scholarly journals Suitable CO2 Solubility Models for Determination of the CO2 Removal Performance of Oxygenators

2021 ◽  
Vol 8 (3) ◽  
pp. 33
Author(s):  
Benjamin Lukitsch ◽  
Paul Ecker ◽  
Martin Elenkov ◽  
Christoph Janeczek ◽  
Christian Jordan ◽  
...  
Keyword(s):  
Removal Rate ◽  
Model Parameters ◽  
Co2 Removal ◽  
Bovine Blood ◽  
Co2 Solubility ◽  
Porcine Blood ◽  
Solubility Model ◽  
Blood Data

CO2 removal via membrane oxygenators during lung protective ventilation has become a reliable clinical technique. For further optimization of oxygenators, accurate prediction of the CO2 removal rate is necessary. It can either be determined by measuring the CO2 content in the exhaust gas of the oxygenator (sweep flow-based) or using blood gas analyzer data and a CO2 solubility model (blood-based). In this study, we determined the CO2 removal rate of a prototype oxygenator utilizing both methods in in vitro trials with bovine and in vivo trials with porcine blood. While the sweep flow-based method is reliably accurate, the blood-based method depends on the accuracy of the solubility model. In this work, we quantified performances of four different solubility models by calculating the deviation of the CO2 removal rates determined by both methods. Obtained data suggest that the simplest model (Loeppky) performs better than the more complex ones (May, Siggaard-Anderson, and Zierenberg). The models of May, Siggaard-Anderson, and Zierenberg show a significantly better performance for in vitro bovine blood data than for in vivo porcine blood data. Furthermore, the suitability of the Loeppky model parameters for bovine blood (in vitro) and porcine blood (in vivo) is evaluated.

scholarly journals Water as a Blood Model for Determination of CO2 Removal Performance of Membrane Oxygenators

Membranes ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 356
Author(s):  
Benjamin Lukitsch ◽  
Raffael Koller ◽  
Paul Ecker ◽  
Martin Elenkov ◽  
Christoph Janeczek ◽  
...  
Keyword(s):  
Boundary Layer ◽  
Removal Rate ◽  
In Vitro Tests ◽  
Co2 Removal ◽  
Reliable Determination ◽  
Fluid Properties ◽  
Membrane Oxygenators

CO2 removal via membrane oxygenators has become an important and reliable clinical technique. Nevertheless, oxygenators must be further optimized to increase CO2 removal performance and to reduce severe side effects. Here, in vitro tests with water can significantly reduce costs and effort during development. However, they must be able to reasonably represent the CO2 removal performance observed with blood. In this study, the deviation between the CO2 removal rate determined in vivo with porcine blood from that determined in vitro with water is quantified. The magnitude of this deviation (approx. 10%) is consistent with results reported in the literature. To better understand the remaining difference in CO2 removal rate and in order to assess the application limits of in vitro water tests, CFD simulations were conducted. They allow to quantify and investigate the influences of the differing fluid properties of blood and water on the CO2 removal rate. The CFD results indicate that the main CO2 transport resistance, the diffusional boundary layer, behaves generally differently in blood and water. Hence, studies of the CO2 boundary layer should be preferably conducted with blood. In contrast, water tests can be considered suitable for reliable determination of the total CO2 removal performance of oxygenators.

scholarly journals In Silico Performance of a Recellularized Tissue-Engineered Transcatheter Aortic Valve

2019 ◽  
Vol 141 (6) ◽  
Author(s):  
Christopher Noble ◽  
Joshua Choe ◽  
Susheil Uthamaraj ◽  
Milton Deherrera ◽  
Amir Lerman ◽  
...  
Keyword(s):  
Mechanical Behavior ◽  
Heart Valves ◽  
Mechanical Response ◽  
Mechanical Performance ◽  
Fe Analysis ◽  
Model Parameters ◽  
Biaxial Testing ◽  
Principal Stresses

