Hindawi Publishing Corporation
International Journal of Biomaterials
Volume 2012, Article ID 707863, 8 pages
Achala de Mel,1BrianG.Cousins,1andAlexanderM.Seifalian1,2
1UCL Centre for Nanotechnology & Regenerative Medicine, University College London, Pond Street, London NW3 2QG, UK
2Royal Free Hampstead NHS Trust Hospital, Pond Street, London NW3 2QG, UK
Correspondence should be addressed to Alexander M. Seifalian, firstname.lastname@example.org
Received 16 September 2011; Accepted 22 February 2012
Academic Editor: Narayana Garimella
Copyright © 2012 Achala de Mel et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cardiovascular implants must resist thrombosis and intimal hyperplasia to maintain patency. These implants when in contact
with blood face a challenge to oppose the natural coagulation process that becomes activated. Surface protein adsorption and
their relevant 3D confirmation greatly determine the degree of blood compatibility. A great deal of research efforts are attributed
towards realising such a surface, which comprise of a range of methods on surface modification. Surface modification methods
can be broadly categorized as physicochemical modifications and biological modifications. These modifications aim to modulate
platelet responses directly through modulation of thrombogenic proteins or by inducing antithrombogenic biomolecules that
can be biofunctionalised onto surfaces or through inducing an active endothelium. Nanotechnology is recognising a great role in
such surface modification of cardiovascular implants through biofunctionalisation of polymers and peptides in nanocomposites
and through nanofabrication of polymers which will pave the way for finding a closer blood match through haemostasis when
developing cardiovascular implants with a greater degree of patency.
Cardiovascular disease accounts for a significant percentage
of mortality and morbidity in the ageing population and
has an estimated increase in the coming years . There is
an urgent clinical need for improved cardiovascular devices,
which mainly include vascular bypass grafts, vascular stents,
and heart valves, which will promote desirable blood-
biomaterial interactions with a high patency. Vascular occlu-
sive disease holds the greatest risk factor most emphasised
in the coronary arteries where cardiac ischemia may lead
to complete heart failure. Main reperfusion-based surgical
intervention options for these diseases involve angioplasty,
stenting, endarterectomy, and bypass graft surgery depend-
ing on the degree of occlusion. Cases with greater than
70% occluded arteries are required to be treated with bypass
grafts. For small diameter bypass grafts, autologous bypass
conduits are preferred for primary revascularisation .
However, 3–30% patients are presented with no autologous
vessels due to previous disease conditions and thus there
is a need for vascular grafts which could perform closely
to autologous vessels . Graft thrombogenicity due to
material surface incompatibility and altered flow dynamics
at the site of anastomosis or distal outflow are recognised
as primary reasons for blood contacting device failure .
There is a great interest in research strategies that focus
upon surface techniques by modifying the physicochemical
properties at the implant surface  and by combining
a biomimetic approach through functionalisation which
presents an exciting challenge to improve patency rates
clinically (Figure 1). This paper aims to review some of the
significant approaches in modifying a material surface to
create optimal interactions with blood.
The initial events leading to thrombosis surrounding the
tissue-implant interface are mediated by surface interactions
with adsorbed proteins (intrinsic pathway) or through the
release of tissue factor (TF) from damaged cells at the site of
2 International Journal of Biomaterials
Blood flow dynamics
Device geometry and
Figure 1: Haemocompatibility-determining factors in a cardiovas-
cular device; marked in red are areas of interest in this paper.
injury (extrinsic pathway)  (Figure 2). The intrinsic path-
a complex composed of collagen, high molecular weight
kininogen (HMWK), prekallikrein, and factor XII. Inactive
precursors (clotting factors) change conformation and are
converted into active enzymes via a biochemical cascade
resulting in platelet activation (with the aid of additional
cofactors). Cleavage of prothrombin via the prothrombinase
complex bound to cellular membranes generates thrombin,
and by converting fibrinogen to fibrin, forms a stable
insoluble gel (red thrombus or clot).
Vascular injury and damage to the endothelium releases
TF, collagen, and von Willebrand factor (vWF) to initiate the
extrinsic pathway. Clotting factors interact with platelet sur-
face receptors and play a fundamental role in the interaction
of collagen to initiate thrombosis, release growth factors and
cytokines to enhance the coagulation cascade and strengthen
the haemostatic plug. The platelets change morphology and
agglomerate forming a thrombus layer. It is important to
note that both pathways converge during the formation of
referred to as the common pathway.
