Chemo-mechanistic multi-scale model of a three-dimensional tumor microenvironment to quantify the chemotherapy response of cancer.

Exploring efficient chemotherapy would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. As in vivo experimental methods are unable to isolate or control individual factors of the TME, and in vitro models often cannot include all the contributing factors, some questions are best addressed with mathematical models of systems biology. In this study, we establish a multi-scale mathematical model of the TME to simulate three-dimensional tumor growth and angiogenesis and then implement the model for an array of chemotherapy approaches to elucidate the effect of TME conditions and drug scheduling on controlling tumor progression. The hyperglycemic condition as the most common disorder for cancer patients is considered to evaluate its impact on cancer response to chemotherapy. We show that combining antiangiogenic and anticancer drugs improves the outcome of treatment and can decrease accumulation of the drug in normal tissue and enhance drug delivery to the tumor. Our results demonstrate that although both concurrent and neoadjuvant combination therapies can increase intratumoral drug exposure and therapeutic accuracy, neoadjuvant therapy surpasses this, especially against hyperglycemia. Our model provides mechanistic explanations for clinical observations of tumor progression and response to treatment and establishes a computational framework for exploring better treatment strategies.

Influences of Polymer-Surfactant Interaction on the Drop Formation Process: An Experimental Study.

The interaction between polymer and surfactant molecules affects the physical properties of liquids, which could be of great importance in an abundance of processes related to drop formation. Polymer and surfactant concentration is a factor that dramatically impacts the shape of molecular networks formed in the fluid bulk and the characteristics of a forming drop. In this study, the deformation and detachment of aqueous carboxymethyl cellulose (CMC) solutions' drops containing different concentrations of sodium dodecyl sulfate (SDS) are studied experimentally. Our purpose is to determine the effects of CMC and SDS concentrations on the parameters related to the formation process, including drop length, minimum neck thickness, and formation time. Our results clearly show that the increment of the SDS amount at a constant low CMC concentration increases the drop detachment length and results in a slower thinning process. However, at higher CMC concentrations, the drop limiting length reaches a maximum, indicating the effects of disintegration of molecular structures as the SDS amount exceeds the critical concentration. Moreover, the drop formation time is found to decrease with the increment of the SDS concentration, which could be attributed to the reduction of dynamic interfacial tension.

A mechanobiological mathematical model of liver metabolism.

The liver plays a complex role in metabolism and detoxification, and better tools are needed to understand its function and to develop liver-targeted therapies. In this study, we establish a mechanobiological model of liver transport and hepatocyte biology to elucidate the metabolism of urea and albumin, the production/detoxification of ammonia, and consumption of oxygen and nutrients. Since hepatocellular shear stress (SS) can influence the enzymatic activities of liver, the effect of SS on the urea and albumin synthesis are empirically modeled through the mechanotransduction mechanisms. The results demonstrate that the rheology and dynamics of the sinusoid flow can significantly affect liver metabolism. We show that perfusate rheology and blood hematocrit can affect urea and albumin production by changing hepatocyte mechanosensitive metabolism. The model can also simulate enzymatic diseases of the liver such as hyperammonemia I, hyperammonemia II, hyperarginemia, citrollinemia, and argininosuccinicaciduria, which disrupt the urea metabolism and ammonia detoxification. The model is also able to predict how aggregate cultures of hepatocytes differ from single cell cultures. We conclude that in vitro perfusable devices for the study of liver metabolism or personalized medicine should be designed with similar morphology and fluid dynamics as patient liver tissue. This robust model can be adapted to any type of hepatocyte culture to determine how hepatocyte viability, functionality, and metabolism are influenced by liver pathologies and environmental conditions.

Simulation of plaque formation in a realistic geometry of a human aorta: effects of endothelial layer properties, heart rate, and hypertension.

Nowadays, cardiovascular diseases are the most common cause of death worldwide. Besides, atherosclerosis is a cardiovascular disease that occurs with persistent narrowing of arteries, especially medium and large-sized arteries. Atherosclerosis begins with a local elevation in the permeability of the arterial wall as a result of endothelial inflammation. Subsequently, excess LDL permeates into the arterial wall. Then, through several chemical responses and reactions, foam cells are produced. These foam cells serve as a crucial indicator for assessing the development of atherosclerosis within the arteries. In this study, the effect of endothelial layer modeling, heart rate (HR) and hypertension on the foam cell accumulation is numerically investigated in a patient-specific geometry of the human thoracic aorta. Navier-Stokes, Darcy, and mass transfer equations are used to obtain the velocity and concentration field within the domain. Regarding the dependence of endothelial cell properties on time-averaged wall shear stress, it is observed that foam cells are mainly concentrated in the outer curvature of the aortic arch, downstream of the left subclavian artery. However, considering oscillatory-shear-rate as the determinant of endothelial cell properties leads to the accumulation of foam cells in the inner curvature of the descending aorta. Regarding the HR, with the increase of HR, the volume average concentration of the foam cell decreases. However, there is no substantial difference between the cases of different HRs. Moreover, foam cell concentration significantly increases in the hypertension case. This result implies that a slight increase in the blood pressure may induce irreparable problems in the circulatory system.