Commercially available heart valves have many limitations, such as a lack of remodeling, risk of calcification, and thromboembolic problems. Many state-of-the-art tissue-engineered heart valves (TEHV) rely on recellularization to allow remodeling and transition to mechanical behavior of native tissues. Current in vitro testing is insufficient in characterizing a soon-to-be living valve due to this change in mechanical response; thus, it is imperative to understand the performance of an in situ valve. However, due to the complex in vivo environment, this is difficult to accomplish. Finite element (FE) analysis has become a standard tool for modeling mechanical behavior of heart valves; yet, research to date has mostly focused on commercial valves. The purpose of this study has been to evaluate the mechanical behavior of a TEHV material before and after 6 months of implantation in a rat subdermis model. This model allows the recellularization and remodeling potential of the material to be assessed via a simple and inexpensive means prior to more complex ovine orthotropic studies. Biaxial testing was utilized to evaluate the mechanical properties, and subsequently, constitutive model parameters were fit to the data to allow mechanical performance to be evaluated via FE analysis of a full cardiac cycle. Maximum principal stresses and strains from the leaflets and commissures were then analyzed. The results of this study demonstrate that the explanted tissues had reduced mechanical strength compared to the implants but were similar to the native tissues. For the FE models, this trend was continued with similar mechanical behavior in explant and native tissue groups and less compliant behavior in implant tissues. Histology demonstrated recellularization and remodeling although remodeled collagen had no clear directionality. In conclusion, we observed successful recellularization and remodeling of the tissue giving confidence to our TEHV material; however, the mechanical response indicates the additional remodeling would likely occur in the aortic/pulmonary position.

A Cadaverically Evaluated Dynamic FEM Model of Closed-Chain TKR Mechanics

2009 ◽  
Vol 131 (5) ◽  
Author(s):  
Joel L. Lanovaz ◽  
Randy E. Ellis
Keyword(s):  
Model Performance ◽  
Element Model ◽  
Joint Kinematics ◽  
Contact Friction ◽  
Model Parameters ◽  
Factors Affecting ◽  
Reaction Forces ◽  
Total Knee

Knowledge of the behavior and mechanics of a total knee replacement (TKR) in an in vivo environment is key to optimizing the functional outcomes of the implant procedure. Computational modeling has shown to be an important tool for investigating biomechanical variables that are difficult to address experimentally. To assist in examining TKR mechanics, a dynamic finite-element model of a TKR is presented. The objective of the study was to develop and evaluate a model that could simulate full knee motion using a physiologically consistent quadriceps action, without prescribed joint kinematics. The model included tibiofemoral (TFJs) and patellofemoral joints (PFJs), six major ligament bundles and was driven by a uni-axial representation of a quadricep muscle. An initial parameter screening analysis was performed to assess the relative importance of 31 different model parameters. This analysis showed that ligament insertion location and initial ligament strain were significant factors affecting simulated joint kinematics and loading, with the contact friction coefficient playing a lesser role and ligament stiffness having little effect. The model was then used to simulate in vitro experiments utilizing a flexed-knee-stance testing rig. General model performance was assessed by comparing simulation results with experimentally measured kinematics and tibial reaction forces collected from two implanted specimens. The simulations were able to reproduce experimental differences observed between the test specimens and were able to accurately predict trends seen in the tibial reaction loads. The simulated kinematics of the TFJ and PFJ were less consistent when compared with experimental data but still reproduced many trends.

scholarly journals Oscillations and variability in neuronal systems: interplay of autonomous transient dynamics and fast deterministic fluctuations

2021 ◽  
Author(s):  
Rodrigo FO Pena ◽  
Horacio G. Rotstein
Keyword(s):  
Initial Conditions ◽  
Experimental Testing ◽  
Gaussian White Noise ◽  
Transient Dynamics ◽  
Target Cells ◽  
Model Parameters ◽  
Stochastic Noise ◽  
Neuronal Systems

Neuronal systems are subject to rapidly fluctuations both intrinsically and externally. In mathematical models, these fluctuations are typically incorporated as stochastic noise (e.g., Gaussian white or colored noise). Noise can be both disruptive and constructive, for example, by creating irregularities and variability in otherwise regular patterns or by creating oscillatory patterns and increasing the signal coherence, respectively. The dynamic mechanisms underlying the interactions between rapidly fluctuating signals and the intrinsic properties of the target cells to produce variable and/or coherent responses are not fully understood. In particular, it is not clear what properties of the target cell's intrinsic dynamics control these interactions and whether the generation of this phenomena requires stochasticity of the input signal and, if yes, to what degree. In this paper we investigate these issues by using linearized and non-linear conductance-based models and piecewise constant (PWC) inputs with short duration pieces and variable amplitudes, which are arbitrarily, but not necessarily stochastically distributed. The amplitude distributions of the constant pieces consist of arbitrary permutations of a baseline PWC function with monotonically increasing amplitudes. In each trial within a given protocol we use one of these permutations and each protocol consists of a subset of all possible permutations, which is the only source of uncertainty in the protocol. We show that sustained oscillatory behavior can be generated in response to additive and multiplicative PWC inputs in both linear and nonlinear systems, independently of whether the stable equilibria of the corresponding unperturbed systems are foci (exhibiting damped oscillations) or nodes (exhibiting overshoots). The oscillatory responses are amplified by the model nonlinearities and attenuated for conductance-based PWC inputs as compared to current-based PWC inputs, consistent with previous theoretical and experimental work. In addition, the responses to PWC inputs exhibited variability across trials, which is reminiscent of the variability generated by stochastic noise (e.g., Gaussian white noise). This variability was modulated by the model parameters and the type of cellular intrinsic dynamics. Our analysis demonstrates that both oscillations and variability are the result of the interaction between the PWC input and the autonomous transient dynamics with little to no contribution from the dynamics around the steady-state. The generation of oscillations and variability does not require input stochasticity, but rather the sequential activation of the transient responses to abrupt changes in constant inputs. Each piece with the same amplitude evokes different responses across trials due to the differences in initial conditions in the corresponding regime. These initial conditions are determined by the value of the voltage at the end of the previous regime, which is different for different trials.The predictions made in this papers are amenable for experimental testing both in vitro and in vivo.

