constant, computation time to compute a transient signal, at the expense of a pre-processing stage. In the calculations in this paper, based on test cases for a single rotor, a counter-rotating open rotor, and a broadband volume source, it is found that transient field calculations require an order of magnitude less computational time for the field from an array of 16 384 sources, a computational advantage that increases with source number.

Inhaled Aerosol Distribution in Human Airways: A Scintigraphy-Guided Study in a 3D Printed Model.

BACKGROUND: While it is generally accepted that inertial impaction will lead to particle loss as aerosol is being carried into the pulmonary airways, most predictive aerosol deposition models adopt the hypothesis that the inhaled particles that remain airborne will distribute according to the gas flow distribution between airways downstream. METHODS: Using a 3D printed cast of human airways, we quantified particle deposition and distribution and visualized their inhaled trajectory in the human lung. The human airway cast was exposed to 6 µm monodisperse, radiolabeled aerosol particles at distinct inhaled flow rates and imaged by scintigraphy in two perpendicular planes. In addition, we also imaged the distribution of aerosol beyond the airways into the five lung lobes. The experimental aerosol deposition patterns could be mimicked by computational fluid dynamic (CFD) simulation in the same 3D airway geometry. RESULTS: It was shown that for particles with a diameter of 6 µm inhaled at flows up to 60 L/min, the aerosol distribution over both lungs and the individual five lung lobes roughly followed the corresponding distributions of gas flow. While aerosol deposition was greater in the main bronchi of the left versus right lung, distribution of deposited and suspended particles toward the right lung exceeded that of the left lung. The CFD simulations also predict that for both 3 and 6 µm particles, aerosol distribution between lung units subtending from airways in generation 5 did not match gas distribution between these units and that this effect was driven by inertial impaction. CONCLUSIONS: We showed combined imaging experiments and CFD simulations to systematically study aerosol deposition patterns in human airways down to generation 5, where particle deposition could be spatially linked to the airway geometry. As particles are negotiating an increasing number of airways in subsequent branching generations, CFD predicts marked deviations of aerosol distribution with respect to ventilation distribution, even in the normal human lung.

A time-domain Kirchhoff formula for the convective acoustic wave equation.

Kirchhoff's integral method allows propagated sound to be predicted, based on the pressure and its derivatives in time and space obtained on a data surface located in the linear flow region. Kirchhoff's formula for noise prediction from high-speed rotors and propellers suffers from the limitation of the observer located in uniform flow, thus requiring an extension to arbitrarily moving media. This paper presents a Kirchhoff formulation for moving surfaces in a uniform moving medium of arbitrary configuration. First, the convective wave equation is derived in a moving frame, based on the generalized functions theory. The Kirchhoff formula is then obtained for moving surfaces in the time domain. The formula has a similar form to the Kirchhoff formulation for moving surfaces of Farassat and Myers, with the presence of additional terms owing to the moving medium effect. The equation explicitly accounts for the influence of mean flow and angle of attack on the radiated noise. The formula is verified by analytical cases of a monopole source located in a moving medium.

Semi-analytical solution for the in-vitro sedimentation, diffusion and dosimetry model: surveying the impact of the Peclet number.

Reducing size of the particles to the nanoscale range gives them new physicochemical properties. Several experiments have shown cytotoxic effects for different kinds of engineered nanoparticles (ENP). In-vitro cell culture assays are widely utilized by researchers to evaluate cytotoxic effects of the ENPs. The present paper deals with the "In vitro Sedimentation, Diffusion and Dosimetry (ISDD)" model. This mathematical model uses an advection-diffusion equation with specific assumptions and coefficients to estimate the dose of the particles delivered to the cells monolayer in the culture medium. In the present work, utilizing the generalized integral transform technique (GITT), a semi-analytical solution is developed for the ISDD model. The parameters affecting the ISDD predictions are integrated into two dimensionless numbers, Pe and τ. The Pe number shows the ratio of the convective to the diffusive mass transport rates and τ is a dimensionless time parameter. The quality of the results for an extensive range of Pe and τ numbers is surveyed through application of the developed formula to two series of test cases. A comparison of the results with those obtained from numerical methods shows deviations in the numerical results at high Pe numbers. Applying the developed formula, ISDD predictions for a wide practical range of Pe and τ numbers are calculated and plotted in two- and three-dimensional plots. The curves and formula obtained in this study facilitate the achievement of ISDD predictions with higher accuracies and capabilities for verification of the results.

A survey on the applications of implantable micropump systems in drug delivery.

Systemic drug delivery is the most prevalent form of the drug administration; but it is not possible to extend this approach to all of diseases. In the traditional approaches of drug delivery, the drug spreads through whole of body and this could cause severe side effects in the healthy parts. In addition, in some parts of our body like the eye, ear and brain, there are biological barriers against drug penetration which made drug delivery to these organs as a challenging work. Micropumps are one of the MEMS based devices with great capabilities in controlled drug administration. The most prevalent application of micropumps in drug delivery is known as continuous subcutaneous insulin infusion (CSII) for diabetic patients; but our study showed that there are some other ongoing investigations to extend application of micropumps in new treatment methods for some incurred diseases.