A multi-objective framework to select numerical options in air quality prediction models: A case study on dust storm modeling.

Numerical weather prediction models are very important tools in predicting severe weather phenomena such as dust storms. However, the prediction accuracy in these models depends on the options considered in the modeling. In this study, a multi-objective framework is presented to determine the optimal options of the weather research forecasting with chemistry (WRF-Chem) model. For this purpose, a severe dust storm that occurred in the center of Iran is considered and the effect of 10 options including grid (computational domain size, modeling start time, horizontal, vertical and temporal resolution), physical (initial conditions, boundary layer and land surface schemes) and chemical options (dust emission schemes and dust source functions) are investigated. In general, the results showed that the WRF-Chem model has a high ability to model dust storms, but its results depend on the options considered in the modeling. Evaluation of grid options showed that inappropriate selection of domain size and modeling start time can lead to the failure in dust storm forecasting. Also, the land surface scheme has the greatest impact on dust concentration among the physical options. In addition, chemical options have the greatest impact on the dust storm forecasting as well. Based on the proposed multi-objective framework, the optimal options for dust storm modeling were determined. The proposed approach is comprehensive and can be used for other atmospheric/air quality modeling.

Simulation of LDL permeation into multilayer wall of a coronary bifurcation using WSS-dependent model: effects of hemorheology.

Atherosclerosis, due to the permeation of low-density lipoprotein (LDL) particles into the arterial wall, is one of the most common and deadly diseases in today's world. Due to its importance, numerous studies have been conducted on the factors affecting this disease. In this study, using numerical simulation, the effects of Wall Shear Stress (WSS), non-Newtonian behavior of blood, different values of hematocrit and blood pressure on LDL permeation into the arterial wall layers are investigated in a 4-layer wall model of a coronary bifurcation. To obtain the velocity and concentration fields in the fluid domain, the Navier-Stokes, Brinkman, and mass transfer equations are numerically solved in the lumen and wall layers. Results show that it is important to consider the effects of WSS on transport properties of endothelium layer in bifurcations and this leads to completely different concentration profiles compared to the constant properties model. Our computations show that a giant accumulation of LDL in the intima layer of the outer wall of the left anterior descending artery, especially in low WSS regions, may lead to atherosclerosis. It is also, necessary to consider the non-Newtonian behavior of blood in bifurcations due to its direct effect on WSS. A pressure-induced increase in the half-width of leaky junctions may be responsible for the higher risk of atherosclerosis in hypertension. In addition, it is shown that the dominant mechanism in LDL permeation into the wall is convection, and also, hypertension increases the effect of mass transfer by convection mechanism more than the diffusion mechanism. Furthermore, our results are consistent with various clinical studies.

Targeted drug delivery with polydisperse particle transport and deposition in patient-specific upper airway during inhalation and exhalation.

Identifying the deposition pattern of inhaled pharmaceutical aerosols in the human respiratory system and understanding the effective parameters in this process is vital for more efficient drug delivery to this region. This study investigated aerosol deposition in a patient-specific upper respiratory airway and determined the deposition fraction (DF) and pressure drop across the airway. An experimental setup was developed to measure the pressure drop in the same realistic geometry printed from the patient-specific geometry. The unsteady simulations were performed with a flow rate of 15 L/min and different particle diameters ranging from 2 to 30 µm. The results revealed significant flow circulation after the nasal valve in the upper and oropharynx regions, and a maximum local velocity observed in the nasopharynx. Transient cumulative deposition fraction showed that after 2 s of the simulation, all particles deposit or escape the computational domain. About 30 % of the injected large particles (dp ≥ 20 µm) deposited in the first 1 cm away from the nostril and more than 95 % deposited in the nasal airway before entering the oropharynx region. While almost 94 % deposition in trachea was composed of particles smaller than 5 µm. Approximately 20 % of inhaled fine particles (2-5 µm) deposited in the upper airway and the rest deposited in oropharynx, larynx and trachea.

