Computational modeling of PET tracer distribution in solid tumors integrating microvasculature

Abstract Background We present computational modeling of positron emission tomography radiotracer uptake with consideration of blood flow and interstitial fluid flow, performing spatiotemporally-coupled modeling of uptake and integrating the microvasculature. In our mathematical modeling, the uptake of fluorodeoxyglucose F-18 (FDG) was simulated based on the Convection–Diffusion–Reaction equation given its high accuracy and reliability in modeling of transport phenomena. In the proposed model, blood flow and interstitial flow are solved simultaneously to calculate interstitial pressure and velocity distribution inside cancer and normal tissues. As a result, the spatiotemporal distribution of the FDG tracer is calculated based on velocity and pressure distributions in both kinds of tissues. Results Interstitial pressure has maximum value in the tumor region compared to surrounding tissue. In addition, interstitial fluid velocity is extremely low in the entire computational domain indicating that convection can be neglected without effecting results noticeably. Furthermore, our results illustrate that the total concentration of FDG in the tumor region is an order of magnitude larger than in surrounding normal tissue, due to lack of functional lymphatic drainage system and also highly-permeable microvessels in tumors. The magnitude of the free tracer and metabolized (phosphorylated) radiotracer concentrations followed very different trends over the entire time period, regardless of tissue type (tumor vs. normal). Conclusion Our spatiotemporally-coupled modeling provides helpful tools towards improved understanding and quantification of in vivo preclinical and clinical studies.

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Liver Blood Flow as a Major Determinant of the Clearance of Recombinant Human Tissue-Type Plasminogen Activator

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648385 ◽

1992 ◽

Vol 67 (01) ◽

pp. 083-087 ◽

Cited By ~ 44

Author(s):

A de Boer ◽

C Kluft ◽

J M Kroon ◽

F J Kasper ◽

H C Schoemaker ◽

...

Keyword(s):

Blood Flow ◽

Rat Liver ◽

Healthy Subjects ◽

Liver Blood Flow ◽

Major Determinant ◽

Tissue Type ◽

Perfused Rat Liver ◽

Liver Model ◽

Type Plasminogen Activator ◽

Proportional Change

SummaryThe influence of changes in liver blood flow on the clearance of rt-PA was studied both in healthy subjects and in a perfused rat liver model. Liver blood flow in healthy subjects was documented indirectly by the clearance of indocyanine green (ICG). Exercise reduced liver blood flow on average by 57% with a 95% confidence interval (95% Cl) ranging from 51% to 62% (n = 5) and increased plasma levels of rt-PA activity (after an i. v. infusion of 18 mg of rt-PA over 120 min) by 119% (95% Cl, 58% - 203%) and rt-PA antigen by 91% (95% Cl, 30% - 140%). In the perfused rat liver model it was shown that halving or doubling of the physiological flow rate of a perfusate, containing rt-PA caused a proportional change in the clearance of rt-PA, while the extraction of rt-PA by the liver remained similar. In conclusion, liver blood flow is a major determinant of the clearance of rt-PA. This may have important implications for dosage of rt-PA in patients with myocardial infarction.

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Failure of prostacyclin analog iloprost to sustain coronary blood flow after recombinant tissue-type plasminogen-induced thrombolysis in dogs

American Heart Journal ◽

10.1016/0002-8703(93)91041-c ◽

1993 ◽

Vol 126 (2) ◽

pp. 285-292 ◽

Cited By ~ 7

Author(s):

W.W. Nichols ◽

F.A. Nicolini ◽

S. Khan ◽

T.G.P. Saldeen ◽

J.L. Mehta

Keyword(s):

Blood Flow ◽

Coronary Blood Flow ◽

Tissue Type ◽

Prostacyclin Analog

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Dynamics of Interstitial Fluid Pressure in Extracellular Matrix Hydrogels in Microfluidic Devices

Journal of Biomechanical Engineering ◽

10.1115/1.4031020 ◽

2015 ◽

Vol 137 (9) ◽

Cited By ~ 5

Author(s):

Joe Tien ◽

Le Li ◽

Ozgur Ozsun ◽

Kamil L. Ekinci

Keyword(s):

Extracellular Matrix ◽

Pressure Distribution ◽

Interstitial Fluid ◽

Scaling Laws ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

External Loading ◽

Interstitial Pressure ◽

Time Resolved ◽

Long Time

In order to understand how interstitial fluid pressure and flow affect cell behavior, many studies use microfluidic approaches to apply externally controlled pressures to the boundary of a cell-containing gel. It is generally assumed that the resulting interstitial pressure distribution quickly reaches a steady-state, but this assumption has not been rigorously tested. Here, we demonstrate experimentally and computationally that the interstitial fluid pressure within an extracellular matrix gel in a microfluidic device can, in some cases, react with a long time delay to external loading. Remarkably, the source of this delay is the slight (∼100 nm in the cases examined here) distension of the walls of the device under pressure. Finite-element models show that the dynamics of interstitial pressure can be described as an instantaneous jump, followed by axial and transverse diffusion, until the steady pressure distribution is reached. The dynamics follow scaling laws that enable estimation of a gel's poroelastic constants from time-resolved measurements of interstitial fluid pressure.

