scholarly journals Characterization of the Microflow Through 3D Synthetic Niche Microenvironments Hosted in a Millifluidic Bioreactor

2021 ◽  
Vol 9 ◽  
Author(s):  
Bogdan Ene-Iordache ◽  
Chiara Emma Campiglio ◽  
Manuela Teresa Raimondi ◽  
Andrea Remuzzi
Keyword(s):  
Flow Field ◽  
Drug Efficacy ◽  
Complex Flow ◽  
Low Velocity ◽  
Fine Grid ◽  
Micro Flows ◽  
Computational Fluid Dynamics Cfd ◽  
Cell Growth And Viability

Background: Development of new medicines is a lengthy process with high risk of failure since drug efficacy measured in vitro is difficult to confirm in vivo. Intended to add a new tool aiding drug discovery, the MOAB-NICHOID device was developed: a miniaturized optically accessible bioreactor (MOAB) housing the 3D engineered scaffold NICHOID. The aim of our study was to characterize the microflow through the 3D nichoid microenvironment hosted in the MOAB-NICHOID device.Methods: We used computational fluid dynamics (CFD) simulations to compute the flow field inside a very fine grid resembling the scaffold microenvironment.Results: The microflow inside the multi-array of nichoid blocks is fed and locally influenced by the mainstream flow developed in the perfusion chamber of the device. Here we have revealed a low velocity, complex flow field with secondary, backward, or local recirculation micro-flows induced by the intricate architecture of the nichoid scaffold.Conclusion: Knowledge of the microenvironment inside the 3D nichoids allows planning of cell experiments, to regulate the transport of cells towards the scaffold substrate during seeding or the spatial delivery of nutrients and oxygen which affects cell growth and viability.

scholarly journals A Novel Infection Protocol in Zebrafish Embryo to Assess Pseudomonas aeruginosa Virulence and Validate Efficacy of a Quorum Sensing Inhibitor In Vivo

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 401
Author(s):  
Pauline Nogaret ◽  
Fatima El El Garah ◽  
Anne-Béatrice Blanc-Potard
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Animal Model ◽  
Quorum Sensing ◽  
Drug Testing ◽  
Drug Efficacy ◽  
Embryo Viability ◽  
Immersion Method ◽  
Opportunistic Human Pathogen

The opportunistic human pathogen Pseudomonas aeruginosa is responsible for a variety of acute infections and is a major cause of mortality in chronically infected cystic fibrosis patients. Due to increased resistance to antibiotics, new therapeutic strategies against P. aeruginosa are urgently needed. In this context, we aimed to develop a simple vertebrate animal model to rapidly assess in vivo drug efficacy against P. aeruginosa. Zebrafish are increasingly considered for modeling human infections caused by bacterial pathogens, which are commonly microinjected in embryos. In the present study, we established a novel protocol for zebrafish infection by P. aeruginosa based on bath immersion in 96-well plates of tail-injured embryos. The immersion method, followed by a 48-hour survey of embryo viability, was first validated to assess the virulence of P. aeruginosa wild-type PAO1 and a known attenuated mutant. We then validated its relevance for antipseudomonal drug testing by first using a clinically used antibiotic, ciprofloxacin. Secondly, we used a novel quorum sensing (QS) inhibitory molecule, N-(2-pyrimidyl)butanamide (C11), the activity of which had been validated in vitro but not previously tested in any animal model. A significant protective effect of C11 was observed on infected embryos, supporting the ability of C11 to attenuate in vivo P. aeruginosa pathogenicity. In conclusion, we present here a new and reliable method to compare the virulence of P. aeruginosa strains in vivo and to rapidly assess the efficacy of clinically relevant drugs against P. aeruginosa, including new antivirulence compounds.

Hemodynamics in the abdominal aorta: a comparison of in vitro and in vivo measurements

1994 ◽  
Vol 76 (4) ◽  
pp. 1520-1527 ◽  
Author(s):  
J. E. Moore ◽  
S. E. Maier ◽  
D. N. Ku ◽  
P. Boesiger
Keyword(s):  
Abdominal Aorta ◽  
Velocity Profiles ◽  
Flow Reversal ◽  
Infrarenal Aorta ◽  
Complex Flow ◽  
Flow Measurements ◽  
In Vivo Measurements ◽  
Made In