scholarly journals Use of Physiologically-Based Kinetics Modelling to Reliably Predict Internal Concentrations of the UV Filter, Homosalate, After Repeated Oral and Topical Application

2022 ◽  
Vol 12 ◽  
Author(s):  
Abdulkarim Najjar ◽  
Andreas Schepky ◽  
Christopher-Tilman Krueger ◽  
Matthew Dent ◽  
Sophie Cable ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Input Parameter ◽  
Internal Exposure ◽  
Model Parameters ◽  
Animal Testing ◽  
Clinical Trial Registration ◽  
Uv Filter ◽  
Physiologically Based

Ethical and legal considerations have led to increased use of non-animal methods to evaluate the safety of chemicals for human use. We describe the development and qualification of a physiologically-based kinetics (PBK) model for the cosmetic UV filter ingredient, homosalate, to support its safety without the need of generating further animal data. The intravenous (IV) rat PBK model, using PK-Sim®, was developed and validated using legacy in vivo data generated prior to the 2013 EU animal-testing ban. Input data included literature or predicted physicochemical and pharmacokinetic properties. The refined IV rat PBK model was subject to sensitivity analysis to identify homosalate-specific sensitive parameters impacting the prediction of Cmax (more sensitive than AUC(0-∞)). These were then considered, together with population modeling, to calculate the confidence interval (CI) 95% Cmax and AUC(0-∞). Final model parameters were established by visual inspection of the simulations and biological plausibility. The IV rat model was extrapolated to oral administration, and used to estimate internal exposures to doses tested in an oral repeated dose toxicity study. Next, a human PBK dermal model was developed using measured human in vitro ADME data and a module to represent the dermal route. Model performance was confirmed by comparing predicted and measured values from a US-FDA clinical trial (Identifier: NCT03582215, https://clinicaltrials.gov/). Final exposure estimations were obtained in a virtual population and considering the in vitro and input parameter uncertainty. This model was then used to estimate the Cmax and AUC(0–24 h) of homosalate according to consumer use in a sunscreen. The developed rat and human PBK models had a good biological basis and reproduced in vivo legacy rat and human clinical kinetics data. They also complied with the most recent WHO and OECD recommendations for assessing the confidence level. In conclusion, we have developed a PBK model which predicted reasonably well the internal exposure of homosalate according to different exposure scenarios with a medium to high level of confidence. In the absence of in vivo data, such human PBK models will be the heart of future completely non-animal risk assessments; therefore, valid approaches will be key in gaining their regulatory acceptance.Clinical Trial Registration: https://clinicaltrials.gov/, identifier, NCT03582215

In Vitro Evaluation of a Vancomycin Radioimmunoassay and Observations on Vancomycin Pharmacokinetics in Dialysis Patients

1981 ◽  
Vol 15 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Ron E. Polk ◽  
A. Espinel-Ingroff ◽  
Robert Lockridge
Keyword(s):  
Serum Levels ◽  
Least Square ◽  
Model Parameters ◽  
Dialysis Patients ◽  
Serum Samples ◽  
Significant Difference ◽  
Marked Accumulation ◽  
Spiked Serum

A recently marketed radioimmunoassay (RIA) for vancomycin (Monitor Science Corp.) was evaluated in vitro and in vivo. The RIA and bioassay results on 15 spiked serum samples found no significant difference between the two assays, although RIA results were significantly less variable. The coefficient of variation (RIA) was 5.5%. Vancomycin showed no significant degradation in plasma at 4°C and —20°C for up to 36 days. Five dialysis patients had a total of 62 serum levels determined. When vancomycin 1 g was given weekly to two anuric adults, marked accumulation occurred. This finding was consistent with vancomycin's long terminal half-life (19.8 and 17.8 days) obtained from a new computer subroutine which obtains least square estimators of model parameters from multiple dose data. Despite serum levels well above the MIC, two patients remained bacteremic. Peritoneal levels of vancomycin in two patients with suspected peritonitis equalled corresponding serum levels.