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Computational Fluid Dynamics (CFD) Study of the 4th Generation Prototype of a Continuous Flow Ventricular Assist Device (VAD)

Journal of Biomechanical Engineering ◽

10.1115/1.1688776 ◽

2004 ◽

Vol 126 (2) ◽

pp. 180-187 ◽

Cited By ~ 32

Author(s):

Xinwei Song ◽

Houston G. Wood ◽

Don Olsen

Keyword(s):

Fluid Dynamics ◽

Computational Fluid Dynamics ◽

Blood Flow ◽

Ventricular Assist Device ◽

Continuous Flow ◽

Surrounding Tissue ◽

Assist Device ◽

Ventricular Assist ◽

Wide Range ◽

Computational Fluid Dynamics Cfd

The continuous flow ventricular assist device (VAD) is a miniature centrifugal pump, fully suspended by magnetic bearings, which is being developed for implantation in humans. The CF4 model is the first actual prototype of the final design product. The overall performances of blood flow in CF4 have been simulated using computational fluid dynamics (CFD) software: CFX, which is commercially available from ANSYS Inc. The flow regions modeled in CF4 include the inlet elbow, the five-blade impeller, the clearance gap below the impeller, and the exit volute. According to different needs from patients, a wide range of flow rates and revolutions per minute (RPM) have been studied. The flow rate-pressure curves are given. The streamlines in the flow field are drawn to detect stagnation points and vortices that could lead to thrombosis. The stress is calculated in the fluid field to estimate potential hemolysis. The stress is elevated to the decreased size of the blood flow paths through the smaller pump, but is still within the safe range. The thermal study on the pump, the blood and the surrounding tissue shows the temperature rise due to magnetoelectric heat sources and thermal dissipation is insignificant. CFD simulation proved valuable to demonstrate and to improve the performance of fluid flow in the design of a small size pump.

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Hyaluronan flux from cat intestine: changes with lymph flow

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.2.h457 ◽

1992 ◽

Vol 262 (2) ◽

pp. H457-H462 ◽

Cited By ~ 2

Author(s):

R. K. Reed ◽

M. I. Townsley ◽

T. C. Laurent ◽

A. E. Taylor

Keyword(s):

Blood Flow ◽

Major Part ◽

Interstitial Fluid ◽

Venous Pressure ◽

Lymph Flow ◽

Fluid Flux ◽

Control Value ◽

One Step ◽

Experimental Group

Isolated and autoperfused ileal segments from pentobarbital-anesthetized cats were used to study turnover of hyaluronan in the intestine. A postnodal lymphatic was cannulated, and transcapillary and interstitial fluid fluxes were increased by raising venous pressure. Lymph hyaluronan concentration in control averaged 20.2 +/- 18.8 (SD) micrograms/ml (range 4.6-50) and increased with increasing lymph flow in all experiments to peak at concentrations two to three times above control values (at 15-20 mmHg increase in venous pressure). At higher lymph flows, hyaluronan concentration fell to below 5 micrograms/ml to an average of 21.3 +/- 19.5% of control value at the highest venous pressures used (30-40 mmHg). Tissue hyaluronan content fell from 349 +/- 191 micrograms/g dry wt in control to 148 +/- 78 micrograms/g dry wt (P less than 0.05) at the end of the experiment. In a second group, vasodilators were administered before elevation of venous pressure to prevent redistribution of blood flow between mucosal and muscular layers. The results were similar to those obtained above. In a third experimental group, venous pressure was elevated in one step to 30 mmHg and maintained at this level. Again, hyaluronan concentration initially increased and later fell well below control values. We conclude that a major part of the intestinal hyaluronan is easily mobilized by increased interstitial fluid flux.

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Renal interstitial pressure in mineralocorticoid escape

AJP Renal Physiology ◽

10.1152/ajprenal.1985.249.3.f396 ◽

1985 ◽

Vol 249 (3) ◽

pp. F396-F399 ◽

Cited By ~ 2

Author(s):

J. C. Burnett ◽

J. A. Haas ◽

M. S. Larson

Keyword(s):

