Thrombosis in the microcirculation
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Microcirculation Lab. Thrombosis in the microcirculation. Bingmei M. Fu Department of Biomedical Engineering The City College of The City University of New York. Embolus. Thrombosis. Normal blood flow. 30 µ m. large vessel. microvessel. Thrombosis. Vessel injury. Surgery Trauma.

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Thrombosis in the microcirculation

Microcirculation Lab

Thrombosis in the microcirculation

Bingmei M. Fu

Department of Biomedical Engineering

The City College of

The City University of New York


Thrombosis

Embolus

Thrombosis

Normal blood flow

30µm

large vessel

microvessel

Thrombosis


Risk factors

Vessel injury

Surgery

Trauma

Altered coagulability

Flow Stasis

Heart failure

Prolonged immobilization

Increased blood

coagulability

Thrombosis

Risk Factors


Thrombosis in microcirculation
Thrombosis in microcirculation

  • Previous studies under conditions

    • flow retarded(Nicolaides et al., 1972);

    • flow disturbed

      • secondary flow in branches (Chen et al., 2004);

    • vessel injured/damaged by

      • electrical (Massad et al., 1987; Wong et al., 2000);

      • mechanical (oude Egbrink et al., 1988);

      • biochemical (Begent et al., 1970);

      • PDT, light/dye(Sato et al., 1990; Sasaki et al., 1996; Rucker et al.,2002).


Question 1
Question 1

Can thrombosis occur in non-injured but bent/stretched microvessels under non-disturbed laminar flow (Re ~0.01) condition?


Question 2
Question 2

What is the structural mechanism by which PDT induces thrombosis?


Experimental setup
Experimental setup

CCD camera


Experimental design
Experimental Design

Sprague-Dawley rat, 250-300g;

The mesentery gently arranged on the surface of a polished quartz pillar;

With a microvessel (post-capillary venule, 20-50 µm) under observation, a rounded-tip glass restraining micropipette used to bend/stretch the microvessel.


micropipette

inlet

outlet

Experimental Observations

  • In 10-60 min, thrombi formed in 19 out of 61 (~31%) sites in 28 non-injured bent/stretched microvessels;

  • all thrombi were initiated from the inner side of the curvature.

(Liu et al, J. Biomech. 2008)


Results
Results

(Liu et al, J. Biomech. 2008)


What are the mechanical factors that initiate thrombosis in these non-injured bent/stretched microvessels?


Vessel geometry
Vessel Geometry these non-injured bent/stretched microvessels?

θ

A

90o

B

2a

A

2b

2r

B

A

180o

B

Ө

microvessel diameter 2r = 25 µm (circular)

equal perimeters of circular and elliptical cross sections

(Liu et al, J. Biomech. 2008)


Numerical methods
Numerical Methods these non-injured bent/stretched microvessels?

  • Fluent used to solve

    • Continuity Eq.

    • Navier-Stokes Eq.

  • Element No.:

    • 610x103, 770 x103 (90o/180o, circular);

    • 1.48x106, 1.52 x106 (90o/180o, elliptical);

  • µ = 2.5 cp (Levenson et al., 1990), ρ = 1050kg/m3;

  • Outlet pressure = 10 cmH2O, mean blood velocity = 1 mm/s, Reynolds No. ~ 0.01;

  • Convergence criteria: 10-8 of residues.


Velocity distributions
Velocity Distributions these non-injured bent/stretched microvessels?

Circular

Elliptical

(Liu et al, J. Biomech. 2008)


Shear rate distributions
Shear Rate Distributions these non-injured bent/stretched microvessels?

A — A

A

A

Circular

max

A

A

A

A

Elliptical

A — A

max

A — A

max

(Liu et al, J. Biomech. 2008)


Shear rate distributions along the curvature
Shear Rate Distributions along the Curvature these non-injured bent/stretched microvessels?