Vascular procedures such as arteriovenous graft place-
ment and angioplasty damage the adventitial and medial
tissues of the arterial wall with injury to the endothelium
lining the intima . For example, angioplasty is a con-
trolled traumatic event, which is aimed at causing plaque
rupture by widening a narrowed or obstructed vessel. These
processes can expose otherwise intact subendothelial matrix
removing the protective endothelium and expose medial
smooth muscle cells (SMC) directly to blood flow, and other
procoagulants and proinflammatory blood constituents.
Tissue trauma rapidly initiates the recruitment of inflam-
matory cells that release potent cytokines and promote SMC
migration and proliferation. The anticoagulant and vascular
protective functions of intact endothelium from prostacyclin
(PGI2) and nitric oxide (NO) required for the regulation of
blood flow soon diminish . Both molecules are necessary
to inhibit platelet adhesion, aggregation and activation to the
endothelium and SMC, which are considered early events in
the development of intimal hyperplasia (IH). Furthermore,
NO inhibits SMC proliferation and migration. In addition,
the adventitial layer is partially removed for creating the
anastomosis during surgery depriving the vessel wall of
oxygen and vital nutrients .
Almost all materials are considered to be thrombogenic
with the exception of the endothelial cell (EC) layer, which
lines the vasculature. Large diameter vascular grafts were
originally thought to be antithrombogenic in nature. For
example, expanded polytetrafluoroethylene (ePTFE) bypass
grafts appear nonthrombogenic due to the high flow rates
of blood past the luminal surface, but in reality, all are
thrombogenic to a certain degree.
In healthy individuals the flow of blood is laminar but
when compared with diseased or occluded arteries may often
be transitional or even turbulent in behaviour. At the blood-
biomaterial interface, haemodynamic forces of shear stress
at the wall surface play a critical role in blood contacting
devices and influence protein adsorption , platelet and
leukocyte adhesion. Leukocytes recognise specific proteins
and adhere under flowing conditions to initiate further
cell signalling and recruitment events. A study evaluating
leukocyte adhesion on polyurethanes materials has shown
that cell density decreased with increasing shear stress.
Certain shear stress models have been studied (particular
when applied to seeded vascular grafts) to promote EC
retention and found to correlate with changes in the EC
phenotype . Various strategies exist to inhibit these
processes and prolong graft patency, including modification
of grafts with various anticoagulants (heparin), antiplatelet
factors (glycoprotein IIb/IIIa inhibitors), and antiproliferat-
minimise complications that arise at the blood-biomaterial
3.Role of ProteinsinOptimal
Cardiovascular implants, in the body, are subjected to
the “Vroman effect”  which highlights the dynamic
interactions with water and proteins to synthetic material.
adsorption of proteins (composed of polar, nonpolar, and
present at the surface, protein molecules interact with water,
electrolytes, and the underlying surface chemistry (and
energy) of the material through hydrogen bonding, van der
Waals, pi-pi (π-π) stacking, and electrostatic interactions.
Exactly which force governs the interaction of proteins on
surfaces depends upon the particular protein and other
factors including size, charge, conformation, and unfolding
rate described by Vroman . Chemical and physical
properties of the materials, for example, surface chemistry,
energy (charge) and topography, influence the interfacial
International Journal of Biomaterials3
Implantation of VG
Contact activation (intrinsic) pathway
Active protein C
(B) Midstage cascade:
(1) thrombin assay (TGA)
(2) fibrinogen reagent
(3) elisa: fibrinopeptide A
(A) Early stage cascade:
(1) prekallikrein assay
(2) ELISA: factor XII
(C) Late stage cascade:
(1) ELISA: Human sP-selectin
(2) Human CXCL4/PF4
(D) End stage cascade:
(E) Tissue response:
α-granule release (PF 4)
(3) WBCs, RBCs...
distinguish as (1) biochemical, (2) platelets, and (3) whole blood (red and white blood cells). Image is adapted from http://en.wikipedia
behaviour adjacent to the biomaterial. The interfacial region
at the blood-biomaterial surface continually alters and
redistributes the protein/electrolyte/water layer, and the host
cells and tissues react to changes in this layer. Material
surfaces with zero interfacial energy and reduced enthalpic
and entropic effects do not strongly support cell/thrombin
adhesion . Surface wettability of a biomaterial is highly
platelets respond differently to hydrophobic or hydrophilic
Adsorption of plasma and extracellular matrix (ECM)
proteins (fibrinogen, albumin, and γ-globulin), and to a
lesser degree fibronectin, collagen, vWF, coagulation factors
XI and XII, and HMWK play a crucial role in balancing
thrombosis and haemostasis . Such proteins direct and
aid the adhesion of red blood cells, platelets (the first cellular
components to adsorb to the protein film), followed by
leukocytes, and EC. The cellular components interact with
the protein layer to guide migration, initiate blood coagula-
tion, and stimulate cell proliferation and differentiation, as
specific proteins present binding sites for macromolecules
and receptors guiding the recruitment of further cells in-
teracting within the vasculature.
