Perfusion modeling
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A mathematical model of myocardial perfusion based on the lattice Boltzmann method (LBM) is proposed and its applicability is investigated in both healthy and diseased cases. The myocardium is conceptualized as a porous material in which the transport and mass transfer of a contrast agent in blood flow is studied. The results of myocardial perfusion obtained using LBM in 1D and 2D are confronted with previously reported results in the literature and the results obtained using the mixed-hybrid finite element method. Since LBM is not suitable for simulating flow in heterogeneous porous media, a simplified and computationally efficient 1D-analog approach to 2D diseased case is proposed and its applicability discussed.
- MeSH
- analýza metodou konečných prvků * MeSH
- kontrastní látky MeSH
- koronární cirkulace fyziologie MeSH
- lidé MeSH
- modely kardiovaskulární * MeSH
- počítačová simulace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Mammalian cell perfusion cultures are gaining renewed interest as an alternative to traditional fed-batch processes for the production of therapeutic proteins, such as monoclonal antibodies (mAb). The steady state operation at high viable cell density allows the continuous delivery of antibody product with increased space-time yield and reduced in-process variability of critical product quality attributes (CQA). In particular, the production of a confined mAb N-linked glycosylation pattern has the potential to increase therapeutic efficacy and bioactivity. In this study, we show that accurate control of flow rates, media composition and cell density of a Chinese hamster ovary (CHO) cell perfusion bioreactor allowed the production of a constant glycosylation profile for over 20 days. Steady state was reached after an initial transition phase of 6 days required for the stabilization of extra- and intracellular processes. The possibility to modulate the glycosylation profile was further investigated in a Design of Experiment (DoE), at different viable cell density and media supplement concentrations. This strategy was implemented in a sequential screening approach, where various steady states were achieved sequentially during one culture. It was found that, whereas high ammonia levels reached at high viable cell densities (VCD) values inhibited the processing to complex glycan structures, the supplementation of either galactose, or manganese as well as their synergy significantly increased the proportion of complex forms. The obtained experimental data set was used to compare the reliability of a statistical response surface model (RSM) to a mechanistic model of N-linked glycosylation. The latter outperformed the response surface predictions with respect to its capability and reliability in predicting the system behavior (i.e., glycosylation pattern) outside the experimental space covered by the DoE design used for the model parameter estimation. Therefore, we can conclude that the modulation of glycosylation in a sequential steady state approach in combination with mechanistic model represents an efficient and rational strategy to develop continuous processes with desired N-linked glycosylation patterns. Biotechnol. Bioeng. 2017;114: 1978-1990. © 2017 Wiley Periodicals, Inc.
- MeSH
- analýza selhání vybavení MeSH
- biologické modely * MeSH
- bioreaktory * MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- design s pomocí počítače MeSH
- design vybavení MeSH
- glykosylace MeSH
- monoklonální protilátky izolace a purifikace metabolismus MeSH
- perfuze přístrojové vybavení metody MeSH
- počítačová simulace MeSH
- polysacharidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Indikátorová mikrodialyzační technika využívá mikrodialýzu ke kvantitativnímu hodnocení regionální tkáňové perfuze. Speciálně konstruovaná tenká sonda se semipermeabilní membránou na jejím konci je zavedena do tkáně a dochází k výměně malých molekul mezi tekutinou v nitru sondy a intersticiem. Látka (indikátor) přiváděná do sondy zčásti difunduje do intersticia, odkud je eliminována resorpcí do krevních kapilár. Stupeň difuze indikátoru ze sondy je ve stacionárním stavu úměrný nejenom perfuzi tkáně, ale i řadě dalších faktorů, jakými jsou tkáňová difuzibilita indikátoru, rychlost perfuze sondy, stupeň ultrafiltrace tekutiny ze sondy, pohyb tkáně nebo sondy, prostorová heterogenita tkáně. Prvotní studie s uměle perfundovanými tkáněmi ukazovaly velmi dobrou korelaci mezi tkáňovou perfuzí a stupněm extrakce indikátoru, ale v pozdějších in vivo studiích byly naměřeny velmi malé nebo žádné změny extrakce při značných změnách tkáňové perfuze. Otázka validity indikátorové mikrodialyzační techniky pro kvantitativní hodnocení tkáňové perfuze dosud není definitivně dořešena. Požadavek na maximální přesnost celého postupu pro získání validních výsledků však téměř vylučuje možnost uplatnění metody v klinické praxi.