90o

180o

straight

(Circular)

(Liu et al, J. Biomech. 2008)


Shear rate along the curvature
Shear Rate along the Curvature these non-injured bent/stretched microvessels?

outlet

inlet

Circular

outlet

inlet

Elliptical

(Liu et al, J. Biomech. 2008)


Velocity along the curvature
Velocity along the Curvature these non-injured bent/stretched microvessels?

inlet

outlet

Circular

outlet

inlet

Elliptical

(Liu et al, J. Biomech. 2008)


Pressure along the curvature

Circular these non-injured bent/stretched microvessels?

Elliptical

Pressure along the Curvature

(Liu et al, J. Biomech. 2008)


Newtonian non newtonian fluid
Newtonian & non-Newtonian fluid these non-injured bent/stretched microvessels?

Casson Model

(Das et al., 1998, 2007)

α= 1.621,

β = 0.627

(Das et al., 1998);

μp= 2.5 cP

(Levenson et al., 1990).

(Liu et al, J. Biomech. 2008)


Summary
Summary these non-injured bent/stretched microvessels?

Thrombosis occurred in 19 out of 61 sites (31%) of 28 non-injured bent/stretched microvessels. Thrombi were initiated at the inner side of these microvessels.

Numerical simulation results showed higher shear stress/rate and higher shear stress/rate gradient at the innersides of the bent/stretched microvessels, suggesting they were two mechanical factors that initiate thrombi.


Light dye treatment
Light-dye Treatment these non-injured bent/stretched microvessels?

Light-dye treatment (Photodynamic Therapy, PDT):

Use of a photosensitizer, activated by a laser of a specific wavelength, to treat tumor and other diseases in the presence of oxygen.


Advantages of pdt
Advantages of PDT these non-injured bent/stretched microvessels?

  • Applied repeatedly at the same site;

  • Selective: photosensitizer can selectively accumulate in the tumor cells;

  • Harmless without light illumination;

  • Treatment for diseases that surgery is not possible (such as the upper bronchi, the structure cannot be removed surgically).


Pdt induced thrombosis
PDT Induced Thrombosis these non-injured bent/stretched microvessels?

  • Thrombi induced by light/dye consist primarily of platelets and occasionally of leukocytes in venules(Rumbaut et al., 2004).

  • The interaction between blood platelets and vessel wall plays an important role in thrombosis.


Surface glycocalyx

glycocalyx these non-injured bent/stretched microvessels?

150 nm

Surface Glycocalyx

(Squire et al., 2001)


Molecular composition of sgl
Molecular Composition of SGL these non-injured bent/stretched microvessels?

(Tarbell and Pahakis, J. Intern. Med , 2006)


Glycocalyx layer damage
Glycocalyx Layer Damage these non-injured bent/stretched microvessels?

Light/dye increases the penetration of macromolecules in the endothelial surface glycocalyx of the vascular wall (Vink & Duling, 1996).

Disruption of the glycocalyx would result in adhesion of platelets and blood cells to the vessel wall(Mulivor & Lipowsky, 2002).


Hypotheses
Hypotheses these non-injured bent/stretched microvessels?

PDT disrupts the endothelial surface glycocalyx

increase microvessel permeabilityto water and solutes

platelet and blood cells bindingto the endothelium and induces thrombi.


Experimental setup1

CCD camera these non-injured bent/stretched microvessels?

Laser Spot

Xenon Laser

(495 nm)

VCR

Experimental Setup


Experimental design1
Experimental Design these non-injured bent/stretched microvessels?

  • Sprague-Dawley rat, 250-300g;

  • Laser: Xenon laser, 495 nm, intensity 0.37 and 0.70 mW/mm2;

  • NaF: 50 mg/kg body wt., injected from the carotid artery;

  • With a microvessel (post-capillary venule, 20-50 µm) under observation, NaF was injected and the laser was turned on simultaneously.


