Biomedical Engineering

Blood Vessel
 Anatomy
heart arteries arterioles
capillaries venules veins
heart
Blood pressure is highest in the
arteries considerably reduced in
the capillaries is lowest in the
veins

Biomedical Engineering
 Structure and Composition
of Blood Vessels: Arteries
Arteries: 1-10 mm; maintain pressure in the circulation
Thick, elastic layer to allow stretching and absorb pressure
(adventitia)
Muscle layer to control the diameter and thus the rate of blood
flow
Collagen: major structural component
of the vessel wall, provides mechanical
strength
Elastin: provides extensibility and recoil
Larger arteries: large amount of elastin
fibers in the media
Smaller arteries: less elastin, mostly
collagen, smooth muscle cells &
fibroblasts in the media and adventitia
layers
http://www.henryfordhealth.org/16461.cfm
Biomedical Engineering
 Structure and Composition of Aorta
Collagenous fibres oriented in
multiple directions in the
adventitia and mainly elastic
fibres in the media

Biomedical Engineering
 Structure and Composition
of Blood Vessels: Veins
Veins: 1-10 mm; Capillaries merge to form venules and
venules merge into veins.
Similar to arteries in overall structure
Differences:
diameter of veins is greater than that
of arteries
No prominent elastic fibers and
circular organization
Presence of valves on the intima
Act as blood reservoirs (contain 50% to
60% of the blood volume) http://www.henryfordhealth.org

Smooth muscle in the walls of veins can expand or contract to

adjust the flow volume returning to the heart and make more
blood available when needed.
Biomedical Engineering
 Structure and Composition of Blood Vessels:
Capillaries
normal rabbit myocardium
Less than 1 mm long, 5-20 microns in
diameter - red blood cells travel single file
Not all of the capillary beds are open at
one time because all of them would hold
1.4 times the total blood volume of the all
the blood in the body.
Different structure than arteries or veins
no substrate or support for tubular cell
layers (no elastin, collagen, few muscle
cells)

Biomedical Engineering
Vessel Biomechanics In Vivo: Forces

4 principal hemodynamic forces:

(1) shear stresses, tangential frictional forces
(2) luminal pressure, a cyclic normal force attributable
to blood pressure;
(3) mechanical stretch, a cyclic circumferential stress
caused by blood pressure;
(4) tension in the longitudinal direction;
Act both independently and synergistically to
modulate the behavior of vascular tissues.

Biomedical Engineering
 Biomechanics & Biological
Functions
Non-thrombogenicity smooth surface for blood flow
provided by endothelium (endothelial cells lining the intima)

Vasoactivity
Mechanical properties
ultimate strength determined by burst pressure (collagen
fibers & the entire structure of blood vessels contribute)
viscoelasticity (elastin fibers)

Biomedical Engineering
 Vasoactivity
Vasodilation and vasoconstriction refers to the
dilation and constriction of blood vessels
Arteries and veins: chemical signals control smooth muscle
cell contraction and thus vessel diameter
artery
Sphincter muscles control the flow of blood to the capillaries
The rate of blood flow is lowest in the capillaries

vein

Biomedical Engineering
 Mechanical Properties of Large Blood
Vessels
Why important?
Increased stiffness of large elastic arteries represents an early risk factor
for CV diseases
atherosclerosis (Dart et al. 1991)
heart failure (Khan et al. 1999)
hypertension (Dzau & Safar 1988; Heints et al. 1993)
diabetes (Liu & Fung 1992; Airaksinen et al. 1993; Salomma et al. 1995)
hyperlipidemia (Lehmann et al. 1992)
Viscoelastic, Nonlinear, Anisotropic
Ultimate strength denoted by burst pressure
Native arteries burst pressure exceeds 2000 mm Hg, while blood
pressure never reaches more than several hundred mm Hg; safety factor
of 10!

Biomedical Engineering
 Assessment of Mechanical
Properties and Function
Ex-vivo (organ culture)
perfusion system:
Vessel chamber, fluid reservoir,
pump, measurement unit
Wall shear stress (0-30
dyn/cm2)
Tests demonstrated normal
artery histology and cell survival
after 7-day cultures

Can be used to measure the properties of native arteries

& engineered grafts Han & Ku, 2001

Biomedical Engineering
 Large Blood Vessels: The Zero
Stress State

Opening angle as
reflection of residual
stress
Describes zero-stress
state
Note there is internal
stress even with zero
blood pressure
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Opening Angle Depends on the
Local Environment

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 Assessment of Function:
Mechanical Testing
Uniaxial or biaxial tensile test (stress-strain relation)
mechanical properties and strength
Intact cylindrical vessel segment (material and structural
properties)
Ring segments (material properties)
Rectangular strips (material properties)

Material properties:
Elastic moduli
(Youngs modulus)
Compliance

Biomedical Engineering
 Stress-Strain Linearity

The relationship is linear up to 120

mmHg (i.e. physiological range)
beyond which it becomes nonlinear.