Investigation of cancer response to chemotherapy: a hybrid multi-scale mathematical and computational model of the tumor microenvironment.

Tumor microenvironment (TME) is a multi-scale biological environment that can control tumor dynamics with many biomechanical and biochemical factors. Investigating the physiology of TME with a heterogeneous structure and abnormal functions not only can achieve a deeper understanding of tumor behavior but also can help develop more efficient anti-cancer strategies. In this work, we develop a hybrid multi-scale mathematical model of TME to simulate the progression of a three-dimensional tumor and elucidate its response to different chemotherapy approaches. The chemotherapy approaches include multiple low dose (MLD) of anti-cancer drug, maximum tolerated dose (MTD) of anti-cancer drug, combination therapy of MLD and anti-angiogenic drug, and combination therapy of MTD and anti-angiogenic drug. The results show that combining anti-angiogenic agent with anti-cancer drug increases the performance of cancer treatment and decreases side effects for normal tissue. Indeed, the vascular normalization caused by anti-angiogenic therapy improves anti-cancer drug delivery for both MLD and MTD approaches. The results show that anti-cancer drug administered in a lower dose than the maximum tolerated dose repetitively over a long period treats cancer with a considerable performance and fewer side effects. We also show that tumor morphology and distribution of cancer cell phenotypes can be considered as the characteristics to distinguish different chemotherapy approaches. This robust model can be applied to predict the behavior of any type of cancer and quantify cancer response to different chemotherapy approaches. The computational results of cancer response to chemotherapy are in good agreement with experimental measurements.

Numerical study of the effect of hemodynamic variables on LDL concentration through the single layer of the Left Anterior Descending coronary artery (LAD) under the heart pulse.

Heart attack is one of the most common causes of death in the world. Coronary artery disease is the most recognized cause of heart attack whose onset and progression have been attributed to low-density lipoprotein (LDL) passing through the wall of the artery. In this paper, hemodynamic variables as well as the concentration of LDL through the coronary porous artery at the Left Anterior Descending coronary artery (LAD), and its first diagonal branch (D1) under the heart motion investigated using computational simulation. The geometry that has been studied in this paper is the first bifurcation of Left Anterior Descending (LAD) that has been placed on a perimeter of hypothetical sphere representative of the heart geometry. Sinusoidal variations of sphere radii, simulated pulsating movement of the heart. Blood has been considered as a Newtonian and incompressible flow with pulsatile flow rate and real physiological profile. The plasma filtration boundary condition used over the walls in order to simulate the concentration of LDL to a one-layer artery wall. Variations in the concentration of LDL on the artery wall and its relation to oscillation on shear stress on the artery wall under different conditions are presented. Moreover, the effects of the pulsating inlet flow and dynamic movement of the artery are explored. The results declared that minimum shear stress and maximum LDL concentration take place at the bifurcation and on the myocardial wall which is in complete agreement with clinical studies. Furthermore, it has been shown that the heart pulse has a slight effect on the average time of concentration (0.1% increase); however, by analyzing all time steps, one could observe that the maximum concentration rises in some time steps; where this increases the possibility of LDL presence and helps them diffuse inside the artery wall.

A new application of multi-criteria decision making in identifying critical dust sources and comparing three common receptor-based models.

Dust storms are a common phenomenon in arid and semi-arid regions in West Asia, which has led to high levels of PM10 in local and remote area. The Yazd city in Iran with a high PM10 level located downstream of dust sources in the Middle East and Central Asia. In this study, based on meteorological and PM10 monitoring data, backward trajectory modeling of air parcels related to dust events at Yazd station was performed using the HYSPLIT model in 2012-2019. The trajectory cluster analysis was used to identify the main dust transport pathways and wind systems. Three methods of Cross-referencing Backward Trajectory (CBT), Potential Source Contribution Function (PSCF) and Concentration Weighted Trajectory (CWT) were used to identify the most critical dust sources. Multi-Criteria Decision Making (MCDM) methods were also used to integrate the results. Nine dust sources affecting central Iran were determined, and six criteria from different aspects were considered. To prioritize the dust sources affecting central Iran from four new MCDM methods, including WASPAS, EDAS, ARAS and TOPSIS were used. The results showed that the Levar wind system (51%), the Shamal wind system (32%) and the Prefrontal wind system (18%) were the most important wind systems to cause dust events in central Iran. The MCDM approach to identify dust sources also showed that Dasht-e-Kavir in central Iran was the most critical dust source. The results also showed that in hot seasons (spring and summer), local and Central Asia dust sources and cold seasons (autumn and winter), Middle East dust sources have the greatest impact on dust events in central Iran. Also, a comparison of common receptor-based methods for identifying dust sources showed that CBT, CWT and PSCF were the most appropriate methods for identifying dust sources, respectively.