Leukocyte removal efficiency of cell-washed and unwashed whole blood: an in vitro study

Perfusion ◽  
2005 ◽  
Vol 20 (6) ◽  
pp. 335-341 ◽  
Author(s):  
M J ten Brinke ◽  
P W Weerwind ◽  
S Teerenstra ◽  
J CM Feron ◽  
W van der Meer ◽  
...  
Keyword(s):  
Removal Efficiency ◽  
Plasma Volume ◽  
Removal Rate ◽  
In Vitro Study ◽  
Vitro Study ◽  
Control Group ◽  
Leukocyte Depletion ◽  
Porcine Blood ◽  
Significant Difference

Leukocyte filtration of the cardiopulmonary bypass (CPB) perfusate after cardiac surgery has evolved as an important technique to prevent effector functions mediated by activated leukocytes. However, little is known about the filtration efficiency. Therefore, an in vitro study was conducted to define the leukocyte removal rate of a transfusion leukocyte-depletion filter, using cell-washed and unwashed whole porcine blood. In addition, the influence of different cell-washing protocols on the elimination rate of blood cells (leukocytes and platelets) was investigated. Fresh, diluted, pooled, heparinized, porcine blood was processed using either a high-flow (HF, n-5) or quality-wash (QW, n-5) protocol on a continuous auto-transfusion system, or was left unprocessed (control n-5). Thereafter, all samples were filtered using a transfusion leukocyte-depletion filter. Blood samples for measurement of hematocrit, white blood cell count, including leukocyte differentiation and platelet count, were taken before and after filtration. To compare the experimental groups, the removal rate was presented as the fraction of leukocytes or platelets removed per plasma volume. Cell washing significantly altered the fraction of leukocytes removed per plasma volume when compared to unprocessed blood (2.07 and 2.36 in the HF and QW groups, respectively, versus 1.34 in the control group, p-0.008 for both). No statistically significant difference in leukocyte removal rate was observed between the different cell-washing protocols. The leukocyte differential count showed that, during all experiments, the neutrophils were removed most efficiently (99.7%). Overall, significantly more platelets were depleted after cell washing compared to the control group (1.47 and 1.60 in the HF and QW groups, respectively, versus 1.12 in the control group, p-0.008 and 0.032, respectively). Furthermore, the amount of blood that could be filtered using a single pass technique did not significantly differ between the experimental groups. However, a larger variation in the total amount of filtered blood was observed in the unprocessed group (5709/398 mL) compared to the cell-washed groups (3609/42 and 4309/97 mL in the HF and QW groups, respectively). In conclusion, blood processing with an auto-transfusion system significantly enhances the leukocyte and platelet removal efficiency of the transfusion leukocyte-depletion filter that was studied. In particular, neutrophils were efficiently removed.

scholarly journals Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species

2021 ◽  
Vol 14 (6) ◽  
pp. 545
Author(s):  
Yoo-Seong Jeong ◽  
William J. Jusko
Keyword(s):  
Tissue Distribution ◽  
Renal Plasma Flow ◽  
Model Parameters ◽  
Distribution Parameters ◽  
Species Specific ◽  
Pharmacologic Actions ◽  
Rats And Mice ◽  
Mpbpk Model

