With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death w... more With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death worldwide. However, the emerging field of microfluidics can potentially shed light on this puzzling disease. Unique characteristics of microfluidic chips (also known as micro-total analysis system) make them excellent candidates for biological applications. The ex vivo approach of tumor-on-a-chip is becoming an indispensable part of personalized medicine and can replace in vivo animal testing as well as conventional in vitro methods. In tumor-on-a-chip, the complex three-dimensional (3D) nature of malignant tumor is co-cultured on a microfluidic chip and high throughput screening tools to evaluate the efficacy of anticancer drugs are integrated on the same chip. In this article, we critically review the cutting edge advances in this field and mainly categorize each tumor-on-a-chip work based on its primary organ. Specifically, design, fabrication and characterization of tumor microenvironment; cell culture technique; transferring mechanism of cultured cells into the microchip; concentration gradient generators for drug delivery; in vitro screening assays of drug efficacy; and pros and cons of each microfluidic platform used in the recent literature will be discussed separately for the tumor of following organs: (1) Lung; (2) Bone marrow; (3) Brain; (4) Breast; (5) Urinary system (kidney, bladder and prostate); (6) Intestine; and (7) Liver. By comparing these microchips, we intend to demonstrate the unique design considerations of each tumor-on-a-chip based on primary organ, e.g., how microfluidic platform of lung-tumor-on-a-chip may differ from liver-tumor-on-a-chip. In addition, the importance of heart-liver-intestine co-culture with microvasculature in tumor-on-a-chip devices for in vitro chemosensitivity assay will be discussed. Such system would be able to completely evaluate the absorption, distribution, metabolism, excretion and toxicity (ADMET) of anticancer drugs and more realistically recapitulate tumor in vivo-like microenvironment.
Abstract This study aims to numerically investigate drug delivery to the tumor through the pores ... more Abstract This study aims to numerically investigate drug delivery to the tumor through the pores in its microvascular wall. A segment of tumor capillaries is modeled as a rigid cylinder with a single pore. Blood flow with nanoparticles is examined by Eulerian–Lagrangian approach in which the blood and particles are modeled as continuous phase and discrete phase, respectively. For investigating of nanoparticle-blood flow, a model is used in which almost all possible effective forces on the motion of particles are considered and blood flow are modeled as a combination of a non-Newtonian core region and Newtonian peripheral region. At the core region, it is considered that the blood flow behaves as non-Newtonian power law model. The effect of different controllable parameters on the particle delivery is investigated and the effectiveness of each of these parameters is discussed and compared with each other. Finally, a correlation was developed for the nanoparticle delivery.
Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors ... more Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors for three-dimensional (3D) multicellular spheroid culture are now considered as the next generation in in vitro diagnostic tools. The feasibility of using 3D cell aggregates to form multicellular spheroids in a microbioreactor with U-shaped barriers has been demonstrated experimentally. A barrier array is an alternative to commonly used microwell traps. The present study investigates oxygen and glucose concentration distributions as key parameters in a U-shaped array microbioreactor using finite element simulation. The effect of spheroid diameter, inlet concentration and flow rate of the medium are systematically studied. In all cases, the channel walls are considered to be permeable to oxygen. Necrotic and hypoxic or quiescent regions corresponding to both oxygen and glucose concentration distributions are identified for various conditions. The results show that the entire quiescent and necrotic regions become larger with increasing spheroid diameter and decreasing inlet and wall concentration. The shear stress (0.5-9 mPa) imposed on the spheroid surface by the fluid flow was compared with the critical values to predict possible damage to the cells. Finally, optimum range of medium inlet concentration (0.13-0.2 mM for oxygen and 3-11 mM for glucose) and flow rate (5-20 µL/min) are found to form the largest possible multicellular spheroid (500 µm), without any quiescent and necrotic regions with an acceptable shear stress. The effect of cell-trap types on the oxygen and glucose concentration inside the spheroid was also investigated. The levels of oxygen and glucose concentration for the microwell are much lower than those for the other two traps. The U-shaped barrier created with microposts allows for a continuous flow of culture medium, and so improves the glucose concentration compared to that in the integrated U-shaped barrier. Oxygen concentration for both types of U-shaped barriers is nearly the same. Due to the advantage of using U-shaped barriers to culture multicellular spheroids, the results of this paper can help to choose the experimental and design parameters of the microbioreactor.
Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. ... more Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. One of the most commonly used types of these chips is perfusion microwells for culturing multicellular spheroids. The main challenge in such systems is the formation of substantial necrotic and hypoxic zones within the cultured spheroids. Herein, we propose a novel acoustofluidic integrated platform to tackle this bottleneck problem. We show that such an approach enhances cell viability and shrinks necrotic and hypoxic zones in these spheroid-on-a-chip platforms without the need to increase the flow rate, leading to a significant reduction in costly reagents' consumption. Proof-of-concept, designing procedures, and finite element numerical simulation are discussed in details. Also, the effects of acoustic and hydrodynamic parameters on the cultured cells are investigated. The results show that by increasing acoustic boundary displacement amplitude (d0), the spheroid’s proliferating z...
Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. ... more Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. One of the most commonly used types of these chips is perfusion microwells for culturing multicellular spheroids. The main challenge in such systems is the formation of substantial necrotic and quiescent zones within the cultured spheroids. Herein, we propose a novel acoustofluidic integrated platform to tackle this bottleneck problem. It will be shown numerically that such an approach is a potential candidate to be implemented to enhance cell viability and shrinks necrotic and quiescent zones without the need to increase the flow rate, leading to a significant reduction in costly reagents’ consumption in conventional spheroid-on-a-chip platforms. Proof-of-concept, designing procedures and numerical simulation are discussed in detail. Additionally, the effects of acoustic and hydrodynamic parameters on the cultured cells are investigated. The results show that by increasing acoustic boun...
Microfluidic cell culture platforms are ideal candidates for modeling the native tumor microenvir... more Microfluidic cell culture platforms are ideal candidates for modeling the native tumor microenvironment because they can precisely reconstruct in vivo cellular behavior. Moreover, mathematical modeling of tumor growth can pave the way toward description and prediction of growth pattern as well as improving cancer treatment. In this study, a modified mathematical model based on concentration distribution is applied to tumor growth in both conventional static culture and dynamic microfluidic cell culture systems. Apoptosis and necrosis mechanisms are considered as the main inhibitory factors in the model, while tumor growth rate and nutrient consumption rate are modified in both quiescent and proliferative zones. We show that such modification can better predict the experimental results of tumor growth reported in the literature. Using numerical simulations, the effects of the concentrations of the nutrients as well as the initial tumor radius on the tumor growth are investigated and ...
A microfluidic system provides an excellent platform for cellular studies. Most importantly, a th... more A microfluidic system provides an excellent platform for cellular studies. Most importantly, a three-dimensional (3D) cell culture model reconstructs more accurately the in vivo microenvironment of tissue. Accordingly, microfluidic 3D cell culture devices could be ideal candidates for in vitro cell culture platforms. In this paper, two types of 3D cellular aggregates, i.e., toroid and spheroid, are numerically studied. The studies are carried out for microfluidic systems containing U-shaped barrier as well as microwell structure. For the first time, we obtain oxygen and glucose concentration distributions inside a toroid aggregate as well as the shear stress on its surface and compare its performance with a spheroid aggregate of the same volume. In particular, we obtain the oxygen concentration distributions in three areas, namely, oxygen-permeable layer, multicellular aggregates and culture medium. Further, glucose concentration distributions in two regions of multicellular aggregates and culture medium are investigated. The results show that the levels of oxygen and glucose in the system containing U-shaped barriers are far more than those in the system containing microwells. Therefore, to achieve high levels of oxygen and nutrients, a system with U-shaped barriers is more suited than the conventional traps, but the choice between toroid and spheroid depends on their volume and orientation. The results indicate that higher oxygen and glucose concentrations can be achieved in spheroid with a small volume as well as in horizontal toroid with a large volume. The vertical toroid has the highest levels of oxygen and glucose concentration while the surface shear stress on its surface is also maximum. These findings can be used as guidelines for designing an optimum 3D microfluidic bioreactor based on the desired levels of oxygen, glucose and shear stress distributions.
Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors ... more Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors for three-dimensional (3D) multicellular spheroid culture are now considered as the next generation in in vitro diagnostic tools. The feasibility of using 3D cell aggregates to form multicellular spheroids in a microbioreactor with U-shaped barriers has been demonstrated experimentally. A barrier array is an alternative to commonly used microwell traps. The present study investigates oxygen and glucose concentration distributions as key parameters in a U-shaped array microbioreactor using finite element simulation. The effect of spheroid diameter, inlet concentration and flow rate of the medium are systematically studied. In all cases, the channel walls are considered to be permeable to oxygen. Necrotic and hypoxic or quiescent regions corresponding to both oxygen and glucose concentration distributions are identified for various conditions. The results show that the entire quiescent and necrotic regions become larger with increasing spheroid diameter and decreasing inlet and wall concentration. The shear stress (0.5–9 mPa) imposed on the spheroid surface by the fluid flow was compared with the critical values to predict possible damage to the cells. Finally, optimum range of medium inlet concentration (0.13–0.2 mM for oxygen and 3–11 mM for glucose) and flow rate (5–20 µL/min) are found to form the largest possible multicellular spheroid (500 µm), without any quiescent and necrotic regions with an acceptable shear stress. The effect of cell-trap types on the oxygen and glucose concentration inside the spheroid was also investigated. The levels of oxygen and glucose concentration for the microwell are much lower than those for the other two traps. The U-shaped barrier created with microposts allows for a continuous flow of culture medium, and so improves the glucose concentration compared to that in the integrated U-shaped barrier. Oxygen concentration for both types of U-shaped barriers is nearly the same. Due to the advantage of using U-shaped barriers to culture multicellular spheroids, the results of this paper can help to choose the experimental and design parameters of the microbioreactor.
With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death w... more With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death worldwide. However, the emerging field of microfluidics can potentially shed light on this puzzling disease. Unique characteristics of microfluidic chips (also known as micro-total analysis system) make them excellent candidates for biological applications. The ex vivo approach of tumor-on-a-chip is becoming an indispensable part of personalized medicine and can replace in vivo animal testing as well as conventional in vitro methods. In tumor-on-a-chip, the complex three-dimensional (3D) nature of malignant tumor is co-cultured on a microfluidic chip and high throughput screening tools to evaluate the efficacy of anticancer drugs are integrated on the same chip. In this article, we critically review the cutting edge advances in this field and mainly categorize each tumor-on-a-chip work based on its primary organ. Specifically, design, fabrication and characterization of tumor microenvironment; cell culture technique; transferring mechanism of cultured cells into the microchip; concentration gradient generators for drug delivery; in vitro screening assays of drug efficacy; and pros and cons of each microfluidic platform used in the recent literature will be discussed separately for the tumor of following organs: (1) Lung; (2) Bone marrow; (3) Brain; (4) Breast; (5) Urinary system (kidney, bladder and prostate); (6) Intestine; and (7) Liver. By comparing these microchips, we intend to demonstrate the unique design considerations of each tumor-on-a-chip based on primary organ, e.g., how microfluidic platform of lung-tumor-on-a-chip may differ from liver-tumor-on-a-chip. In addition, the importance of heart–liver–intestine co-culture with microvasculature in tumor-on-a-chip devices for in vitro chemosensitivity assay will be discussed. Such system would be able to completely evaluate the absorption, distribution, metabolism, excretion and toxicity (ADMET) of anticancer drugs and more realistically recapitulate tumor in vivo-like microenvironment.