Blood Flow ◽

Glomerular Filtration Rate ◽

Hydrostatic Pressure ◽

Arterial Pressure ◽

Filtration Rate ◽

Interstitial Pressure ◽

Peritubular Capillary ◽

Renal Interstitium ◽

Vasa Recta ◽

Peritubular Capillaries

Studies were performed in normal and DOCA-treated rats to determine renal hydrostatic pressures within superficial peritubular capillaries, the vasa recta, and renal interstitium during mineralocorticoid escape to test the hypothesis that mineralocorticoid escape is associated with elevated renal interstitial hydrostatic pressure. Fractional sodium excretion was greater in the DOCA-treated rats (3.20 +/- 0.51%) compared with control rats (1.23 +/- 0.12%) with no difference in glomerular filtration rate and renal blood flow between the two groups. Superficial peritubular capillary hydrostatic pressure (13.4 +/- 0.6 vs. 8.3 +/- 0.3 mmHg), vasa recta hydrostatic pressure (13.8 +/- 0.5 vs. 9.0 +/- 0.4 mmHg), renal interstitial hydrostatic pressure (9.8 +/- 0.4 vs. 4.5 +/- 0.4 mmHg), and arterial pressure (145 +/- 6 vs. 120 +/- 7 mmHg) were greater in the DOCA-treated compared with the control rats. These studies establish that mineralocorticoid escape is characterized by high renal interstitial hydrostatic pressure.

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Influence of fibrin and liver blood flow on the turnover and the systemic fibrinogenolytic effects of recombinant human tissue-type plasminogen activator in rabbits

Blood ◽

10.1182/blood.v67.5.1493.1493 ◽

1986 ◽

Vol 67 (5) ◽

pp. 1493-1497 ◽

Cited By ~ 26

Author(s):

H Bounameaux ◽

JM Stassen ◽

C Seghers ◽

D Collen

Keyword(s):

Blood Flow ◽

Plasminogen Activator ◽

Human Tissue ◽

Femoral Vein ◽

Liver Blood Flow ◽

Tissue Type ◽

Tissue Type Plasminogen Activator ◽

Cardiovascular Failure ◽

Type Plasminogen Activator ◽

Impaired Liver

Abstract The influence of the presence of fibrin microclots on the systemic fibrinogenolytic effects of intravenous (IV) recombinant human tissue- type plasminogen activator (rt-PA) was studied by injection of a homogenized fibrin suspension in the femoral vein or artery in rabbits. A linear correlation (P less than .001) was found between the extent of fibrinogen breakdown and the amount of fibrin (0 to 32 mg/kg) injected just prior to the IV infusion of rt-PA at a rate of 10 micrograms/kg/min for 60 minutes. This finding suggests that the systemic activation of the fibrinolytic system observed in some patients during infusion of rt-PA may be due, at least in part, to the presence of fibrin in the vascular bed. The effect of blood flow in the liver on the turnover of rt-PA was measured in rabbits after ligation of the hepatic artery and monitoring of the blood flow in the portal vein with a peristaltic pump. The half-life (t1/2) of rt-PA in plasma was inversely correlated with the logarithm of the rate of the liver blood flow. A doubling of the plasma t1/2 of rt-PA was observed after an eightfold reduction of the liver blood flow, suggesting that delayed clearance of rt-PA may occur in patients with severe cardiovascular failure and impaired liver blood flow.

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Cerebral blood flow and interstitial fluid adenosine during hemorrhagic hypotension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.5.h1211 ◽

1988 ◽

Vol 255 (5) ◽

pp. H1211-H1218 ◽

Cited By ~ 18

Author(s):

D. G. Van Wylen ◽

T. S. Park ◽

R. Rubio ◽

R. M. Berne

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Adenosine Receptor ◽

Cerebral Autoregulation ◽

Interstitial Fluid ◽

Adenosine Receptor Antagonist ◽

Arterial Blood ◽

Artificial Cerebrospinal Fluid ◽

Adenosine Concentration ◽

Group 2

This study was designed to assess the role of adenosine in autoregulation of cerebral blood flow (CBF) with the use of the brain dialysis technique to sample cerebral interstitial fluid (ISF) and hydrogen clearance to measure local CBF in ketamine-anesthetized rats. In group 1 (n = 11), animals were hemorrhaged to reduce mean arterial blood pressure (MABP) from control levels (MABP = 101.1 +/- 2.6) to 80, 70, 60, 50, 40, and 30 mmHg. Cerebral autoregulation was evidenced by no significant decrease in CBF until MABP decreased to 60 mmHg. However, dialysate adenosine concentration did not increase until MABP decreased to 50 mmHg. In group 2 (bilateral dialysis; n = 11), in which the left carotid artery was ligated before reductions in MABP, left-side dialysate adenosine concentration increased at a MABP of 70 mmHg. In group 3 (bilateral dialysis; n = 6), one dialysis probe was perfused with artificial cerebrospinal fluid containing 10(-3) M 8(p-sulfophenyl)theophylline (8-SPT), an adenosine receptor antagonist, during reduction of MABP to 50 mmHg. Although there were similar reductions in CBF with or without adenosine receptor blockade, dialysate adenosine concentration was greater on the side of locally infused 8-SPT at a MABP of 50 mmHg. These data suggest that adenosine is not responsible for cerebral autoregulation at blood pressures greater than 50 mmHg but may contribute to the decrease in cerebral vascular resistance observed at arterial pressures below the autoregulatory range.

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