The objective of this study was to systematically assess literature datasets and quantitatively analyze metformin PK in plasma and some tissues of nine species. The pharmacokinetic (PK) parameters and profiles of metformin in nine species were collected from the literature. Based on a simple allometric scaling, the systemic clearances (CL) of metformin in these species highly correlate with body weight (BW) (R2 = 0.85) and are comparable to renal plasma flow in most species except for rabbit and cat. Reported volumes of distribution (VSS) varied appreciably (0.32 to 10.1 L/kg) among species. Using the physiological and anatomical variables for each species, a minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue compartments (Tissues 1 and 2) was used for modeling metformin PK in the nine species. Permeability-limited distribution (low fd1 and fd2) and a single tissue-to-plasma partition coefficient (Kp) value for Tissues 1 and 2 were applied in the joint mPBPK fitting. Nonlinear regression analysis for common tissue distribution parameters along with species-specific CL values reasonably captured the plasma PK profiles of metformin across most species, except for rat and horse with later time deviations. In separate fittings of the mPBPK model to each species, Tissue 2 was considered as slowly-equilibrating compartment consisting of muscle and skin based on in silico calculations of the mean transit times through tissues. The well-fitted mPBPK model parameters for absorption and disposition PK of metformin for each species were compared with in vitro/in vivo results found in the literature with regard to the physiological details and physicochemical properties of metformin. Bioavailability and absorption rates decreased with the increased BW among the species. Tissues such as muscle dominate metformin distribution with low permeability and partitioning while actual tissue concentrations found in rats and mice show likely transporter-mediated uptake in liver, kidney, and gastrointestinal tissues. Metformin has diverse pharmacologic actions, and this assessment revealed allometric relationships in its absorption and renal clearance but considerable variability in actual and modeled tissue distribution probably caused by transporter differences.

scholarly journals 786 Dose selection for DuoBody®-PD-L1×4-1BB (GEN1046) using a semimechanistic pharmacokinetics/pharmacodynamics model that leverages preclinical and clinical data

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A821-A821
Author(s):  
Gaurav Bajaj ◽  
Fereshteh Nazari ◽  
Marc Presler ◽  
Craig Thalhauser ◽  
Ulf Forssmann ◽  
...  
Keyword(s):  
T Cell ◽  
Bispecific Antibody ◽  
Receptor Occupancy ◽  
Model Parameters ◽  
Cell Trafficking ◽  
Dynamic Binding ◽  
Dose Selection ◽  
Trimer Formation

BackgroundDuoBody-PD-L1×4-1BB (GEN1046) is a class-defining bispecific antibody, designed to elicit an anti-tumor immune response by simultaneous and complementary blockade of PD-L1 on tumor cells and conditional stimulation of 4-1BB on T-cells and NK cells. Optimizing target engagement for a bispecific antibody is challenging, as it involves binding with two targets, and predicting trimer levels in tumors based on affinity of individual arms and target expression. Here we describe a semimechanistic, physiologically based pharmacokinetic/pharmacodynamic (PK/PD) model that predicts a dosing regimen for DuoBody-PD-L1×4-1BB, which results in the formation of maximum levels of a therapeutically active 4-1BB-bispecific antibody-PD-L1 trimolecular complex (trimer), and optimal PD-L1 receptor occupancy (RO).MethodsAn integrated semimechanistic PK/PD model that describes the distribution of DuoBody-PD-L1×4-1BB into central and peripheral compartments and partitioning into tumor/lymph nodes was developed. The model used PK/PD data and physiological parameters from the literature for parameterizations of PD-L1 and 4-1BB expression levels and T-cell trafficking. The model incorporates dynamic binding of DuoBody-PD-L1×4-1BB to its targets to predict trimer formation and RO for PD-L1 in tumors. Model parameters were calibrated to match in vitro PD studies, such as analyses of T-cell proliferation and cytokine release, as well as clinical PK data. Sensitivity to model assumptions were assessed by varying PK/PD parameters, and assessing their impact on trimer formation and PD-L1 RO. The model was subsequently used to explore in vivo trimer levels and PD-L1 RO in tumors at various dosing regimens.ResultsThe model was able to adequately describe the PK of DuoBody-PD-L1×4-1BB in the central compartment. Simulations showed a bell-shaped response for average trimer levels in tumors that peaked at 100 mg every 3 weeks (Q3W), with doses >100 mg resulting in reduced trimer formation. Average PD-L1 receptor occupancy at the 100 mg dose was predicted to be approximately 70% over 21 days and increased at higher doses. Based on these model predictions, and available safety, anti-tumor activity, and PD data from the ongoing GCT1046-01 trial (NCT03917381), 100 mg Q3W was chosen as the expansion dose for further evaluation in Part 2 of the study.ConclusionsThis semimechanistic PK/PD model provides a novel approach for dose selection of bispecific antibodies such as DuoBody-PD-L1×4-1BB, by using preclinical and clinical PK/PD data to predict formation of optimal trimer levels and PD-L1 receptor occupancy.AcknowledgementsThe authors thank Friederike Gieseke and Zuzana Jirakova at BioNTech SE; Kalyanasundaram Subramanian at Applied Biomath LLC for their valuable contributions.Trial RegistrationWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

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