Indicator microdialysis technique employs microdialysis for quantitative assessment of regional tissue perfusion. A special slim probe with a semi-permeable membrane at the tip is inserted into the tissue where small molecules are interchanged between the fluid inside the probe and the interstitial tissue. The indicator substance is supplied to the probe where it partly diffuses into the interstitial fluid and gets drawn into blood capillaries. In steady state diffusion of the indicator out of the probe is proportional to tissue perfusion. It is also influenced by many other factors such as tissue diffusibility of the indicator, intensity of probe perfusion, ultrafiltration of the fluid out of the probe, movement of the tissue or probe, spatial heterogeneity of the tissue etc. The first studies with artificial perfusion of tissues displayed a good correlation between tissue perfusion and tissue extraction of the indicator but later in-vivo studies showed little or no changes of indicator extraction with gross changes in tissue perfusion. The question of validity of indicator microdialysis technique for quantitative assessment of tissue perfusion is not finally answered yet. Because of the requirement for maximal precision when performing this technique to gain valid results, the use of this technique is almost excluded from clinical practice.
- MeSH
- chemoterapie nádorů pomocí regionální perfúze MeSH
- ethanol farmakokinetika MeSH
- finanční podpora výzkumu jako téma MeSH
- indikátorové diluční techniky MeSH
- lidé MeSH
- mikrodialýza metody MeSH
- modely nemocí na zvířatech MeSH
- radioaktivní indikátory MeSH
- voda farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
Cardiovascular diseases represent an economic burden for health systems accounting for substantial morbidity and mortality worldwide. Despite timely and costly efforts in drug development, the cardiovascular safety and efficacy of the drugs are not always fully achieved. These lead to the drugs' withdrawal with adverse cardiac effects from the market or in the late stages of drug development. There is a growing need for a cost-effective drug screening assay to rapidly detect potential acute drug cardiotoxicity. The Langendorff isolated heart perfusion technique, which provides cardiac hemodynamic parameters (e.g., contractile function and heart rate), has become a powerful approach in the early drug discovery phase to overcome drawbacks in the drug candidate's identification. However, traditional ex vivo retrograde heart perfusion methods consume a large volume of perfusate, which increases the cost and limits compound screening. An elegant and cost-effective alternative mode for ex vivo retrograde heart perfusion is the constant-flow with a recirculating circuit (CFCC), which allows assessment of cardiac function using a reduced perfusion volume while limiting adverse effects on the heart. Here, we provide evidence for cardiac parameters stability over time in this mode. Next, we demonstrate that our recycled ex vivo perfusion system and the traditional open one yield similar outputs on cardiac function under basal conditions and upon ?-adrenergic stimulation with isoproterenol. Subsequently, we validate the proof of concept of therapeutic agent screening using this efficient method. ?-blocker (i.e., propranolol) infusion in closed circulation countered the positive effects induced by isoproterenol stimulation on cardiac function. Keywords: Drug development, Drug screening, Cardiovascular safety, Langendorff method, Closed circulation.
INTRODUCTION: There is still a lack of organs for kidney transplantation. The aim of our experimental animal study was to improve the quality of the kidney grafts from donors after cardiac death (DCD) using immediate start of machine perfusion instead of perfusion based on hydrostatic pressure. METHODS: Ten rabbits were used as an experimental model. In group A, 5 kidneys after ischemic injury were perfused in situ using hydrostatic pressure. In group B, 5 kidneys were perfused in situ using machine pulsatile perfusion. After nephrectomy kidney parenchyma was histologically analyzed. We have evaluated the maximum perfusion flow rate, temperature drop rate, and degree of parenchymal injury. RESULTS: The flow rate in the group of machine-perfused animals (group B) was significantly higher than in the control group (group A), and temperature was significantly decreased in group B (P < .001). Qualitative histopathologic evaluation of the perfusion quality of the grafts was statistically significant, again in favor of machine perfusion in group B (P = .005). DISCUSSION: According to our results, the immediate start of machine perfusion is a superior method of kidney graft preservation in DCDs. All observed modalities were superior in the group with machine perfusion compared with usual clinical practice.
- MeSH
- dárci tkání MeSH
- králíci MeSH
- ledviny * MeSH
- modely nemocí na zvířatech MeSH
- nefrektomie MeSH
- odběr tkání a orgánů metody MeSH
- perfuze metody MeSH
- pulzatilní průtok MeSH
- smrt MeSH
- transplantace ledvin metody MeSH
- transplantáty MeSH
- uchovávání orgánů metody MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The paper deals with modeling the liver perfusion intended to improve quantitative analysis of the tissue scans provided by the contrast-enhanced computed tomography (CT). For this purpose, we developed a model of dynamic transport of the contrast fluid through the hierarchies of the perfusion trees. Conceptually, computed time-space distributions of the so-called tissue density can be compared with the measured data obtained from CT; such a modeling feedback can be used for model parameter identification. The blood flow is characterized at several scales for which different models are used. Flows in upper hierarchies represented by larger branching vessels are described using simple 1D models based on the Bernoulli equation extended by correction terms to respect the local pressure losses. To describe flows in smaller vessels and in the tissue parenchyma, we propose a 3D continuum model of porous medium defined in terms of hierarchically matched compartments characterized by hydraulic permeabilities. The 1D models corresponding to the portal and hepatic veins are coupled with the 3D model through point sources, or sinks. The contrast fluid saturation is governed by transport equations adapted for the 1D and 3D flow models. The complex perfusion model has been implemented using the finite element and finite volume methods. We report numerical examples computed for anatomically relevant geometries of the liver organ and of the principal vascular trees. The simulated tissue density corresponding to the CT examination output reflects a pathology modeled as a localized permeability deficiency.