Atheroprone sites of coronary artery bifurcation: Effect of heart motion on hemodynamics-dependent monocytes deposition.

Atherosclerosis as a common cardiovascular disease is a result of both adverse hemodynamics conditions and monocyte deposition within coronary arteries. It is known that the adhesion of monocytes on the arterial wall and their interaction with the vascular surface are one of the main parameters in the initiation and progression of atherosclerosis. In this work, hemodynamic parameters and monocyte deposition have been investigated in a 3D computational model of the Left Anterior Descending coronary artery (LAD) and its first diagonal branch (D1) under the heart motion. A one-way Lagrangian approach is performed to trace the monocyte particles under different blood flow regimes and heart motion conditions. The hemodynamic results show that the myocardial wall, and also the flow divider wall can be candidates for atheroprone sites. The dynamic movement and pulsatile inlet changed the flow rate between branches about 21% compared to the static case and steady inlet. On the other hand, the calculation of monocytes' depositional behavior illustrates that they settle down downstream the LAD-D1 bifurcation and on the myocardial wall. The deposition rate is closely associated with the inlet type and changing the steady inlet to the sinusoidal and real physiologic profile showed a 150% increase in the deposition rate. These results ensure that the myocardial wall and LAD-D1 bifurcation are the desirable locations for atherosclerosis. These results are in good agreement with the clinical observations.

High-Throughput, Label-Free Isolation of White Blood Cells from Whole Blood Using Parallel Spiral Microchannels with U-Shaped Cross-Section.

Rapid isolation of white blood cells (WBCs) from whole blood is an essential part of any WBC examination platform. However, most conventional cell separation techniques are labor-intensive and low throughput, require large volumes of samples, need extensive cell manipulation, and have low purity. To address these challenges, we report the design and fabrication of a passive, label-free microfluidic device with a unique U-shaped cross-section to separate WBCs from whole blood using hydrodynamic forces that exist in a microchannel with curvilinear geometry. It is shown that the spiral microchannel with a U-shaped cross-section concentrates larger blood cells (e.g., WBCs) in the inner cross-section of the microchannel by moving smaller blood cells (e.g., RBCs and platelets) to the outer microchannel section and preventing them from returning to the inner microchannel section. Therefore, it overcomes the major limitation of a rectangular cross-section where secondary Dean vortices constantly enforce particles throughout the entire cross-section and decrease its isolation efficiency. Under optimal settings, we managed to isolate more than 95% of WBCs from whole blood under high-throughput (6 mL/min), high-purity (88%), and high-capacity (360 mL of sample in 1 h) conditions. High efficiency, fast processing time, and non-invasive WBC isolation from large blood samples without centrifugation, RBC lysis, cell biomarkers, and chemical pre-treatments make this method an ideal choice for downstream cell study platforms.

Endothelial Cells Morphology in Response to Combined WSS and Biaxial CS: Introduction of Effective Strain Ratio.

INTRODUCTION: Endothelial cells (ECs) morphology strongly depends on the imposed mechanical stimuli. These mechanical stimuli include wall shear stress (WSS) and biaxial cyclic stretches (CS). Under combined loading, the effect of CS is not as simple as pure CS. The present study investigates the morphological response of ECs to the realistic mechanical stimuli. METHODS: The cell population is theoretically studied using our previous validated model. The mechanical stimuli on ECs are described using four parameters; WSS magnitude (0 to 2.0 Pa), WSS angle (- 50° to 50°), and biaxial CS in two perpendicular directions (0 to 10%). The morphology of ECs is reported using four parameters; average shape index (SI) and orientation angle (OA) of the cell population as well as the standard deviation (SD) of SI and OA as measures for scattering of cells' SI and OA from these average values. RESULTS: A new effective strain ratio (ESR) is defined as the ratio of the undesirable CS to the desirable one. The obtained results of the model, illustrated that the SI and OA of cells increase with absolute value of ESR. In addition, the scattering in the SI of cells decreases with the absolute value of ESR, which means that the cell shapes become more regular. It is shown that the angular irregularity of cells increases at higher ESR values. CONCLUSIONS: The results indicated that, the defined ESR is a stand-alone parameter for describing the realistic mechanical loading on the ECs and their morphological response.