With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death w... more With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death worldwide. However, the emerging field of microfluidics can potentially shed light on this puzzling disease. Unique characteristics of microfluidic chips (also known as micro-total analysis system) make them excellent candidates for biological applications. The ex vivo approach of tumor-on-a-chip is becoming an indispensable part of personalized medicine and can replace in vivo animal testing as well as conventional in vitro methods. In tumor-on-a-chip, the complex three-dimensional (3D) nature of malignant tumor is co-cultured on a microfluidic chip and high throughput screening tools to evaluate the efficacy of anticancer drugs are integrated on the same chip. In this article, we critically review the cutting edge advances in this field and mainly categorize each tumor-on-a-chip work based on its primary organ. Specifically, design, fabrication and characterization of tumor microenvironment; cell culture technique; transferring mechanism of cultured cells into the microchip; concentration gradient generators for drug delivery; in vitro screening assays of drug efficacy; and pros and cons of each microfluidic platform used in the recent literature will be discussed separately for the tumor of following organs: (1) Lung; (2) Bone marrow; (3) Brain; (4) Breast; (5) Urinary system (kidney, bladder and prostate); (6) Intestine; and (7) Liver. By comparing these microchips, we intend to demonstrate the unique design considerations of each tumor-on-a-chip based on primary organ, e.g., how microfluidic platform of lung-tumor-on-a-chip may differ from liver-tumor-on-a-chip. In addition, the importance of heart-liver-intestine co-culture with microvasculature in tumor-on-a-chip devices for in vitro chemosensitivity assay will be discussed. Such system would be able to completely evaluate the absorption, distribution, metabolism, excretion and toxicity (ADMET) of anticancer drugs and more realistically recapitulate tumor in vivo-like microenvironment.
Abstract This study aims to numerically investigate drug delivery to the tumor through the pores ... more Abstract This study aims to numerically investigate drug delivery to the tumor through the pores in its microvascular wall. A segment of tumor capillaries is modeled as a rigid cylinder with a single pore. Blood flow with nanoparticles is examined by Eulerian–Lagrangian approach in which the blood and particles are modeled as continuous phase and discrete phase, respectively. For investigating of nanoparticle-blood flow, a model is used in which almost all possible effective forces on the motion of particles are considered and blood flow are modeled as a combination of a non-Newtonian core region and Newtonian peripheral region. At the core region, it is considered that the blood flow behaves as non-Newtonian power law model. The effect of different controllable parameters on the particle delivery is investigated and the effectiveness of each of these parameters is discussed and compared with each other. Finally, a correlation was developed for the nanoparticle delivery.
Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors ... more Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors for three-dimensional (3D) multicellular spheroid culture are now considered as the next generation in in vitro diagnostic tools. The feasibility of using 3D cell aggregates to form multicellular spheroids in a microbioreactor with U-shaped barriers has been demonstrated experimentally. A barrier array is an alternative to commonly used microwell traps. The present study investigates oxygen and glucose concentration distributions as key parameters in a U-shaped array microbioreactor using finite element simulation. The effect of spheroid diameter, inlet concentration and flow rate of the medium are systematically studied. In all cases, the channel walls are considered to be permeable to oxygen. Necrotic and hypoxic or quiescent regions corresponding to both oxygen and glucose concentration distributions are identified for various conditions. The results show that the entire quiescent and necrotic regions become larger with increasing spheroid diameter and decreasing inlet and wall concentration. The shear stress (0.5-9 mPa) imposed on the spheroid surface by the fluid flow was compared with the critical values to predict possible damage to the cells. Finally, optimum range of medium inlet concentration (0.13-0.2 mM for oxygen and 3-11 mM for glucose) and flow rate (5-20 µL/min) are found to form the largest possible multicellular spheroid (500 µm), without any quiescent and necrotic regions with an acceptable shear stress. The effect of cell-trap types on the oxygen and glucose concentration inside the spheroid was also investigated. The levels of oxygen and glucose concentration for the microwell are much lower than those for the other two traps. The U-shaped barrier created with microposts allows for a continuous flow of culture medium, and so improves the glucose concentration compared to that in the integrated U-shaped barrier. Oxygen concentration for both types of U-shaped barriers is nearly the same. Due to the advantage of using U-shaped barriers to culture multicellular spheroids, the results of this paper can help to choose the experimental and design parameters of the microbioreactor.
Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. ... more Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. One of the most commonly used types of these chips is perfusion microwells for culturing multicellular spheroids. The main challenge in such systems is the formation of substantial necrotic and hypoxic zones within the cultured spheroids. Herein, we propose a novel acoustofluidic integrated platform to tackle this bottleneck problem. We show that such an approach enhances cell viability and shrinks necrotic and hypoxic zones in these spheroid-on-a-chip platforms without the need to increase the flow rate, leading to a significant reduction in costly reagents' consumption. Proof-of-concept, designing procedures, and finite element numerical simulation are discussed in details. Also, the effects of acoustic and hydrodynamic parameters on the cultured cells are investigated. The results show that by increasing acoustic boundary displacement amplitude (d0), the spheroid’s proliferating z...
Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. ... more Microfluidic lab-on-chip devices are widely being developed for chemical and biological studies. One of the most commonly used types of these chips is perfusion microwells for culturing multicellular spheroids. The main challenge in such systems is the formation of substantial necrotic and quiescent zones within the cultured spheroids. Herein, we propose a novel acoustofluidic integrated platform to tackle this bottleneck problem. It will be shown numerically that such an approach is a potential candidate to be implemented to enhance cell viability and shrinks necrotic and quiescent zones without the need to increase the flow rate, leading to a significant reduction in costly reagents’ consumption in conventional spheroid-on-a-chip platforms. Proof-of-concept, designing procedures and numerical simulation are discussed in detail. Additionally, the effects of acoustic and hydrodynamic parameters on the cultured cells are investigated. The results show that by increasing acoustic boun...
Microfluidic cell culture platforms are ideal candidates for modeling the native tumor microenvir... more Microfluidic cell culture platforms are ideal candidates for modeling the native tumor microenvironment because they can precisely reconstruct in vivo cellular behavior. Moreover, mathematical modeling of tumor growth can pave the way toward description and prediction of growth pattern as well as improving cancer treatment. In this study, a modified mathematical model based on concentration distribution is applied to tumor growth in both conventional static culture and dynamic microfluidic cell culture systems. Apoptosis and necrosis mechanisms are considered as the main inhibitory factors in the model, while tumor growth rate and nutrient consumption rate are modified in both quiescent and proliferative zones. We show that such modification can better predict the experimental results of tumor growth reported in the literature. Using numerical simulations, the effects of the concentrations of the nutrients as well as the initial tumor radius on the tumor growth are investigated and ...
A microfluidic system provides an excellent platform for cellular studies. Most importantly, a th... more A microfluidic system provides an excellent platform for cellular studies. Most importantly, a three-dimensional (3D) cell culture model reconstructs more accurately the in vivo microenvironment of tissue. Accordingly, microfluidic 3D cell culture devices could be ideal candidates for in vitro cell culture platforms. In this paper, two types of 3D cellular aggregates, i.e., toroid and spheroid, are numerically studied. The studies are carried out for microfluidic systems containing U-shaped barrier as well as microwell structure. For the first time, we obtain oxygen and glucose concentration distributions inside a toroid aggregate as well as the shear stress on its surface and compare its performance with a spheroid aggregate of the same volume. In particular, we obtain the oxygen concentration distributions in three areas, namely, oxygen-permeable layer, multicellular aggregates and culture medium. Further, glucose concentration distributions in two regions of multicellular aggregates and culture medium are investigated. The results show that the levels of oxygen and glucose in the system containing U-shaped barriers are far more than those in the system containing microwells. Therefore, to achieve high levels of oxygen and nutrients, a system with U-shaped barriers is more suited than the conventional traps, but the choice between toroid and spheroid depends on their volume and orientation. The results indicate that higher oxygen and glucose concentrations can be achieved in spheroid with a small volume as well as in horizontal toroid with a large volume. The vertical toroid has the highest levels of oxygen and glucose concentration while the surface shear stress on its surface is also maximum. These findings can be used as guidelines for designing an optimum 3D microfluidic bioreactor based on the desired levels of oxygen, glucose and shear stress distributions.
Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors ... more Microfluidic devices have been widely used for biological and cellular studies. Microbioreactors for three-dimensional (3D) multicellular spheroid culture are now considered as the next generation in in vitro diagnostic tools. The feasibility of using 3D cell aggregates to form multicellular spheroids in a microbioreactor with U-shaped barriers has been demonstrated experimentally. A barrier array is an alternative to commonly used microwell traps. The present study investigates oxygen and glucose concentration distributions as key parameters in a U-shaped array microbioreactor using finite element simulation. The effect of spheroid diameter, inlet concentration and flow rate of the medium are systematically studied. In all cases, the channel walls are considered to be permeable to oxygen. Necrotic and hypoxic or quiescent regions corresponding to both oxygen and glucose concentration distributions are identified for various conditions. The results show that the entire quiescent and necrotic regions become larger with increasing spheroid diameter and decreasing inlet and wall concentration. The shear stress (0.5–9 mPa) imposed on the spheroid surface by the fluid flow was compared with the critical values to predict possible damage to the cells. Finally, optimum range of medium inlet concentration (0.13–0.2 mM for oxygen and 3–11 mM for glucose) and flow rate (5–20 µL/min) are found to form the largest possible multicellular spheroid (500 µm), without any quiescent and necrotic regions with an acceptable shear stress. The effect of cell-trap types on the oxygen and glucose concentration inside the spheroid was also investigated. The levels of oxygen and glucose concentration for the microwell are much lower than those for the other two traps. The U-shaped barrier created with microposts allows for a continuous flow of culture medium, and so improves the glucose concentration compared to that in the integrated U-shaped barrier. Oxygen concentration for both types of U-shaped barriers is nearly the same. Due to the advantage of using U-shaped barriers to culture multicellular spheroids, the results of this paper can help to choose the experimental and design parameters of the microbioreactor.
With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death w... more With a mortality rate over 580,000 per year, cancer is still one of the leading causes of death worldwide. However, the emerging field of microfluidics can potentially shed light on this puzzling disease. Unique characteristics of microfluidic chips (also known as micro-total analysis system) make them excellent candidates for biological applications. The ex vivo approach of tumor-on-a-chip is becoming an indispensable part of personalized medicine and can replace in vivo animal testing as well as conventional in vitro methods. In tumor-on-a-chip, the complex three-dimensional (3D) nature of malignant tumor is co-cultured on a microfluidic chip and high throughput screening tools to evaluate the efficacy of anticancer drugs are integrated on the same chip. In this article, we critically review the cutting edge advances in this field and mainly categorize each tumor-on-a-chip work based on its primary organ. Specifically, design, fabrication and characterization of tumor microenvironment; cell culture technique; transferring mechanism of cultured cells into the microchip; concentration gradient generators for drug delivery; in vitro screening assays of drug efficacy; and pros and cons of each microfluidic platform used in the recent literature will be discussed separately for the tumor of following organs: (1) Lung; (2) Bone marrow; (3) Brain; (4) Breast; (5) Urinary system (kidney, bladder and prostate); (6) Intestine; and (7) Liver. By comparing these microchips, we intend to demonstrate the unique design considerations of each tumor-on-a-chip based on primary organ, e.g., how microfluidic platform of lung-tumor-on-a-chip may differ from liver-tumor-on-a-chip. In addition, the importance of heart–liver–intestine co-culture with microvasculature in tumor-on-a-chip devices for in vitro chemosensitivity assay will be discussed. Such system would be able to completely evaluate the absorption, distribution, metabolism, excretion and toxicity (ADMET) of anticancer drugs and more realistically recapitulate tumor in vivo-like microenvironment.
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Papers by Maryam Barisam