- MeSH
- analýza metodou konečných prvků MeSH
- biologické modely MeSH
- jaterní oběh * fyziologie MeSH
- játra krevní zásobení diagnostické zobrazování MeSH
- kontrastní látky farmakokinetika MeSH
- lidé MeSH
- matematické pojmy MeSH
- počítačová rentgenová tomografie statistika a číselné údaje MeSH
- počítačová simulace MeSH
- poréznost MeSH
- vylepšení rentgenového snímku metody MeSH
- zobrazování trojrozměrné statistika a číselné údaje MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A convenient geometrical description of the microvascular network is necessary for computationally efficient mathematical modelling of liver perfusion, metabolic and other physiological processes. The tissue models currently used are based on the generally accepted schematic structure of the parenchyma at the lobular level, assuming its perfect regular structure and geometrical symmetries. Hepatic lobule, portal lobule, or liver acinus are considered usually as autonomous functional units on which particular physiological problems are studied. We propose a new periodic unit-the liver representative periodic cell (LRPC) and establish its geometrical parametrization. The LRPC is constituted by two portal lobulae, such that it contains the liver acinus as a substructure. As a remarkable advantage over the classical phenomenological modelling approaches, the LRPC enables for multiscale modelling based on the periodic homogenization method. Derived macroscopic equations involve so called effective medium parameters, such as the tissue permeability, which reflect the LRPC geometry. In this way, mutual influences between the macroscopic phenomena, such as inhomogeneous perfusion, and the local processes relevant to the lobular (mesoscopic) level are respected. The LRPC based model is intended for its use within a complete hierarchical model of the whole liver. Using the Double-permeability Darcy model obtained by the homogenization, we illustrate the usefulness of the LRPC based modelling to describe the blood perfusion in the parenchyma.
PURPOSE: Computational models of microwave ablation (MWA) are widely used during the design optimization of novel devices and are under consideration for patient-specific treatment planning. The objective of this study was to assess the sensitivity of computational models of MWA to tissue biophysical properties. METHODS: The Morris method was employed to assess the global sensitivity of the coupled electromagnetic-thermal model, which was implemented with the finite element method (FEM). The FEM model incorporated temperature dependencies of tissue physical properties. The variability of the model was studied using six different outputs to characterize the size and shape of the ablation zone, as well as impedance matching of the ablation antenna. Furthermore, the sensitivity results were statistically analyzed and absolute influence of each input parameter was quantified. A framework for systematically incorporating model uncertainties for treatment planning was suggested. RESULTS: A total of 1221 simulations, incorporating 111 randomly sampled starting points, were performed. Tissue dielectric parameters, specifically relative permittivity, effective conductivity, and the threshold temperature at which they transitioned to lower values (i.e., signifying desiccation), were identified as the most influential parameters for the shape of the ablation zone and antenna impedance matching. Of the thermal parameters considered in this study, the nominal blood perfusion rate and the temperature interval across which the tissue changes phase were identified as the most influential. The latent heat of tissue water vaporization and the volumetric heat capacity of the vaporized tissue were recognized as the least influential parameters. Based on the evaluation of absolute changes, the most important parameter (perfusion) had approximately 40.23 times greater influence on ablation area than the least important parameter (volumetric heat capacity of vaporized tissue). Another significant input parameter (permittivity) had 22.26 times higher influence on the deviation of ablation edge shape from a sphere than one of the less important parameters (latent heat of liver tissue vaporization). CONCLUSIONS: Dielectric parameters, blood perfusion rate, and the temperature interval across which the tissue changes phase were found to have the most significant impact on MWA model outputs. The latent heat of tissue water vaporization and the volumetric heat capacity of the vaporized tissue were recognized as the least influential parameters. Uncertainties in model outputs identified in this study can be incorporated to provide probabilistic maps of expected ablation outcome for patient-specific treatment planning.
- MeSH
- ablace metody MeSH
- algoritmy MeSH
- analýza metodou konečných prvků MeSH
- biomechanika MeSH
- elektromagnetické jevy MeSH
- individualizovaná medicína metody MeSH
- játra fyziologie MeSH
- lidé MeSH
- mikrovlny * MeSH
- počítačová simulace * MeSH
- regionální krevní průtok MeSH
- teoretické modely * MeSH
- teplota MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