Thrombosis by light dye

20 these non-injured bent/stretched microvessels?µm

Thrombosis by Light/dye


Thrombus growth rate

15.5 these non-injured bent/stretched microvessels?± 1.8

29.3 ± 2.2

2.5

3.8

Thrombus Growth Rate

(Liu et al., BMMB, 2010)


Technique of lp measurement curry 1984

Micropipette these non-injured bent/stretched microvessels?

Marker Cell

L0

2r

dL/dt

Blocker

Technique of Lp Measurement (Curry, 1984)


Lp measurement

30 these non-injured bent/stretched microvessels?µm

Lp Measurement


Lp change under light dye treatment
Lp Change under Light/Dye Treatment these non-injured bent/stretched microvessels?

(Liu et al., BMMB, 2010)


Early change of lp under light dye treatment

* these non-injured bent/stretched microvessels?

Early Change of Lp under Light/Dye Treatment

(Liu et al., BMMB, 2010)


Results1
Results these non-injured bent/stretched microvessels?

(Liu et al., BMMB, 2010)


Dye side these non-injured bent/stretched microvessels?

Washout side

400 µm

Measuring Window

200 µm

10 seconds

(dI/dt)0

∆Ifo

Technique of P Measurement

(Fu et al., 2005)


P measurement
P Measurement these non-injured bent/stretched microvessels?


P to albumin
P to albumin these non-injured bent/stretched microvessels?

*

(Liu et al., BMMB, 2010)


Early change of p under light dye treatment

* these non-injured bent/stretched microvessels?

Early Change of P under Light/dye Treatment

(Liu et al., BMMB, 2010)


Results2
Results these non-injured bent/stretched microvessels?

(Liu et al., BMMB, 2010)


Comparison of permeability change w w o blood cells

Lp these non-injured bent/stretched microvessels?

P to albumin

Baseline NaF + laser

Baseline NaF + laser

Comparison of Permeability Change w. & w/o. Blood Cells

(Liu et al., BMMB, 2010)


What are the most likely these non-injured bent/stretched microvessels?structural mechanisms by which light-dye treatment induced microvascular hyperpermeability and thrombosis?


Model geometry
Model Geometry these non-injured bent/stretched microvessels?

Y

2a

Junction strand

Δ

Surface glycocalyx

Lumen side

Tissue side

Tissue side

2D

X

O

2d

Lumen side

Lf

L

Z

X

Y

2B

2d

L

2D

Lf

(revised from Fu et al., 1994)


Model predictions
Model Predictions these non-injured bent/stretched microvessels?

(Liu et al., BMMB, 2010)


Model predictions and exp results
Model Predictions and Exp. Results these non-injured bent/stretched microvessels?

0.08


Model predictions and exp results1

0.14 these non-injured bent/stretched microvessels?

Model Predictions and Exp. Results


Growth rate vs permeability
Growth Rate vs. Permeability these non-injured bent/stretched microvessels?


Summary1
Summary these non-injured bent/stretched microvessels?

Light/dye treatment with 0.37mW/mm2 induced thrombosis in 3.8 min, complete occlusion at ~29 min.

This power gradually increased Lp and Palbumin to a plateau in 3 – 5 min by 2.2-fold and 4.1-fold respectively.

Our model predictions indicated that Lp and P increase under light/dye treatment was most likely due to 86% - 92% diminishmentof the endothelial surface glycocalyx.


Summary2
Summary these non-injured bent/stretched microvessels?

Increased Lp would increase the radial fluidflow and enable more platelets and leukocytes move towards the vessel wall.

Degradation of glycocalyx layer exposes endothelium and increases the binding of platelets and other blood cells to the endothelial cells, therefore induces thrombosis.


Acknowledgements
Acknowledgements these non-injured bent/stretched microvessels?

Dr. Qin Liu

David Mirc

Min Zeng

NSF CBET- 0133775 and 0754158

CUNY Graduate Fellowship

Thank you!


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