Biomedical Engineering
 Mechanical Properties of Capillaries

capillary

http://www.udel.ed
u/biology/Wags/his
topage

No smooth muscle layer or adventitia should be weak

Extremely difficult to study experimentally
Apparently rigid behavior tunnel in the gel
Properties of surrounding tissue integrated with the capillary
largely determine the compliance or rigidity of capillaries
Biomedical Engineering
 Biomechanics & Remodeling: Structure-
Function Relationship
Blood vessels are not a passive system it is an
active system that must perform biological functions in
order to achieve its mechanical purpose
If biological requirements change, the vascular system
must respond by changing its biomechanics
In turn, alterations in biomechanics lead to changes in
biological functions
atherosclerosis forms predominantly in the areas of low flow
& high turbulence

Biomedical Engineering
 Vessel Biomechanics In Vivo: Adaptation To
Changes
Wall shear stress (blood flow)
Pries & Secomb, 2005
Murrays law for connecting large vessels
to small: wall shear stress is uniform in all
vessels (before and after branching)
If the blood flow changes, the resulting
change in wall shear stress stimulates a
response in vessel wall cells and change in
vessel wall diameter to restore the initial
shear stress value
Circumferential stress (transmural pressure)
adaptation similar to shear stress: increased transmural pressure
(hypertension) leads to wall thickening, which results in decrease in
confirmed experimentally
vessel structural adaptation to altered biomechanical conditions
is essential function of vascular system
Biomedical Engineering
 Example: Venous Graft Adaptation

A: low stress due to Pries & Secomb, 2005

low pressure & low

oxygen content in the
venous system
B: initial passive
distention due to higher
blood pressure in
arterial system
C: adaptation results in
decrease in luminal
diameter and high,
arterial shear stress
level
Biomedical Engineering
 Blood vessel remodeling due to
change in blood pressure

Fung & Liu, 1991

hypoxia-induced
hypertension

Chemically-induced hypertension (increased blood pressure)

Remodeling: the media is thickened first, adventitia is thickened
later, changes in elastin fibers structure (dark layers) Biomedical Engineering
 Remodeling Mechanism

Strain hypothesis:
Remodeling starts at the cell level: altered equilibrium strain state can
affect cell binding to the extracellular matrix (force transduction via adhesion
molecules) initiates a biochemical signaling cascade within the cell and
tissue remodeling

Biomedical Engineering
 Need: Blood Vessel Substitute

Annually, more than 500 000

surgical procedures are
performed in the US
involving replacement of
small-caliber blood vessels.
Success has been limited to
arterial replacements of
large-caliber vessels (using
Dacron and expanded Hughes et al, J Thorac Cardiovasc
Surg 2008;136:21-8.
polytetrafluorethylene grafts)
Biomedical Engineering
 Need: Blood Vessel Substitute
Small-caliber (<6 mm) arterial substitutes
(account for a majority of the demand) have
generally proved inadequate largely
because of acute thrombogenicity,
anastomotic intimal hyperplasia, aneurysm
formation, infection, and progression of
atherosclerotic disease
Saphenous veins or internal mammary
arteries are normally used
Unfortunately, many patients do not have
native vessels available

Wilson et al, Ann Vasc Surg

1997;11:383-386

Biomedical Engineering
 Functional Requirements of a
Blood Vessel Substitute
Nonthrombogenicity (endothelium)
Appropriate physiological (vasomotor) responses
(endothelial and smooth muscle cells)
Appropriate remodeling responses (endothelial and smooth
muscle cells)
Appropriate mechanical properties (collagen & elastin)
Sufficient burst pressure to avoid rupture
Mechanical strength to retain sutures and sustain cyclic loads
Appropriate compliance to avoid mechanical mismatching between
vascular grafts and native arteries (stiff grafts lead to high failure
rates)

Biomedical Engineering
 Blood Vessel Substitute:
Engineering Constraints

Engineering such vessels requires

addressing issues ranging from cell source to
integration into the living system
Achieving 3-D construct that mimics native tissue
both in architecture and function
Scaling up fabrication process to address
widespread patient need
Preserving the product to provide off-the-shelf
availability