Protein adsorption and subsequent cell attachment and
behaviour in response to an implanted foreign material is
determined by a variety of material properties including sur-
face chemistry, topography, dissolution rate, and the micro-
/macromechanical elasticity. Material surface properties can
therefore be modified by physicochemical modification
and/or biofunctionalisation to promote desirable protein
and cellular interactions. Figure 3 summarizes the main
mechanisms, which influence blood compatibility.
Much effort has focused on surface modification to optimise
antithrombogenic surface properties and two approaches
exist in the development of cardiovascular grafts. The
first approach involves the design of a permanent vascular
replacement, which has a nonadhesive, inert, nonbiofouling
surface. Physicochemical methods have been applied to
achieve this aim using electrochemical polishing, surface
roughening, ordered patterning, plasma treatment ,
chemical etching, and passive or covalent surface coatings.
The second approach aims to functionalise the grafts in such
a way that it facilitates (or activates) a cascade of biological
events which eventually regenerates or replaces functioning
tissue. Biofunctionalisation of surfaces is a popular research
theme, which relies on the tools of biology to create
biomimetic surfaces to incorporate biologically active (or
inactive) molecules to generate specific response(s) [18–22].
Figure 4, Table 1 present a summary of the principle
methods in applied surface modification techniques. In this
the following: (1) protein adsorption (2), the generation of
thrombin (and its formation leading to blood coagulation),
4International Journal of Biomaterials
Protein confirmation changes
Surface protein adsorption
The Vroman effect
Affinity for fibrinogen, albumin, etc.
activation, and aggregation
Blood compatibility determining influential
events on blood contacting surfaces
Endothelial/stem cell receptor
binding to surface ligands
Figure 3: Main mechanisms influencing blood compatibility.
(3) platelet adhesion (followed by aggregation and activa-
sis. All strategies are designed to optimise patency-limiting
thrombogenic events at the blood-biomaterial interface. For
example, vascular graft endothelialisation has been high-
lighted as the ultimate solution to address thrombogenicity,
and its associated complications.
4.1. Physicochemical Modification. A range of physical tech-
niques has been applied to modify the surface topography
of vascular graft materials. Topography on the micron and
nanometre scale is an important physical property, which
influences protein adsorption, platelet adhesion, thrombo-
genicity, and cell behaviour . The inclusion of pores,
pits, and groves become unavoidable at this scale during
the manufacturing process of blood contacting devices. For
example, a recent study revealed that the surface roughness
of ePTFE graft luminal surfaces was significantly higher
Plasma proteins such as fibrinogen have been shown to
adhere to nanostructures and bind to platelet receptors more
efficiently than flat structures . Albumin, fibrinogen,
and fibronectin all interact with a dialysis membrane’s
surface topography, which plays a crucial role in the adsorp-
tion process. Such surfaces have been shown to promote
fibronectin and vitronectin adsorption and direct a cascade
of interactions from the blood and surrounding tissues.
Surface porosity is a crucial factor when considering the
topography of vascular graft materials . A recent study
looked at the effect of porosity (ranging from 5 to 90μm in
diameter) on EC growth. It was found that EC cell growth
was enhanced by smaller pores (5–20μm in diameter) and at
a lower interpore distances.