In vivo measurements of blood velocity profiles are difficult to obtain and interpret, since the parameters that govern the normally highly complex flow situation may not be fully quantified or understood at the time of measurement. In vitro flow models have been used often to better understand vascular hemodynamics. The assumptions made in the design of these models limit the applicability of the results. In this study, in vitro flow measurements made in a carefully designed model of the abdominal aorta were compared with in vivo measurements obtained with magnetic resonance imaging. In the suprarenal aorta, the velocity profiles were mostly forward and axisymmetric in both the in vitro and in vivo cases. In the infrarenal aorta, there was extensive flow reversal noted near the posterior wall in both cases. In the aortic bifurcation, two peaks of flow reversal were noted near the lateral posterior walls, and M-shaped velocity profiles were observed in late diastole. The in vitro and in vivo measurements exhibited good qualitative agreement. The in vitro model was accurate in modeling the in vivo hemodynamics of the abdominal aorta. The complex phenomena observed in vivo were explained on the basis of knowledge gained from the in vitro study.

α1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 713-715 ◽  
Author(s):  
Heather G. Jørgensen ◽  
Moira A. Elliott ◽  
Elaine K. Allan ◽  
Christine E. Carr ◽  
Tessa L. Holyoake ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Proteins ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Drug Efficacy ◽  
Acid Glycoprotein ◽  
Proliferation In Vitro ◽  
Normal Controls

Abstract Despite the efficacy of STI571 (Glivec, Novartis, Basle, Switzerland) in treating chronic myeloid leukemia (CML), drug resistance has already been noted both in vitro and in vivo. As plasma proteins, including alpha-1-acid glycoprotein (AGP), may reduce drug efficacy through binding, AGP was investigated for its ability to interact with STI571.  At all stages of CML, AGP plasma level was significantly higher than in normal controls (P < .05). The glycoprotein was purified from normal plasma and individual chronic myeloid leukemia (CML) patients' plasma by low-pressure chromatography. The influence of α1-acid glycoprotein (AGP), in the presence of STI571, on the proliferation of Philadelphia chromosome–positive (Ph+) cells was examined. Normal AGP, even at supraphysiological concentrations, did not block the effect of STI571 on K562-cell proliferation in vitro. Moreover, CML-derived AGP failed to block the effect of STI571 on Ph+ cells in vitro. Thus, these in vitro findings suggest that AGP will not abrogate the antileukemic activity of STI571.

scholarly journals Design of Targeted Nanostructured Coordination Polymers (NCPs) for Cancer Therapy

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3449 ◽  
Author(s):  
Fernando Novio
Keyword(s):  
Coordination Polymers ◽  
Imaging Techniques ◽  
Drug Efficacy ◽  
Active Targeting ◽  
Drug Side Effects ◽  
Stimuli Responsive ◽  
Site Selective ◽  
Tumoral Cells

Conventional cancer chemotherapy presents notable drug side effects due to non-selective action of the chemotherapeutics to normal cells. Nanoparticles decorated with receptor-specific ligands on the surface have shown an important role in improving site-selective binding, retention, and drug delivery to the cancer cells. This review summarizes the recent reported achievements using nanostructured coordination polymers (NCPs) with active targeting properties for cancer treatment in vitro and in vivo. Despite the controversy surrounding the effectivity of active targeting nanoparticles, several studies suggest that active targeting nanoparticles notably increase the selectivity and the cytotoxic effect in tumoral cells over the conventional anticancer drugs and non-targeted nanoparticle platform, which enhances drug efficacy and safety. In most cases, the nanocarriers have been endowed with remarkable capabilities such as stimuli-responsive properties, targeting abilities, or the possibility to be monitored by imaging techniques. Unfortunately, the lack of preclinical studies impedes the evaluation of these unique and promising findings for the translation of NCPs into clinical trials.

Rhinomanometry Versus Computational Fluid Dynamics: Correlated, but Different Techniques

2020 ◽  
pp. 194589242095015
Author(s):  
Giancarlo B. Cherobin ◽  
Richard L. Voegels ◽  
Fábio R. Pinna ◽  
Eloisa M. M. S. Gebrim ◽  
Ryan S. Bailey ◽  
...  
Keyword(s):  
Fluid Dynamics ◽  
Computational Fluid Dynamics ◽  
Nasal Resistance ◽  
Nasal Patency ◽  
Low Correlation ◽  
Before And After ◽  
Computational Fluid Dynamics Cfd ◽  
Flow Experiments