Biomedical Engineering
 Functional Requirements

Biomechanics is important at each step in the engineering

of a blood vessel substitute: cell & tissue assembly,
remodeling & vessel function in vivo
Influence of biomechanics for in vivo models may differ
from what observed in vitro
Immune acceptance of implant
Without engineering immune acceptance, use of allogeneic
endothelial cells will not be viable
Development of a model system for research studies
Investigate how differences in mechanical properties result in
different in vivo outcomes
Biomedical Engineering
 Recent Approaches: Grafts

Currently available concepts

Acellular approaches (synthetic
grafts)
Seeding endothelial cells onto the
lumen of grafts (to mitigate the
thrombogenic nature of the synthetic
surface
Clearly demonstrated that a biological
component can lead to superior
outcomes Deutsch et al, 2009. 1-year follow-up
angiography of an endothelialized 6mm
Still, complications remain graft used in a distal reconstruction.
(inflammation, stenosis, and infection). Smooth surface of the endothelialized
prosthesis () and no distal
anastomotic narrowing.
Biomedical Engineering
 Recent Approaches: Building Vessels

Tested concepts:
Cell-seeded scaffolds
Collagen/fibrin scaffolds
Rolled sheet

(cell-secreted materials)
Polymeric scaffolds

Currently available concepts fall short in achieving at least

one of the desirable characteristics
Biomedical Engineering
 Cell-Seeded Scaffolds: Collagen & Fibrin

Control of collagen fibril orientation (Tranquillo & coworkers, 1996-2008)

better mechanical properties
Cyclic strain (Nerem & coworkers, 2001-2004) better mechanical properties
Better results with fibrin+growth factor (TGF-b) & neonatal smooth muscle
cells (Tranquillo & coworkers, 2004-2008)
Still, strength not sufficient to withstand biological pressure, poor suture
retention, immune response to allogeneic cells

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Cell-Seeded Scaffolds: Clinical Studies-
Shinoka & co-workers

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 Cell-Seeded Scaffolds: Biodegradable
Polymers (PGA) Niklason & co-workers

SMC migrated into

scaffold; EC
retained
High burst
pressure (2150 mm
Hg) for pulsatile
cultures at 8 wks
Collagen content similar to that of native arteries; no elastin
deposition compliance mismatch (anastomotic intimal
hyperplasia)
Suture retention strength lower than that of native arteries
Responses to contractile agonists

(Niklason & coworkers 1999-2008)

Biomedical Engineering
 Rolled Cell Sheet Construct
(LHeureux & co-workers, 1993-2012)

Smooth muscle cell sheet rolled over an acellular inner membrane; cultured
for 1 wk
Fibroblast sheet is wrapped around the outer surface; cultured for 7 wks
ECs injected in the lumen & seeded on the inner membrane

Biomedical Engineering
 Rolled Cell Sheet Construct

Oversized internal elastic lamina, media and

adventitia similar to those of a native vessel
Presence of organized collagen network and
elastin fibers
High burst pressure (2500 mm Hg)
High rate of thrombosis (50% at 1 wk)

Biomedical Engineering
 Vascular Tissue Engineering: Nano
Mironov et al., 2008

Nanotechnology
goal: to have a
bioreactor-free process
nanopatterning of the
vascular graft surface to
prevent thrombosis

electrospinning of nanofibers (collagen and elastin) to improve

scaffold architecture and direct cell differentiation
nanopatterned growth factors and ECM components of the hydrogel
to control cell behavior
Problems: complexicity of the process, high cost, maintaining
thromboresistance long-term
Biomedical Engineering
 Vascular Tissue Engineering:
Magnetic
Mironov et al., 2008

Magnetic-force-driven vascular tissue

engineering
cells (endothelial or smooth muscle) labeled
with magnetic iron oxide nanoparticles
cells embedded in the hydrogel or porous
scaffold or seeded inside the rigid scaffold
(gray)
magnet (purple) is placed outside the scaffold to
direct cell migration and distribution
Problems:
undesirable cell activation by magnetic nanoparticles
development of intimal thickening

Biomedical Engineering
 Tissue Engineering Of Blood Vessels:
Perspective
Elastic fiber incorporation critical issue
use of fibrin matrices may help to synthesize
native elastin
Cell sources:
technically difficult to obtain autologous
endothelial and smooth muscle cells from blood
vessels
stem cells? from circulating blood or bone marrow

Biomedical Engineering