Changing the surface topography on the micron and
nanometre scale also lead to localised changes in surface
chemistry as both physicochemical cues are intrinsically
linked. The primary aim of topographical and chemical sur-
face modification is to encourage desirable protein, cellular,
and tissue interactions at the blood-biomaterial interface,
thus improving patency and performance of the material,
since all are known contributory factors that influence
offer favourable solutions as biomaterials for cardiovascular
implants. Nanocomposite polymers in general have found
to be amphiphilic, thermodynamically stable and, when
used in vascular bypass graft development, they have shown
to exert novel advantageous properties such as favourable
blood response , biostability , and enhanced
mechanical properties compared to grafts with conventional
material. While being viscoelastic, polyhedral-oligomeric-
has been shown to have strength similar to natural arter-
ies. POSS-nanocomposite polymer, used for cardiovascular
implants, which include vascular bypass grafts, stents, and
heart valves has been proved to have antithrombogenic
Nonfouling surfaces have been used to prevent pro-
tein adsorption and platelet adhesion. Much effort has
focused upon the passivation of materials using polymers
to achieve a nonadhesive, nonbiofouling surfaces such as
PEG (polyethylene glycol), hydrogels (containing dextran),
and PEO (polyethylene oxide). For example, ePTFE grafts
have been coated with polypropylene sulphide (PPS)-
PEG and evaluated in arteriovenous models. This study
included heparinised and nonheparinised graft perfusion
and evaluated cell adhesion and thrombus formation. No
difference was observed in cell adhesion when compared
with controls; however, the surface coating significantly
decreased thrombus formation when used in conjunction
with heparin. Dextrans (hydrophilic polysaccharides) show
a similar effect to PEG with regard to protein adsorption.
Dextrans, PEG, and PEO can be further chemically modified
along the polymer backbone with cell-selective peptides to
promote specific cell adhesion. Spin coating of the luminal
elastomer poly(1,8-octanediol citrate) (POC). The POC
coatings had no effect on graft compliance and delayed
highlighted that POC-ePTFE grafts maintained EC adhesion
and proliferation of porcine cells similar to that of the native
tissues, and within 10 days the EC was confluent, while only
random patches were evident on ePTFE controls.
4.2.1. Endothelialisation. The endothelium is in intimate
contact with the blood flow and consists of a single layer
of EC, which functions as a dynamic organ and covers the
entire surface of the circulating system from the heart to
the smallest capillary. Endothelialisation of cardiovascular
International Journal of Biomaterials5
(a) Topographical-surface roughening
(b) Ordered patterning
(c) Chemical modification
(d) Passive coating
(e) Covalently linked
(f) Peptide linker
Figure 4: Examples of various physical, chemical, and biofunctionalisation techniques to enhance haemocompatibility. Biofunctionalised
surfaces interact with cell surface receptors, that is integrins. Whereas physiochemical modification can influence cell-material interactions
through charge, topography, and attractive/repulsive forces due to hydrophobic and hydrophilic interactions .
Table 1: Summary of the various modification techniques currently employed for optimising blood-material interactions .
Polymer gelling (growth factor mixed with the material in the liquid state and change temp, pH or ion
concentration to obtain a gel with nanopores)
Emulsion techniques (factors which are insoluble in aqueous solutions)
High pressure gas foaming (incorporate GF into porous scaffolds, without the use of solvents)
Surface distribution of ligands
Distribution of ligands through the bulk of the material
Passive adsorption driven by secondary interactions between the molecule and the protein
Self-assembled monolayers (SAMs) adsorption of the peptide (which is designed with hydrophobic tail
and a spacer) from solution
Microcontact printing of alkanethiol SAMs, photolithography (on hard materials), soft lithography (on
Direct protein patterning: drop dispensing, microfluidic patterning
Exposure to plasma discharge
Deposition of polymer films/islands, nanoparticles, metallographic paper or diamond paste polishing,
sand blasting, photolithography, and e-beam etching
Altering surface wettability
Altering surface roughness
implants is considered most favourable as this would protect
the vessels by producing natural biochemicals, for example,
NO for vasoprotection. There is a great deal of research
involved in inducing endothelialisation of cardiovascular
implants and insitu endothelialisation is considered to be
most favourable. This need for insitu endothelialisation has
led to a considerable interest in stem cells which have
the potential to induce endothelialisation. This interest in
endothelial progenitor stem cells inturn has given rise to
an exciting area of research on “stem cell technology” for
Stem cells/EPC are on the threshold of realising their
great potential in cardiovascular therapy and stem cell in-
teractions with various biomaterials which have been exten-
sively studied [30–34]. Cells are inherently sensitive to
physical, biochemical, and chemical stimuli from their
surroundings. Cells are in intimate contact with the ECM,
which is formed from a complex connection of proteins,
glycoproteins, and proteoglycans. The ECM provides not
only structural support but also contains a reservoir of cell
signalling motifs (ligands) and growth factors that guide
6International Journal of Biomaterials
or “niche” provides defined environmental cues that deter-
mine cell-specific behaviour, including selective recruitment,
proliferation, differentiation, and the production of the
numerous proteins needed for hierarchical tissue organisa-
tion. The plethora of ECM compositions contain insoluble
macromolecules fibrillar proteins (e.g., collagen) and glyco-
proteins (e.g., elastin, fibronectin, laminin) which interact
with proteins on cell surfaces and soluble macromolecules
such as growth factors. The organisation, density, spatial
geometry, and biochemistry of these ECM components
determine mechanical strength, cell response, and ultimately
hierarchical tissue organization.