Background Past studies reported a low correlation between rhinomanometry and computational fluid dynamics (CFD), but the source of the discrepancy was unclear. Low correlation or lack of correlation has also been reported between subjective and objective measures of nasal patency. Objective: This study investigates (1) the correlation and agreement between nasal resistance derived from CFD (RCFD) and rhinomanometry (RRMN), and (2) the correlation between objective and subjective measures of nasal patency. Methods Twenty-five patients with nasal obstruction underwent anterior rhinomanometry before and after mucosal decongestion with oxymetazoline. Subjective nasal patency was assessed with a 0-10 visual analog scale (VAS). CFD simulations were performed based on computed tomography scans obtained after mucosal decongestion. To validate the CFD methods, nasal resistance was measured in vitro (REXPERIMENT) by performing pressure-flow experiments in anatomically accurate plastic nasal replicas from 6 individuals. Results Mucosal decongestion was associated with a reduction in bilateral nasal resistance (0.34 ± 0.23 Pa.s/ml to 0.19 ± 0.24 Pa.s/ml, p = 0.003) and improved sensation of nasal airflow (bilateral VAS decreased from 5.2 ± 1.9 to 2.6 ± 1.9, p < 0.001). A statistically significant correlation was found between VAS in the most obstructed cavity and unilateral airflow before and after mucosal decongestion (r = −0.42, p = 0.003). Excellent correlation was found between RCFD and REXPERIMENT (r = 0.96, p < 0.001) with good agreement between the numerical and in vitro values (RCFD/REXPERIMENT = 0.93 ± 0.08). A weak correlation was found between RCFD and RRMN (r = 0.41, p = 0.003) with CFD underpredicting nasal resistance derived from rhinomanometry (RCFD/RRMN = 0.65 ± 0.63). A stronger correlation was found when unilateral airflow at a pressure drop of 75 Pa was used to compare CFD with rhinomanometry (r = 0.76, p < 0.001). Conclusion CFD and rhinomanometry are moderately correlated, but CFD underpredicts nasal resistance measured in vivo due in part to the assumption of rigid nasal walls. Our results confirm previous reports that subjective nasal patency correlates better with unilateral than with bilateral measurements and in the context of an intervention.

scholarly journals OOCHIP: Compartmentalized Microfluidic Perfusion System with Porous Barriers for Enhanced Cell–Cell Crosstalk in Organ-on-a-Chip

Micromachines ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 565
Author(s):  
Qasem Ramadan ◽  
Sajay Bhuvanendran Nair Gourikutty ◽  
Qingxin Zhang
Keyword(s):  
Drug Efficacy ◽  
Human Adipose Tissue ◽  
Cell Types ◽  
Cell Interaction ◽  
The Body ◽  
Close Proximity ◽  
Porous Barriers ◽  
Cell Cell

Improved in vitro models of human organs for predicting drug efficacy, interactions, and disease modelling are crucially needed to minimize the use of animal models, which inevitably display significant differences from the human disease state and metabolism. Inside the body, cells are organized either in direct contact or in close proximity to other cell types in a tightly controlled architecture that regulates tissue function. To emulate this cellular interface in vitro, an advanced cell culture system is required. In this paper, we describe a set of compartmentalized silicon-based microfluidic chips that enable co-culturing several types of cells in close proximity with enhanced cell–cell interaction. In vivo-like fluid flow into and/or from each compartment, as well as between adjacent compartments, is maintained by micro-engineered porous barriers. This porous structure provides a tool for mimicking the paracrine exchange between cells in the human body. As a demonstrating example, the microfluidic system was tested by culturing human adipose tissue that is infiltrated with immune cells to study the role if the interplay between the two cells in the context of type 2 diabetes. However, the system provides a platform technology for mimicking the structure and function of single- and multi-organ models, which could significantly narrow the gap between in vivo and in vitro conditions.

scholarly journals Simultaneous targeting of DNA replication and homologous recombination in glioblastoma with a polyether ionophore

2019 ◽  
Author(s):  
Yi Chieh Lim ◽  
Kathleen S Ensbey ◽  
Carolin Offenhäuser ◽  
Rochelle C J D’souza ◽  
Jason K Cullen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
First Generation ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Tumor Formation ◽  
Dna Lesions ◽  
Dual Functions

Abstract Background Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair. Methods In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships. Results Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell–like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action. Conclusion Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.

scholarly journals Multi-scale modeling of drug binding kinetics to predict drug efficacy

