In-vitro Blood Flow Models for the Assessment of Device Thrombosis



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In-vitro Blood Flow Models for the 

Assessment of Device Thrombosis 

Sivaprasad (SP) Sukavaneshvar, Ph.D.

Vice President, Thrombodyne, Inc.

Research Faculty

Department of Pharmaceutics

University of Utah

Salt Lake City, UT



Virchow’s 

Triad

Flow

Blood

Surface

Vascular wall

(Endothelium)

Device


Biomaterial

Proteins


Cells

Streamlined

Disturbed

Slow/stagnant

Fast


Fluid Dynamics

Shear Stress

Platelet activation 

Normal velocity

Platelet adhesion & aggregation

Residence time

Coagulation and consolidation

Vorticity

Platelet aggregation (fluid phase)


Virchow’s 

Triad


Blood

Flow

Surface

Flow

In-vitro Blood

flow

Models


Device

surface 


Blood

Assessment of Device Thrombosis

Surface 


characterization

In-vitro static 

blood contact 

studies


Clinical 

studies


In-vitro flow 

model studies

In-vivo animal 

studies


In-vitro Blood Flow Model Configuration

37˚C


Pump

Device

Blood

reservoir

Polymer 

Tubing 

37˚C


Variations: Branched flow, Single pass, Chandler loop, etc.

Test


Control/predicate

In-vitro Blood Flow Models:

Key Features

• Relative assessment of thrombosis and 

related processes

• Fresh, anticoagulated whole blood

– Heparin, citrate (recalcified), hirudin

• Blood flow conditions approach clinical use

– Flow rate and conduit size

• Experiment time: ~hours


In-vitro Blood Flow Models:

Key Features

• Measured output

– Macroscopic thrombus (

Weight, Visual analysis, Radiolabeling)

– Microscopic components (SEM)

– Fluid phase biomarkers

– Thromboemboli

– Device dysfunction caused by thrombus (occlusion)

• Test conditions selected to focus on the device and 

minimize the impact of other model components

– Surface/Volume ratio

– Edge effects


MERITS OF IN-VITRO FLOW MODELS

• Useful template for comparing device thrombosis 

under similar conditions

• Some control over blood parameters

• Control of other important parameters (e.g. flow)*

• Quantification of thrombosis



LIMITATIONS OF IN-VITRO FLOW MODELS

• Experiment duration

• Absence of long-term effects

– Blood vessel wall-device interactions

– Comprehensive hemostatic pathways (e.g. lytic 

pathway)


– Inflammatory and foreign body response

• Need anticoagulation

• Control of other parameters (e.g. flow)!


EXAMPLES

Device Thrombosis

Device geometry

(flow disturbance)

Vascular response



Surface modification

Blood reactivity

?


Coronary Stents

Model Configuration(s)

Conventional model

Peristaltic 

pump


Blood

Reservoir

Stent

Polymer


conduit

Branched flow model

Flow probe

Initial flow rate: 75 ml/min

Heparin: 1 U/ml

Expt. Time: 60-90 min

Conduit: 3.2 mm ID

111-In labeled platelets



THROMBUS ON STENTS

Uncoated (control)

Coating A

Coating B



Thrombotic Occlusion

Flowrate


ml/min

75

50



25

0

15



30

45

60



75

Time (min)

Coating B

Control


Coating A

Thrombus Accumulation

% of


control

100


75

50

25



0

Control


Coating B

Coating A



ONE PASS CONFIGURATION

Blood

reservoir

37˚C

Useful for assessing thrombosis

and embolism on small devices:

Stents, distal embolic protection …

Circumvents recirculation & 

recounting of released emboli

Less extraneous blood activation

Limited range of flow rate, time,

and number of simultaneous

devices to be tested due to blood 

volume constraints

Devices

Polymer 

Tubing 

(1/8” ID)

Pump

37

°



C

Hemodialysis Cartridge

37˚C


Pump

Cartridge

Blood

reservoir

Dialysis

tubing 

37˚C


A

P

B



P

Flow rate: 300-400 ml/min

Heparin: 2-3 U/ml

111-In labeled platelets



Hemodialysis Cartridge

Thrombus Accumulation

A

B



Thrombus

(radiation cpm)

5000

10000


Out

Middle


In

Thrombotic Occlusion

A

10



20

30

40



50

P-Po (mm Hg)

50

100


150

Time (min)

B


Relative Device Thrombosis 

Assessed In-vitro and In-vivo

Coronary Stents

From Kocsis, et al. Journal of Long Term effects of Medical Implants 2000

In-vitro flow model

Baboon 2 hr ex-vivo shunt

Clinical studies

Uncoated


coated

Catheters (PICCs)

From Smith, et al., Sci Transl Med 2012

Control

Test


Control

Test


Control

Test


Control

Test


IN-VITRO FLOW MODEL

CANINE IN-VIVO JUGULAR IMPLANT (~4 hours)



Roller pump. External flow=1-3 L/min

Roller


pump

37˚C

37

°



C

Internal flow

300 ml/min

Roller


pump

37˚C

37

°



C

Internal flow

300 ml/min

Hemodialysis Catheters



coated

control

Hemodialysis Catheters

From Lotito, et al. ASN 2006

IN-VITRO FLOW MODEL

SHEEP IN-VIVO IMPLANT (up to 30 days)

Uncoated

Coated


Uncoated

Coated


% of Uncoated

% of Uncoated

100

50

100



50

In-vitro Blood Flow Models

Summary


• Useful template for comparing device 

thrombosis under similar conditions

– Relative Assessment 

– Universal/absolute acceptance criteria elusive

• Has Limitations

– Long-term biological processes

– Pre-conditioning?

• Model Configuration

– Clinical conditions and in-vitro framework

– Anticoagulation, flow conditions, time, objective




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