Features of the ECM such as nanoscale topography,
optimised mechanical properties, and presentation of bio-
responsive motifs have inspired multiple examples of bioma-
terials design for tissue engineering scaffolds. One strategy
in vascular research is to present endothelium-derived
macromolecules or their cell interacting domains onto
vascular grafts to mimic these features of the ECM and to
assist specific cell adhesion. Bioresponsive vascular grafts
can target several biological processes to promote insitu
endothelialisation including: (1) promoting the mobilisation
of EPC from the bone marrow, (2) encouraging cell-specific
(circulating EC, EPC, and/or stem cells) homing to the
vascular graft site, (3) providing cell-specific adhesion motifs
(peptides) on the vascular grafts (of a predetermined spatial
concentration), and (4) directing the behaviour of the cells
after adhesion to rapidly form a mature, fully functioning
endothelium capable of self-repair.
Optimal cell attachment, migration, proliferation, and
differentiation on a biomaterial require a surface which
mimics the natural ECM. Natural ECM proteins range in
effect of peptides such as RGD , which are derived from
functional domains of ECM components and their effects
on enhancing accelerated endothelialisation. Nevertheless,
nonreceptor-mediated interaction of ECM such as porosity,
3D spatial arrangement also has a great influence in cell
The microtopography of scaffold materials is not entirely
ideal for vascular cells, particularly EC as they are naturally
placed in a nanometre scale environment. Nanotopography
including polymers have shown enhanced cellular adhesion
[36–40]. Recent reviews have discussed various nanotech-
niques which could potentially be applied to vascular graft
engineering. Nanostructures has been shown to facilitate
protein interactions which then promote cell adhesion
[9, 41, 42]. Some of these proteins are selective such as
vitronectin and fibronectin where they mediate enhanced
vascular cell interactions with the polymer [37, 38]. Three
main nanotechnology approaches, electrospinning [43, 44],
and to create a nanoarchitecture bypass graft surface for
optimal cell interactions .
In addition to mimicking an ECM, research has looked
into antibody-mediated stem cell recruitment as a rather
impressive approach in stem cell technology for applications
in vascular graft endothelialisation. EC and EPC have been
found to express CD34+, and therefore CD34+ antibodies
can be attached onto bypass graft surfaces to facilitate
interaction between graft and progenitor cells. Antihuman
CD34 monoclonal antibodies (IgG2a, epitope class III) were
immobilised to the ePTFE graft material (Orbus Medical
Technologies) with a proprietary multistep process.
In additional, furtherstudies have shown that superpara-
magnetic nanoparticles labelled endothelial cells can be used
to obtain an endothelial cell lining, for instance, as on the
luminal surface PTFE tubular grafts, coated with fibronectin
with the aid of a customized electromagnet .
4.2.2. Antithrombogenic Surfaces Independent of an Endothe-
lium. The cardiovascular protective role of the endothelium
is recognized to be attributed to NO. Therefore, there is a
great interest in inducing NO from cardiovascular implants
and this has recently been reviewed in depth . Recent
reviews have also detailed numerous anticoagulant and
antiplatelet agents that include, heparin, warfarin, hirudin,
dipyridamole clopidogrel, aspirin, cilostazol, and glycopro-
tein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban),
which are clinically used in addition to their applications in
engineered vascular graft surfaces [4, 48].
Blood contacting materials, which are used to fabricate
cardiovascular implants, are expected to preferably promote
endothelial adhesion but resist other blood cell adhesion
that can give rise to thrombosis and intimal hyperplasia. A
greater understanding of the interactions of blood proteins
withmaterialsurfaceswillenablebetter designing of surfaces
for blood contact. Surface modifications of materials will
be highly influenced by nanotechnology as this enables
to impart favourable properties without influencing the
structural and mechanical properties of the base material,
which forms the structure of a device of interest. It is also
of significance that a particular surface modification should
be always tailored to the implant of interest and should
be tested for its efficacy in physiological haemodynamic
conditions. We believe that a reasonable progress has been
made in the search for optimal blood contacting materials,
but research into NO eluting polymers, endothelialisation,
and nanotechnology associated with surface modification of
such materials may promise more sophisticated solutions in
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