2019 ◽  
Vol 77 (3) ◽  
pp. 381-394 ◽  
Author(s):  
Fabrizio Clarelli ◽  
Jingyi Liang ◽  
Antal Martinecz ◽  
Ines Heiland ◽  
Pia Abel zur Wiesch
Keyword(s):  
Mathematical Models ◽  
Drug Efficacy ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Multi Scale ◽  
Drug Concentrations ◽  
Body Compartments ◽  
Target Binding

AbstractOptimizing drug therapies for any disease requires a solid understanding of pharmacokinetics (the drug concentration at a given time point in different body compartments) and pharmacodynamics (the effect a drug has at a given concentration). Mathematical models are frequently used to infer drug concentrations over time based on infrequent sampling and/or in inaccessible body compartments. Models are also used to translate drug action from in vitro to in vivo conditions or from animal models to human patients. Recently, mathematical models that incorporate drug-target binding and subsequent downstream responses have been shown to advance our understanding and increase predictive power of drug efficacy predictions. We here discuss current approaches of modeling drug binding kinetics that aim at improving model-based drug development in the future. This in turn might aid in reducing the large number of failed clinical trials.

scholarly journals Efficacies of Fluconazole, Caspofungin, and Amphotericin B in Candida glabrata-Infected p47phox−/− Knockout Mice

2002 ◽  
Vol 46 (5) ◽  
pp. 1240-1245 ◽  
Author(s):  
Justina Y. Ju ◽  
Cynthia Polhamus ◽  
Kieren A. Marr ◽  
Steven M. Holland ◽  
John E. Bennett
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Murine Model ◽  
Knockout Mice ◽  
Candida Glabrata ◽  
Drug Efficacy ◽  
Fungal Burden ◽  
Lethal Infection

ABSTRACT Candida glabrata is the second leading cause of adult candidemia, resulting in high mortality. Amphotericin B is considered the treatment of choice, while the efficacy of fluconazole is controversial and caspofungin efficacy is unknown. To ascertain drug efficacy in vivo, the utility of a murine model of C. glabrata infection was investigated. C. glabrata was found to cause progressive, lethal infection when injected intravenously into C57BL/6 mice with reduced oxidative microbicidal capacity due to knockout of the p47phox gene. Spleen and kidney organ CFU counts were determined in groups of mice 2 days after the mice completed 6 days of daily intraperitoneal drug treatment, which began on the day of infection. Daily injections of fluconazole at 80 mg/kg did not reduce spleen or kidney CFU counts after infection with C. glabrata strains having in vitro fluconazole MICs of 2, 32, or 256 μg/ml compared to saline-treated controls. However, this fluconazole regimen reduced spleen CFU counts in mice infected with Candida albicans, an infection that is known to be responsive to fluconazole. Caspofungin at 5 mg/kg and amphotericin B at 5 mg/kg were both effective in reducing fungal burden in spleens and kidneys of C. glabrata-infected mice. Ten mice treated for 6 days with caspofungin at 1 mg/kg survived for 15 days, though all 10 saline-injected mice died or were so ill that they had to be sacrificed by 96 h postinfection. This murine model provided evidence of the efficacy of amphotericin B and caspofungin but not of fluconazole against C. glabrata infection.

scholarly journals Merging Microfluidics with Microtitre Technology for More Efficient Drug Discovery

2008 ◽  
Vol 13 (5) ◽  
pp. 275-279 ◽  
Author(s):  
Nicole V. Tolan ◽  
Luiza I. Genes ◽  
Dana M. Spence
Keyword(s):  
Cellular Response ◽  
Simultaneous Detection ◽  
Drug Efficacy ◽  
Cell Types ◽  
Microtitre Plate ◽  
Multiple Components ◽  
Multiple Cell ◽  
Improve Blood Flow

Detecting multiple components from a single red blood cell (RBC) sample within a flow-based system in less than 20 min will enable improved in vitro determinations of drug efficacy and cellular response to administered drugs. Here, an example of an improved in vitro measurement involving iloprost, a pharmaceutical reported to improve blood flow, has been determined by incorporating multiple cell types onto a single device. The method allows fluid flow to address individual rows of wells contained within an 18-well microfluidic array that serves as a precursor to a 96-well microtitre plate device. The ability to better mimic the in vivo circulation by incorporating the flow of blood components, coupled with simultaneous detection and laboratory automation in place for microtitre plates, suggests that the microfluidic array presented here will allow for improved mechanistic drug research studies. Using fluorescence microscopy, concentrations of multiple metabolites present within the RBC can also be determined using the microfluidic array. The current progress toward using this device for personalized medicine is presented here.

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