A multi-scale model for determining the effects of pathophysiology and metabolic disorders on tumor growth.

The search for efficient chemotherapy drugs and other anti-cancer treatments would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. Because in vivo experimental methods are unable to isolate or control individual factors of the TME and in vitro models often do not include all the contributing factors, some questions are best addressed with systems biology mathematical models. In this work, we present a new fully-coupled, agent-based, multi-scale mathematical model of tumor growth, angiogenesis and metabolism that includes important aspects of the TME spanning subcellular-, cellular- and tissue-level scales. The mathematical model is computationally implemented for a three-dimensional TME, and a double hybrid continuous-discrete (DHCD) method is applied to solve the governing equations. The model recapitulates the distinct morphological and metabolic stages of a solid tumor, starting with an avascular tumor and progressing through angiogenesis and vascularized tumor growth. To examine the robustness of the model, we simulated normal and abnormal blood conditions, including hyperglycemia/hypoglycemia, hyperoxemia/hypoxemia, and hypercarbia/hypocarbia - conditions common in cancer patients. The results demonstrate that tumor progression is accelerated by hyperoxemia, hyperglycemia and hypercarbia but inhibited by hypoxemia and hypoglycemia; hypocarbia had no appreciable effect. Because of the importance of interstitial fluid flow in tumor physiology, we also examined the effects of hypo- or hypertension, and the impact of decreased hydraulic conductivity common in desmoplastic tumors. The simulations show that chemotherapy-increased blood pressure, or reduction of interstitial hydraulic conductivity increase tumor growth rate and contribute to tumor malignancy.

High precision invasive FFR, low-cost invasive iFR, or non-invasive CFR?: optimum assessment of coronary artery stenosis based on the patient-specific computational models.

The objective of this paper is to apply computational fluid dynamic (CFD) as a complementary tool for clinical tests to not only predict the present and future status of left coronary artery stenosis but also to evaluate some clinical hypotheses. In order to assess the present status of the coronary artery stenosis severity, and thereby selecting the most appropriate type of treatment for each patient, fractional flow reserve (FFR), instantaneous wave free-ratio (iFR), and coronary flow reserve (CFR) are calculated. To examine FFR, iFR, and CFR results, the effect of geometric features of stenoses, including diameter reduction (%), lesion length (LL), and minimum lumen diameter (MLD), is studied on them. It is observed that FFR is a more conservative index than iFR and CFR to assess the severity of coronary stenosis. In addition, it is seen that FFR, iFR, and CFR decrease by increasing LL and decreasing MLD. Therefore, the morphological indices, LL/MLD and LL/MLD̂4, with the calculated conservative cut-off values equal to 5.5 and 3.6, are considered. Next, some controversial clinical hypotheses about the assessment of the severity of coronary stenosis are evaluated numerically. These include the examination of FFR, iFR, and CFR accuracies, investigating the effect of coronary hyperemia on iFR, as well as the reliability of the hybrid iFR-FFR decision-making strategy. The presented numerical model can also be used as a predictive tool to identify the atherosuseptible sites of arteries by calculating the time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT).

Numerical Investigations of Hepatic Spheroids Metabolic Reactions in a Perfusion Bioreactor.

Miniaturized culture systems of hepatic cells are emerging as a strong tool facilitating studies related to liver diseases and drug discovery. However, the experimental optimization of various parameters involved in the operation of these systems is time-consuming and expensive. Hence, developing numerical tools predicting the function of such systems can significantly reduce the associated cost. In this paper, a perfusion-based three dimensional (3D) bioreactor comprising encapsulated human liver hepatocellular carcinoma (HepG2) spheroids are analyzed. The flow and mass transfer equations for oxygen as well as different metabolites such as albumin, glucose, glutamine, ammonia, and urea were solved in three different domains, i.e., free flow, hydrogel, and spheroid porous media sections. Since the spheroids were encapsulated inside the hydrogel, shear stress imposed on them were found to be less than tolerable thresholds. The predicted cumulative albumin concentration over the 7 days of culture period showed a good agreement with the experimental data. Based on the critical role of oxygen supply to the hepatocytes, a parametric study was performed and the effect of various parameters was investigated. Results illustrated that convection mechanism was the dominant transport mechanism in the main-stream section contrary to the intra spheroids parts where the diffusion was the prevailing transport mechanism. In the hydrogel parts, the rate of diffusion and convection mechanisms were almost identical. As expected, higher perfusion rate would provide high oxygen level for the cells and, smaller spheroids with a diameter of 100 µm were at the low risk of hypoxic conditions due to short diffusive oxygen penetration depth. Numerical results evidenced that spheroids with diameter size >200 µm at low porosities (ε = 0.2-0.3) were at risk of oxygen depletion, especially at locations near the core center. Therefore, these results could be beneficial in preventing hypoxic conditions during in vitro experiments. The presented numerical model provides a numerical platform which can help researchers to design and optimize complex bioreactors and obtain numerical indexes of the main metabolites in a very short time prior to any fabrications. Such numerical indexes can be helpful in certifying the outcomes of forensic investigations.

Simulation of Low Density Lipoprotein (LDL) permeation into multilayer coronary arterial wall: Interactive effects of wall shear stress and fluid-structure interaction in hypertension.

Due to increased atherosclerosis-caused mortality, identification of its genesis and development is of great importance. Although, key factors of the origin of the disease is still unknown, it is widely believed that cholesterol particle penetration and accumulation in arterial wall is mainly responsible for further wall thickening and decreased rate of blood flow during a gradual progression. To date, various effective components are recognized whose simultaneous consideration would lead to a more accurate approximation of Low Density Lipoprotein (LDL) distribution within the wall. In this research, a multilayer Fluid-Structure Interaction (FSI) model is studied to simulate the penetration of LDL into the arterial wall. Distention impact on wall properties is taken into account by considering FSI and Wall Shear Stress (WSS) dependent endothelium properties. The results show intensified permeation of LDL whilst the FSI approach is applied. In addition, luminal distension prompted by FSI reduces WSS along lumen/wall interface, especially in hypertension. This effect leads to a lowered endothelial resistance against LDL permeation, comparing to the case in which WSS effect is overlooked. The results are in an acceptable consistency with the clinical researches on WSS effect on atherosclerosis development.

A multiscale approach for determining the morphology of endothelial cells at a coronary artery.

The morphology of endothelial cells (ECs) may be an indication for determining atheroprone sites. Until now, there has been no clinical imaging technique to visualize the morphology of ECs in the arteries. The present study introduces a computational technique for determining the morphology of ECs. This technique is a multiscale simulation consisting of the artery scale and the cell scale. The artery scale is a fluid-structure interaction simulation. The input for the artery scale is the geometry of the coronary artery, that is, the dynamic curvature of the artery due to the cardiac motion, blood flow, blood pressure, heart rate, and the mechanical properties of the blood and the arterial wall, the measurements of which can be obtained for a specific patient. The results of the artery scale are wall shear stress (WSS) and cyclic strains as the mechanical stimuli of ECs. The cell scale is an inventive mass-and-spring model that is able to determine the morphological response of ECs to any combination of mechanical stimuli. The results of the multiscale simulation show the morphology of ECs at different locations of the coronary artery. The results indicate that the atheroprone sites have at least 1 of 3 factors: low time-averaged WSS, high angle of WSS, and high longitudinal strain. The most probable sites for atherosclerosis are located at the bifurcation region and lie on the myocardial side of the artery. The results also indicated that a higher dynamic curvature is a negative factor and a higher pulse pressure is a positive factor for protection against atherosclerosis.

Pulsatile blood flow in total cavopulmonary connection: a comparison between Y-shaped and T-shaped geometry.

Single-ventricle anomaly is a hereditary heart disease that is characterized by anatomical malformations. The main consequence of this malformation is desaturated blood flow, which without proper treatment increases the risk of death. The classical treatment is based on a three-stage palliative procedure which should begin from the first few days of patient's life. The final stage is known as Fontan procedure, in which inferior vena cava is directly connected to pulmonary arteries without going through the ventricle. This connection is called total cavopulmonary connection (TCPC). After surgery, the single ventricle supplies adequate and saturated systemic blood flow to the body; however, TCPC contains low pressure and low flow pulsatility. To overcome this problem, a new method is proposed wherein pulsatile blood will be directed to the TCPC through the stenosed main pulmonary artery. In this study, through the use of Computational Fluid Dynamics, T-shaped (MRI-based) and Y-shaped (computer-generated) geometries are compared in order to determine the influence of this modification on pulsation of blood flow as well as energy loss in pulmonary arteries. The results indicate that energy loss in Y-shaped geometry is far less than T-shaped geometry, while the difference in flow pulsatility is insignificant.

Organ-Tumor-on-a-Chip for Chemosensitivity Assay: A Critical Review.

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.